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Case 4:  62yo man of Greek origin presents with fatigue, otherwise healthy, by Anna S.F. Lok

A 62-year-old man presented to his primary care physician in June of 2000 with fatigue. He gave a history of two similar episodes of extreme fatigue in the past five years. During one of these episodes, elevated liver enzymes were found. He did not seek further attention at that time. An examination showed that he was otherwise healthy. He was not on medications, and he denied drinking. He had no known family history of liver disease. He had been born in Greece, and moved to the United States in 1980. Physical examination did not reveal any significant findings. There was no evidence of jaundice.

Laboratory Results:
AST: 349
ALT: 452
Total bilirubin: 0.9
Platelet count: 210k
HBsAg: positive
Anti-HCV: negative

The patient was referred to a gastroenterologist. By August of 2000, when he first saw the gastroenterologist, his symptoms had resolved. Repeat testing at this time showed the following:

Laboratory Results:
AST: 55
ALT: 68
Total bilirubin: 0.7
HBeAg: negative
Anti-HBe: positive
HBV DNA: 125,000 copies/mL

What is your diagnosis?
1. Acute antigen-negative hepatitis B
2. Chronic antigen-negative hepatitis B
3. Clinically resolved case of hepatitis B
Dr. Lok (OC): This is very classical of patients with E-antigen negative chronic Hepatitis, they tend to run a fluctuating course. The fact that he's E-antigen negative, does not mean that he does not have active virus replication, because we now know that there's a variant of Hepatitis B virus these patients can continue to have active HBV DNA level and active liver disease.

Which would you do?
1. Nothing; monitor patient
2. Begin anti-viral therapy
3. Order more tests
Dr. Lok (OC): Given the fact that we know that most patients with E-antigen negative chronic Hepatitis will require a very long duration of therapy. We want to have a much better understanding of the severity of his liver disease before committing him to this long course of therapy.

Which test(s) would you order?
1. Anti-HDV
2. Liver biopsy
3. Both
Dr. Lok: ....Because he came from Greece, it is possible that he actually acquired Hepatitis B way back in his childhood and therefore it is important to test him for the Delta virus.... We also did the liver biopsy on him because of the fact that by the time he came to see us, his liver enzymes were close to normal.

Subsequent test results showed the following:

Anti-HDV: negative
Liver biopsy: moderate inflammation, fibrosis

Adefovir was not available at this time. Which treatment would you choose?
1. Interferon
2. Lamivudine
Dr. Lok: Well in August in 2000, there're really two choices of therapy. One is interferon and the other is lamivudine. In fact, both choices were being discussed with the patient....The downside of interferon obviously is the side effects. And to some extent, cost because for patients of E-antigen negative chronic Hepatitis, one would have to give the patients at least a 12-month pulse and some studies would actually suggest that you should be giving 24 months treatment. The advantage of interferon is that you can stop treatment in some patients. And certainly with 12 months treatment about 15-20 percent of patients would have a sustained response with two years treatment... Whereas in patients treated with lamivudine we know that if we try to stop treatment after one year, the likelihood of relapse is more than 90 percent and most of these patients end up receiving very long durations of therapy, which then is associated with increasing risks of drug resistance.... If we had seen this patient now, we would have a third option which would be adefovir therapy.... The benefit of adefovir is that the risk of drug resistance is very low, so continuation of treatment is going to be associated with maintained response in majority of patients, but that's going to be a fairly expensive therapy if we keep going year after year.

The patient chose oral therapy. He began lamivudine 100 mg/d. He responded well. His virus level became barely detectable, his liver enzymes became normal, and he felt significantly better. Two years after starting lamivudine treatment, the laboratory reported the following:

Laboratory Results
AST: 42
ALT: 59
Total bilirubin: 0.8
HBV DNA: 6,500,000 copies/mL

Which would you do?
1. Stop lamivudine; do not treat with any anti-viral therapy; monitor patient
2. Continue lamivudine; do not add another anti-viral drug; monitor patient
3. Stop lamivudine, treat with adefovir
4. Continue lamivudine, add adefovir
The attending physician had the capability to test for mutation resistance. A sample from the patient tested positive for YMDD mutation. Although the patient's liver enzymes were still well controlled, the attending physician decided to initiate salvage therapy because of the marked increase in HBV DNA levels.

Dr. Lok (OC): There is indeed one study-granted on a very small number of patients, 19 patients in each arm-showing that in patients who've developed lamivudine resistance, you can stop lamivudine and just switch them over to adefovir therapy and it results in a similar rate of viral suppression. However, there is a small risk of Hepatitis flairs during the transition period. And we now know that by putting the patient on adefovir alone, instead of leaving them on combination of lamivudine and adefovir, there is perhaps some higher chance of resistance to adefovir over time.... Because the two drugs select for different resistance mutation, continuation of both drugs might minimize selection of adefovir resistant mutation.... That's the reason why we chose to leave this patient on lamivudine and just add adefovir.

Dr. Lok (OC to VO): Adefovir dipivoxil 10 milligram daily was started in January of 2003. He had a very slow drop in HBV DNA level but it kept coming down. And in May of 2004, his HBV DNA level was still detectable by PCRSA, but at extremely low levels.
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Notes on “Hepatitis B Virus: Inactive carriers,” Yogesh Chwla, Virology Journal 2005, 2:82.

Inactive carriers forms the largest group in chronic HBV infected patients. Around 300 million people are inactive carriers The inactive HBsAg carrier state is diagnosed by absence of HBeAg and presence of anti-HBe, undetectable or low levels of HBV DNA in PCR-based assays, repeatedly normal ALT levels, and minimal or no necroinflammation, slight fibrosis, or even normal histology on biopsy. Inactive cirrhosis may be present in patients who had active liver disease during the replicative phase of infection. The prognosis of the inactive HBsAg carrier state is usually benign. Long-term follow- up (up to 18 years) of these carriers has indicated that the vast majority show sustained biochemical remission and very low risk of cirrhosis or hepatocellular carcinoma (HCC). Rarely, patients, even noncirrhotics, may develop liver cancer during the inactive HBsAg carrier state. In addition, approximately 20 to 30% of persons in the inactive HBsAg carrier state may undergo spontaneous reactivation of hepatitis B during follow-up. Multiple episodes of reactivation or sustained reactivation can cause progressive hepatic damage and even hepatic decompensation. Introduction

Hepatitis B virus (HBV) infection and its sequelae are major global health problems [1]. It is estimated that 400 million people worldwide are HBV carriers [2]. The natural history of hepatitis B is complex and is influenced by many factors, including age at infection, viral factors (HBV genotype, viral mutations, level of HBV replication), host factors (gender, age, and immune status), and exogenous factors such as concurrent infection with other hepatotropic viruses or alcohol. The clinical spectrum of HBV infection ranges from subclinical to acute symptomatic hepatitis or, rarely, fulminant hepatitis during the acute phase and from the inactive hepatitis B surface antigen (HBsAg) carrier state to chronic hepatitis, cirrhosis, and its complications during the chronic phase [3,4]. Approximately 15 to 40% of people who develop chronic HBV infection are expected to progress to cirrhosis and end-stage liver disease [1]. Difficulties in defining the natural history of chronic hepatitis B include the indolent course of the disease, the lack of symptoms during the early stages, and the heterogeneity of the disease. Understanding the natural history and prognosis of hepatitis B is the basis for disease management and for designing better therapeutic strategies.

Hepatitis B Virus

HBV belongs to the family hepdnaviruses. The HBV genome is a relaxed circular, partially double stranded DNA of approximately 3,200 base pairs. There are four partially overlapping open reading frames encoding the envelope (pre-S/S), core (precore/core), polymerase, and X proteins [5]. The pre-S/S open reading frame encodes the large, middle, and small surface glycoproteins. The precore/core open reading frame is translated into precore polypeptide which is modified in to a soluble protein, the hepatitis B e antigen (HBeAg), and the nucleocapsid core protein hepatitis B core antigen (HBc Ag) [5]. The polymerase protein functions as reverse transcriptase as well as DNA polymerase. The X protein is a potent transactivator and may play role in hepatocarcinogenesis.

Prevalence

Hepatitis B is spread predominantly parenterally, through intimate personal contact, and perinatally. Individuals at risk are intravenous drug users, children of mothers with HBV, men who have sex with men, patients on hemodialysis and those exposed to blood or blood products [6,7]. Approximately 5% of the world's populations are carriers of HBV, defined as being positive for hepatitis B surface antigen. HBV is endemic in many areas of the world, such as Asia, Micronesia, and sub-Saharan Africa as well as in certain populations in Australia, New Zealand, South America, the Middle East and the Arctic. An estimated 1.25 million people in the United States are positive for hepatitis B surface antigen. Fifteen percent to forty percent of these carriers may develop hepatitis B-related sequelae in their lifetimes [8-10].

Natural History

Perinatal infection of infants from infected mothers and horizontal infection early in childhood from exposure to HBsAg-positive family members are the main routes of HBV transmission in highly endemic areas, such as Southeast Asia, Africa, the Pacific Islands, and the Arctic. In regions of low endemicity, such as Western countries, hepatitis B is primarily a disease of adolescents and adults as a result of high-risk sexual behavior and injection drug use. HBV infection is a dynamic process with replicative and nonreplicative (or low replicative) phases based on virus-host interaction. The presence of circulating HBsAg, hepatitis B e antigen (HBeAg), and high levels of serum HBV DNA characterizes the immunotolerant phase. This first phase is seen in patients with perinatal infection and often lasts for decades. During this phase patients have no symptoms, normal or slightly increased serum alanine aminotransferase (ALT) levels, and minimal histological activities, which imply that there is a lack of or a very weak immune response against the infected hepatocytes.

Experimental results in transgenic mice suggested HBeAg induces a state of immunological tolerance to HBV in neonates [11]. During the course of chronic HBV infection, for unknown reasons, the tolerogenic effect is and patients may enter the immunoactive phase, which is associated with a decrease in HBV DNA concentrations and increased ALT levels and histologic activity, reflecting immune-mediated lysis of infected hepatocytes. This second phase has a variable duration from months to years. The third low or nonreplicative phase occurs seroconversion from HBeAg to antibody to HBeAg. This phase is usually preceded by a marked reduction of serum HBV DNA to levels that are not detectable by hybridization techniques, followed by normalization of ALT levels and resolution of liver necroinflammation. In many patients, serum HBV DNA remains detectable by the sensitive technique of polymerase chain reaction (PCR). This phase is also referred as the inactive HBsAg carrier state [3,4]. The inactive carrier state may for a lifetime, but a proportion of patients may undergo subsequent spontaneous or immunosuppressioninduced reactivation of HBV replication with reappearance of high levels of HBV DNA with or without HBeAg seroreversion and a rise in ALT levels [3]. For reasons that are not yet known, replication-competent HBV variants with mutations in the precore or core promoter regions preventing or down-regulating HBeAg production may be selected during or after HBeAg seroconversion.

Patients who become HBsAg negative and develop antibody to HBsAg (anti-HBs) are diagnosed as having resolved hepatitis B [3,4]. This is an uncommon phenomenon in chronic HBV infection. During stage HBV DNA may still be detectable by PCR in serum and more often in the liver.[12] In rare cases severe immune suppression, such as cancer chemotherapy or after organ transplantation, HBV can be reactivated in patients with resolved hepatitis B [13].

Clinical spectrum

HBeAg positive Chronic Hepatitis
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Patients with HBeAg-positive chronic hepatitis B usually present in the third or fourth decade of life. Men outnumber women, [14,15] liver damage ranges from mild (24 to 42%) to moderate or severe chronic hepatitis (44 to 63%) or active cirrhosis (10 to 24%) [16-20]. Chronic hepatitis B tends to be milder in children. Nevertheless, severe liver disease including cirrhosis may occur in a small proportion of patients during childhood [21,22]. A key event in the natural history of HBeAg positive chronic hepatitis is HBeAg seroconversion. Several studies have shown that seroconversion with marked reduction of HBV replication is associated with biochemical and histologic remission of inflammatory activity in the majority of patients [23-25]. Regression of fibrosis occurs gradually months to years after HBeAg seroconversion.[26] In longitudinal studies the observed probability of clearing HBeAg was about 50% and 70% within 5 and 10 years of diagnosis, respectively [23,27-29]. Most studies have found that the mean annual rate of spontaneous HBeAg seroconversion ranges from 8 to 15% in children or adults with elevated ALT [3,4,23-25,29-31,31]. Among Asian, most of whom have normal ALT, spontaneous HBeAg seroconversion occurs at a very low rate, less than 2% during the first 3 years of age and 4 to 5% in children older than 3 years [32]. Several determinants for HBeAg seroconversion have been reported, including gender, age, ALT level, and more recently HBV genotypes. Older carriers and females are more likely to clear HBeAg [33].

Frequent acute exacerbation of hepatitis, reflecting immune-mediated lysis of HBV-infected hepatocytes with ALT elevations to more than 10 times ULN and more than twice the baseline value and with HBV DNA levels rising before and falling during the flare, precede seroconversion of HBeAg to anti-HBe. These exacerbations usually last 2 to 4 months [34]. In some cases these spontaneous flares of hepatitis are not followed by subsequent HBeAg seroconversion and can be viewed as an abortive attempt at seroconversion. These flares of hepatitis are usually asymptomatic and frequently unrecognized, but some are accompanied by symptoms of acute hepatitis and rarely, primarily in patients with cirrhosis or advanced fibrosis, may lead to hepatic decompensation and even death due to massive necrosis [34].

HBsAg-negative chronic hepatitis

The diagnosis of HBeAg-negative chronic hepatitis B is based on the presence of HBsAg for more than 6 months, undetectable HBeAg, presence of anti-HBe, detectable serum HBV DNA exceeding 105 to 106 copies/mL, increased ALT levels, and hepatic necroinflammation on histology. Other causes of liver disease, such as superinfection with other hepatitis viruses, alcohol abuse, hepatotoxic drug use, and autoimmune or metabolic liver disease, should be excluded [3,4]. The atypical serological profile is related to the predominance of HBV variants, which are unable to express HBeAg. The most frequent variant has a G-to-A change at nucleotide 1896 (G1896A), which creates a stop codon in the precore region of the HBV genome and completely abolishes the production of HBeAg [35]. Other variants include changes in the start codon of the precore region or a two-nucleotide substitution (A1762T, G1764A) in the core promoter region, which reduces precore messenger RNA synthesis and HBeAg production [36].

Patient with HBeAg negative are older than patients with HBeAg-positive chronic hepatitis (median 40, range 36–45 years). Males predominate and data indicate that liver disease is more active and advanced, minimal or mild chronic hepatitis is infrequent, and severe necroinflammation is seen in more than 50% patients at diagnosis [37-39]. In reports from Mediterranean area, 29 to 38% had cirrhosis at presentation. The older age and the high rate of advanced liver damage at presentation suggest that HBeAg-negative chronic hepatitis represents a late phase in the natural history of chronic HBV infection rather than de novo infection with HBV variants that do not produce HBeAg. To further support this concept, a recent long-term study reported that HBeAg-negative chronic hepatitis accumulated over time after HBeAg seroconversion with a cumulative incidence of approximately 25% after 16 years of follow-up [40]. Thus, the increasing prevalence of HBeAg-negative. Fluctuation in level of viremia and ALT are more common and sustained response is rare. Delayed spontaneous HBsAg clearance has been estimated to occur at a low rate of 0.5% per year [40].

Inactive HBsAg Carrier State

Inactive carriers forms the largest group in chronic HBV infected patients. Around 300 million people are inactive carriers The inactive HBsAg carrier state is diagnosed by absence of HBeAg and presence of anti-HBe, undetectable or low levels of HBV DNA in PCR-based assays, repeatedly normal ALT levels, and minimal or no necroinflammation, slight fibrosis, or even normal histology on biopsy [3,4]. Inactive cirrhosis may be present in patients who had active liver disease during the replicative phase of infection. The prognosis of the inactive HBsAg carrier state is usually benign. Long-term follow- up (up to 18 years) of these carriers has indicated that the vast majority show sustained biochemical remission and very low risk of cirrhosis or hepatocellular carcinoma (HCC) [40-42]. Rarely, patients, even noncirrhotics, may develop liver cancer during the inactive HBsAg carrier state [40-43]. In addition, approximately 20 to 30% of persons in the inactive HBsAg carrier state may undergo spontaneous reactivation of hepatitis B during follow-up [29,33,34,40]. Multiple episodes of reactivation or sustained reactivation can cause progressive hepatic damage and even hepatic decompensation. HBV reactivation is usually asymptomatic but on occasion can mimic acute viral hepatitis [44]. Acute flares of hepatitis should be differentiated from superinfection with other hepatotropic viruses. As many as 20 to 30% of these acute exacerbations may be caused by superinfection with HDV, HCV, or hepatitis A virus and can be associated with an increased risk of fulminant hepatic failure [44]. Some carriers eventually become HBsAg negative and develop anti-HBs. The incidence of delayed HBsAg clearance has been estimated to be 1 to 2% per year in Western countries, where HBV infection is usually acquired in adulthood, but a lower rate from 0.05 to 0.8% per year in endemic areas, where HBV infection is mostly acquired perinatally or in early childhood. Clearance of HBsAg has been reported to be higher in women than in men and in older than younger carriers. Prognosis is improved by loss of HBsAg as liver disease is usually inactive and nonprogressive, but HBsAg clearance does not completely prevent occurrence of decompensation or HCC in patients who have already developed cirrhosis [45,46].

Change in the terminology of HBV carriers

HBV infection is termed as chronic if it continues to be HBsAg +ve for ≥6 months. Chronic HBV infection is a dynamic process with a wide spectrum of spectrum of affliction. On one hand patients are asymptomatic with no clinical evidence of liver diseases, while on other being end-stage cirrhosis and hepatocellular carcinoma. For many decades the patients were considered to have a benign, non progression infection and were designated as hepatitis B "carriers". Probably the word 'carrier' was mistakenly chosen for hepatitis B as in true sense, a carrier is an individual who (i) harbors a specific infectious agent (ii) has no discernible clinical disease and (iii) serves as a potential source of infection. For this infection the second and third points should be looked at carefully. One the basis of Asian collaborative survey the term 'carrier' was replaced by the term 'chronic hepatitis B virus infection' [47,48]. Later on for this infection the term 'Inactive HBsAg carrier' was adopted [49].
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Management of Inactive HBsAg Carrier

Differentiation from chronic HBsAg negative hepatitis B, requires serial testing of ALT and HBV DNA for one year before designating carrier state [49]. In subject with inactive carrier state testing of HBV DNA and liver biopsy are not recommended. Treatment is not recommended as there is no evidence that available therapy affects HBsAg status. Family screening with HBsAg and anti-HBs, if negative vaccinate them and success of vaccination should be confirmed with anti-HBs testing. Protected sexual intercourse until partner has developed protective antibodies. The offspring need active and passive vaccination [4,47]. Use of alcohol should be avoided, possibility of reactivation or super infection by other viruses and advised if there is jaundice, malaise or increased fatigue. Regular follow-up at every 6–12 months intervals with ALT [4]. If the age of the patient is more than 50 yrs family history of HCC-AFP and ultrasonography every 6–12 monthly should be done. Universal precaution should be taken while treating these patients in the hospital. They should not be allowed to donate the blood or organ or semen. For pregnant women vaccinate the new born at birth with active and passive immunization with in 12 hours of the birth, close monitoring required if undergoing chemotherapy or immunosuppressive medication.
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Notes on “Milk Thistle,” Francine Rainone, D.O., Ph.D., M.S. AMERICAN FAMILY PHYSICIAN

Milk thistle has been used as a cytoprotectant for the treatment of liver disease, for the treatment and prevention of cancer, and as a supportive treatment of Amanita phalloides poisoning. Clinical studies are largely heterogeneous and contradictory. Aside from mild gastrointestinal distress and allergic reactions, side effects are rare, and serious toxicity rarely has been reported. In an oral form standardized to contain 70 to 80 percent silymarin, milk thistle appears to be safe for up to 41 months of use. Significant drug reactions have not been reported. Clinical studies in oncology and infectious disease that are under way will help determine the efficacy and effectiveness of milk thistle. (Am Fam Physician 2005;72:1285-8. Copyright © 2005 American Academy of Family Physicians.)

Milk thistle (Silybum marianum) was used in classical Greece to treat liver and gallbladder diseases and to protect the liver against toxins. It recently has been investigated for use as a cytoprotectant, an anticarcinogen, and a supportive treatment for liver damage from Amanita phalloides poisoning. Its active ingredient is silymarin, found primarily in the seeds. Silymarin undergoes enterohepatic recirculation, which results in higher concentrations in liver cells than in serum.1 It is made up of components called flavonolignans, the most common being silybin.2

Pharmacology

A number of studies have suggested that silymarin is an anti-inflammatory. It regulates inflammatory mediators such as tumor necrosis factor (TNF),3 TNF-alpha,4 nitrous oxide, interleukin-6, and interleukin-1 receptor antagonist.5 Silymarin also increases lymphocyte proliferation, interferon gamma, interleukin-4, and interleukin-10 cytokines, in a dose-dependent manner.6,7 Taken together, these effects suggest a possible role in preventing or treating infectious disease.
SORT: Key Recommendations for Practice
Clinical recommendation Evidence rating References
Patients should be informed that there is insufficient evidence to recommend milk thistle for viral hepatitis and alcoholic liver disease, but that it appears to be safe. B 25-33
Patients who ask about milk thistle for hepatic cytoprotection from a variety of toxins should be informed that there is weak evidence for its effectiveness. C 26
Milk thistle shows promise as supportive therapy for Amanita phalloides poisoning. C 37
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1154 or http://www.aafp.org/afpsort.xml.

Several mechanisms of cytoprotection have been identified. In some studies,8 milk thistle promoted neuronal differentiation and survival. In others, silymarin inhibited leukotriene formation by Kupffer cells9 and increased expression of growth factor beta-1 and c-myc.10 In animal studies, it has shown protective effects against damage to the pancreas from cyclosporine (Sandimmune)11; damage to the kidney from acetaminophen, cisplatin (Platinol), and vincristine (Oncovin)12; and damage to the liver from carbon tetrachloride,13,14 partly by reducing lipid peroxidation. In another study,15 silymarin slowed the progression of alcohol-induced liver fibrosis in baboons. In vitro and animal studies support the possibility that milk thistle has anticarcinogenic effects for cancers of the prostate, breast, skin, colon, tongue, and bladder.16-24

Uses and Effectiveness

liver disease

In the United States, milk thistle is most commonly used to treat viral infections and cirrhosis of the liver. Clinical trials have produced conflicting results. In a study25 of patients with cirrhosis, 170 patients (46 with alcoholism) were randomized to Legalon, a proprietary product standardized to contain 70 to 80 percent silymarin, or placebo. In the 146 patients who completed 24 to 41 months of therapy, there was a lower mortality rate among the patients treated with Legalon. The greatest benefit occurred in those whose cirrhosis was caused by alcoholism and in those who had less severe cirrhosis on entry.25

In a six-month double-blind study26 of 36 patients with chronic alcoholic liver disease, the group given Legalon showed normalization of their bilirubin, aspartate transaminase and alanine transaminase serum levels, and also showed improvement in histology. These effects did not occur in the placebo group. In another study,27 106 patients with mild acute and subacute liver disease characterized by elevated serum transaminase levels were randomized to receive silymarin or placebo. Of the 97 patients who completed the four-week study, there was a statistically significant greater decrease in transaminase levels in the silymarin group. In addition, results of a smaller study28 of 20 patients with chronic active hepatitis randomized to placebo or silybin showed that the milk thistle group had significantly lower transaminase, bilirubin, and gamma-glutamyltranspeptidase levels than the placebo group. This study used a complex of silybin with phosphatidylcholine, which appears to increase bioavailability.
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Other studies have not duplicated these positive effects. In a study29 of 200 patients with alcoholic cirrhosis, there were no differences in time to death or progression to liver failure in the 125 patients who completed 24 months of therapy. Similarly, in a study30 of 72 patients with alcoholic liver disease, there were no differences in mortality or laboratory values between the placebo and silymarin groups. Finally, a three-month study31 of 116 patients with histologically proven alcoholic hepatitis randomized to placebo or silymarin showed no significant differences in serum transaminase activity or histologic fibrosis scores.

Two meta-analyses of milk thistle for liver disease32,33 detail the major limitations of prior studies and conclude that data are insufficient to support its use at this time. The two main limitations are the heterogeneity of the study populations, caused by lack of precise inclusion and exclusion criteria and the noncomparability of doses received. Most studies did not report or use objective criteria to determine the severity and etiology of cirrhosis and did not control for confounding factors such as infection with hepatitis B or C and ongoing alcohol intake. In addition, the trials vary considerably in duration, ranging from one week to 41 months, without agreement on the minimum duration needed to see effect. The effect of silymarin is thought to be dose-dependent, and it is not known whether the bioavailability of different formulations is equivalent.6,7 Because the studies used different products, it is not known whether participants in the different studies received equivalent doses. These limitations make comparisons of studies difficult to interpret. Efforts are under way to isolate, semisynthesize, and extensively characterize the biologic activities of the flavonolignans that constitute silymarin.34 Developing products that contain standardized percentages of precise ratios of the components of silymarin will improve the ability to test its effectiveness.

cytoprotectant

Studies of the use of milk thistle as a cytoprotectant in humans have been limited. In one study,35 49 of 200 workers exposed to toluene or xylene for five to 20 years developed persistent elevations in transaminase levels; 30 of these heterogeneous patients were treated with Legalon, whereas the others were not treated. In the Legalon group, transaminase activity decreased and platelet count increased when compared with the untreated group. Patients two to 21 years of age with acute lymphoblastic leukemia who are receiving hepatotoxic chemotherapy are being recruited for a second phase randomized pilot trial of silymarin.

anticarcinogen

Researchers are investigating the use of milk thistle's active ingredients for the prevention and treatment of cancer. Two additional animal studies on prostate cancer chemoprevention and treatment are ongoing, and a third phase trial in human prostate cancer patients with rising prostate-specific antigen also is under way.

amanita phalloides poisoning

The A. phalloides mushroom, called the "death cap," produces severe nausea, vomiting, and watery diarrhea within five to 12 hours of ingestion. This often causes hypovolemia and hypoglycemia. Silymarin inhibits the binding of the toxins in the mushroom to hepatocytes and interrupts the enterohepatic circulation of the toxins.36 Several journals have published case reports of silymarin treatment (intravenously and orally) for A. phalloides poisoning in humans, but the largest series37 followed only 18 patients. In every case, silymarin was used in combination with other agents, usually being added when standard treatment appeared to fail. The relative contribution of silymarin to these treatment regimens is unknown. The intravenous form of silymarin was used in these studies, but it is not available in the United States.
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Adverse Effects and Interactions

The Agency for Healthcare Research and Quality reviewed the effects of milk thistle on liver disease and cirrhosis,32 noting that serious adverse reactions are virtually unheard of. The most common reported complaints were gastrointestinal disturbances, but the overall incidence was no different from placebo. Allergic reactions, ranging from pruritus and rash to eczema and anaphylaxis, are rare.

Drug interactions do not appear to be problematic. Silybin inhibits the activities of CYP2D6, CYP2E1, and CYP3A4, but at physiologic concentrations far higher than those given clinically.38 In a study39 of 10 healthy volunteers, administration of 175 mg of milk thistle three times daily for three weeks had no significant effect on concomitantly administered indinavir (Crixivan).
Table 1Key Points About Milk Thistle
Efficacy Acute and chronic viral hepatitis, alcoholic liver disease: conflicting evidenceCytoprotection: rigorous randomized controlled trials ongoing; limited evidence suggests benefit.Anticarcinogen: clinical trials ongoingAmanita phalloides poisoning: insufficient data
Adverse effects Generally well tolerated; infrequent reports of gastrointestinal disturbances; rare reports of pruritus, eczema, rash, and anaphylaxis*CAUTION: do not use in patients with allergies to members of the aster family.
Interactions No significant drug interactions
Dosage Milk thistle seed extract, 150- to 175-mg capsule, standardized to 80 percent silymarin, three times dailyUltrathistle (seed extract bound to phosphatidylcholine), 360-mg capsule, three times daily
Cost $15 to $30 per month at 150 to 175 mg three times daily$42 per month at 360 mg three times daily
Bottom line Safe, no known drug interactions; insufficient data to recommend for treatment of liver disease; under investigation for anticarcinogenic and chemoprotective effects
*-Three nonfatal case reports, only one of which is sufficiently attributed to the herb.
Dosage

Most clinical trials have used daily dosages of 420 to 480 mg silymarin, divided into two or three doses daily. Until the specific effects of each of the flavonolignans is known and products are available that contain standardized ratios of these components, the optimal dosage will remain unknown. Table 1 outlines the efficacy, safety, tolerability, dosage, and cost of milk thistle.
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Notes on “Highlight on Special Hepatic Issues and Populations,” CCO Independent Conference Coverage of the 2008 Annual Meeting of the European Association for the Study of the Liver.

1.  Risk Score for Predicting Long-term Probability of HCC Development in Chronic Hepatitis B Patients.

Josep M. Llovet, MD: Yuen and colleagues[14] presented a large longitudinal analysis to identify independent risk factors for HCC in a cohort of 820 chronic hepatitis B patients with an initial visit to the Queen Mary Hospital, Hong Kong, between 1995 and 2005 (Risk Score Predicts Long-term Probability of HCC Development). Every 3-6 months, patients were evaluated for HBsAg, HBeAg, anti-HBe, liver biochemistry, and alpha-fetoprotein. In addition, ultrasound assessments were performed. Diagnosis of cirrhosis required an aspartate aminotransferase–to-platelet ratio index > 2, serum albumin < 35 g/L, and confirmation on ultrasound. Overall, HCC was detected in 4.9% of patients. Patients who developed HCC tended to be older at baseline, with a median age at presentation of 54.2 years vs 39.8 years for non-HCC patients (P < .001). In the multivariate analysis, older age (relative risk [RR]: 1.07; 95% confidence interval [CI]: 1.04-1.09), male sex (RR: 2.98; 95% CI: 1.15-7.78; P = .025), higher HBV DNA (RR: 1.28; 95% CI: 1.04-1.58; P = .02), cirrhosis (RR: 7.31; 95% CI: 3.76-14.21), and a core promoter mutation (RR: 3.66; 95% CI: 1.42-9.47; P = .007) were all independently associated with HCC. Yuen and colleagues developed a risk score equation for predicting development of HCC based on the 5 independent risk factors identified in multivariate analysis. The equation was 16 x sex (male = 1; female = 0) + age (years) + 3 x HBV DNA (log10 copies/mL) + 19 x core promoter (mutation = 1; no mutation = 0) + 30 x cirrhosis (yes = 1; no = 0). The risk for HCC development increased by 7% for every punctual increase in risk score. The area under the curve for 5-year prediction was 0.88 (95% CI: 0.82-0.93) and the area under the curve for 10- year prediction was 0.89 (95% CI: 0.85-0.93). Therefore, this study evaluated several parameters to understand which were the independent risk factors for the development of HCC. Nevertheless, most of the parameters described by Yuen and colleagues are already known and this study serves as a confirmation of these factors. For example, it is known that male sex is associated with a 3-fold greater risk of HCC development compared with females.[15] (A recent study suggests that estrogens may inhibit the action of IL-6 in inducing HCC, which may be one mechanism for this finding.[16]) It is also clear that age is a factor; sometimes it is difficult to differentiate age from the status of fibrosis, although in this study age appeared to be an independent factor. Furthermore, higher levels of HBV DNA are a factor that has been described previously. The presence of cirrhosis is the most important of these factors. It is important to remember that patients with chronic hepatitis B have a 1% annual risk of developing HCC, whereas patients with established cirrhosis have a 2.5% annual risk of developing HCC.[17] Robert G. Gish, MD: The use of precore mutations to predict HCC is not a new concept and has been used in clinical practice for a number of years. In addition, historically, it has been thought that hepatitis B patients with genotype C are at a higher risk of developing liver cancer than those with genotype B.[18] Several studies involving univariate and multivariate analyses have illustrated this. In this study, 40% of the patients had genotype B and 60% had genotype C infections. To identify associations with HCC in a mixed genotype population with the presence of both precore and core promoter mutations, a large study with multivariate analysis is needed to identify the specific mutation(s) causing the effect. The study by Yuen and colleagues was not able to accomplish this since there were only single comparisons within these groups. For example, some Asian studies have shown that the precore mutations are associated with HCC risk in genotype C patients.[19] Paul Martin, MD: I agree that the study by Yuen and colleagues reiterated much that is already known. In terms of managing individual patients, these data are too preliminary to guide clinical practice. For example, there does not seem to be sufficient data at this time to support using the presence of a core promoter mutation as a signal for starting therapy to reduce the risk of developing HCC. Robert G. Gish, MD: I was surprised to see that there was no difference in increased risk for HCC at HBV DNA levels < 10,000 copies/mL; this may be because of the size of the study. In the analysis from the REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer) study, an increased risk of HCC could be determined at much lower HBV DNA levels.[20,21] The current study was likely underpowered to identify differences in risk at those levels, even though the duration of follow-up is comparable.
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Notes on “The Facts About Liver Biopsy,” Katie West,

If you will be having a liver biopsy it is important that you thoroughly discuss with your doctor both the procedure and purpose of the biopsy and get all of your questions answered before it is scheduled. These points will help to inform you of biopsy procedure and in guiding your questions.

What is a liver biopsy?
A liver biopsy is a procedure in which a small sample of liver tissue is removed from the liver in order to more closely analyze the liver and diagnose liver conditions. Before a biopsy is performed, other less intrusive tests such as x-rays and blood tests are usually issued. It is only after those tests come back and your doctor decides she/he needs more information that a biopsy is scheduled.

Why is a liver biopsy performed?
A liver biopsy can be especially helpful in diagnosing liver abnormalities and diseases, especially hepatitis and liver cancer, when other tests are inconclusive.

Biopsies can also help to predict treatment outcomes for chronic Hepatitis C patients and in the management of Hepatitis C.

How is a live biopsy performed?
There are several kinds of biopsy procedures, however the most common is a percutaneous biopsy. In this type of biopsy the procedure is performed at the hospital. The patient will lie on her/his back, placing their right hand above their head. The patient is given a local anesthetic starting at the skin level and continuing through the chest wall, into the liver to numb the biopsy area.

After the patient is fully numb, a biopsy needle is quickly inserted and removed while the patient holds her/his breathe. Ultrasound is sometimes used in guiding the biopsy needle. This needle is used to remove a small section of the liver. Because the area is numbed, the patient should only feel a small amount of dull pain and pressure during the biopsy.

The entire procedure typically takes about 20 minutes, with approximately 5 to 10 seconds where the patient will have to remain completely still, holding her/his breath.

What to expect before the biopsy
Before the biopsy is performed, a doctor will run a series of blood tests and take a complete medical history. In most instances, patients are instructed to stop taking aspirin, ibuprofren, anticoagulants, and possibly other medications for one week leading up to the biopsy and to not eat and drink for the 8 hours directly before the procedure.

After the biopsy
Most patients feel a minimal amount of pain after the biopsy procedure. A bandage is placed over the incision and the patient is instructed to lie on her/his right side for up to 2 hours to help stop the bleeding. In most cases, patients are sent home the same day. Patients must have a ride home from the hospital and will need to be on bed rest for 8 to 12 hours.

The most common complaints after a liver biopsy is soreness around the incision and pain in the right shoulder. Similar to before the procedure, it is essential that patients do not take aspirin, ibuprofren, or other blood thinning medications for one week after the procedure to ensure the incision and biopsy site heals properly.

What are possible complications of a liver biopsy?
Bleeding from the liver (at the site of the biopsy) is the most common complication of a liver biopsy. It is reported that this occurs in 1 out of every 100 patients. In most cases the bleeding is not severe enough to require a blood transfusion, however in some cases a transfusion and/or surgery is required to stop the bleeding. Other less common complications include puncture of the lung or gallbladder and infection. It is your right as a patient to be informed of and your doctor’s responsibility to inform you of these complications, however it is also important to remember that any surgery has the risk of complications, and that often those complications are rare.
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Notes on “Relationship of Genotypes of Hepatitis B Virus to Mutations, Disease Progression and Response to Antiviral Therapy,” A. Kramvis; M. C. Kew, J Viral Hepat.  2005;12(5):456-464.


Summary

Phylogenetic analysis has led to the classification of hepatitis B virus into eight genotypes, designated A to H. The genotypes have differences in biological properties and show heterogeneity in their global distribution. These attributes of the genotypes may account not only for differences in the prevalence of hepatitis B virus mutants in various geographic regions, but also be responsible for differences in the clinical outcome and response to antiviral treatment in different population groups.

Introduction

Hepatitis B virus (HBV), a DNA virus, is a member of the family Hepadnaviridae [1] that replicate by reverse transcription of the encapsidated pregenomic RNA by the viral encoded polymerase.[2] The viral polymerase lacks proofreading activity and sequence heterogeneity is therefore a feature of HBV.

Phylogenetic analysis has led to the classification of HBV into eight genotypes, defined by an inter-group divergence of >8% in the complete genome sequence [3,4] and of >4% in the S gene.[5] Since the first description of four genotypes (A-D) of HBV in 1988,[4] four more have been identified, designated E and F,[6] G [7] and H.[6-8] Moreover, subgenotypes with distinctive sequence characteristics and a divergence in the complete genome of >4% have been found within genotypes A,[9-11] B,[12-14] C[15] and F.[16,17]

The eight genotypes show a distinctive geographical distribution. Genotype A is prevalent in north-western Europe, North America and Africa.[18-20] Genotypes B and C are characteristic of Asia,[4,19,20] whereas genotype D has a worldwide distribution but predominates in the Mediterranean area.[19,20] Genotype E is found in Africans,[6,19,21] genotype F in the aboriginal populations of South America[18,22] and genotype H is confined to the Amerindian populations of Central America.[8,23] To date, the isolation of genotype G has been limited to HBV carriers in France and Georgia, USA,[7] UK,[20] Italy[20] and Germany.[24]

The first instance of genotype-related differences in the biological properties of HBV was the observation that the precore 1896 stop-codon mutant was commonly found in regions where genotype D prevailed and was absent in regions were genotype A occurred.[25] The reason for the association of the 1896 mutant with genotype D was that this mutation enhanced the stability of the encapsidation signal (ε) allowing replication, whereas in genotype A it would lead to its destabilization and therefore prevent replication.[26] Subsequently, it has become increasingly evident that the heterogeneity in the global distribution of HBV genotypes may account not only for differences in the prevalence of HBV mutations in the different populations but also be responsible for differences in the clinical outcomes of HBV infections and the response to antiviral treatment.

Relationship of Mutations to Genotypes

1896 Stop Codon Mutation

The precore-core region of the HBV genome codes for the precore-core fusion protein that is post-translationally modified to give rise to hepatitis B e antigen (HBeAg).[27,28] Although HBeAg is not required for viral replication or infectivity,[29,30] its exact function is not known. It is thought to play a role in immune modulation and can alter the host response to core protein.[31,32] Thus, the emergence of the 1896 G to A stop-codon mutation[33,34] that prevents expression of HBeAg may be a means of immune evasion. The occurrence of the 1896 mutation is restricted by the secondary structure of the encapsidation signal (ε),[26,35-37] which is transcribed from the same region of the HBV genome coding for HBeAg (Fig. 1). Destabilization of this structure by the disruption of the G-C base pair between positions 1858 and 1896 (that would result from a G-to-A mutation at 1896) would be detrimental to viral replication,[26] as has been shown by transfection experiments.[25,35] Thus the development of the 1896 mutation depends on the presence or absence of C or T at position 1858 and shows geographic variation that is related to the distribution of the various genotypes.[25] Genotypes B, D and E have T1858, whereas A and H have C1858. Genotype C and F isolates can have either C1858 or T1858: genotype F strains in Central America have a T1858[22] and Japanese genotype C strains have T1858 exclusively,[38,39] whereas C1858 is confined to carriers of genotype C in South-east Asia.[19,40-44] Some studies found no difference in the prevalence of 1896 mutants between genotypes B and C.[45,46] This is to be expected because both these studies were carried out in Japan where genotype C with T1858 predominates. It is of interest that although both subgenotypes of genotype B, identified in Asia (Ba and **) have T1858, the 1896 mutation was found to occur more often in subgenotype **.[47] The 1896 mutation is found most frequently in anti-HBe positive patients infected with genotype D[25,26,48-51] and E[52] and is rarely found in genotype A,[25,50,51] genotype H[8] and in a minority only of genotype C[19,41,42] and genotype F strains.[6,17,19,22]
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Figure 1.

The nucleotide sequence and predicted secondary structure of the HBV encapsidation signal of genotype A (AY233274).[126] The DNA instead of the RNA sequence are shown for ease of interruption.

    

T1762 A1764 Basic Core-Promoter Mutations

An adenine (A) to thymine (T) transversion at position 1762 together with a guanine (G) to A transition at 1764 in the basic core promoter (BCP) were first described in HBV isolates from Japanese patients.[53,54] The presence of the mutations precedes seroconversion from HBeAg to anti-HBe in genotype A strains but not in genotype D.[48,55] Their presence results in reduced levels of precore mRNA and HBeAg expression in transfection studies [56-59]. The T1762A1764 mutations develop more frequently in genotypes A and H with C1858, but in a minority of genotype C with C1858[39] and more often in subgenotype Ba than in ** or genotype C.[47] However, in other analyses, they are equally distributed among the HBV genotypes.[49,51] Yet other studies show a higher frequency of the T1762A1764 in genotype C compared with genotype B,[41,42,45,46,60,61] and this does not correlate with HBeAg status.[45,46] Only 25% of carriers infected with genotype E possess the T1762A1764 mutations and this finding is independent of HBeAg status.[52] These mutations are found to be significantly associated with more severe liver disease [liver cirrhosis with or without hepatocellular carcinoma (HCC)] and an older age (>35 years).[45,62,63]

Pre-S Mutants

Various mutations in the pre-S region have been described. These range from point mutations and small deletions and insertions[64] to very large deletions[65,66] and deletions that prevent the expression of the pre-S2 protein.[67] A few studies have analyzed the relationship between genotypes and the occurrence of pre-S mutants. In two independent studies, pre-S deletion mutants were found to occur more frequently in genotype C than in genotype B isolates[68] and in adr (corresponding to genotype C) than in adw (corresponding to genotype B) isolates.[69] In contrast, in another study, although these mutants are found more frequently in genotypes B and C than in the other genotypes, no statistical difference was found between their incidence in genotypes B and C.[70] This discrepancy may be explained by the different geographic distributions of the isolates or the fact that the latter study was not a case-control study. Moreover, these deletion mutants are more frequently detected in isolates from patients with severe liver disease (liver cirrhosis and HCC) than other patients.[68,70]

Deletions within the pre-S region can lead to impaired viral clearance without affecting HBV binding to hepatocytes and their subsequent penetration, and therefore could contribute to chronicity of infection.[71] In keeping with this possibility is the observation that pre-S deletion mutations are more frequently detected in isolates from patients with cirrhosis or HCC.[68,70]

Mutation Clustering Regions Within The Core Region

Ehata et al.[72] have identified mutation clustering regions (MCR) within the core region of HBV isolates from individuals with liver disease and speculated that these may be immunological targets for cytotoxic T lymphocytes.[73] MCRs have been mapped to different positions in the different genotypes. Genotypes B (most) and C (adr subtype) have mutations clustering at positions 84 to 99 of the core gene and genotypes A, B and D (adw subtype) at positions 48 to 60.[74] The MCR of genotype F residues was mapped between positions 57 and 68 of the core protein.[22]

Splice Variants

These HBV variants arise from the encapsidation and reverse transcription of spliced pregenomic RNA.[75] Using in vitro tranfection studies, there is no difference in the dominant splice variant produced by genotypes D, C and E, whereas the minor splice variants synthesized by isolates belonging to the different genotypes vary.[75] Splicing in HBV may contribute to the pathogenicity and/or persistence of the virus.[75-77]
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The variation in the presence and the development of mutations in the different genotypes of HBV may be a contributing factor to the influence of genotypes in disease progression.

Genotypes and Disease Progression

Because disease progression can be affected by a number of factors, such as the age of acquisition and route of the infection,[41] the immune competence of the host, and the influence of environmental factors such as alcohol intake, iron overload and exposure to aflatoxin, care should be exercised when interpreting the role of genotypes in disease progression.

The majority of studies on the effect of genotypes on disease progression have been undertaken in South-east Asia where HBV is hyperendemic and genotypes B and C prevail. A greater frequency and severity of liver dysfunction was initially reported in patients infected with serotype ayr (mainly genotype C) compared with adw (mainly genotype B).[78-80] Seroconversion from HBeAg- to anti-HBe positivity occurs much earlier in genotype B than genotype C carriers.[42,45,46,61,78,81-85] Higher HBV-DNA levels have been detected in patients infected with genotype C compared with those infected with genotype B in some studies,[44,81,86] but not in others.[45,46] The difference might be attributed to the HBeAg status of the patients. Genotype C was found to have lower HBV DNA levels than genotype A, B and D in the HBeAg-positive phase.[20] In south-western Japan carriers of genotype D were younger and exhibited earlier anti-HBe seroconversion than carriers with genotype C.[87]

Patients infected with genotype B are more likely to have a sustained biochemical remission after spontaneous HBeAg seroconversion than patients infected with genotype C,[85] who are more likely to develop chronic and advanced liver disease.[44,86] Genotype C is more prevalent in patients with fibrosis or cirrhosis[43,46,82] and is associated with more severe histological liver damage than genotype B[88] or genotype D.[87] Patients infected with genotype C have higher scores of histological activity and fibrosis[41,42] and higher alanine aminotransferase (ALT) levels relative to those infected with genotype B,[44,83] genotype A or D.[89]

The majority of studies in Far Eastern countries have shown a greater risk of HCC development with genotype C than with genotype B.[43,68,90,91] However, patients infected with genotype B exhibit earlier HBe seroconversion and progress to liver fibrosis and HCC at a slower rate than those infected with genotype C, and it has been suggested that the life-long risk of progression to advanced fibrosis and development of HCC may not differ among genotype B- and C-related chronic liver disease.[46,61] Because most studies have been cross-sectional, it will be helpful if prospective, longitudinal studies are undertaken to determine whether the genotypes influence the incidence of disease in the long term.

In contrast to genotype B found in Taiwan[82] and China,[83] which is associated with the development of HCC at a young age, in Japan, the mean age of HCC patients infected with genotype B is significantly older than those infected with genotype C.[46,81,92] Although it has been suggested that this discrepancy between Chinese and Japanese HCC patients, could be a result of host factors and the intake of aflatoxin in Taiwan,[81] the difference is probably the consequence of the different subgenotypes found in mainland Asia (Ba) and Japan (**).[12] Further studies are required to resolve this issue. When matched HBV carriers were compared, HBeAg-positivity occurred in a significantly lower proportion of those infected with subgenotype ** compared with Ba or genotype C (and loss of HBeAg occurs earlier in carriers of **).[13,47] Subgenotype Ba occurred more frequently in acute than in chronic hepatitis patients.[13]

Genotypes A and D were found to be prevalent in the Indian subcontinent. In one study genotype D was associated with more severe liver disease and with HCC in young patients,[93] whereas in another study, where the majority of patients were infected with genotype D, it was concluded that genotype D did not influence the clinical outcome of infection.[94]

There have been fewer studies on the effect of genotype on disease progression in western countries. The long-term outcome of HBV infection was found to be different in patients infected with different genotypes in Europe. Chronic infection with genotype A is more frequent than when individuals are infected with genotype D.[95] Genotype A was more prevalent in HBeAg-positive chronic hepatitis patients, whereas genotype D was more prevalent in those positive for anti-HBe.[20,49,50,96] HBeAg-positive and HBeAg-negative carriers infected with genotype D were found to have higher levels of HBV-DNA when compared with genotype A, B and C.[20,41] The prognosis of chronic hepatitis B may be better in patients infected with genotype A than in those infected with either genotypes D or F because concomitant sustained biochemical remission and decrease in HBV-DNA levels occurred at a higher rate in genotype A- than in genotype D- or genotype F-infected patients.[96] Genotype D was also found to be associated with severe recurrent disease post-transplantation.[97] In a single study, genotype F-infected individuals showed a higher mortality rate than those infected with genotype A or D.[96] However, this does not agree with other reports that showed a low pathogenicity of genotype F.[22,98]
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Very few isolates of genotype G have been characterized making it difficult to draw any conclusions regarding the influence of this genotype on disease progression. Nevertheless a trend is observable. Chronic hepatitis patients infected with genotype G are characterized by high HBV-DNA and HBeAg levels[20,24,99-101] and elevated ALT levels.[102] However, coinfection with genotype A may account for these attributes.[101,102] One patient infected with genotype G had cirrhosis[100] and two were found to lack an anti-HBc response.[24,99]

Genotypes and Response to Antiviral Therapy

Although mass vaccination programmes have begun to control the spread of HBV infection, therapeutic intervention is the only option for those with established chronic HBV-associated disease.

Interferon

One of the more effective therapies available is treatment with interferon (IFN)-α, a naturally occurring cytokine primarily produced by B lymphocytes, null lymphocytes and macrophages.[103-105] IFN has anti-viral, anti-proliferative and immunomodulatory effects.[106] The molecular virological factors that contribute to the responsiveness of HBV infection to IFN treatment and may play a significant role in predicting whether IFN can be used effectively for treatment are largely unknown. The ability to predict responsiveness is important in the clinical setting, considering the fact that IFN treatment is expensive, is administered by injection, and can have side-effects and be poorly tolerated.

To date, the most important viral factor that has convincingly been shown to determine the response to IFN is the pretreatment HBV-DNA titre, the lower the titre the better the response.[107] Other viral factors that may play a role include the presence of BCP and precore mutations. It has been proposed, although not proven, that the BCP mutations together with a low HBV-DNA level and elevated ALT may be favourable factors of response in IFN-induced anti-HBe seroconversion.[108] The data on the relevance of precore mutants and their influence on the long term response to IFN is also inconclusive. In some studies precore mutants were considered to be necessary for response to IFN.[107,109,110] These data differ from other studies that showed that the precore mutants do not have prognostic value for virus elimination following IFN therapy in HBeAg-positive or -negative patients.[111-113] These differences in responsiveness to IFN treatment may possibly be the result of different genotypes of the virus and therefore an analysis of how various mutations influence the therapeutic response to IFN also requires knowledge about the genotype.[114]

In a study of German patients a higher rate of HBeAg seroconversion following IFN treatment was found in those infected with genotype A than those with genotype D (37%vs 6%).[115] The rate of HBeAg loss was also significantly higher in patients with genotype B compared with those with genotype C in a Taiwanese study (41%vs 15%).[60] In the former study, additional factors besides genotype, including the number of BCP mutations and low DNA levels, were found to be related to a better response and in the latter study; young age was found to be an additional positive predictive factor. Because genotype B-infected patients have a high HBeAg seroconversion rate, Wai et al.[116] compared treated and untreated Chinese patients with chronic hepatitis B. They showed that, in addition to low pre-treatment HBV-DNA levels and elevated ALT levels, genotype B was associated with a higher antiviral response to IFN treatment. The response to IFN treatment of genotype A-infected Chinese patients was found to be better than those infected with genotype D/E (70%vs 40%).[117] In contrast, in a study performed in Japan, IFN was given to seven patients with chronic HBV infection. Of the four responders, one was infected with HBV genotype B and three with genotype C. HBsAg persisted in the remaining three patients, all of whom were infected with genotype A, and HBeAg remained positive in one of them.[118] In a longitudinal study, no difference was reported in the rates of sustained seroconversion to anti-HBe in IFN-treated patients compared with those that were untreated, and this was not affected by the HBV genotype with which the patient was infected. However, the cumulative probability of HBsAg clearance was greater in patients infected with genotype A than those infected with genotype D.[96] These studies involved a small number of patients, which may be the reason for the conflicting observations.

Genotype switching has also been observed after IFN treatment indicating infection with a mixture of genotypes prior to treatment.[65,119,120] The minor populations, however, were not detected by either standard genotyping assays or direct sequencing and were detected using either a genotype-specific PCR plus RFLP or cloning.

Thus the results of studies from one geographical region cannot be extrapolated to other regions, without a thorough knowledge of the HBV strains circulating in each of the regions.

Lamivudine

Lamivudine, a nucleoside analogue, has been approved for the treatment of chronic hepatitis B. In addition to reducing inflammatory activity in liver, lamivudine reduces HBV-DNA levels in most patients. A drawback of this treatment, however, is the appearance of lamivudine-resistant mutants.
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Genotype B has a better virological response to lamivudine than genotype C in Taiwan. However both genotypes have a similar risk of developing lamivudine resistance after 1 year of therapy.[121] On the contrary, adw has been shown to have a 20-fold higher risk of lamivudine resistance than ayw infections.[122] Emergence of resistance was also found to be more rapid in adw carriers. The appearance of the lamivudine-resistance mutations was predicted to result in a change in hydrophilicity in the S region of the ayw subtype but not in the adw subtype[122] and this could explain the reduced risk of developing resistance in ayw subtype. The genotypes can be deduced to be genotype A (adw) and genotype D (ayw) because these are the genotypes predominant in Germany and the serotypes associated with them. When comparing patients infected with genotype A and D isolates, it was found that although the risk of emergence of lamivudine resistance mutations was higher during the first year of treatment in genotype A-infected patients, there was no difference when the time of treatment was prolonged to 2 or 3 years. In other words, lamivudine resistance mutations took longer to develop in genotype D.[123] In a large-scale study in Japan, the emergence rate of lamivudine resistance was independent of genotype A, B and C. On the contrary, the emergence rate was significantly higher in subgenotype Ba than in **.[124] This study also suggested that the risk of HBeAg-positivity on the development of lamivudine resistance may differ between the genotypes and that the risk of severe breakthrough hepatitis may be higher in patients infected with genotype C.[124]

Adefovir Dipivoxil

Adefovir dipivoxil, an oral prodrug of adefovir, has been tested in phase III trials and was approved recently for the treatment of chronic hepatitis B in the USA.[20] There was no significant difference in the antiviral response between patients infected with the different genotypes of HBV.[20]

Conclusion

It is becoming increasingly evident that the genotype of HBV may have a role to play in predicting the response to various therapies and that this should be taken into account as a variable before initiating any treatment. However, differences in host and environmental factors make it difficult to extrapolate findings from one geographical region to another. Therefore larger, in-depth studies are necessary, in various regions of the world, especially in regions where HBV is hyperendemic such as South-east Asia and sub-Saharan Africa. Although some studies have shown that HBV serotypes may influence the efficacy of HBV vaccination,[125] to our knowledge, no studies have been undertaken to find the relationship between genotypes of HBV in response to vaccination and/or the emergence of vaccine-escape mutants. This is another area that requires further research. As most studies to date have been cross-sectional, more longitudinal prospective studies could provide more information on the relationship of HBV genotypes to the severity of liver disease and therefore clinical outcome. Moreover, the advent of new molecular antivirals makes it paramount that the genotypes are well characterized, so that the drugs can be tailor-made to the sequence of the virus prevalent in the different regions of the world.
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Notes on “Hepatitis B: It can happen to you,” Henrylito D. Tacio, Health 101, August

QUICK, what kills more Asians each year than AIDS and is a hundred times more infectious? If you answered hepatitis B, you're right. According to the Geneva-based World Health Organization (WHO), there are 350 million chronic hepatitis B carriers worldwide, and over half of them live in Asia. In the Philippines, for instance, 40 out of every 100,000 Filipinos are suffering from the disease.

The word hepatitis simply means "inflammation of the liver". So far, medical scientists have discovered six different kinds of hepatitis. A different virus causes each but the most important in terms of public health is hepatitis B virus (HBV).

Like most hepatitis viruses, HBV is all too easy to catch. It is more common than the human immunodeficiency virus (HIV), the microorganism that causes AIDS and far more infectious. "While 90 percent of the people who get hepatitis B recover spontaneously with their body's defenses, the 10 percent who maintain the infection for six months or longer and who do not produce an effective antibody response are considered chronic carriers," explains Dr. Ernesto Domingo, a hepatologist at the College of Medicine, University of the Philippines.

A small percentage of these chronic carriers will ultimately develop cirrhosis (scarring of the liver) or liver cancer. "Hepatitis B virus is the most common cause of liver cancer around the world," says Professor Mei-Hwei Chang, chairman of the Department of Pediatrics at the National Taiwan University Hospital in Taipei. "Although hepatitis C virus is the most prevalent cause of liver cancer in some countries where HBV infection is not prevalent, HBV is still the most prevalent cause worldwide."

The HBV may be found in blood, semen, vaginal fluids, tears, and saliva. The virus, however, is not spread by contaminated food or water, and cannot be spread casually in the workplace. You can't also get HBV from a mosquito bite.

"All viruses transmitted by a mosquito must go through a replication before sufficient viruses is available for infection," explains Professor John S. Tam, of the Department of Microbiology at the Chinese University of Hong Kong. "HBV doesn't grow in mosquitoes."

The main ways of getting infected with HBV are perinatal (from mother to baby at birth), child-to-child transmission, unsafe injections and transfusions, and sexual contact. "Worldwide, most infections occur from infected mother to child, from child to child contact in household settings, and from reuse of unsterilized needles and syringes," the WHO says.

There are reports that HBV may also be transmitted by puncturing the skin with sharp instruments--such as those used for acupuncture, dental, and medical procedures, even for ear piercing and manicures--that have been contaminated.

"But the most effective means of transmission is sexual contact other than kissing," says Dr. Dominic Garcia, an infectious disease specialist. "The scary thing is that a lot of people don't know they have it."

The UN health agency says that the incubation period of the HBV takes a long 45 to 180 days usually without any manifestations or symptoms.

Thus, people infected with hepatitis B may not even realize that they have it until the latter stages of the disease. And even when symptoms are present, they are vague, often mimicking other, less life threatening diseases.

What happens to a person infected with HBV? "When a person becomes infected by the hepatitis B, the virus travels to the liver where it enters individual liver cells," said Prof. Nancy Leung, consultant and honorary associate professor and chief of hepatology at the Prince of Wales Hospital in the Chinese University of Hong Kong.

"Here, it replicates and may reenter the blood stream or reinfect other liver cells. Symptoms of initial infection with hepatitis B result from the body's attempt to defend itself against infection.

Prof. Leung continues: "Those individuals with the most severe of symptoms are therefore most likely to eliminate the virus from their body while those with no symptoms or have very mild complaints--typically children--are most likely to retain the virus and become long-term carriers."

Prof. Leung added that the HBV may remain in some individuals after the initial infection and the patients are said to be chronic hepatitis B carriers when part of the surface of the virus remains in the blood for more than six months. "The result of long-term carriage of the HBV is continuing inflammation of the liver, which may lead to serious liver damage and cancer," she said.

Liver cancer is almost always fatal, and usually develops between the age of 35 and 65 years of age, when people are maximally productive and are trying to raise their own children. It occurs more commonly among Asians.

In Singapore, for instance, liver cancer is the third most common cancer and the second most common cancer among males. "The risk of liver cancer increases with smoking and consumption of alcohol," says Professor Mei-Hwei Chang, chairman of the Department of Pediatrics at the National Taiwan University Hospital in Taipei.
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Notes on “What you need to know about viral hepatitis,” SHELBA DURSTON RN, CCRN, MSN, Nursing2005:35(8) 36-41.

THE WORLD has become a smaller place: You can fly to another continent in hours, and fresh produce grown in one country is eaten in another. These are just two factors that have hastened the spread of viral hepatitis around the world in recent years. In this article, I'll review the major types of viral hepatitis and discuss new treatments that can help a patient cope with acute and chronic disease.

In the beginning
Despite their individual differences, all hepatitis viruses have similar effects on the liver. Symptoms may include right upper quadrant abdominal pain, anorexia, dark-colored urine, diarrhea, nausea and vomiting, fatigue, jaundice, and joint pain. For characteristic changes in lab values, see How hepatitis affects lab values .

Some patients infected with a hepatitis virus are asymptomatic. For example, about 30% of patients with positive hepatitis B titers and 80% of those with positive hepatitis C titers don't recall experiencing symptoms. Children are commonly asymptomatic regardless of virus type.

Hepatitis viruses are classified according to mode of transmission. The enteric viruses, hepatitis A and E, are primarily transmitted via the fecal-oral route. Recent outbreaks of hepatitis A have been attributed to tainted produce and poor sanitation practices by infected food service workers. Although the fecal-oral route is the primary mode of transmission, enteric hepatitis viruses also may be transmitted by blood or sexual activity.

The other hepatitis viruses—B, C, D, G, and the recently identified transfusion-transmissible disease—are transmitted via blood and body fluid . People at risk for these infections include those with multiple sexual partners, day care and health care workers, people suffering needle-stick injuries from improperly disposed medical waste, people using recreational drugs, and people receiving tattoos and piercings. Even seemingly innocent behaviors, such as sharing a toothbrush or a razor, can lead to contact with tainted blood.

In the past, blood transfusion was a significant mode of transmission. But today, donor blood is screened for these viruses and tainted blood is discarded.

New hepatitis viruses are still being identified. One, called transfusion-transmissible virus, has been identified in children who've received blood transfusions. This hepatitis variant is considered a chronic but benign infection. No treatment is considered necessary, and widespread screening isn't needed.

When caring for any patient with hepatitis, protect yourself by avoiding exposure to the patient's blood and body fluids. Now let's look more closely at each type of hepatitis, from A to G and beyond.

Hepatitis A: The news maker
Recent outbreaks of hepatitis A, an RNA virus, have been attributed to tainted raw produce. In 2003, an outbreak near Pittsburgh, Pa., killed 3 people and sickened nearly 700. The virus was traced to green onions served in one restaurant. (See “Calming the Panic over Hepatitis A” in the June issue of Nursing2004. )

Human or animal feces in the soil, tainted water used for irrigation or food preparation, or food handled by infected persons all have the potential to contaminate the food we eat. Seafood may be tainted when improperly treated sewage is released into waterways.

However, foodborne or waterborne infection account for only about 3% of all cases of hepatitis A. In most cases, the cause is unknown. When the cause can be determined, it's usually contact with an infected person.

The virus incubates for about 4 weeks before symptoms appear. During this time, and for 7 to 10 days after symptoms appear, the patient is infectious. Up to 20% of patients become ill enough to require hospitalization, but fewer than 1% die. Most patients recover without treatment and become immune to future bouts of hepatitis A.

However, hepatitis A infection may have a longer-lasting impact on health than once believed. A study found that hepatitis A seropositivity is an independent risk factor for coronary artery disease (CAD), raising the possibility that hepatitis A plays a role in CAD development.

The most important defense against infection is good hand hygiene. If your patient is planning to travel in an area where hepatitis A is endemic, warn her to eat only cooked produce and meat and to use bottled or boiled water for drinking and toothbrushing. Also remind her not to put ice in beverages unless she's sure it was made from boiled or bottled water.

After sanitary precautions, the next best protection against hepatitis A is vaccination. A multidose vaccine combining hepatitis A and B protection is available. A single-dose hepatitis A vaccine on the horizon may improve patient compliance with completing the recommended vaccination schedule.

For short-term protection from the virus, hepatitis A immune globulin can be administered 2 weeks before or after exposure.

Hepatitis B: Blood and beyond
This double-shelled DNA virus has been isolated in all body tissues and fluids and can live for up to 72 hours on surfaces that look clean. The virus can be spread perinatally and during sexual contact with an infected person; other risk factors include needle sharing during recreational intravenous (I.V.) drug use, acupuncture, hemodialysis (because of possible equipment contamination and the patient's decreased immune response), tattooing, and ear and body piercing. Health care and public safety workers are at high risk for contracting hepatitis B from sharps injuries with contaminated equipment and from other exposures to infected body fluid.

The virus incubates for 30 to 180 days. Anyone who's been exposed to infected body fluids should be evaluated by his primary care provider for hepatitis B virus. Anyone diagnosed with hepatitis B infection should be evaluated for liver disease and for human immunodeficiency virus (HIV) infection.

Before symptoms appear, the patient will have increased hepatitis B surface antigens and increased liver function test results. After symptoms appear, the body produces immunoglobulins to the antigens; antigens and viral DNA in the patient's blood indicate that he's infectious.

Vaccination has dramatically reduced the rate of new hepatitis B infections. The three-dose vaccination series is recommended for health care and public safety workers, children under age 18, international travelers, recreational drug users, men who have sexual relations with other men, patients with clotting disorders or liver disease, and anyone sharing a household with an infected person.

An estimated 1.25 million Americans are chronically infected with hepatitis B. Infection is more likely to become chronic if acquired early in life. Chronic carriers of hepatitis B may be asymptomatic.

Treatment for chronic hepatitis B may include interferon, lamivudine, or famciclovir. Treatment for hepatitis B usually lasts 4 to 12 months. Some genotypes of hepatitis B respond to treatment better than others
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Hepatitis C: Quick-change artist
Hepatitis C, an enveloped RNA virus, mutates rapidly to create multiple variants that respond differently to treatment. Consequently, this virus has foiled vaccine development. The disease can remain asymptomatic for years, but 70% of those infected eventually develop chronic liver disease. An estimated 3.9 million Americans have been infected with hepatitis C; 2.7 million have chronic liver disease from the infection.

Those at high risk for exposure to hepatitis C include health care and public safety workers and recreational I.V. drug users. Factors increasing a person's risk include receiving clotting factors before 1987 or blood or solid organs before 1992, undergoing hemodialysis, having multiple sexual partners, and getting tattoos or piercings. Infants born to infected mothers are at some risk: The rate of disease transmission is about 5%. Hepatitis C virus also has been detected in breast milk, but large studies have shown that transmission via this route is possible only if the patient's viral titers are high and she's experiencing hepatitis symptoms.

The virus incubates for 14 to 180 days. Within the first few weeks after exposure, hepatitis C RNA can be found in the blood although the patient may be asymptomatic for years. Patients eventually produce anti–hepatitis C antibodies, usually within 6 months. Diagnosis is made by testing for viral RNA or antibodies via enzyme-linked immunosorbent assay.

New hope for patients with hepatitis C comes from peginterferon alfa-2a and ribavirin (Pegasys/Copegus). This form of interferon, which is given with ribavirin, has been dramatically more effective than the previous interferon and ribavirin combination therapy. In a recent study, 62% of patients with hepatitis C genotypes 2 and 3 achieved a sustained virologic response with the new combination therapy, compared with 12% of patients on the older combination. In addition, 29% of patients with genotype 1, considered the hardest strain to treat, achieved a sustained virologic response.

Prevention strategies for health care professionals include using safety engineered sharps, limiting contact with blood and body fluids, and properly sterilizing multiuse equipment. As appropriate, teach patients to avoid needle sharing and to use only single-use needles and ink for tattooing and properly sterilized instruments for body piercing.

Hepatitis D: Not a solitary traveler
An incomplete RNA virus, hepatitis D depends on hepatitis B envelope proteins to reproduce. As a coinfection with hepatitis B, hepatitis D may lead to potentially fatal fulminant hepatitis (see Fulminant hepatitis: Trouble's brewing ). Endemic to Mediterranean regions, hepatitis D is transmitted in the same ways as hepatitis B and can be prevented by hepatitis B vaccination.

The virus is identified by the presence in serum of intrahepatic delta antigens or antibodies in chronic disease. Treatment with interferon alfa-2b may help patients with hepatitis D/hepatitis B coinfection.

Hepatitis E: In the water and a lot more
Responsible for large disease outbreaks in Southeast and Central Asia, the Middle East, Africa, and Mexico, hepatitis E is a single-stranded RNA virus rarely seen in the United States. Diagnosis of this enteric virus is made by ruling out other hepatitis viruses in a patient with active, symptomatic hepatitis.

Symptoms occur 15 to 60 days after exposure, with the incubation period ranging from 2 to 9 weeks. Children usually are asymptomatic; the severity of illness increases with age. Although the illness generally is self-limiting and benign, up to 3% of patients die, usually from dehydration. Up to 25% of pregnant women who become infected die. Treatment with immune globulin can minimize symptoms, but Western preparations of immune globulin aren't effective against this virus.

Good hand hygiene, boiling drinking water, avoiding ice made from contaminated water, and thoroughly cooking meat and produce can help prevent the virus from spreading. Travelers should avoid raw foods or prepare their own using a pure water supply.

Hepatitis F: “F” is for false
A few cases of hepatitis that didn't quite fit the A, B, C, D, or E profile were identified in the early 1980s and labeled “hepatitis F” in 1994. These viruses have now been identified as variants of hepatitis C. The “hepatitis F” label isn't currently used for any virus.

Hepatitis G: Growing in prominence
The latest virus to be named is hepatitis G, a single-stranded, enveloped RNA virus similar to hepatitis C. As with hepatitis B and C, this virus is transmitted by blood and body fluids and can probably be found in all body tissues. Two variants of hepatitis G have been identified, and researchers are working to identify other suspected variants. Identified in blood samples from around the world, hepatitis G is diagnosed by seroconversion or detection of hepatitis G RNA in blood or liver tissue.

The long-term effects of hepatitis G aren't known. Public health reports include patients who developed flulike symptoms for a limited period and recovered (although they were still seropositive) and patients who developed fulminant hepatitis and died.

After recovery, patients may have persistent viremia lasting several years, but coinfection with other hepatitis viruses doesn't seem to worsen their condition. Production of cytokines in people with hepatitis G has been reported to slow the progression of HIV coinfection to acquired immunodeficiency syndrome (AIDS).

No vaccine has been developed against hepatitis G. Current treatment is supportive and focused on symptom management and reducing hepatitis G titers. Some patients benefit from interferon treatment.

Caring for your patient
Nursing care is aimed at encouraging healing, preventing complications, and supporting the patient. Encourage him to perform activities of daily living to the best of his ability, pausing to rest frequently throughout the day.

Because nausea may increase during the day, administer antiemetic medications as ordered. Advise the patient to eat a hearty breakfast and then smaller, frequent meals of high-calorie, nutrient-dense, low-fat foods throughout the day. To avoid stressing the liver, which detoxifies ammonia (a by-product of protein digestion), tell him to limit his protein consumption.

Monitor the patient for fluid and electrolyte imbalances and weigh him daily. Report abnormal electrolyte levels and weight gain of more than 2 pounds (0.9 kg) in one day. Administer I.V. fluids as ordered to prevent dehydration and correct electrolyte imbalances.
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Monitor the patient's clotting studies and administer vitamin K if his international normalized ratio is elevated. Teach the patient to avoid alcohol during acute illness and for 6 months after recovery. He should also avoid substances that may affect liver function, such as some herbs and medications.

Living with chronic hepatitis
Someone with chronic hepatitis infection may live for many years with his disease. Teaching him about the disease can help him lengthen his life, avoid complications, and slow disease progression. Encourage him to make healthful lifestyle choices, including sticking to a low-fat diet and limiting red meats; avoiding alcohol, tobacco, and illicit drugs; exercising regularly; managing stress; and getting enough rest.

Explain that changes in protein synthesis influence hormone production and regulation. A female patient may notice shorter or skipped menses initially; as liver damage increases in severity and clotting factors diminish, menses may become heavy and prolonged. Her breasts may become pendulous because of decreased estrogen. Men may develop breast tissue because of hepatitis-related inability to produce testosterone.

A women being treated with immune globulins or ribavirin should use two types of birth control simultaneously because these drugs may cause birth defects. Warn her that oral contraceptives may be ineffective because of changes in protein synthesis and hormone production during hepatitis therapy. She should use condoms, spermicidal foam or jelly, or a diaphragm if abstinence isn't possible.

Intercourse during menses increases the risk of transmitting hepatitis to an uninfected partner. Tell the patient to dispose of used sanitary supplies in containers with tight lids or to double-bag them in plastic bags.

Provide emotional support. A patient who feels helpless, anxious, or guilty may engage in risky behavior. Depression, which may be linked to concerns about the illness, can also be related to changes in body chemistry or adverse drug reactions. Encourage the patient to discuss emotional and social problems with his primary care provider, who can explore possible causes and offer treatments.

The patient's fear of infecting others may lead him to isolate himself at a time when he most needs support from friends and family. Let him talk about his fears, answer his questions, provide information, and help him explore appropriate coping behaviors. Refer him to a hepatitis support group and, if appropriate, to support groups such as Alcoholics Anonymous or Narcotics Anonymous. Encourage him to see his health care provider regularly for monitoring and follow-up testing.

Hope for the future
As a nurse, you can help patients understand how to prevent hepatitis transmission, follow prescribed treatments, and learn to live with chronic infection.

How hepatitis affects lab values
* Serum aspartate aminotransferase—increases in prodromal stage
* Serum alanine aminotransferase—increases in prodromal stage
* Serum alkaline phosphatase—increases in prodromal stage
* White blood cell counts—transient neutropenia and lymphopenia, followed by lymphocytosis
* Serum bilirubin—rises in acute disease and may remain elevated as the disease becomes chronic. The liver can't conjugate bilirubin, resulting in clay-colored stools and decreased urobilinogen.
* Prothrombin time (PT)—increases as liver damage increases. A PT of 3 seconds or more indicates severe liver damage. The patient is at increased risk for bleeding because of decreased fibrinogen production. If esophageal varices develop, the patient is at risk for life-threatening hemorrhage.
* Albumin—decreases in liver disease, leading to muscle atrophy
* Globulin—decreases in liver disease, putting the patient at increased risk for infection
* Gamma-aminobutyric acid and ammonia—rise as the liver becomes less efficient, leading to hepatic encephalopathy
Fulminant hepatitis: Trouble's brewing
A rare but serious complication of hepatitis is fulminant hepatitis, or sudden and severe liver dysfunction leading to massive hepatocellular necrosis. Viral hepatitis is a common cause of this complication, which can lead to hepatic encephalopathy and death if not treated. Because fulminant hepatitis has a poor prognosis, liver transplantation is the treatment of choice.

Signs and symptoms of fulminant hepatitis include jaundice, an enlarged and tender liver during the acute inflammatory stage, liver function tests consistent with severe liver failure, decreased hemoglobin and hematocrit levels, prolonged clotting times, and blood in the patient's stool.

Intervene rapidly to treat acute liver failure and support the patient. Maintain adequate perfusion and oxygenation. Administer sedatives and mannitol as ordered to maintain normal intracranial pressure. Monitor for fluid and electrolyte imbalances and maintain normal blood glucose levels and body temperature. If ordered, give neomycin and lactulose to reduce ammonia levels. The patient may need inotropes for circulatory support. If liver transplant is indicated, prepare the patient for transplant.
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Notes on “Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D,” A Erhardt, et al., HEPATITIS, 2005.

ABSTRACT
Background an aims: Current interferon alfa (IFN) treatment of chronic hepatitis B has limited efficacy. The role of hepatitis B virus (HBV) genotypes for response to IFN was investigated.

Patients and methods: HBV genotype was determined by direct sequencing of
the HBV X gene in 165 consecutive patients with chronic replicative
hepatitis B treated with standard IFN. HBV genotype A or D was found in 144
cases.

Results: Sustained response (six months after treatment) to standard IFN therapy was higher in HBV genotype A compared with HBV genotype D infected patients (49% v 26%; p<0.005). Sustained response to IFN was 46% versus 24% (p<0.03) in hepatitis B e antigen (HBeAg) positive hepatitis (n = 99) and 59% versus 29% (p2xupper limit of normal) as independent positive predictive parameters of IFN response.

Conclusions: The present study indicates that HBV genotypes A and D are important and independent predictors of IFN responsiveness in chronic hepatitis B. HBV genotype adapted treatment regimens may further improve treatment efficacy in chronic hepatitis B.
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Notes on “Resistance to antiviral drugs is climbing,” Zosia Kmietowicz, BMJ  2005;331:308 (6 August).

Public health experts have warned of a worrying increase in resistance to antiviral drugs that is making infections such as HIV and hepatitis B more difficult to manage.

Evidence from research that followed 4500 British patients infected with HIV indicates that after two years of standard treatment with a combination of three different classes of antiretroviral drugs 10% of people become resistant to at least one drug. Six years after starting treatment 27% of patients are resistant to at least one of their drugs.

Speaking at the launch of the annual report of the Health Protection Agency for England and Wales, Peter Borriello, interim director of the agency's Centre of Infections, said the most worrying development is the emergence of strains of HIV that are resistant to all three classes of antiretroviral drugs currently available. Such triple resistance now affects one in 25 people with HIV, and although some antiviral drugs may dampen down the viral load in these patients their prognosis is much worse than in someone who shows no drug resistance.

"Up to one in five people who are being diagnosed with HIV are resistant to at least one drug, which suggests they have acquired the infection from someone who is already receiving treatment," said Professor Borriello. "This tells us we have to now reinforce behaviour messages."

There is also evidence that 20% of strains of hepatitis B viruses are now resistant to standard treatment, and work with the World Health Organization indicates that resistance to drugs for influenza was emerging, although less than 1% of people were showing resistance.

William Stewart, chairman of the agency, said: "The worrying trend is that viruses that are resistant to antiviral drugs are beginning to emerge. To a micro-biologist this may be unsurprising, but it is worryingly reminiscent of the development of antibiotic resistant bacteria over 50 years ago. The fight against microbial diversity is endless."

Although the development of resistance to antiviral drugs was inevitable, cooperation from public health departments in other countries would help in monitoring the situation and in devising protocols to limit the spread of resistance, experts agree. Development of new classes of drugs by pharmaceutical companies would also provide doctors with the means to treat infections with a reduced risk of resistance developing, said Professor Borriello.
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Notes on “When a Patient Should Be Treated, and What the First Hepatitis B Treatment Drug Should Be,” Christine Kukka, WWW.HBVADVOCATE.ORG HBV JOURNAL REVIEW Hepatitis B, Volume 5, Issue 7 July 01, 2008.

Leading experts on hepatitis B virus (HBV) infection addressed a variety of important treatment issues at a recent Clinical Care Options workshop. When Should You Treat Hepatitis B? Anna S. F. Lok, MD, director of clinical hepatology at the University of Michigan at Ann Arbor, discussed when to treat hepatitis B. She explained that physicians should answer three key questions before beginning treatment: . How active or advanced is the HBV-related liver disease now? . What is the risk that a patient will progress to cirrhosis or severe liver damage or cancer in the next 10-20 years? . And, what is the chance that once viral load (HBV DNA) is lowered from a limited course of treatment, it can be maintained for up to 3-5 years? Example1: Lok the case of a 27-year-old woman who had a high viral load but normal alanine aminotransferase (ALT) levels, which indicates no liver damage was occurring. This is called the immune tolerant stage, which is common in younger patients. Doctors are uncertain whether to treat this group of patients. While liver damage is still possible when a patient has high viral loads and normal ALTs, it occurs most frequently in patients age 40 and older, she noted. Given the risks of viral resistance from long-term antiviral treatment and the lack of success of interferon in patients with normal ALT levels, she did not recommend treatment in immune-tolerant patients who were younger than 35 years of age. Example 2: Lok explored whether to treat a 30-year-old woman with high viral load and normal ALTs, and who also had a family history of liver cancer in HBV-infected relatives. It is unclear whether the family “clusters” of HBV-related liver cancer is related to genetic or environmental factors or a more virulent strain of HBV, Lok HBV Journal Review A publication of the Hepatitis C Support Project Executive Director Editor-in-Chief, HCSP Publications Alan Franciscus Contributor Christine Kukka Managing Editor, Webmaster C.D. Mazoff, PhD Contact Information: The Hepatitis C Support Project PO Box 427037 San Francisco, CA 94142 www.hbvadvocate.org . 2008 Hepatitis C Support Project 1 noted. While some experts advocate treating all patients with a strong family history of liver cancer, even if they are in the immune tolerant stage, “it must be emphasized that there are no data to support the hypothesis that antiviral therapy can completely prevent liver cancer and there is no model to predict the risk of cancer in this patient. The potential benefits of antiviral therapy must be balanced against the risks of years of antiviral therapy that may indeed be lifelong, and those potential risks must be weighed particularly carefully for a young woman who might be planning to start a family in the near future,” she explained. Lok stressed that treatment is recommended if there is a high risk of liver damage and death in the next 5 to 10 years, and if there is a good chance of achieving or maintaining low HBV DNA throughout treatment. Treatment is not recommended if the risk of liver damage over the next 20 years is low, or if there is the possibility of achieving low viral load after a defined course of treatment is low, she added. Should you use interferon or an antiviral first? Ira M. Jacobson, MD, medical director of the Center for the Study of Hepatitis C at Weill Medical College of Cornell University, tackled what treatment to use first in patients who qualified for treatment. Pegylated interferon, which boosts the immune system, requires a weekly injection for up to one year, and may cause side effects such as depression and fatigue--while oral antivirals cause few side effects. But starting a patient on antivirals, “for most clinicians … is tantamount to the decision to continue (antiviral) therapy indefinitely,” Jacobson explained. As a result, interferon is favored for first-line therapy in patients who test negative for the hepatitis B “e” antigen (HBeAgnegative), but it is also a recommended option for HBeAg-positive patients. In HBeAg-positive patients, interferon causes HBeAg seroconversion (loss of “e” antigen and development of the “e” antibody) in 30% of patients after one year of treatment, compared to a 12% to 23% seroconversion rate after one year of antiviral treatment. However, researchers are discovering that longer-term antiviral treatment also causes seroconversion, with a 30% seroconversion rate after two years of treatment, and a 40% rate after three years. Interferon, however, has the advantage of inducing permanent clearance of the hepatitis B surface antigen (HBsAg), which indicates a patient has nearly cleared the infection. Interferon causes 3% to 8% of HBeAg–positive patients to lose HBsAg. Antivirals such as adefovir (Hepsera), lamivudine (Epivir-HBV) and telbivudine (Tyzeka) cause a HBsAg loss of less than 1% after one year of treatment and entecavir causes a 2% loss of HBsAg after one year. However, HBeAg-positive patients lost HBsAg at a rate of 5% and 3% after two years of treatment with entecavir (Baraclude) or lamivudine, respectively. In a recent trial of tenofovir (Viread-an antiviral that is expected to be approved soon by the U.S. Food and Drug Administration), 3% of HBeAg-positive patients lost HBsAg after one year. In HBeAg-negative patients, one year of interferon produces a sustained undetectable HBV DNA level, which continues in about 20% of patients four years after treatment ended. Which antiviral to use first? Doctors should select an antiviral that will cause the least viral resistance, experts say. All experts agree that the antiviral lamivudine should never be used as a patient’s first antiviral treatment unless it’s used to prevent reactivation in inactive HBsAg carriers who receive chemotherapy, which weakens the immune system. HBV quickly develop “resistance” to lamivudine at a rate of 23% after one year, and up to 71% after four or five years of treatment. The two antivirals recommended as first-line choices are entecavir and adefovir. Tenofovir has been commonly used “offlabel” by doctors and has been used for years 2 in HIV-infected patients, confers a much higher level of viral suppression than adefovir and should replace adefovir as the preferred antiviral for first-line therapy along with entecavir once the FDA approves it, according to Jacobson. When should you use an antiviral combination? There are no clear guidelines, but some clinicians routinely use two antivirals to prevent any potential viral cross-resistance in the following patients: . Those who already have developed resistance to one drug or more drugs, such as lamivudine and adefovir . Those who have cirrhosis, in whom it is critical to avoid a hepatitis “flare” or sudden resurgence of viral load and liver damage. . And, those with HIV-HBV coinfection, in whom it is important to prevent the development of antiviral resistance by either virus. When can you stop using an antiviral? Patients who seroconvert while on antivirals face a 10% to 25% risk of reverting back to HBeAgpositive status. But despite that risk, doctors recommend that patients make an attempt to discontinue treatment, although treatment should be continued for at least 6-12 months after seroconversion to reduce the risk of seroreversion. For HBeAg-negative patients, there is a paradox – it is easier for them to achieve undetectable viral load on antivirals, yet more than 95% will relapse if therapy is discontinued after one year. As a result, antiviral use should be continued indefinitely
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because of the risk of relapse is so great. Researchers Consider Using Antivirals During Third Trimester of Pregnancy to Prevent HBV Transmission While antivirals are used in pregnant HIV-infected women to lower viral load and prevent transmission to newborns, this preventive antiviral treatment is rare in pregnant, HBV-infected women. However, even with immediate administration of the hepatitis B vaccine and HBIG (hepatitis B antibodies) in newborns, between 5-10% of newborns still contract HBV infection from their mothers, due to the mother’s high viral load. Researchers also believe some HBV strains or genotypes are also more effective at infecting newborns. In China, there has been some experimentation with administering lamivudine in pregnant HBV-infected women during the third trimester of pregnancy to prevent HBV transmission. During the Clinical Care Options conference, Dr. Jacobson suggested that tenofovir and telbivudine may also be used in pregnant women with HBV. They are both category B drugs, considered safe during pregnancy, and tenofovir has reportedly been used to prevent HIV transmission in pregnant women. However, to date the FDA has not approved any antiviral for use during pregnancy to prevent HBV transmission. Longer Treatment with Conventional Interferon Improved Success Rate While most doctors use pegylated interferon today to treat hepatitis B, Chinese researchers tried using conventional interferon, the first interferon developed to treat hepatitis B, for just six months in a control group of 127 HBeAgpositive patients and for an average 10 months or longer in 247 HBeAg-positive patients to see if the extended treatment would benefit patients. The interferon treatment in the second, study group continued for as long as viral load was decreasing and ranged from 6 to 24 months. According to researchers’ report in the June 2008 issue of the Journal of Viral Hepatitis, when treatment ended 39% in the study had achieved normal ALT levels and low viral load, compared to 24% in the six-month treatment control group. After a three-year follow-up period, 40.5% of the study group maintained healthy ALT levels and low viral load, compared to 33% in the 3 control group. Inter-feron-alpha treatment tailored in length demonstrated significantly increased effectiveness, researchers noted. Severe Fibrosis More Common if Patients are Male, Older, and Have High ALT Levels Chinese researchers evaluated when Asian patients with HBV began developing liver fibrosis (inflammation) and cirrhosis (scarring) by performing “transient elastography,” a procedure involving sounds waves that can assess the condition of liver tissue. According to their report in the June 2008 issue of the American Journal of Gastroenterology, severe fibrosis was documented more frequently in older patients, reaching 20% in patients 65 years and older. Higher prevalence of severe fibrosis was seen in HBeAgpositive patients who were age 45 or older, compared to HBeAgnegative patients (58% vs. 43% respectively), and in patients with higher viral loads and ALT levels. Patients who had received antiviral treatment had lower ALT levels and prevalence of cirrhosis. Researchers concluded that the prevalence of severe fibrosis was 34% in the study group, with higher rates of fibrosis associated with older patients, males, and those with elevated ALT levels. Occult Hepatitis B Can Transmit Infection Through Blood Donations Historically, HBV is not considered a threat when blood donors have hepatitis B surface antibodies present, but several months after a blood transfusion, two patients developed acute hepatitis B, according to an article by Slovenian researchers published in the June 2008 Journal of Hepatology. A sample from the donated blood contained core and surface antibodies, but it also contained HBV DNA. Increasingly, researchers are recognizing that “occult” hepatitis – with no HBsAg or even surface antibodies – can still contain HBV DNA and transmit infection. Tenofovir and Lamivudine Combination Effective in Patients with Cirrhosis Who Don’t Respond to Adefovir Six patients with cirrhosis who did not respond to, or developed viral resistance to adefovir were treated with a combination of tenofovir and lamivudine for six months minimum. South Korean researchers monitored their response to see how effective the combination therapy was against adefovirresistant hepatitis B. Reporting in the journal Liver International, the researcher wrote that HBV DNA became undetectable in four patients after six months, and in all six patients after 12 months of treatment. ALT levels became normal in four patients after 12 months of treatment. “This study suggests that this combination may be a promising rescue therapy for these patients, particularly those with liver cirrhosis or pre-existing lamivudine resistance,” the researchers noted. Silymarin Cures Liver Inflammation Quickly in Laboratory Rats Researchers are beginning to analyze and test the benefits of silymarin, a traditional liver herbal treatment found in milk thistle, in improving liver health when viral infection occurs. Taiwanese researchers studied the impact high doses of silymarin had on the liver of rats, whose livers had inflammation and fibrosis. They reported in a recent issue of the Journal of Viral Hepatitis that liver fibrosis significantly decreased in rates treated with silymarin. HBV Genotype Has Little Impact on Antiviral Success, But Plays a Prominent Role in Interferon’s Success German researchers reviewed 20 studies that linked treatment success, such as HBeAg seroconversion and decline in viral load, to patients’ HBV genotype to explore whether hepatitis B treatment should ever be guided by a patient’s 4 genotype. Writing in the journal Antiviral Therapy, they concluded that response to antiviral treatment was not “significantly influenced by HBV genotype in HBeAg-positive or HBeAg-negative individuals.” “In contrast,” they noted, “HBV genotypes are informative concerning responses to interferon treatment in all patients with genotype A versus D and in HBeAg-positive patients with genotype B versus C. “Interferon may be considered as first-line therapy in all genotype A patients and in individuals with genotype B who are HBeAgpositive,” they concluded. Past HBV Infection Worsens Hepatitis C Prognosis, Weakens Interferon’s Effectiveness Two studies found that infection with HBV, common in many patients infected with the hepatitis C virus (HCV), worsens patients’ disease progression and limits the success of interferon treatment. In a recent article in Liver International, Brazilian researchers evaluated 31 HCV carriers who had previously been exposed to HBV, but were not currently infected. Compared to HCV patients without a past HBV infection, these patients had more liver damage and inflammation. They concluded that after 20 years of HCV infection, advanced liver fibrosis could be expected in 13% of those who acquired HCV before the age of 30 but had no prior HBV infection, and in 57% of those infected with HCV after age 30 who had a prior HBV infection. In another study, Turkish researchers, writing in the May 2008 Netherlands Journal of Medicine, examined the impact of interferon on patients
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currently coinfected with HBV and HCV. Researchers evaluated their response to conventional or pegylated interferon combined with the antiviral ribavirin (the recommended treatment for hepatitis C) on patients, whose average age was 47. Fourteen patients were given standard interferon either alone or in combination with ribavirin, and 12 were given pegylated interferon and ribavirin. None tested positive for HBV DNA but all had HCV RNA and elevated ALT levels. Only two patients (one from each group) cleared the HCV following treatment. Researchers concluded that neither pegylated nor conventional interferon were highly effective for HBV-HCV coinfection, in which the dominant virus was HCV.
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Notes on “Good news for Hep B patients,” New Zealand Herald, 27.07.05


      Scientists have created a powerful new treatment for hepatitis using a revolutionary technique that switches off harmful genes, providing hope for the two billion infected worldwide with the B strain of the virus.

      The scientists have found that a few regular injections of the new drug can result in a 90 per cent reduction in the amount of virus circulating in the bloodstream of infected animals.

      The replication of the hepatitis B virus is blocked by the phenomenon of RNA interference, which switches off the genes it needs for survival.

      Results of a study have shown that RNA interference can work so effectively against invading viruses such as hepatitis that scientists believe the technique can be developed to produce an entirely new class of antiviral drugs.

      RNA interference has been described as one of the most exciting developments in medical science and the latest study has shown it is able to stop the spread of hepatitis B virus in infected laboratory mice.

      The results of the study, published in the journal Nature Biotechnology, are so encouraging that the scientists are planning to begin the first human trials of RNA interference on hepatitis B patients at the end of next year.

      Some two billion people have been infected with the hepatitis B virus and more than 350 million have chronic or lifelong infections that often kill by causing liver cirrhosis and cancer.

      Although there are vaccines to protect against infection, the drugs to treat hepatitis B are relatively ineffective as well as being prohibitively expensive for most of the people in the developing world who are chronically infected.

      The latest study by David Morrissey and colleagues at the biotechnology company Sirna Therapeutics in Boulder, Colorado, used a form of RNA interference that switches off key genes of the hepatitis virus that it needs to replicate.

      Dr Morrissey wrapped short molecules of RNA that were specifically targeted against the hepatitis B virus in a fatty globule that was able to carry or "deliver" the drug into infected cells of the liver.

      A few daily injections were followed by a single injection given once a week, which reduced the amount of hepatitis B virus in the bloodstream by 90 per cent, with the effect lasting six weeks.

      RNA interference was first described in 1998 and since then it has caused a stir inside the medical community because of its potential to deal with a range of illness, from cancer and viruses to inherited disorders such as Huntington's disease.

      Sirna Therapeutics has already begun a trial of RNA interference on patients suffering from age-related macular degeneration, which causes visual impairment in many thousands of people over 50.

      About a quarter of people over the age of 65 are affected by the disorder.

      Sirna has developed a form of RNA interference designed to switch off or silence a key gene that is thought to stimulate the growth of blood vessels at the back of the eye which leads to macular degeneration.
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Notes on “Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects,” 2005

This evidence report details a systematic review summarizing clinical studies of milk thistle in humans.

Overview
The scientific name for milk thistle is Silybum marianum. It is a member of the aster or daisy family and has been used by ancient physicians and herbalists to treat a range of liver and gallbladder diseases and to protect the liver against a variety of poisons.

Two areas are addressed in the report:

· Effects of milk thistle on liver disease of alcohol, viral, toxin, cholestatic, and primary malignancy etiologies.

· Clinical adverse effects associated with milk thistle ingestion or contact.

The report was requested by the National Center for Complementary and Alternative Medicine, a component of the National Institutes of Health, and sponsored by the Agency for Healthcare Research and Quality.

Reporting the Evidence
Specifically, the report addresses 10 questions regarding whether milk thistle supplements (when compared with no supplement, placebo, other oral supplements, or drugs):

· Alter the physiologic markers of liver function.

·  Reduce mortality or morbidity, or improve the quality of life in adults with alcohol-related, toxin-induced, or drug-induced liver disease, viral hepatitis, cholestasis, or primary hepatic malignancy (hepatocellularcarcinoma).

One question addresses the constituents of commonly available milk thistle preparations, and three questions address the common and uncommon symptomatic adverse effects of milk thistle.

Methodology
Search Strategy
Eleven electronic databases, including AMED, CISCOM, the Cochrane Library(including DARE and the Cochrane Controlled Trials Registry), EMBASE, MEDLINE, and NAPRALERT, were searched through July 1999 using the following terms:

· Carduus marianus.

· Legalon.

· Mariendistel.

· Milk thistle.

· Silybin.

·  Silybum marianum.

· Silybum.

·  Silychristin.

· Silydianin.

· Silymarin.

An update search limited to PubMed was conducted in December 1999. English and non-English citations were identified from these electronic databases, references in pertinent articles and reviews, drug manufacturers, and technical experts.

Selection Criteria
Preliminary selection criteria regarding efficacy were reports on liver disease and clinical and physiologic outcomes from randomized controlled trials (RCTs) in humans comparing milk thistle with placebo, no milk thistle, or another active agent. Several of these randomized trials had dissimilar numbers of subjects in study arms, raising the question that these were not actually RCTs but cohort studies. In addition, among studies using non placebo controls, the type of control varied widely. Therefore, qualitative and quantitative syntheses of data on effectiveness were limited to placebo-controlled studies. For adverse effects, all types of studies in humans were used to assess adverse clinical effects.

Data Collection and Analysis
Abstractors (physicians, methodologists, pharmacists, and a nurse) independently abstracted data from trials; a nurse and physician abstracted data about adverse effects. Data were synthesized descriptively, emphasizing methodologic characteristics of the studies, such as populations enrolled, definitions of selection and outcome criteria, sample sizes, adequacy of randomization process, interventions and comparisons, cointerventions, biases in outcome assessment, and study designs.

Evidence tables and graphic summaries, such as funnel plots, Galbraith plots, and forest plots, were used to examine relationships between clinical outcomes, participant characteristics, and methodologic characteristics. Trial outcomes were examined quantitatively in exploratory meta-analyses that used standardized mean differences between mean change scores as the effect size measure.

Findings
Mechanisms of Action
Evidence exists that milk thistle may be hepato protective through a number of mechanisms: antioxidant activity, toxin blockade at the membrane level, enhanced protein synthesis, antifibriotic activity, and possible anti-inflammatory or immunomodulating effects.

Preparations of Milk Thistle
The largest producer of milk thistle is Madaus (Germany), which makes an extract of concentrated silymarin. However, numerous other extracts exist, and more information is needed on comparability of formulations, standardization, and bioavailability for studies of mechanisms of action and clinical trials.

Benefit of Milk Thistle for Liver Disease
· Sixteen prospective trials were identified. Fourteen were randomized, blinded, placebo-controlled studies of milk thistle's effectiveness in a variety of liver diseases. In one additional placebo-controlled trial, blinding or randomization was not clear, and one placebo-controlled study was a cohort study with a placebo comparison group.

· Seventeen additional trials used non placebo controls; two other trials studied milk thistle as prophylaxis in patients with no known liver disease who were starting potentially hepatotoxic drugs. The identified studies addressed alcohol-related liver disease, toxin-induced liver disease, and viral liver disease. No studies were found that evaluated milk thistle for cholestatic liver disease or primary hepatic malignancy (hepatocellular carcinoma, cholangiocarcinoma).

·  There were problems in assessing the evidence because of incomplete information about multiple methodologic issues, including etiology and severity of liver disease, study design, subject characteristics, and potential confounders. It is difficult to say if the lack of information reflects poor scientific quality of study methods or poor reporting quality or both.

·  Detailed data evaluation and syntheses were limited to the 16 placebo-controlled studies. Distribution of durations of therapy across trials was wide (7 days to 2 years), inconsistent, and sometimes not given. Eleven studies used Legalon®, and eight of those used the same dose. Outcome measures varied among studies, as did duration of therapy and the followup for which outcome measures were reported.

· Among six studies of milk thistle and chronic alcoholic liver disease, four reported significant improvement in at least one measurement of liver function (i.e., aminotransferases, albumin, and/or malondialdehyde) or histologic findings with milk thistle compared with placebo, but also reported no difference between groups for other outcome measures.
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·   Available data were insufficient to sort six studies into specific etiologic categories; these were grouped as chronic liver disease of mixed etiologies. In three of the six studies that reported multiple outcome measures, at least one outcome measure improved significantly with milk thistle compared with placebo, but there were no differences between milk thistle and placebo for one or more of the other outcome measures in each study. Two studies indicated a possible survival benefit.

· Three placebo-controlled studies evaluated milk thistle for viral hepatitis. The one acute viral hepatitis study reported latest outcome measures at 28 days and showed significant improvement in aspartate aminotransferase and bilirubin. The two studies of chronic viral hepatitis differed markedly in duration of therapy (7 days and 1 year). The shorter study showed improvement in aminotransferases for milk thistle compared with placebo but not other laboratory measures. In the longer study, milk thistle was associated with a nonsignificant trend toward histologic improvement, the only outcome measure reported.

·  Two trials included patients with alcoholic or nonalcoholic cirrhosis. The milk thistle arms showed a trend toward improved survival in one trial and significantly improved survival for subgroups with alcoholic cirrhosis or Child's Group A severity. The second study reported no significant improvement in laboratory measures and survival for other clinical subgroups, but no data were given.

· Two trials specifically studied patients with alcoholic cirrhosis. Duration of therapy was unclear in the first, which reported no improvement in laboratory measures of liver function, hepatomegaly, jaundice, ascites, or survival. However, there were nonsignificant trends favoring milk thistle in incidence of encephalopathy and gastrointestinal bleeding and in survival for subjects with concomitant hepatitis C. The second study, after treatment for 30 days, reported significant improvements in aminotransferases but not bilirubin for milk thistle compared with placebo.

·  Three trials evaluated milk thistle in the setting of hepatotoxic drugs: one for therapeutic use and two for prophylaxis with milk thistle. Results were mixed among the three trials.

· Exploratory meta-analyses generally showed positive but small and nonsignificant effect sizes and a sprinkling of significant positive effects.

· No studies were identified regarding milk thistle and cholestatic liver disease or primary hepatic malignancy.

·  Available evidence does not establish whether effectiveness of milk thistle varies across preparations. One Phase II trial suggested that effectiveness may vary with dose of milk thistle.

Adverse Effects
Adverse effects associated with oral ingestion of milk thistle include:

· Gastrointestinal problems (e.g., nausea, diarrhea, dyspepsia, flatulence, abdominal bloating, abdominal fullness or pain, anorexia, and changes in bowel habits).

· Headache.

· Skin reactions (pruritus, rash, urticaria, and eczema).

· Neuropsychological events (e.g., asthenia, malaise, and insomnia).

· Arthralgia.

· Rhinoconjunctivitis.

· Impotence.

· Anaphylaxis.

However, causality is rarely addressed in available reports. For randomized trials reporting adverse effects, incidence was approximately equal in milk thistle and control groups.

Conclusions
Clinical efficacy of milk thistle is not clearly established. Interpretation of the evidence is hampered by poor study methods and/or poor quality of reporting in publications. Problems in study design include heterogeneity in etiology and extent of liver disease, small sample sizes, and variation in formulation, dosing, and duration of milk thistle therapy.

Possible benefit has been shown most frequently, but not consistently, for improvement in aminotransferases and liver function tests are overwhelmingly the most common outcome measure studied.

Survival and other clinical outcome measures have been studied least often, with both positive and negative findings. Available evidence is not sufficient to suggest whether milk thistle may be more effective for some liver diseases than others or if effectiveness might be related to duration of therapy or chronicity and severity of liver disease.

Regarding adverse effects, little evidence is available regarding causality, but available evidence does suggest that milk thistle is associated with few, and generally minor, adverse effects.

Despite substantial in vitro and animal research, the mechanism of action of milk thistle is not fully defined and may be multifactorial. A systematic review of this evidence to clarify what is known and identify gaps in knowledge would be important to guide design of future studies of the mechanisms of milk thistle and clinical trials.

Future Research
The type, frequency, and severity of adverse effects related to milk thistle preparations should be quantified. Whether adverse effects are specific to dose, particular preparations, or additional herbal ingredients needs elucidation, especially in light of equivalent frequencies of adverse effects in available randomized trials. When adverse effects are reported, concomitant use of other medications and product content analysis should also be reported so that other drugs, excipients, or contaminants may be scrutinized as potential causal factors.

Characteristics of future studies in humans should include:

· Longer and larger randomized trials.

· Clinical as well as physiologic outcome measures.

· Histologic outcomes.
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· Adequate blinding.

· Detailed data about Systematic standardized surveillance for adverse effects.

· Attention to specific study populations (e.g., patients with hepatitis B virus [HBV], or hepatitis C virus [HCV], or mixed infection or coinfection with human immunodeficiency virus [HIV]), comorbidities, alcohol consumption, and potential confounders.

There also should be detailed attention to preparation, standardization, and bioavailability of different formulations of milk thistle (e.g., standardized silymarin extract and silybin-phosphatidylcholine complex).

Precise mechanisms of action specific to different etiologies and stages of liver disease need explication. Further mechanistic investigations are needed and should be considered before, or in concert with, studies of clinical effectiveness. More information is needed about effectiveness of milk thistle for severe acute ingestion of hepatotoxins, such as occupational exposures, acetaminophen overdose, and amanita poisoning.
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Notes on “Combination of Nucleoside Analogues in the Treatment of Chronic Hepatitis B,” 2005.

Long-term antiviral therapy is therefore required in most patients with chronic hepatitis B who do not mount a vigorous immune response, to avoid relapse of viral replication after treatment withdrawal.

However, the major drawback of prolonged therapy is the selection of drug-resistant mutants generated by the spontaneous error rate of the viral polymerase. Therefore, one of the major research areas is the evaluation of combination anti-HBV therapy to delay or prevent the occurrence of drug-resistant mutants.

Owing to the persistence of hepatitis B virus (HBV) and the selection of drug-resistant mutants, a new concept of antiviral therapy for chronic hepatitis B relies on the combination of nucleoside analogues. In experimental models of HBV infection, several key points concerning these combinations were addressed:

(i)  Is it possible to achieve a synergic antiviral effect with polymerase inhibitors?

(ii) Is it possible to impact on intracellular viral covalently closed circular DNA?

(iii) What is the impact of the cross-resistance patterns of the different nucleoside analogues?

(iv) What is the effect of viral load suppression on the restoration of specific antiviral cellular responses?

The clinical impact of these key issues is discussed in the perspective of new clinical trials.

It is important to note that most of the nucleoside analogues administered in monotherapy may select for drug-resistant mutants, as this was shown with HIV. It was shown that lamivudine (Epivir-HBV) and emtricitabine share the same cross-resistance profile with the selection of the M204V or M204I polymerase mutants that are susceptible to adefovir (Hepsera).

To date, telbivudine is associated with the emergence of the M204I mutant, which is resistant to lamivudine and emtricitabine.

Adefovir selects for the A181V and N236T mutants, which are susceptible to lamivudine.

Entecavir is less active against lamivudine-resistant strains and selects for specific resistance mutations on a genetic background of lamivudine resistance mutations.

Clevudine is not active against the lamivudine-resistant strains and was shown to select for the same resistant mutants in woodchucks chronically infected with WHV. It also exhibits some antiviral activity against the adefovir-resistant strains in vitro.

Elvucitabine is not active against the lamivudine-resistant mutants but is active against the adefovir-resistant strains.

Tenofovir shows a good antiviral efficacy against the lamivudine-resistant strains and slightly decreased activity against the adefovir-resistant mutants. A tenofovir-resistant mutant was also recently described.

Given the cross-resistance profile of these drugs, the rationale is to combine the drugs that would inhibit the emergence of drug-resistant strains to one or the other drug. This may lead to an improved management of antiviral therapy of chronic HBV infection in the long term.

Perspectives for the Treatment of Chronic Hepatitis B

The current understanding of chronic HBV infection and its treatment suggest that the patients who are more likely to seroconvert anti-HBeAg antibodies should first receive a course of pegylated interferon alfa.

In this setting, pegylated interferon therapy may be the best option because of the possibility of short-term therapy and the absence of selection of resistant mutants. On the other hand, the majority of patients who are non-seroconverters or are infected with a pre-core mutant will require long-term maintenance therapy to control viral replication and liver disease. In this view, the development of clevudine and emtricitabine opens new avenues in the management of these patients.

Clevudine, with its unusual antiviral activity profile, may be the first nucleoside analogue to be used as a relative short-term treatment and to achieve sustained control of viral replication even after treatment withdrawal.

On the other hand, emtricitabine, as well as other drugs in development, offers a new option for combination of nucleoside analogues that do not share the same cross-resistance profile. For instance, it may be used in combination with adefovir or tenofovir.

The evaluation of these combination strategies will need to rely on accurate endpoints and timing for such analysis.
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Notes on “Viral Load in Chronic Hepatitis B Emerges as Strong Predictor of
Hepatocellular Carcinoma Risk,” Bruce Sylvester.

CHICAGO, IL -- May 17, 2005 -- An elevated level of serum hepatitis B virus (HBV) DNA is a strong predictor of hepatocellular carcinoma (HCC) in chronically infected patients, regardless of their serum alanine aminotransaminase level (ALT), researchers report.

The findings were presented here in a "Poster of Distinction" on May 16th at the 2005 Digestive Diseases Week.

Treatment guidelines for HCC, which exclude chronic hepatitis B patients with normal serum ALT need to be reevaluated, said presenter and lead investigator Uchenna Iloeje, MD, director, Epidemiology and Outcome Research in Virology, Bristol-Myers Squibb, Wallingford, Connecticut, United States.

"Subjects who are currently on the guidelines and have normal serum ALT don't qualify for treatment," Dr. Iloeje said.

"We found that, in this subset of patients, you can use the hepatitis B DNA viral level to stratify patients for risk of progression to hepatocellular carcinoma, and identifying those who might become candidates for beneficial therapy who are now being overlooked," Dr. Iloeje said.

"For the practicing physician, this would mean that for the patient who has normal ALT who is now viewed as at no risk, a change of clinical attitude is needed, he explained.

Dr. Iloeje said that physicians should be aware of the viral load in HBV patients with normal ALT, and depending on the viral load, determine the need for progressive monitoring and whether treatment intervention will be needed.

The investigators enrolled 3851 subjects who had been diagnosed with chronic HBV from seven townships in Taiwan between 1991 and 1992. Cohort baseline serum samples were analyzed for hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg), and serum ALT. HBV DNA was evaluated by polymerase chain reaction.

They determined diagnoses of HCC using data linkage with computerized profiles of the National Cancer Registry and Death Certification System in Taiwan.

Based on data from 43,993 person-years of follow-up over 11 years, 176 subjects were eventually diagnosed with HCC (4.6%).

Of the 3851 subjects, 84.9% were seronegative for HBeAg at entry and of these, 34.3% had elevated serum HBV DNA levels, and 32.2% had normal serum ALT levels.

The researchers noted that 15% of the total cohort were found to be HBeAg-positive, with 96% of them having elevated HBV DNA at study entry and 83% having normal serum ALT levels.

"In subjects with normal ALT, HBV DNA level strongly predicts future HCC events, the investigators concluded. "Serum HBV DNA may be a better and more reliable predictor of subjects at risk of a future HCC event than serum ALT level.

"Patients with normal serum ALT and high levels of circulating virus are at high risk of HCC and deserve consideration for therapy," they added.
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Notes on “Entecavir Could Dominate First-Line Hepatitis-B Monotherapy,” Reports Pharmaprojects, 2005.

LONDON, May 19 /PRNewswire/ -- Bristol-Myers Squibb's recently-launched anti-hepatitis B (HBV) drug, entecavir (Baraclude), could dominate the hepatitis-B therapeutic market, according to information reported in Pharmaprojects, the leading pharmaceutical pipeline-tracking database. Results presented at the recent 18th International Conference on Antiviral Research held in Barcelona, Spain, last month appeared to support entecavir's superiority over the widely-used anti-hepatitis-B drug, lamivudine (Epivir). Hepatitis-B is seen as a growing threat across the world, with calls in the UK last week for vaccination to be offered to all infants, and not just at-risk populations.

Bristol Myers Squibb's entecavir, indicated for the first-line treatment of chronic HBV infection in previously-untreated adults and as second-line therapy in patients who have failed lamivudine therapy, was launched in early April 2005 in the US, and is awaiting EU registration. It acts by inhibiting viral replication and slowing the progression of chronic hepatitis-B. Its initial approval is based on 3 clinical trials conducted in hepatitis-B, where it was compared to lamivudine over 48 weeks. As Pharmaprojects' extensive clinical trial information reports, patients treated with entecavir showed significant improvement in liver histology, including reduced liver inflammation and liver scarring, and there was a greater reduction in HBV viral load compared to lamivudine. Furthermore, a higher proportion of patients treated with entecavir showed significant improvement compared to lamividine. It also demonstrated comparable safety to lamivudine and the adverse events were typical of those seen with HBV therapy.

There are currently 58 drugs in active development for the treatment or prevention of HBV, of which 10 are listed on Pharmaprojects as being launched. These include the antivirals lamivudine and adefovir, adefovir dipivoxil, and a number of unmodified pegylated interferons. Other interesting candidates which have not yet reached the market include Novartis' telbivudine, which is in a multicentre Phase III trial which is expected to be completed by late 2005. Further back along the pipeline are projects such as MIV-210, an antiviral prodrug inhibitor of HBV, underdevelopment by Medivir. Phase I trials for this promising candidate are complete, and a Phase II a trial is scheduled for 2005. However, now launched, entecavir could be set to be the primary therapeutic option for the foreseeable future.

Chronic hepatitis-B is a potentially life-threatening disease affecting approximately 1.25 million Americans, according to the US Centers for Disease Control and Prevention. Worldwide, it afflicts 400 million people, 75% of which live in the Asia-Pacific region. It is caused by the hepatitis-B virus which attacks the liver, and can lead to lifelong infection, cirrhosis of the liver, liver cancer, liver failure and even death. The HBV market in 2004 was estimated at US $551 million with 2-fold more sales accounted for by antivirals than immunomodulators. Some sources suggest that entecavir will exceed the US $300 million per year mark before its patent expires, and will dominate first-line HBV therapy.
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Notes on “Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B,” Chih-Lin Lin et al., Liver International, Volume 25 Issue 3 Page 564  - June 2005.

Background/Aims: The long-term outcomes in hepatitis B e antigen  (HBeAg)-negative chronic hepatitis B are distinct from those in  HBeAg-positive chronic hepatitis. However, the molecular virological factors  that contribute to the progression of liver disease in this special clinical  setting remain largely unknown. We thus investigated the association of  hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter  mutations with the clinical and virological characteristics of patients with  HBeAg-negative chronic hepatitis B in Taiwan.

Methods: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease.

Results: HBV carriers with older age (>50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.2225, P<0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.4112.03, P=0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.3014.52, P=0.02).

Conclusions: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.
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Notes on “Can Hepatitis B Be Cured?” Norah Terrault, 2008.

Introduction:  Chronic hepatitis B remains a major health problem worldwide.[1] Progression to cirrhosis, decompensated liver disease, and hepatocellular carcinoma are the major adverse consequences of untreated disease. Therefore, the goals of therapy are to prevent these complications to ultimately prevent premature death from chronic hepatitis B. Six drugs are now approved for the treatment of chronic hepatitis B in the United States: interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine.[1] The nucleos(t)ide analogues control viral replication very well with variable levels of long-term durability. However, viral replication typically returns to detectable levels after nucleos(t)ide therapy is stopped, even in patients who are initially hepatitis B e antigen (HBeAg) positive but who undergo HBeAg loss and develop antibody to HBeAg (anti-HBe)HBeAg seroconversionor who lose hepatitis B surface antigen (HBsAg) during their treatment. Therefore, although chronic hepatitis B virus infection can be controlled with these agents, it is rarely, if ever, cured by them. The probable explanation lies with a viral form termed covalently closed circular DNA (cccDNA), which plays a key role in viral persistence and viral reactivation after treatment withdrawal. This module highlights the critical role of cccDNA in the course of natural and treated hepatitis B virus (HBV) infection.

What Is cccDNA?:   Hepatitis B virus cccDNA constitutes a stable form of the viral DNA genome. The cccDNA resides in an infected hepatocyte nucleus as a nonintegrated minichromosome or episome, where it acts as a template for the transcription of viral genes.[2] The number of copies of cccDNA present in any given hepatocyte is highly variable but generally ranges from 10-50 copies per hepatocyte.[2]

How Is cccDNA Produced and Maintained?:   The cccDNA is produced during viral replication. Although HBV is a partially double-stranded DNA virus, it replicates through an RNA intermediate by employing a viral polymerase with reverse transcriptase activity. Replication of HBV predominantly occurs in hepatocytes.[2] Upon entry into the cell, the virus sheds its protein coat, and the relaxed, partially double-stranded genome is transported into the nucleus.[2] In the nucleus, host and viral polymerases repair the relaxed, partially circular genome to a fully double-stranded, covalently closed circular genome or cccDNA (Figure 1). The cccDNA serves as the template for transcription of all viral messenger RNAs (mRNAs). The viral mRNAs include 1) the pregenomic RNA, which serves as the template for both reverse transcription and the synthesis of the core protein and polymerase enzyme; 2) 3 subgenomic mRNAs necessary for the translation of the envelope proteins; and 3) the X protein, the function of which is poorly understood.[2,3] Once synthesized, the viral mRNAs are transported to the cytoplasm where translation of viral proteins, nucleocapsid assembly, and viral replication occur.

Figure 1. The HBV life cycle.


Replication occurs within the viral nucleocapsid that consists of the core protein, pregenomic RNA, and polymerase.[2,3] Nucleocapsid formation requires coordinated binding of the polymerase to an RNA stem-loop structure called epsilon that is located at the 5 end of the pregenomic RNA䡪a process that triggers encapsidation by core particles. The epsilon-bound polymerase serves as a protein primer for DNA synthesis, with epsilon serving as the template for this reaction. After the negative strand of DNA has been completely synthesized, the RNA is degraded by the viral RNase H that is part of the polymerase. Positive-strand synthesis and circularization of the viral genome then follows. Once replication is complete, the viral nucleocapsid interacts with envelope proteins in the endoplasmic reticulum to form mature virions that are secreted from the cell. Viral nucleocapsids can also be transported back to the nucleus, which represents a critically important pathway for maintenance of cccDNA within the hepatocyte. This pathway is thought to be regulated by the large surface protein.[4]

How Is cccDNA Eliminated?:  The immune response plays a fundamental role in viral clearance as well as in mediating disease. Therefore, it is beneficial to review the immune response to HBV infection to understand how viral replication is controlled. Successful control of HBV is dependent on the complex interplay between the innate, cellular, and humoral responses to the infecting virus (Figure 2). However, the exact role of the innate response in acute HBV infection is unclear. The nonspecific innate immune response involves
production of interferon, activation of natural killer cells, and activation of Kupffer cells, all of which may help to control viral replication and limit the spread of the virus during the early stages of infection.[5,6] The roles of the cellular and humoral responses are better defined. The T-cell response during acute, self-limited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and helper T-cell response. By contrast, the immune response in chronic carriers is feeble or undetectable. The CD4+ helper T lymphocytes recognize processed viral antigen presented by major histocompatibility complex class II molecules.[5,6] There are 2 subsets of these CD4+ helper T cells. The first is type 1 helper T cells which secrete interferon gamma, interleukin (IL)-2, and tumor necrosis factor-alpha and clear HBV-infected hepatocytes through cytolytic and noncytolytic mechanisms. The second are the type 2 helper T cells that secrete IL-4, IL-5, IL-6, and IL-10 and lead to B-cell antibody production, which is necessary for neutralizing free viral particles and preventing reinfection of hepatocytes.

Figure 2. Control of HBV by the immune system.


The immune system is thought to eliminate cccDNA by 2 possible mechanisms: 1) a cytolytic mechanism in which infected hepatocytes are killed and replaced by noninfected cells and 2) a noncytolytic mechanism in which antiviral cytokines downregulate HBV gene expression and eliminate HBV from hepatocytes without cell death.[7] Hepatocytes have a long half-life; therefore, elimination of cccDNA by hepatocyte turnover is not a major means of clearance, except perhaps during periods of rapid cell turnover, such as during acute hepatitis infection. The observation that cccDNA may persist even in patients with serologic evidence of viral clearance highlights the important role of the immune response in controlling viral replication and offers insight into potential nonvirologic approaches to the treatment of chronic hepatitis B (Capsule Summary).[8] [Coder link to: Hep JO Werle-Gastro-2004-06]
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cccDNA as a Therapeutic Target:   The HBV cccDNA is an attractive target for therapy because of the critical role it plays in viral replication and persistence. Nucleos(t)ide analogues inhibit the viral polymerase but do not inhibit the intracellular recycling pathway that replenishes cccDNA. As a consequence, viral replication often returns to pretreatment levels after withdrawal of these agents. Using a variety of molecular techniques, studies examining changes in patients cccDNA during nucleos(t)ide analogue therapy, either alone or in combination with peginterferon, have demonstrated a 1.0-2.4 log10 copies/cell decline in cccDNA levels, but not eradication, compared with the other HBV replicative DNA forms in the liver.[8-10] Based on these data, mathematical models predict that it would take longer than 14 years to completely clear a chronically HBV-infected human liver of intracellular cccDNA.[11] The clinical implications of this finding are that nucleos(t)ide analogues have to be administered for extremely long periods of time, if not indefinitely. The goal of a cure of chronic hepatitis B with currently available oral agents is not possible because these agents cannot be effectively administered for this length of time, and they are inefficient at eradicating cccDNA from the liver. Recently, other novel approaches have been explored to target cccDNA. In one study, a genetically modified cytotoxic T cell carrying a chimeric T-cell receptor directed against HBV surface proteins present on HBV-infected cells was developed and used to provide primary human T cells with antibody-like specificity.[12] When coincubated with HBV-infected primary human hepatocytes, these engineered, antigen-specific T cells selectively eliminated HBV-infected and, therefore, cccDNA-positive target cells. However, finding a delivery system for this therapeutic modality and the potential risk of liver damage may limit this approach. Another in vitro study used a small interfering RNA targeted against the nuclear localization signal within the HBV core protein and observed that this agent markedly inhibit cccDNA amplification.[13] Based on this result, further studies in animal models of this class of agents is clearly warranted.

Is There a Role for cccDNA in Predicting the Response to Antiviral Therapy?:   Given the role of cccDNA in the persistence of viral replication, quantification of cccDNA may have clinical utility. Studies have shown a correlation between cccDNA and intrahepatic HBV DNA levels; however, it is not practical to measure cccDNA in liver biopsies during routine clinical practice.[14] Therefore, a surrogate marker for cccDNA levels would be a useful tool for monitoring the activity of HBV-related liver disease. Given that cccDNA is the major template for the transcription and translation of viral antigens, including HBsAg, changes in serum HBsAg levels might be used as a surrogate marker for changes in cccDNA levels. One study that examined this potential relationship between pretreatment serum HBsAg levels and total intrahepatic HBV DNA and cccDNA levels in patients undergoing therapy with peginterferon and lamivudine found a correlation between serum HBsAg levels and intrahepatic HBV DNA levels.[15] Patients with lower baseline cccDNA, intrahepatic HBV DNA, and HBsAg levels, but not serum HBV DNA levels, were more likely to develop sustained virologic suppression. Similar results have been observed in patients treated with peginterferon alfa and adefovir.[8,9] These studies provide preliminary evidence that might explain why spontaneous or treatment-induced HBsAg loss is the most robust serologic indicator of sustained virologic suppression, although the findings need to be confirmed by other studies that include larger numbers of subjects.

What Is the Rate of HBsAg Loss With Current Therapies?:   As mentioned previously, HBsAg loss is the most robust surrogate marker of a long-term response to antiviral therapy. The rates of HBsAg loss during treatment with approved monotherapies and experimental anti-HBV agents and regimens are shown in the Table 1. Loss of HBsAg is rarely achieved during treatment with nucleos(t)ide analogues[16-25] [22] ( 1.0% to 3.2%).[23] Marginally better results (3.0% to 7.8%)[16,17,25] are obtained with interferon alfa regimens.[17] Combining peginterferon alfa with lamivudine provides no additional benefit in HBsAg clearance over peginterferon alfa alone.[16] The effects of antiviral therapy on cccDNA levels are shown in Table 2.

Table 1. Rates of HBsAg Loss at 1 Year With Monotherapies and Combination
Regimens

Table 2. Median Change in Intrahepatic cccDNA, Intrahepatic HBV DNA, and Serum
HBV DNA Levels During Antiviral Therapy for 48-52 Weeks[8,10,15,28,29]


The Impact of Antiviral Therapy on Liver Disease Outcomes and the Development of Hepatocellular Carcinoma Improvements in HBV-related liver disease and mortality have been observed in patients who are able to maintain long-term HBV DNA suppression either on or off treatment. Long-term data (> 5 years) on clinical outcomes following antiviral therapy are available for interferon alfa and lamivudine, whereas shorter-term follow-up data (4-5 years) are available for adefovir and entecavir. Long-term follow-up of Western studies of HBeAg-positive patients treated with interferon alfa demonstrated improved patient survival and a decreased incidence of hepatic decompensation in patients who achieved persistent clearance of HBeAg.[30-32] By contrast, the long-term clinical benefits of interferon alfa therapy in Asian HBeAg-positive patients are unclear, and no long-term benefit in the prevention of hepatocellular carcinoma or other cirrhosis-related complications has been observed in Asian patients who underwent HBeAg seroconversion compared with controls over a median follow-up of 9 years.[33] Although the rate of sustained HBV DNA clearance with interferon alfa therapy is lower in HBeAg-negative patients compared with HBeAg-positive patients, decreased rates of progression to cirrhosis and liver-related death have also been observed.[34] Finally, the role of interferon alfa in preventing hepatocellular carcinoma is uncertain. The administration of nucleos(t)ide analogue therapy for 1 year or more has been associated with improvements in biochemical, virologic, and histologic parameters in the absence of antiviral resistance. Reductions in hepatic necroinflammation and fibrosis, and even regression of cirrhosis, have been observed in patients who maintained viral suppression on lamivudine for more than 3 years.[35,36] By contrast, histologic benefits were lost among patients with drug resistance.[36] A randomized, placebo-controlled trial reported that patients with advanced liver disease who were treated with lamivudine had lower rates of hepatic decompensation, reduced need for liver transplantation, reduced development of hepatocellular carcinoma, and lower liver-related mortality compared with controls.[37]

In one study, long-term treatment with adefovir for 5 years was associated with decreased fibrosis in patients who maintained a virologic response.[38] Nonetheless, 2% of patients developed hepatocellular carcinoma, indicating that long-term antiviral treatment does not completely prevent this complication. Short-term studies of entecavir, telbivudine and tenofovir therapy report higher rates of viral suppression compared with lamivudine and adefovir.[24,39] Given the superior potency and durability of entecavir and telbivudine, one would predict similar or even superior outcomes with long-term use. However, long-term data on the impact of these agents on the development of hepatocellular carcinoma remains to be demonstrated. Evidence for Lack of Cure: Reactivation With Seroreversion From Anti-HBs and Anti-HBc Positivity to HBsAg Positivity
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Reactivation of HBV is poorly defined in clinical studies. The term reactivation is used interchangeably in the literature to refer to an increase in serum HBV DNA and/or an increase in serum alanine aminotransferase (ALT) levels and/or reappearance of HBsAg in serum (Table 3). This latter scenario is better termed HBsAg seroreversion, which can occur with or without hepatitis, although HBsAg seroreversion is almost always accompanied by an increase in HBV DNA levels and hepatitis. During cytotoxic therapy, a proposed definition of HBV reactivation used in several studies is a rise in HBV DNA level of > 1 log10 when compared with baseline or an absolute increase that exceeds 1000 x 106 genome equivalents/mL together with hepatitis defined as a 3-fold increase in serum ALT that exceeds the reference range or an absolute increase of serum ALT > 100 IU/L.[40-42]

Table 3. Definition of HBV Reactivation During Cytotoxic Therapy


Seroreversion of HBsAg has been described following chemotherapy,[40] high-dose steroid use,[43] and bone marrow or hematopoietic stem cell transplantation.[44,45] In addition, de novo HBV infection following liver transplantation has been reported in HBsAg-negative individuals who received anti-HBcCpositive donor livers.[46] These multiple clinical observations provide the most convincing evidence that HBV may persist following serologic recovery and that long-term control of HBV replication is dependent on an intact immune response that is probably maintained by continuous priming from residual virus. Rates of reactivation during chemotherapy are lower in HBsAg-negative (serologically recovered) compared with HBsAg-positive (inactive carriers) patients.[40] It has been difficult to accurately determine the prevalence of seroreversion because of several factors: small sample sizes, the sensitivity of the assays used, the different periods of follow-up, the different chemotherapeutic regimens administered, and the different populations studied. Based on case-series, the seroreversion rate ranges from 14% to 30% in patients receiving chemotherapy,[40,47] 11% to 50% in patients undergoing bone marrow or stem cell transplantation,[44,48-50] and 50% to 78% in HBsAg-negative individuals receiving anti-HBcpositive liver grafts.[46,51,52]

Seroreversion and reactivation of HBsAg most likely results from the low-level persistence of cccDNA within hepatocytes with immunosuppression-induced augmentation of HBV replication.[53] Seroreversion with reactivation usually occurs later (6-52 months; median: 19 months) compared with reactivation in HBsAg-positive patients.[54] In the setting of allogeneic bone marrow or stem cell transplantation, the absence of donor immunity may also play a role in HBsAg seroreversion.[50] Recurrence of clinical hepatitis may be mediated by cytotoxicity resulting from very high intracellular levels of HBV DNA or by loss of immune-mediated control of HBV replication with rapid clearance of virally infected hepatocytes upon immune reconstitution.

Which Patients Are at Risk for HBsAg Seroreversion?:  Seroreversion of HBsAg may occur either during or after the period of immunosuppression. Identifying risk factors for seroreversion has been difficult because of the small numbers of patients included in published reports. Some risk factors that have been identified are the use of high-dose corticosteroids, the administration of regimens containing rituximab and corticosteroids, the lack of anti-HBs in liver donors, and the development of graft-vs-host disease. In general, the risk of HBsAg seroreversion is related to the degree and duration of immunosuppression and the level of detectable HBV DNA before immunosuppression. Therefore, the risk of HBsAg seroreversion is higher in patients undergoing hematopoietic bone marrow or stem cell transplantation or in those receiving specific monoclonal antibodies directed against B and T cells, such as rituximab and alemtuzumab. The severity of hepatitis following HBsAg seroreversion is influenced by the stage of liver disease. Patients with cirrhosis are at higher risk for decompensation and hepatic failure following HBsAg seroreversion with clinical reactivation. A high baseline level of cccDNA in HBsAg-positive patients has been shown to be predictive of HBsAg seroreversion during chemotherapy.[55] However, quantifying cccDNA is not a practical strategy for risk assessment in the general clinical care setting. Predictors of HBsAg seroreversion that have been identified in uncontrolled studies include declining anti-HBs levels and a 100-fold increase in serum HBV DNA.[50,56]

Clinical Presentation and Management of HBV HBsAg Seroreversion With Clinical Reactivation:   The presentation of HBsAg seroreversion with clinical reactivation may range from an asymptomatic, mild increase in serum ALT levels to frank hepatic decompensation and fulminant hepatitis.[41] Mortality of patients with fulminant hepatitis are high and range from 5% to 40%, even with the institution of antiviral therapy.[56,57] Seroreversion-related hepatitis usually leads to severe liver dysfunction and is also independently associated with a higher risk of developing fulminant hepatic failure.[56] The management of established hepatitis involves aggressive supportive therapy and the discontinuation of chemotherapy with prompt, early institution of antiviral therapy with the most potent agent available. The goal should be to suppress HBV DNA levels as rapidly as possible. Once clinical hepatitis develops, there is high mortality despite initiation of antiviral therapy. This highlights the need to monitor patients closely by following HBV DNA levels using a sensitive assay and to intervene before the development of clinical hepatitis. A suggested approach would be to monitor serum HBV DNA levels every 2-4 weeks for the first 3 months after chemotherapy is discontinued and every 3 months thereafter. In one study, a 100-fold increase in serum HBV DNA level preceded seroreversion and clinical hepatitis in all patients.[56] This approach needs to be evaluated in other prospective trials.

Can HBsAg Seroreversion and Reactivation Be Prevented?:   Because serum HBV DNA rises before serum ALT levels increase, antiviral therapy initiated before the start of chemotherapy or transplantation should reduce or prevent clinical hepatitis. Indeed, this has been demonstrated in HBsAg-positive inactive carriers. In a randomized controlled trial, 30 lymphoma patients undergoing chemotherapy with or without hematopoietic stem cell transplantation were randomized to receive immediate lamivudine as prophylactic therapy or deferred lamivudine initiated upon clinical evidence of HBV reactivation (as previously defined).[42] Compared with deferred lamivudine, prophylactic lamivudine significantly reduced the rate of HBV reactivation (0% vs 53%, respectively) and improved hepatitis-free survival compared with deferred lamivudine. Based on this, another randomized study, and several case reports,[58] clinicians are advised to initiate antiviral therapy 1 month before the institution of chemotherapy and to continue antiviral therapy for 6 months after immune-system recovery in patients with HBV DNA levels  2000 IU/mL.[1]
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The rate of seroreversion and viral reactivation in HBsAg-negative patients receiving chemotherapy or undergoing bone marrow transplantation is lower (3.3%)[56] than that in HBsAg-positive patients (26.0%),[59] but there is insufficient data to recommend routine prophylaxis. However, if prophylaxis is not used, it is important to monitor patients closely with serial HBV DNA level and HBsAg determinations to detect reactivation and seroreversion. The issue that needs to be resolved is whether routine prophylaxis is more or less cost-effective than intensive monitoring. Until such data are available, an individualized approach is recommended. By contrast, because of the high rate of HBsAg seroreversion following liver transplantation using anti-HBc positive donor livers in seronegative recipients, prophylaxis is advised. Strategies that have been used with varying success include hepatitis B immune globulin alone, lamivudine alone, or a combination of the 2.[60-64] No firm recommendations can be made because of the absence of controlled trials.

A suggested approach for managing HBsAg-positive and HBsAg-negative individuals undergoing chemotherapy or bone marrow or stem cell transplantation is given in Figure 3. Lamivudine or telbivudine can be used as prophylaxis in HBeAg-positive individuals if the anticipated duration of treatment is short (< 12 months).[1] Adefovir or entecavir are preferred if longer treatment durations are anticipated.[1] Patients should be monitored closely while receiving antiviral therapy and after discontinuation to ensure that reactivation does not occur. It is equally important to closely monitor untreated patients by collecting serial HBV DNA measurements for the first 12 months after the completion of chemotherapy.[56] The frequency of monitoring can be decreased after this period but should continue indefinitely, since HBsAg seroreversion has been reported beyond 3 years after bone marrow transplantation. Antiviral therapy should be started immediately if HBV DNA levels increase.

Figure 3. Suggested Approach for Managing Immunosuppressed HBV-Infected
Individuals to Prevent HBV Reactivation
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Summary: Implications for Clinical Practice:  . Hepatitis B virus is a partially double-stranded DNA virus that replicates through an RNA intermediate. Replication occurs within the viral nucleocapsid in the cytoplasm of the hepatocyte. . A robust polyclonal and multispecific cytotoxic and helper T-cell response is necessary for control of HBV replication. . The cccDNA represents a stable, episomal form of HBV DNA that resides in the hepatocyte nucleus. It is the template for transcription of all viral mRNAs. . Levels of cccDNA are maintained by an intracellular recycling pathway from nascent viral nucleocapsids. Elimination of cccDNA primarily occurs through cytolytic and noncytolytic mechanisms induced by the immune system. . Levels of cccDNA may decline during antiviral therapy but usually persist following serologic recovery from HBV infection. This accounts for the viral rebound observed when antiviral agents are stopped. Therefore, patients who achieve spontaneous or treatment-induced recovery need to be monitored lifelong for HBsAg seroreversion. The frequency of monitoring should be every 6-12 months. . Loss of HBsAg is the most robust endpoint of nucleos(t)ide therapy but is achieved in < 3% of treated patients. Rates of HBsAg loss are higher with interferon/peginterferon therapy (3% to 8%) but are still poor overall. . Long-term therapy with nucleos(t)ide analogues has been associated with decreased progression of liver disease, improved survival, and decreased rates of hepatocellular carcinoma. The development of drug resistance is associated with loss of clinical benefit. . Seroreversion of HBsAg has been described following immunosuppression with high-dose steroids, cancer chemotherapy, and bone and stem cell transplantation for hematologic and solid organ malignancies as well as following orthotopic liver transplantation in HBsAg-negative individuals receiving livers from anti-HBcCpositive donors. . Patients receiving chemotherapy consisting of potent immunosuppressive agents should be screened for HBsAg. Positive individuals should receive anti-HBV prophylaxis against HBsAg seroreversion. . There is insufficient evidence to recommend anti-HBV prophylaxis in HBsAg-negative patients. Patients at high risk for HBsAg seroreversion (ie, those receiving a steroid-containing regimen or a monoclonal antibody against B or T cells, those with detectable HBV DNA, or those with underlying cirrhosis) should be considered for prophylaxis. . Patients who do not receive anti-HBV prophylaxis should be monitored indefinitely.
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Notes on “A Practical Approach to Management of Chronic Hepatitis B,” Ke-Qin Hu, 2005.

Indications of HBV Treatment

Historically, levels of HBV DNA and ALT, and histological activity of liver biopsy have been used as the three main factors to determine if a patient needs HBV treatment or not [1-3].

HBV DNA Levels

It is known that HBV is not directly pathogenic to hepatocytes and host immune response to HBV antigens expressed on the infected hepatocytes is the principle determinants of the liver injury. Thus, a high HBV load has been the primary indication for HBV infection. However, the threshold HBV level that is associated with progressive liver disease remains to be determined. In addition, patients with CHB may have fluctuating HBV DNA levels. A study revealed that only one third of patients with HBeAg-negative CHB and elevated ALT had HBV DNA levels persistently > 105 copies/ml [19]. This suggested that an even lower HBV DNA threshold might be reasonable to indicate HBV treatment in patients HBeAg-negative CHB. Thus, it has recently been recommended that different HBV DNA levels should be used to determine HBV treatment depending on HBeAg status and clinical presentation of CHB [3]. As summarized in Figure 1, HBV treatment should be considered in patients with HBeAg-positive CHB and HBV DNA ? 105 copies/ml in combination with elevated ALT level and histological activity. While in patients with HBeAg negative-CHB and patients with compensated HBV cirrhosis regardless HBeAg status, HBV treatment should be considered when HBV DNA ? 104 copies/ml [3]. It should be noted that above cutoff HBV DNA levels are arbitrarily made based on limited research results, and not endorsed by all guidelines [1-3]. Additional studies will be needed to verify these criteria.

Histological Activity and Stage

Liver biopsy provides us with valuable information of histological activity and stage of HBV disease in patients with HBV infection. It is known that patients with chronic HBV infection and active hepatic inflammation carry a significantly higher risk of disease progression. Histological staging of HBV disease is clinically very valuable in assessing degree of fibrosis and predicting disease progression. Good response to HBV treatment has been well associated with improved histology. Therefore, a pre-HBV treatment liver biopsy is usually preferred by most hepatologists. However, for those with clear-cut indications for HBV treatment, a liver biopsy may not be necessary. As it will be discussed below, histological assessment is very valuable in determining HBV treatment in patients with persistently normal transaminases.

ALT Levels

For many years, ALT has been used as a standard surrogate for the activity of CHB. Thus, ALT level in combination with HBV DNA level and histological activity has been used as a determinant for HBV treatment [1-3]. It is well accepted that elevated ALT should be used as one of the determinants for HBV treatment in patients with CHB. However, it remains controversial on at what level of ALT elevation a patient with CHB should be considered for HBV treatment [3].

On the other hand, patients with detectable HBV load (i.e. by HBV hybridization or HBV ? 105 copies/ml), but persistently normal transaminases have historically not been considered as candidates for HBV treatment based on the assumption that these patients usually have a slow progression and evidence that these patients usually have a low response rate to HBV treatments. However, the extent of liver injury and fibrosis is not always correlated with ALT levels [20]. Furthermore, a sustained suppression of HBV replication is now more achievable than before. In addition, an active HBV replication has been associated with increased risk for HCC [21]. Thus, it has become more accepted that a normal ALT level alone should not be used to determine HBV treatment in these patients. Instead, in patients with HBV DNA ? 105 copies/ml and persistently normal ALT levels, a liver biopsy might be considered (Figure 1). If active liver inflammation or advanced fibrosis is histologically confirmed, the patient should be considered for HBV treatment. Additional studies will be needed to further assess the efficacy and benefit of HBV treatment in this group of patients.
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Notes on “Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications,” Yuen Mf. et al. Gut. 2005 May 4.

BACKGROUND: Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria.

AIM: To determine risk factors for the development of complications in Asian CHB patients.

PATIENTS AND METHODS: 3,233 Chinese CHB patients (mean follow-up 46.8 months) were monitored for liver biochemistry, viral serology, HBV DNA levels, acute exacerbation, HBeAg seroconversion, and development of cirrhotic complications and hepatocellular carcinoma. RESULTS: The median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years respectively. Patients with alanine aminotransferase (ALT) levels of 0.5 - 1 X upper limit of normal (ULN) and 1 - 2 X ULN had increased risk for the development of complications compared to patients with ALT levels < 0.5 X ULN (p<0.0001 for both). HBeAg/ anti- HBe status, and the number of episodes, duration and peak ALT levels of acute exacerbations were not associated with increased risk of complications. In patients with complications, 43.6% had the HBV DNA levels less than 1.42 X 105 copies/ml. Male gender, stigmata of chronic liver disease, old age, low albumin and high AFP levels on presentation were independently associated with increased cumulative risk of complications. Male gender, presence of hepatitis symptoms, old age, low albumin level and presence of complications on presentation were independently associated with shorter survival.

CONCLUSION: Prolonged low-level viremia causing insidious and continual liver damage as reflected by ALT levels of 0.5 - 2 X ULN is the most likely pathway for the development of complications in Asian CHB patients.
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Notes on “Your Child's Immunizations,” KidsHealth.org, 2005.

When a child is born, she usually has immunity to certain diseases. This is a result of the disease-fighting antibodies that have passed through the placenta from the mother to the unborn child. After birth, the breastfed baby gets the continued benefits of additional antibodies in breast milk. But in both cases, the immunity is only temporary.

Immunization (vaccination) is an artificial way of creating immunity to certain diseases - by using relatively harmless substances called antigens that come from or are similar to the components of microorganisms that cause the diseases.

Microorganisms can be viruses, such as measles virus, or they can be bacteria, such as pneumococcus. Vaccines stimulate the immune system into reacting as if there were a real infection. The immune system then fights off the "infection" and remembers the organism so it can fight it off quickly if it enters the body at some future time.

Some parents may hesitate to give their children a vaccine because they are concerned about complications or their children developing the illness the vaccine is supposed to prevent. Although it's true that some vaccines could have these effects, the likelihood of that happening is very small. Not immunizing your child exposes her to greater health risks associated with contracting the disease the vaccine is intended to prevent.

Immunization is one of the best means of protecting your child against contagious diseases. The following vaccinations and schedule are recommended by the American Academy of Pediatrics (AAP). Please note that some variations are acceptable and that changes in recommendations frequently occur as new vaccines are developed; your child's doctor will determine the best vaccinations and schedule for your child.

Hep B
Hepatitis B (HBV) is a virus that infects the liver. Those who are infected can become lifelong carriers of the virus and may develop long-term problems such as cirrhosis (liver disease) or cancer of the liver.

Immunization Schedule
Hepatitis B vaccine usually is given as a series of three injections. The first shot is given to infants shortly after birth. If the mother of a newborn carries the hepatitis B virus in her blood, the infant needs to receive the first shot within 12 hours after birth. If a newborn's mother shows no evidence of HBV in her blood, the infant may receive the shot any time prior to leaving the hospital. It also may be deferred until the 4- or 8-week visit to the child's doctor.

If the first shot is given shortly after birth, the second shot is given at 1 to 2 months and the third at 6 months. For infants who do not receive the first shot until 4 to 8 weeks, the second shot is given at 3 to 4 months and the third at 6 to 18 months. In either case, the second and third shots usually are given in conjunction with other routine childhood immunizations.

Why Receive the Vaccine?
The hepatitis B vaccine probably creates lifelong immunity. Infants who receive the HBV series should be protected from hepatitis B infection not only throughout their childhood but also into the adult years. Eliminating the risk of HBV infections also decreases risk for cirrhosis of the liver, chronic liver disease, and liver cancer. Young adults and adolescents should also receive the vaccine if they did not as infants.

Possible Risks
Serious problems associated with receiving the HBV vaccine are rare. Problems that do occur tend to be minor, such as fever or redness or tenderness at the injection site.

When to Delay or Avoid the Immunization
if your child is currently sick, although simple colds or other minor illnesses should not prevent immunization
if severe allergic reaction (anaphylaxis) occurs after an injection of the HBV vaccine

How to Care for Your Child After the Immunization
The vaccine may cause mild soreness and redness at the place the shot was given; this may be treated with pain relievers like acetaminophen or ibuprofen.

When to Call Your Child's Doctor
if you are not sure of the recommended schedule for the hepatitis B vaccine
if you have concerns about your own HBV carrier state
if moderate or serious adverse effects appear after an HBV injection has been given to your child.
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Notes on “Milk thistle does not reduce deaths from liver diseases,” best studies find, Center for the Advancement of Health, 2-May-2005.

Milk thistle, a widely used alternative medicine, is not proven effective in lowering mortality in alcoholic or hepatitis B or C liver disease, according to a systematic review of current evidence.While some studies found that liver-related mortality may be significantly reduced in patients treated with milk thistle, these findings were not duplicated in the higher quality clinical trials.

However, milk thistle was found safe to us with no serious side effects and with participants perceiving improvement in symptoms -- although no more than with placebo.

Dr. Andrea Rambaldi, visiting researcher at the of the Centre for Clinical Intervention Research at Copenhagen University Hospital, led a team that reviewed 13 randomized clinical trials involving 915 patients who were treated with milk thistle or its extracts.

Participants had acute or chronic alcoholic liver cirrhosis, liver fibrosis, hepatitis and/or steatosis, and viral-induced liver disease (hepatitis B and/or hepatitis C). Patients with rarer specific forms of liver disease were excluded.

All the trials compared the efficacy of milk thistle or any milk thistle constituent versus placebo or no intervention in patients with liver disease. "There is no evidence supporting or refuting milk thistle for alcoholic and/or hepatitis B or C virus liver diseases," the authors found.

The review appears in the most recent issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

According to the Centers for Disease Control and Prevention, 170 million people worldwide are infected with hepatitis C, and 2 billion are infected with hepatitis B.

While a vaccine exists to prevent hepatitis B, there is no vaccine for hepatitis C.

Although the virus can be cleared in a handful of patients, many strains are resistant to treatment. Drug therapies that focus on long-term suppression of the virus are expensive, and many patients develop a resistance. The current gold standard treatment, which combines injections of interferon and ribavirin, has serious side effects and is hard for patients to tolerate.

With lack of effective treatment for liver disease, researchers have been looking for alternative therapies that curb symptoms with minimum adverse effects on patients. Milk thistle and its extracts have been used since the time of ancient Greece for medicinal purposes, are currently widely used in Europe for liver disease, and are readily available in the United States at alternative medicine outlets and outdoor markets.

G. Thomas Strickland, M.D., Ph.D., professor at the University of Maryland School of Medicine, has been studying the role of silymarin, an extract of milk thistle, in preventing complications of chronic hepatitis virus infection. Strickland says that the exact mechanism of action of silymarin is unclear.

A problem with current trials, according to Dr. Strickland, is that the dose of silymarin administered, typically 140 mg three times daily, is too low. "I would certainly double it," he says, "especially since at the current dose we're not seeing any improvement in acute viral or chronic hepatitis, and we've shown that silymarin is totally safe."

"The problem is, there is no cure for viral hepatitis except bed rest and diet, and treatments like silymarin are worth pursuing," Strickland says, calling for more research funding.

"We should consider doing randomized clinical trials with higher doses of silymarin," Dr. Rambaldi concurs.

According to the National Center for Complementary and Alternative Medicine , a part of the National Institutes of Health, studies in laboratory animals suggest that silymarin may benefit the liver by promoting the growth of certain types of liver cells, demonstrating a protective effect, fighting oxidation (a chemical process that damages cells) and inhibiting inflammation.

In their review, Dr. Rambaldi and colleagues conclude, "Milk thistle could potentially affect alcoholic and/or hepatitis B or C virus liver diseases. Therefore, large-scale randomized clinical trials on milk thistle for alcoholic and/or hepatitis B or C liver diseases versus placebo may be needed."
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Notes on “VIRAL LOAD IS A STRONG PREDICTOR OF LIVER CIRRHOSIS RISK IN PEOPLE CHRONICALLY INFECTED WITH HEPATITIS B VIRUS REGARDLESS OF HEPATITIS B E ANTIGEN STATUS,” C.J. Chen, et al.  2005.

Introduction: HBeAg is considered a marker of active viral replication often associated with high levels of viremia. This study was carried out to examine the impact of HBV DNA level on the risk of disease progression to cirrhosis stratified by HBeAg status.

Methods: A population based prospective cohort of 3,851 subjects chronically infected with HBV was established was from seven townships in Taiwan between 1991 and 1992. Subjects were prospectively followed by hepatologists by clinical examinations including ultrasonography through June 30th 2004. The diagnosis of cirrhosis was based on ultrasonographic findings. All cirrhosis cases diagnosed within 6 months of enrollment were excluded from analyses. Multivariable adjusted relative risks (RRadj) were derived using Cox proportional hazard models.

Results: Overall, 3774 subjects with 42,115 person years of follow up contributed data to this analysis. There were 395 cases of cirrhosis. Of the 3774 participants, 3,214 (85%) were seronegative for HBeAg, of which 1082 (34%) had serum HBV DNA level ³104 copies/mL; 560 (15%) were HBeAg positive of which 538 (96%) had serum HBV DNA ³104 copies/mL at enrollment. There was a dose dependent relationship between HBV DNA and cirrhosis risk within the HBeAg strata. With the HBeAg negative undetectable DNA group as reference, the highest risk of progression was found in the HBeAg positive group with HBD DNA over 105 copies/mL.

Conclusion: Elevated serum HBV DNA is a strong predictor of cirrhosis risk in HBV infected persons regardless of HBeAg status. Effective suppression of HBV DNA to very low levels especially in HBeAg negative persons could reduce progression of CHB to cirrhosis.
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Notes on “CHINA:   "China Cuts Off Hepatitis Patients" Toronto Star, (07.11.08

On May 29, a popular Web site for people in China living with hepatitis B went silent, at least, for people in China. It has not been seen there since.  "At first I thought it was just a technical glitch, maybe a problem with the server," said Lu Jun, a former IT specialist who devotes his time to helping people with hepatitis B. But the site may be another victim of Chinese government efforts to heighten social control before the Beijing Olympic Games in August.  The Web site offered support to hepatitis B virus (HBV) patients, and it also informed patients about their rights. Though about 95 million people live with HBV in China, discrimination against patients is widespread, HBV awareness is poor, and many believe the infection can be casually transmitted.  From 2005, government departments have been prohibited from barring applicants with HBV. "Still, today there are 20 different laws that contain articles that discriminate against [HBV] carriers," Lu said. For example, people with HBV cannot work as teachers, bus drivers or as department store shop assistants.  Under Lu's nonprofit Beijing Yirenping Center, 40 lawsuits have been filed on behalf of HBV patients since 2003, and 10 of the last 13 have been successful.  "Many people have told me the government doesn't want any 'noise,' either before or during the Olympic Games," said Lu. The shutdown of the Web site "has caused a lot of anger among the HBV community," he said, "toward the Games, the government and the [Communist] Party." Some expressed their frustration at the popular Tianya Web site.  The Olympics is making it difficult for all non-governmental organizations, said Nicholas Bequelin of the Human Rights Watch Hong Kong office. "People pointing to a defect in the public health system, or issues of discrimination" would annoy the government, he said.
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Notes on “Approach to Managing the Pregnant Woman With Chronic Hepatitis B and Detectable Viral Load?” William F. Balistreri, from Medscape Gastroenterology, Ask the Experts about Liver Disease, Posted 07/09/2008

Question: Should pregnant women with chronic hepatitis B with detectable viral load be treated with antiviral agents during pregnancy to decrease the risk for transmission to the baby?

Response:

Let me first frame the question -- what problem are we trying to solve? Infection with hepatitis B virus (HBV) in infancy or early childhood often leads to persistent infection, as evidenced by the fact that in countries with a high prevalence of chronic hepatitis B, perinatal transmission from mother to infant accounts for the majority of cases.[1] Approximately 90% of untreated infants born to mothers positive for hepatitis B e-antigen (HBeAg) will develop "immune tolerance." This is traditionally explained by transplacental transfer of viral antigens, which induces a specific nonresponsiveness of helper T cells to HBeAg and hepatitis B core antigen (HBcAg). Spontaneous HBeAg seroconversion (to anti-HBe positive) may develop with time, but liver damage may occur during the process of immune clearance of HBeAg.[1] Screening for maternal hepatitis B surface antigen (HBsAg), followed by administration of HBV vaccine and hepatitis B-specific immunoglobulin (HBIG) to the newborn within 24 hours of birth, is the most effective way to prevent perinatal HBV infection. The first universal HBV immunization program in the world was launched in Taiwan over 20 years ago; thus, the HBV infection rate and the incidence of hepatocellular carcinoma and fulminant hepatitis in children have been reduced.[1] Current published guidelines state that newborns of HBV-infected mothers should receive passive-active immunoprophylaxis with HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series.[2] This strategy is approximately 95% effective in reducing the risk for HBV transmission, but is less effective in HBeAg-positive mothers with very high serum HBV DNA levels. Maternal serum HBV DNA concentrations>107 IU/mL have been associated with a 5% to 10% failure of immunoprophylaxis.[3]

In highly viremic HBsAg-positive mothers, reduction of viremia in the last month of pregnancy may be an effective and safe measure to decrease the risk for failure of prophylaxis. Two separate strategies have been used to reduce the "viral burden" during pregnancy: prenatal HBIG administration and specific antiviral therapy. However, prophylactic therapy is complex, controversial, and not well studied.

HBIG: In a prospective randomized controlled trial, Xu and colleagues[4] administered either placebo or HBIG (200 IU intravenously every 4 weeks for 3 times) from the 28th week of gestation in HBsAg-positive mothers. There was a significant difference in the rate of HBeAg and HBV DNA positivity in the newborns (positivity rates: 25% in those born to mothers who received HBIG vs 83% in placebo recipients). In addition, the HBV DNA load of newborns was lower than that of their treated mothers and significantly lower than that of untreated controls.

Specific Antiviral Therapy: The only oral antiviral agent studied in this setting is lamivudine. When given in the last 4 weeks of pregnancy, lamivudine has been shown to reduce high-level viremia. van Zonneveld and colleagues[5] treated 8 highly viremic (HBV DNA>1.2 x 109 IU/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. Children (n = 24) born to untreated HBsAg-positive mothers with similar HBV DNA levels served as controls. All children received passive-active immunization with HBIG and HBV vaccine at birth and were followed up for 12 months. Seven of the 8 lamivudine-treated mothers had a decrease in their serum HBV DNA concentrations. One of the 8 children (12.5%) in the lamivudine group remained HBsAg- and HBV DNA-positive at the age of 12 months; all other children seroconverted to anti-HBs. In the untreated control group, perinatal transmission occurred in 7 of 25 children (28%). Other studies have evaluated the efficacy and safety of lamivudine for the treatment of chronic hepatitis B in pregnancy.[6-9] Li and colleagues[6] investigated the effect of lamivudine vs HBIG on HBV intrauterine transmission. HBsAg-positive pregnant women (n = 56) were given either 200 IU of HBIG intramuscularly every 4 weeks from the 28th week of gestation, or lamivudine (n = 43) 100 mg orally every day from the 28th week of gestation until the 30th day after labor. Subjects in the control group (n = 52) received no specific treatment. The rate of neonatal HBV infection was significantly lower among those patients receiving HBIG (16%) or lamivudine (16%) compared with those in the control group (33%; P  .05). No side effects occurred in the pregnant women or their newborns.

Lamivudine therapy may not prevent perinatal transmission of HBV infection in every newborn. Kazim and colleagues[8] reported the development of chronic HBV infection in a newborn despite suppression of HBV DNA to undetectable levels in the mother by prolonged lamivudine therapy. The newborn received neonatal vaccination and treatment with HBIG, yet had still had increased aminotransferase levels and was persistently positive for HBV DNA. On HBV DNA sequencing, complete sequence homology and a similar precore mutation was found in the mother and child, indicating vertical transmission.

A major question, in addition to efficacy, is, of course, safety. Again, to place the issue in perspective, it is important to remember that hepatitis B during pregnancy does not increase maternal morbidity or mortality or the risk for fetal complications.[1,3] In addition, the use of lamivudine did not directly lead to adverse events in the infected mothers. However, in one study, when compared with untreated women, there was a significant increase in liver disease activity after delivery in those patients treated with lamivudine.[9] And what about the potential effects of these drugs on the fetus? Lamivudine, adefovir, and entecavir are designated as category C drugs, which indicates that these drugs are capable of exerting teratogenic or embryocidal effects in animals; however, there are no controlled studies in humans.[3] With the emergence of additional nucleos(t)ide analogs (telbivudine and tenofovir [currently undergoing review by the FDA for use in chronic hepatitis B], which are category B drugs), studies are needed to evaluate their role in reducing viral burden during pregnancy.[3,10]

The bottom line: The strategy of using antiviral therapy to reduce viremia during pregnancy to decrease the risk for transmission of HBV to the baby is reasonable. However, at present, the data are not sufficient to make broad recommendations. The approach should be evaluated in a large controlled trial using new antiviral agents in combination with HBIG to prevent intrauterine HBV infection.
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Notes on “Hepatitis B Patients Face Broad Discrimination in China. Ostracized and unable to secure jobs, victims turn to a support web site, now banned by the communist regime.” Wu Xue'er, Epoch Times Staff Jul 04, 2008

Yirenping Center General Coordinator Lu Jun speaks in Hong Kong on the government's interference with the forum. (Wu Xue'Er/The Epoch Times)  HONG KONG—Having passed a civil service exam, a Zhejiang University graduate was subsequently rejected when he was found to have hepatitis B. In a fury, he killed the recruiting official.  It was 2003, and he had graduated from one of China's finest schools. The court found him guilty of murder and handed down the death penalty. He tore the court document stating his sentence into pieces.  A Ph.D. from Xiamen University was unable to secure a job when he was found to be a carrier of hepatitis B. He ended his life by hanging himself in a bathroom.  Many such tragedies occur in China every year, according to Lu Jun, coordinator of the Yirenping Center in Beijing and host of the "Liver and Gallbladder Care" Web site.  Hepatitis B patients face serious discrimination in China. Lu says that such discrimination leads directly to hatred, social exclusion, and tragedies such as these. People with hepatitis B have difficulty finding employment or attending school.  Eighty percent of foreign companies with branches in China also refuse to hire people with hepatitis B.  It is estimated that approximately 100 million people in China carry the hepatitis B virus. Since 2003, many have connected through the "Liver and Gallbladder Care Forum" (bbs.hbvhbv.com).  The forum has become a home for hepatitis B patients who seek information and basic human rights. It enables them to fight discrimination, including organizing anti-discrimination lawsuits against government agencies.  Instead of supporting the forum, however, Lu says that the Chinese communist regime has responded by suppressing and banning it. This has led to much anger and disappointment among those affected.  Lu identifies three factors that have contributed to the widespread discrimination against hepatitis B patients.  First, a lack of government regulation of advertising practices used by pharmaceutical companies resulted in exaggerated claims of the infectious nature of hepatitis B. Though their intention was to increase sales, their tactics led the public to fear and misunderstand the disease.  Second, the government process for hiring civil service employees included screening for hepatitis B beginning in 1997. Many private enterprises followed suit, rejecting hepatitis B patients from employment.  Third, laws have been passed banning hepatitis patients in China from holding certain jobs, including janitor, elevator operator, cashier, schoolteacher, and all jobs in the food industry. These laws, over 20 in number, have deprived hepatitis B patients of their basic rights.  
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Notes on “The case for combination antiviral therapy for chronic hepatitis B virus infection,” Kathryn L Nash, THE LANCET INFECTIOUS DISEASES, Volume 8, Issue 7, July 2008, Pages 444-448

Summary:  The treatment of hepatitis B virus (HBV) infection has been revolutionised in the past decade by the increased availability of effective antiviral agents. Many studies have shown the benefits of single agent therapy, but there is an alarming and rising rate of viral resistance, and clear evidence that viruses that harbour resistant mutations can cause liver disease and death. Current national guidelines for the treatment of HBV recommend a programme that starts with monotherapy, followed by sequential monotherapy or add-on therapy for those infections in which mutations have arisen. Very few studies starting with combination therapy have been undertaken, so there is little evidence of the clinical benefit of this approach to treatment. The studies that have been done have been short term and have concentrated on clinical parameters rather than virological resistance, which is likely to be the key determinant in the longer term. We argue that we should not wait for the evidence to use combination therapy for the treatment of HBV, since such trials may never be done and it would take several years for a benefit to become apparent. In the meantime, multidrug-resistant strains continue to hinder HBV control.
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Notes on “Strategies in the Management of Chronic Hepatitis B  CME,” Deanna L. Oliver, BS   Tarek Hassanein, MD, FACP, FACG, Hepatitis B: Advances in Screening, Diagnosis, and Clinical Management -- Volume 2, 2008.

History of Present Illness

A 32-year-old Korean-American man who worked as a software engineer came to the clinic in July 2002 complaining of fatigue, low energy, and right upper quadrant discomfort. The discomfort was dull in character and radiated to the back. He denied nausea, vomiting, and diarrhea. He reported weight loss of 30 pounds in 8 months. He also complained of polyuria, polydipsia, and dry mouth. The patient was diagnosed 1 year ago with non-insulin-dependent diabetes mellitus and was being treated with glipizide. However, he was not adherent to his therapy. He admitted to smoking a pack of cigarettes per day and to regularly drinking alcoholic beverages. His family history was significant for hepatitis B infection in one brother and diabetes mellitus in both parents. His physical examination showed no peripheral signs of chronic liver disease and no hepatomegaly, splenomegaly, or ascites.

Hepatitis B virus (HBV) is highly endemic in areas such as Southeast Asia and Africa, and individuals from regions with high or intermediate prevalence of HBV should be offered screening.[1] Other populations who would benefit from screening include individuals of Asian descent and close contacts of HBV-infected individuals.[1]

This patient was an Asian American who had a family history of hepatitis B. Accordingly, he should be screened for HBV infection. The standard serologic markers used to screen for HBV include hepatitis B core antibody (anti-HBc), hepatitis B surface antigen (HBsAg), and hepatitis B surface antibody (HBsAb). See Table 1.[1,2] HBcAb positivity indicates prior exposure and infection with HBV; HBcAb-IgG class indicates previous exposure, whereas the HBcAb-IgM class defines acute infection or viral reactivation and should be screened for in patients with jaundice and signs of acute hepatitis. The presence of HBsAg positivity for more than 6 months defines chronic infection, whereas HBsAb indicates immunity.

Table 1. Screening for Hepatitis B Infection

3 tests:
   Hepatitis B core antibody (IgG HBcAb)
   Hepatitis B surface antigen (HBsAg)
   Hepatitis B surface antibody (HBsAb)


Initial Evaluation
The patient underwent the following laboratory investigations:

Complete blood count (CBC) with differential and coagulation parameters

Comprehensive metabolic panel, gamma-glutamyl transferase (GGT), total protein, uric acid, iron, iron binding capacity, ferritin, lipid panel, thyroid-stimulating hormone (TSH), alpha-fetoprotein (AFP), and glycosylated hemoglobin

Viral serologies

Hepatitis B virus (HBcAb, HBsAg, HBsAb)

Others: hepatitis A virus antibody (HAV Ab), hepatitis C virus antibody (HCV Ab), HIV Ab

Autoantibodies: Antinuclear antibodies (ANA), and anti-smooth muscle antibody (ASMA)
The patient also underwent ultrasound examination of the abdomen and liver.

Results of key initial laboratory investigations are shown in Table 2.

Table 2. Results of Initial Laboratory Investigations

Test Comment
Serologies
HBcAb: positive
HBsAg: positive
HBsAb: negative Indicates patient has chronic hepatitis B infection
CBC
WBC: 5.8 103/mm3
Hemoglobin: 14.5 g/dL
Platelets: 154 x 103/mm3 Low platelet count

Chemistries
Alanine aminotransferase (ALT): 154 IU/L
Aspartate aminotransferase (AST): 261 IU/L
Alkaline phosphatase: 85 IU/L
Glucose: 198 mg/dL
AFP: 11 ng/mL
Total bilirubin: 1.1 mg/dL
Creatinine: 0.8 mg/dL
Total protein: 7.0 g/dL
Albumin 4.7 g/dL
Globulin: 2.3
ANA: negative
ASMA: negative Indicates active liver inflammation (ALT/AST high), normal synthetic liver functions (albumin, total bilirubin normal), diabetes (fasting glucose), no renal dysfunction (normal creatinine), and no autoimmune hepatitis (negative ANA and ASMA)
Ultrasound
Liver measured 14.4 cm by long axis; echogenicity was within normal limits; spleen was normal in size; no ascites Indicates no signs of portal hypertension

Follow-up Visit
The patient returned for his first follow-up visit 4 weeks later. At this time, he was diagnosed with chronic hepatitis B infection in addition to his diabetes mellitus type 2.

Additional serologic and virologic work-up was ordered to fully characterize the status/type of chronic active hepatitis B. Specifically, the patient was tested for hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), and antibody to hepatitis D virus (HDV Ab), and viral load (HBV DNA) was determined. In addition, glycosylated hemoglobin was measured. See Table 3.

Table 3. Additional Tests for Characterizing Status of Chronic Hepatitis B Infection

3 tests:
   HBeAg
   HBeAb
   HBV DNA

Patients with chronic hepatitis B infection (HBsAg -positive) present in different immune stages. The presence of HBeAg and HBeAb, while the virus is replicating at high levels (HBV-DNA> 104 or 105 IU/mL) in the presence of elevated ALT due to viral-induced hepatitis, are the benchmarks for considering antiviral therapy. Accordingly, any patient with HBsAg positivity should be further classified according to their HBeAg, HBeAb, and HBV DNA titer (Table 4).[3] In addition, any patient with chronic hepatitis B infection should be screened for HDV infection as well, as it might modify the therapy of an HBV-infected patient.

Results of these additional laboratory investigations revealed the following:

HBeAg: negative; HBeAb: positive; HBV DNA: positive; 7.5 million copies/mL (1.5 million IU/mL)

HDV Ab: negative

Glycosylated hemoglobin: 5.3%

ALT: 130 IU/L; AST: 199 IU/L
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Patients chronically infected with HBV do not always remain in the same phase of infection. The interaction between the virus and the immune system of the patient affect viral replication, the extent of liver injury, and the patient's symptomatology. Over the lifetime of the infection, patients who perinatally acquired HBV can present with one of 4 main phases of infection (Table 4).[3] Early in the course of infection, when the patient is still an infant, the immune system does not mount a reaction against the viral infection. During that time, the patient is considered to be in the immune-tolerant phase, which can last for decades. However, some patients develop fluctuations in their serum aminotransferases, usually associated with active inflammation on liver biopsy. This phase is considered the HBeAg-positive phase and is characterized by HBeAg positivity. Although HBV DNA levels fluctuate, they remain significantly elevated and is associated with elevated aminotransferases. In this phase, there is immune-mediated lysis of the HBV-infected hepatocytes. In most patients this phase precedes another phase in which HBeAg loss occurs and HBeAb develops (seroconversion). As patients move out of this phase, they may progress to the inactive carrier state or the HBeAg-negative state. The inactive carrier state is characterized by HBeAg negativity, low viral titer or HBV DNA negativity, normal aminotransferases, and the absence of active inflammation on liver biopsy. The HBeAg-negative state is characterized by HBeAg loss, but viral replication continues, albeit at a lower level than it was in the HBeAg-positive phase of infection. This phase is also associated with elevated aminotransferases and active inflammation on liver biopsy. Although patients may remain in one phase for the life of the infection, movement across phases is more common. It is rare that a patient spontaneously loses HBsAg (seroclearance) and develops HBsAb. These patients have undetectable HBV DNA, normal liver enzymes, and no active inflammation on liver biopsy.[3]

Table 4. Phases of Chronic Hepatitis B[3]

Phases Laboratory Findings
Immune tolerant HBsAg (+); HBeAg (+);HBV DNA> 20,000 IU/mL; normal ALT
HBeAg-positive HBsAg (+); HBeAg (+); HBV DNA> 20,000 IU/mL; elevated ALT
Inactive carrier HBsAg (+); HBeAg (-); HBV DNA (-) or  2000 IU/mL; elevated ALT


Diagnosis
The patient was diagnosed with chronic active hepatitis B infection (HBsAg positive> 6 months); phase: HBeAg negative with high viral replication (HBV DNA> 2000 IU/mL and elevated ALT [130 IU/L]).

Treatment
In some patients, chronic HBV infection can lead to chronic progressive hepatitis, fibrosis, and cirrhosis. Patients who develop cirrhosis are at high risk for liver decompensation and death. In addition, chronic HBV infection is the main cause of liver cancer worldwide.[4] Chronically infected patients could develop hepatocellular carcinoma even in the absence of liver fibrosis or cirrhosis. Treatment of HBV infection is essential and involves either boosting the immune system through the use of immune modulators or using oral antiviral agents to suppress viral replication and allow the immune system to control further viral replication when therapy ends. The more commonly applied therapeutic approach is oral antiviral therapy to suppress viral replication and decrease or eliminate the chronic inflammatory process in the liver. This normalizes aminotransferases, regresses fibrosis, and possibly decreases the risk of developing hepatocellular carcinoma. Some patients require long-term treatment with the oral antiviral agents.[4] The FDA has approved a number of medications for patients with chronic actively replicating hepatitis B virus who present with increased aminotransferase levels and/or histopathologic hepatitis (Table 5). These include interferon alfa-2b, pegylated interferon alfa-2a, and the oral antiviral agents lamivudine (nucleoside analog), adefovir (nucleotide analog), entecavir (nucleoside analog), and telbivudine (nucleoside analog).

Table 5. Therapies for Hepatitis B

Therapy Comments
Interferon alfa-2b
(daily or 3-times-weekly injection) Immune modulator
Pegylated interferon alfa-2a
(once-weekly injection) Immune modulator
Lamivudine First nucleoside analog used in the treatment of HBV; not
recommended as initial therapy due to high risk for resistance
Adefovir, entecavir, telbivudine* First-line viral suppressors
Tenofovir** Under FDA review for likely approval in 2008; first-line therapy
following licensure (will likely replace adefovir)
Emtricitabine**, clevudine** In clinical trials

*Alternative option
**The US Food and Drug Administration has not approved this medication for
this use.
Our patient had 3 of the major criteria for therapy (Table 6). He is
HBsAg-positive and HBeAg-negative, with high viral replication and elevated
serum ALT. Therefore, he was a candidate for antiviral therapy.

Table 6. Whom to Treat (3 Criteria)

HBsAg positive
HBV DNA> 2000 IU/mL
Elevated serum ALT or normal ALT and chronic active hepatitis on liver biopsy

The patient was started on lamivudine 100 mg/day (standard treatment in 2002)[5] and was encouraged to stop smoking and to minimize his alcohol intake. He was advised to adhere to a diabetic diet and continued treatment for his diabetes (glipizide).

3-Month Follow-up Visit
At 3 months, the patient had no complaints, was feeling well, and reported that his energy had improved. His HBV DNA level was < 50 IU/mL and his serum ALT and AST levels were 34 IU/L and 23 IU/L, respectively.

6-Month Follow-up Visit
At 6 months, the patient returned for evaluation. He continued to feel well and had no symptoms. His HBV DNA level was still < 50 IU/mL, and he was HBeAg-negative and HBeAb-positive. His serum ALT and AST were 18 IU/L and 20 IU/L, respectively.

12-Month Follow-up Visit
At 12 months, the patient was doing well, but was diagnosed with the metabolic syndrome (hypertension, hyperlipidemia, and diabetes mellitus). His primary care provider started him on lisinopril, ezetimibe, and gemfibrozil.
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His laboratory studies revealed the following:

Glycosylated hemoglobin: 5.8%
HBV DNA: 62,500 IU/mL
HBsAg (+), HBsAb (-), HBeAg (-) and HBeAb (+)
AFP: 6 ng/mL
ALT: 40 IU/L
AST: 35 IU/L
Total bilirubin: 0.9 mg/dL
Creatinine: 0.9 mg/dL
Blood urea nitrogen: 25 mg/dL

Evaluation of 12-month follow-up. The patient was receiving treatment for metabolic syndrome. His HBV DNA became positive after being undetectable for more than 1 year while on lamivudine.

On the basis of these findings, we suspected that the patient had a virologic breakthrough most probably as a result of development of the YMDD mutation and resistance to lamivudine. At this point in management, adefovir 10 mg/day was added to continued lamivudine therapy.

Lamivudine Resistance
Currently available antiviral agents for chronic hepatitis B are either nucleoside (lamivudine, entecavir, telbivudine) or nucleotide (adefovir, tenofovir**) analogs. Using oral antivirals requires long-term therapy (and in most patients, indefinite treatment) to maintain viral suppression. Long duration of therapy increases the risk for antiviral drug resistance. Lamivudine resistance occurs in approximately 20% of patients after 1 year and in up to 65% after 5 years.[6] The characteristic mutations occur in the YMDD motif of the HBV DNA polymerase. When this mutation occurs, the sensitivity to lamivudine decreases greater than 100-fold. Lamivudine-resistant mutations confer cross-resistance to other nucleosides, such as emtricitabine,** telbivudine, and clevudine.** They also decrease susceptibility to entecavir. The main approach to managing lamivudine resistance is to add adefovir or tenofovir (when approved) to ongoing lamivudine therapy.[7]

Until now, the recommended approach to managing HBV infection has involved the use of monotherapy, which is associated with a high risk of developing drug resistance. It has been recommended that patients should be closely monitored for virologic and biochemical response every 3-6 months. When viral breakthrough occurs, the mutant virus replicates, and its titer increases; this is then followed by an increase in aminotransferase levels (biochemical breakthrough) and histopathologic changes on liver biopsy.[2,7]

Strategies for the Management of Drug-Resistant HBV Infection Close follow-up allows for early detection of viral breakthrough and implementation of appropriate management strategies (Table 7) before the patient develops biochemical breakthrough and histopathologic deterioration.[1,2,7]

Table 7. Potential Management of HBV Antiviral Drug Resistance[1,2,7]

Resistance to HBV Antivirals Strategy
Lamivudine Add adefovir or tenofovir**or switch to tenofovir/emtricitabine**
Adefovir Add lamivudine or telbivudine or add/switch to entecavir if not prior
lamivudine resistance or switch to tenofovir/emtricitabine**
Telbivudine Add adefovir or tenofovir** or switch to tenofovir/emtricitabine**
Entecavir Switch to or add adefovir or tenofovir** Switch to
emtricitabine/tenofovir**

**Not currently approved by US FDA
Continued Management (2008)
Since mid-2003, the patient has been on lamivudine 100 mg daily in combination with adefovir 10 mg daily. His current laboratory values are as follows:

ALT: 28 IU/L
AST: 32 IU/L
HBV DNA: < 29 IU/mL
HBsAg: positive
HBsAb: negative
HBeAg: negative
HBeAb: positive.
Platelets: 189 x 103/mm3
AFP: 5 ng/mL
Total bilirubin: 1.1 mg/dL
Albumin: 4.8 g/dL.
Cholesterol: 161 mg/dL
Serum triglycerides: 136 mg/dL
High-density lipoprotein: 57 mg/dL
Low-density lipoprotein: 77 mg/dL
Glycosylated hemoglobin: 6.6%

Long-term Management Plan
The patient continues his clinic visits for follow-up of his HBV infection at 6-month intervals, during which time he undergoes laboratory work-up to assess his liver enzyme levels and serum HBV DNA. He undergoes biannual screening for hepatocellular carcinoma mainly with ultrasound examination. Serum AFP as a single test for hepatocellular carcinoma has lost favor, although it is commonly done in conjunction with an ultrasound of the liver.[8-10]

Conclusion
When screening, diagnosing, and managing hepatitis B infection, clinicians should always consider the "rule of 3's":

3 tests to screen: HBcAb, HBsAg, HBsAb


3 tests to diagnose: HBeAg, HBeAb, HBV DNA


3 findings to contemplate therapy:


HBsAg positivity and


HBV DNA ™ 2000 IU/mL (if HBeAg negative) or ™ 20,000 IU/mL (if HBeAg positive), and


Elevated ALT or normal ALT and a liver biopsy showing chronic active hepatitis


3 findings indicating when to stop treatment of oral antivirals: HBV DNA undetectable, HBsAg-negative, and HBsAb-positive (the stopping rules apply for all types of HBV, and they are rarely achievable) Patients with chronic hepatitis B, in any of the various phases of the infection, require close observation and frequent testing to initiate treatment and to monitor response to therapy. Failure to respond after the first 6 months of treatment (primary treatment failure), or virologic breakthrough after achieving initial response (secondary treatment failure), requires adding another agent to the initial therapy or switching therapies. Lamivudine resistance is very common, and patients who continue to use lamivudine should be closely monitored to detect any genotypic mutations. They should be managed by adding either adefovir or tenofovir** before they develop biochemical breakthrough and lose the histopathologic improvement that they gained from previous therapy. Currently, lamivudine is no longer recommended as initial therapy due to the high rate of resistance. The oral antiviral drugs with a high genetic barrier to resistance and/or high potency (eg, entecavir or tenofovir) are generally recommended as initial treatment.[1,2] The current strategy for managing the development of resistance to any monotherapy involves adding a second drug that is not cross-resistant with the first (eg, adding a nucleotide drug when resistance to a nucleoside agent is detected, and vice versa; Table 7).
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Update on Hepatitis B Management, 2008.

Peginterferon alfa-2a in HBeAg-Negative Chronic Hepatitis B

Patrick Marcellin, MD: With hepatitis B, we have 2 treatment strategies: peginterferon alfa or nucleos(t)ide analogues. The advantage of peginterferon alfa is that when it works, its effects are durable and it is associated with a high rate of hepatitis B surface antigen (HBsAg) suppression. The disadvantages are its subcutaneous administration, adverse effects, and relatively low overall efficacy rate. Advantages of nucleos(t)ide analogues are ease of administration (1 pill daily), a good safety profile, and substantial efficacy with new agents, such as entecavir or tenofovir, with 70% to 90% of patients achieving undetectable HBV DNA.[1-4] The disadvantage of nucleos(t)ide analogues is that treatment must be continued for many years—possibly lifelong—and the rate of HBsAg loss or seroconversion is very low. Let us being the discussion with 2 studies that look at the use of peginterferon alfa-2a inpatients with hepatitis B e antigen (HBeAg)–negative chronic hepatitis B. Worldwide, HBeAg negative infection is the predominant form of hepatitis B and is associated with high relapse rates.[5,6] In a previously published, randomized, controlled trial conducted by a group of which I was a member, the efficacy and safety of 48 weeks of peginterferon alfa-2a, lamivudine, or acombination of the 2 treatments were evaluated in 537 patients with HBeAg-negative chronic hepatitis B.[7] In that analysis, peginterferon alfa-2a was more effective than lamivudine at achieving sustained suppression of HBV DNA to < 400 copies/mL for 6 months after completion of treatment (19% vs 7%, respectively), with the combination of peginterferon alfa-2a plus lamivudine offering no additional benefit compared with peginterferon alfa-2a alone(20% vs 19%, respectively). Loss of HBsAg occurred in 12 patients receiving peginterferonalfa with or without lamivudine vs none receiving lamivudine alone. Forty-two of the original 54 study centers participated in a long-term observational follow-up of patients. In the current analysis presented at the European Association for the Study of the Liver (EASL) in Milan, Italy, we evaluated long-term response and relapse rates 4 years after completion of treatment in 230 patients who received peginterferon alfa-2a with or without lamivudine and 85 patients who received lamivudine alone.[8] Patients entering the long-term study who had received lamivudine only were more likely to have achieved an end-of treatment response at Week 48 than those who received peginterferon alfa-2a with or without lamivudine. However, by a modified intent-to-treat analysis, significantly more patients had HBV DNA < 400 copies/mL at 4 years after end of treatment in the group who received peginterferon alfa-2a with or without lamivudine compared with those treated with lamivudine alone (17% vs 7%, respectively; P = .042). Most interestingly, the rate of HBsAg clearance increased over time after end of treatment, reaching 11% of patients in the peginterferon alfa-2a with or without lamivudine group at 4 years after end of treatment compared with 2% of patients who were treated with lamivudine alone (P = .021).These findings indicate that in 17% of patients who respond well to peginterferon alfa-2a and achieve HBV DNA < 400 copies/mL, the response is usually sustained and a increasing number of those patients (66% at 4 years) achieves HBsAg loss, which is considered to be the clinical cure of hepatitis B. The other three quarters of patients do not respond well to treatment or relapse and, in those cases, should receive alternative treatment such as nucleos(t)ide analogues because previous interferon exposure does not decrease the chance of response to these drugs. This message supports the continued inclusion of peginterferon alfa treatment as a first-line option for some patients, as detailed in many international guidelines. Clinicians must weigh the advantages and disadvantages of peginterferon vs nucleos(t)ide analogues. I do not think there is any conflict between the 2 strategies, but we must learn which strategy is best for individual patients.

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Peginterferon has several unique attributes that warrant consideration of its use as a first-line therapy for chronic hepatitis B. HBeAg-positive patients without cirrhosis who have genotype A infection, especially if associated with relatively low levels of viremia and activenecro inflammation on liver biopsy, may represent ideal candidates for consideration of peginterferon as first-line therapy. I have also found peginterferon an attractive option in women of childbearing age who wish to pursue a finite course of therapy and are concerned about possible teratogenic risks with nucleos(t)ide agents.

Predicting Responses to Peginterferon alfa-2a

Patrick Marcellin, MD: Based on these results, the next important question is how to identify the approximately 25%of patients who will respond well to peginterferon. To investigate this important issue, Brunetto and colleagues[9] evaluated the association between HBsAg decline on treatment and long-term HBsAg clearance in 315 patients from the same cohort (Magnitude of HbsAg Decline on Treatment Predicts Posttreatment HBsAg Clearance Following Peginterferon alfa-2a–Based Therapy). There was a clear association between reductions in serum HbsAg levels during treatment and sustained posttreatment HBsAg clearance. Two predictors of HBsAg loss following peginterferon-based therapy were identified: achieving HBsAg  2 log10 IU/mL during therapy. HBsAg clearance was seen in 42% to 52% of patients achieving these on-treatment reductions in HBsAg.

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: The approximately 50% rate of HBsAg clearance among patients achieving these HbsAg reduction on therapy is very high, and if these results are confirmed, HBsAg decline may become a useful marker. The authors proposed measuring quantitative HBsAg at baseline and during therapy, perhaps at Week 24. At that point, one might consider stopping therapy inpatients not achieving an adequate rate of HBsAg decline. This is based on the concept of the 24-week milestone used for assessing response to several of the oral agents.[10]
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Norah Terrault, MD, MPH: HBsAg titer tests are not currently commercially available in the United States. However, that would presumably change if this association is confirmed and becomes important in predicting response to peginterferon.  It would be of particular interest if the investigators had been able to identify baseline predictors of HBsAg decline, which might allow us to identify a target group who would respond well to peginterferon alfa treatment and avoid the unnecessary 24-48 week treatment in patients who are unlikely to achieve a response to this treatment. It would also be particularly helpful if the ideal duration of peginterferon alfa treatment in HBeAg-negative patients could be better defined as this issue is not currently clear.

Patrick Marcellin, MD: In a related abstract, Brunetto and colleagues[11] also evaluated the association between HBsAg level reduction and HBV DNA level at end of treatment. Among patients receiving peginterferon, the mean decline in HBsAg level from baseline to Week 48 was significantly greater in patients with HBV DNA ≤ 400 copies/mL at Week 72 vs those with HBV DNA > 400copies/mL at Week 72 (1.077 vs 0.263 log10 IU/mL, respectively; P < .001). This relationship only held true for peginterferon because HBsAg levels did not decline with lamivudine, regardless of the degree of HBV DNA suppression.

Tenofovir vs Adefovir in Chronic Hepatitis B

Patrick Marcellin, MD: Updates on 2 pivotal large, randomized, controlled trials comparing tenofovir vs adefovir in treatment-naive patients with chronic hepatitis B were presented at EASL. Study 102 enrolled375 patients with HBeAg-negative chronic hepatitis B (Rapid, Persistent HBV DNA Suppression With Tenofovir Treatment in HBeAg-Negative Chronic Hepatitis B)[12] whereas Study 103 enrolled 266 patients with HBeAg-positive chronic hepatitis B (Continued Efficacy With Tenofovir Through Week 72 of Therapy in HBeAg-Positive Patients).[13] In both studies, patients were randomized to 48 weeks of tenofovir or adefovir; after 48 weeks, all patients on adefovir were switched to tenofovir regardless of response to adefovir. Forty-eight–week data from these studies were previously presented at the 2007 Annual Meeting of the American Association for the Study of Liver Diseases, in which superior potency with tenofovir was demonstrated at Week 48 in both HBeAg-positive patients (A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HbeAgpositive chronic hepatitis B (CHB)[1] and HBeAg-negative patients (A randomized, doubleblind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB)).[2] Tenofovir was associated with HBV DNA levels< 400 copies/mL at Week 48 in 93% of HBeAg-negative patients and 76% of HBeAg-positive patients (compared with 63% of HBeAg-negative and 13% of HBeAg-positive patients treated with adefovir). This high rate of undetectable HBV DNA at 48 weeks is comparable with that seen with entecavir.[3,4] Both tenofovir and adefovir were associated with biochemical responses and histologic improvement. Based on these results, tenofovir was recently approved for the treatment of chronic hepatitis B virus (HBV) infection in Europe.

The updated analyses present at EASL provide an additional 6 months of follow-up since the previous reports and also encompass 24 weeks of tenofovir therapy in patients who initially received 48 weeks of adefovir. Among the patients initially randomized to tenofovir, the investigators showed that the proportions with HBV DNA < 400 copies/mL were maintained in91% of HBeAg-negative patients and 79% of HBeAg-positive patients between Week 48 and Week 72. No cases of resistance were noted in HBeAg-positive or HBeAg-negative patients, and no new safety findings were reported. Although there had been some concern about the potential for nephrotoxicity, this was not observed at a significant rate. Importantly, rates of viral suppression increased among patients who initially received adefovir for 48 weeks and then switched to tenofovir. By Week 72, 88% of HBeAg-negative patients and 76% of HBeAg-positive switch patients had HBV DNA < 400 copies/mL, which was not significantly different from the rates of suppression observed in patients who were treated with tenofovir from the study outset.

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: The high rate of response to tenofovir in patients initially treated with adefovir is an important finding from these extended studies, especially for those patients who are suboptimal responders to adefovir after 48 weeks of treatment. In HBeAg-negative patients, there were no significant differences in rates of alanine aminotransferase (ALT) normalization or adverse events between those assigned to continuous tenofovir vs those who switched from adefovirto tenofovir. In HBeAg-positive patients, there were no significant differences in HBeAg loss and seroconversion rates between these groups, but higher percentages of patients who received continuous tenofovir vs those who switched therapy achieved normal serum ALT levels at Week 72 (77% vs 61%, respectively; P = .014) and HBsAg loss at Week 64 (5% vs0%, respectively; P = .004). Otherwise, it appears that exposure to 48 weeks of adefovir therapy before the switch to tenofovir did not place these patients at any particular disadvantage in follow-up to date. The rate of HBsAg loss was notable in the HBeAg-positive study. Among these patients randomized to tenofovir from the outset, rates of HBsAg loss were 3% at Week 48[1] and, as mentioned, 5% at Week 64. With the exception of interferon alfa–based treatments, no other treatment has achieved comparable rates of HBsAg loss. Rates of HBsAg seroconversion among patients receiving tenofovir were 1% at Week 48[1] and 2% at Week 64, which are quite remarkable. By contrast, none of the HBeAg-positive patients initially treated with adefovir had HBsAg loss or seroconversion. It will be important to confirm these results to demonstrate whether this is a true treatment effect of tenofovir or simply a chance occurrence.
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Patrick Marcellin, MD: I agree that longer-term follow-up is necessary to see if this phenomenon is confirmed. I was surprised that HBsAg loss was observed only in HBeAg-positive patients. One might expect itto occur in HBeAg-negative patients too, as has been observed with interferon alfa–based treatments.[7] I agree, however, that a 5% HBsAg loss rate is impressive and has not been demonstrated with any other nucleos(t)ide analogue. If these rates are confirmed in subsequent studies, that could provide an advantage for using tenofovir compared with other nucleos(t)ide analogues. Moreover, if it transpires that tenofovir induces HBsAg loss and seroconversion through a different mechanism of action from interferon-based therapy, that may provide a rationale for studying the combination of both drugs, with the goal of inducing HBsAg loss in as many patients as possible, rather than keeping patients on therapy all their lives.

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: It seems unlikely that simple differences in potency are sufficient to explain the phenomenon of HBsAg loss and seroconversion because although tenofovir was more potent than adefovirin these studies, comparable rates of HBV DNA suppression have been observed in separate studies with telbivudine or entecavir. Regardless of whether this observation is simply random chance or reflects some unique mechanism of action of tenofovir, this novel finding definitely bears watching closely.

Long-term Efficacy of Entecavir

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Several studies on the long-term efficacy of entecavir were presented at EASL. Leung and colleagues[14] presented 96-week data from the EARLY study of entecavir 0.5 mg/day vs adefovir 10 mg/day in 69 treatment-naive HBeAg-positive patients with high baseline HBVDNA of ≥ 108 copies/mL. The number of patients with data available at Year 2 was relatively small—29 for entecavir and 20 for adefovir—but the results were consistent with those from previous comparisons of these agents. At Week 12, the mean viral reduction from baseline was -6.23 log10 copies/mL with entecavir vs -4.42 log10 copies/mL with adefovir (P < .0001).The mean decrease in HBV DNA at Week 96 from baseline was -7.82 log10 copies/mL with entecavir vs -5.96 log10 copies/mL vs adefovir. Rates of undetectable HBV DNA for entecavir vs adefovir at Year 2 were 79% and 50%, respectively. Seroconversion rates of HBeAg were comparable (24% and 25%), and no virologic breakthroughs were reported in either arm. There were similar rates of any-grade adverse events in the entecavir and adefovir arms(83% vs 82%), but more grade 3/4 adverse events and treatment discontinuations occurred in the adefovir arm.

Patrick Marcellin, MD: Even though the number of patients was small, this head-to-head comparison of entecavir with adefovir confirms that adefovir has a less potent antiviral effect than entecavir, as was previously suggested by cross-study comparison of the pivotal studies of adefovir and entecavir.[3,4,15,16]In another small study, Mochida and colleagues[17] evaluated the safety and efficacy of entecavir 0.5 mg/day in 68 treatment-naive Japanese patients enrolled in 3 studies (ETV-047,ETV-053, and ETV-060) (Long-term Entecavir Treatment Safe and Effective in Japanese Treatment-Naive Chronic Hepatitis B Patients Through Year 3). The proportion of patients with HBV DNA < 400 copies/mL increased over time, reaching 87% after 3 years. Entecavir continued to show a high barrier to resistance, with a 1.7% cumulative rate of resistance or resistance with subsequent virologic breakthrough at Year 3. This study confirmed the findings from the pivotal studies. However, a general limitation of the pivotal studies was the difficulty in interpreting the exact incidence of entecavir resistance as the long-term follow-up of those studies (ETV-022) restricted the calculation to a subgroup of patients receiving therapy. It is, therefore, reassuring to have another independent long-term follow-up of patients on entecavir confirming the low rate of cumulative resistance. However, the number of patients in this analysis is small and the follow-up duration is currently only 3 years, whereas data from the pivotal studies through 5 years of follow-up have recently been presented.[18]

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I agree with Dr. Marcellin. Some have been critical of the resistance data from the long-term entecavir rollover treatment study because of the higher dose of entecavir used (1.0 vs 0.5mg) and the fact that not all treated patients in the pivotal trials entered the rollover long-term treatment study. However, the fact that the incidence of resistance in this study, albeit with smaller sample size, is very similar to that previously reported in the rollover study confirms the very low resistance risk with extended treatment with entecavir in nucleos(t)ide-naïve patients.
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Durability of HBeAg Seroconversion With Telbivudine or Lamivudine

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Two large pivotal phase III trials compared telbivudine 600 mg/day or lamivudine 100 mg/day over a 2-year period in a predominantly HBeAg-positive population. The GLOBE study enrolled 1367 patients from 20 countries,[19] whereas Study 015[20] was conducted in China and enrolled 332 patients. Poynard and colleagues[21] conducted a retrospective combined analysis of these 2 studies evaluating the durability of HBeAg loss and HBeAg seroconversion, which occurred during therapy in 1211 HBeAg-positive patients (HBeAg Seroconversion Sustained for 52 Weeks in Chronic Hepatitis B Patients Treated With Telbivudine or Lamivudine Following Consolidation Therapy). These patients were subsequently treated for ≥ 6 months with consolidation therapy followed by treatment discontinuation because of efficacy at the discretion of the investigator. The inclusion criteria for this analysis required patients to have received at least 1 year of therapy and to have had HBV DNA  104 copies/mL at the start of tenofovir therapy, of whom 93%were lamivudine experienced and 85% were adefovir experienced. Of 113 available genotypic analyses from serum samples, YMDD mutations were present in 61 patients (54%)at baseline and adefovir resistance was detected in 19 patients (17%). Overall, 85% of patients achieved HBV DNA undetectability. The percentage of patients achieving undetectable HBV DNA (< 400 copies/mL) with tenofovir was not significantly affected by the presence of genotypic lamivudine resistance at baseline, but was significantly decreased by either pretreatment with adefovir (P < .0001) or the presence of adefovir genotypic resistanceat baseline (P < .0001). The probability of achieving undetectable HBV DNA was 90% inpatients without adefovir resistance vs 30% in adefovir-resistant patients (P = .001),suggesting that tenofovir may have a limited role in adefovir-resistant patients.

Norah Terrault, MD, MPH: This study involved only 19 adefovir-resistant patients, so caution is warranted before drawing conclusions about the efficacy of tenofovir in this setting. In addition, the median duration of tenofovir therapy in patients who did not achieve undetectable HBV DNA was 11 months vs18 months for patients who did achieve undetectable HBV DNA, which was a significant difference (P = .002). Therefore, it is possible that more patients may achieve undetectability if treated for a longer duration. Another baseline factor associated with response in patients with genotypic adefovir resistance was the mean HBV DNA level at baseline, which was 3.3 x108 copies/mL in nonresponders vs 1.4 x 108 copies/mL in responders (P = .047).

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I do not think the small numbers involved necessarily invalidate these conclusions because the viral kinetic response curves from this study show the 2 groups separating out quickly over time, and therefore, there is no reason to think this would be different with larger numbers.

Norah Terrault, MD, MPH: I agree that separation in the viral response curves did occur early. However, it is difficult topredict how those curves might evolve with longer durations of therapy.
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Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I think another key issue is how tenofovir resistance is defined. At present, it is being reported that no signature mutation(s) for tenofovir resistance have been found. The investigators noted that polymorphisms are being selected for in some patients during therapy, but HBVDNA still decreases during tenofovir treatment. Therefore, the impact of those mutations on tenofovir resistance is unclear. Nevertheless, it is clear that the presence of signature mutations for adefovir was associated with a reduced rate of response to tenofovir, and so those mutations clearly confer reduced susceptibility to tenofovir.

Norah Terrault, MD, MPH: Although all the adefovir-resistant patients had documented adefovir resistance mutations, the investigators could not identify a specific mutation or pattern of mutations that was associated with a poor response and that could be, therefore, considered a tenofovir signature mutation or mutations. Even in the patients with adefovir resistance, there were no cases of virologic breakthrough observed.

Patrick Marcellin, MD: Despite the caveats of this study previously discussed, the results raise the possibility that a different potent analogue such as entecavir might be preferred in patients who developed resistance to adefovir. In vitro data support this strategy since viral strains resistant to adefovir show no cross-resistance to entecavir and less susceptibility to tenofovir.[24]

Norah Terrault, MD, MPH: Continuing our review of tenofovir use in nucleos(t)ide-experienced patients, Berg and colleagues[25] compared the safety and efficacy of tenofovir monotherapy vs coformulated tenofovir/emtricitabine in patients with persistent viremia following treatment with adefovir(Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBV-Infected Patients With Persistent Viremia on Adefovir). Coformulated tenofovir/emtricitabine iscurrently approved for the treatment of HIV and because emtricitabine has also been shown to also have efficacy against HBV, there is the potential to use a single tablet containing 2drugs with activity against HBV. Interestingly, however, there was no incremental benefit observed with the addition of emtricitabine to tenofovir, and there were no significant differences between tenofovir monotherapy and tenofovir/emtricitabine at Week 48 regarding the percentage of patients achieving HBV DNA < 400 copies/mL, normalization of ALT, or HBeAg seroconversion, and no difference in the mean reduction in HBV DNA levels.

One important aspect of the study was that the investigators analyzed the impact of adherence on treatment response. In an analysis in which both study arms were combined, there was a nonsignificant trend toward higher response rates in patients with high adherence vs low adherence (87% vs 71%, respectively; P = .15). This is what would be expected, but itwas good to see the numbers. To me, that was the most significant finding of this study.

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Of note, the slope of the viral suppression curve was clearly blunted in patients with preexisting adefovir resistance mutations (A181T or N236T), consistent with the previous study demonstrating reduced efficacy of tenofovir in adefovir-resistant patients. However, theoverall rates of suppression were similar.[23]

Patrick Marcellin, MD: All of these studies confirm data from in vitro studies regarding susceptibility of adefovirresistant viruses to other nucleos(t)ide analogues. These clinical observations are notsurprising since adefovir and tenofovir are structurally closely related drugs

Adefovir Plus Lamivudine in Lamivudine-Resistant HBV

Norah Terrault, MD, MPH: Lampertico and colleagues[26] evaluated the long-term safety and efficacy of adefovir/lamivudine combination therapy in 63 patients with lamivudine-resistant chronic hepatitis B (Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBVInfected Patients With Persistent Viremia on Adefovir). By a median follow-up of 57 months, more than 80% of patients achieved undetectable HBV DNA levels (< 35 copies/mL) and nearly all patients (90%) experienced ALT normalization. This study was not controlled but nevertheless touched on the important question of whether nucleos(t)ide analogue therapycan effectively reduce the risk of hepatocellular carcinoma. Data previously published by Liawand colleagues[27] suggest that treatment of cirrhosis does reduced the risk of hepatocellular carcinoma, but this study enrolled a more mixed population of whom 73% were cirrhotic. After a median follow-up of 24 months, 17 patients developed hepatocellular carcinoma, a higher number than would be predicted from Lau and colleagues[28] data in patients with similar rates of viral suppression. The investigators concluded that treating lamivudine-resistant patients by the addition of adefovir to ongoing lamivudine does provide clinical benefits and viral suppression, but the risk for hepatocellular carcinoma remains relatively high. The study population was relatively small—63 patients. Moreover, with a treatment duration of approximately 4 years, the lead time for liver cancer means that some of those patients may have developed cancer in the first or second year that then subsequently became detectable. It is therefore hard to interpret these data on hepatocellular carcinoma, although they do underscore the important message that providing antiviral treatment to a cirrhotic patient does not eliminate the risk of cancer.
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Norah Terrault, MD, MPH: Treatment of cirrhotics is associated with clinical benefits such as preventing progression to decompensation, but the benefit in terms of cancer reduction is uncertain. These patients clearly should continue to be monitored for hepatocellular carcinoma.

Patrick Marcellin, MD: We do not know well the mechanisms responsible for the occurrence of hepatocellular carcinoma in cirrhotic patients. Even if antiviral therapy inhibits HBV replication and decreases liver necroinflammation, the “precancer” cirrhotic lesions and persistent HBVinfection in the liver might explain the continuing risk for hepatocellular carcinoma. Largecohort studies with long follow-up are needed to determine the magnitude of the risk and for how long it persists.

Long-term Entecavir in Chinese Patients With Lamivudine-Refractory HBV

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Yao and colleagues[29] evaluated the long-term efficacy of entecavir monotherapy in 138Chinese patients with lamivudine-refractory chronic hepatitis B who enrolled in the ETV-056and ETV-050 studies (Increasing Rates of Virologic Suppression Through Year 3 of Entecavir Treatment in Chinese Cohort With Lamivudine Resistance). In ETV-056, patients received 12weeks of entecavir 1 mg daily or placebo followed by 36 weeks of open-label entecavir 1 mgdaily. A total of 141 patients from ETV-056 rolled over into ETV-050 and continued entecavir1 mg daily. These patients were relatively young (mean age: 35 years), 76% were male with a moderately high HBV DNA (8.78 log10 copies/mL), and 90% were HBeAg positive. In this study, the proportion of patients achieving undetectable HBV DNA increased over time, from 30% at Year 1 to 47% at Year 2 and 55% at Year 3. This contrasts with findings from thepivotal entecavir studies that showed an increasing rate of HBV DNA negativity for the first 2years in lamivudine-refractory patients, followed by a decrease in rates of undetectable HBVDNA by the third year along with the emergence of entecavir resistance (Assessment at threeyears shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients).[30]In addition, there was a fairly acceptable rate of cumulative HBeAg loss (11%, 13%, and 17%at Years 1, 2, and 3, respectively) and cumulative HBeAg seroconversion (7%, 11%, and12% at Years 1, 2, and 3). By contrast, however, the proportion of patients with ALT ≤ 1 xupper limit of normal (ULN) decreased from 85% at Year 1 to 65% at Year 3.Although entecavir monotherapy is approved for use in lamivudine-experienced patients, many experts feel that there are more effective treatment options for this patient population.

Patrick Marcellin, MD: This study confirms that patients with lamivudine-resistant HBV respond less well to entecavir than do treatment-naive patients. In addition, we know that they are at increased risk of developing entecavir resistance. Therefore, there is some consensus that it is more appropriate to use drugs without cross-resistance with lamivudine, such as adefovir ortenofovir. In addition, the use of interferon may be another option in these patients, especially in countries where adefovir or tenofovir is not available.

Preexisting Resistance Mutations in Treatment-Naive Patients

Norah Terrault, MD, MPH: It has been postulated that a proportion of treatment-naive HBV-infected patients may have resistance mutations present at baseline. Indeed, a previous study using direct sequencing reported that 10% of treatment-naive patients had preexisting lamivudine resistance mutations.[31] However, in general, only viral variants present at a prevalence of ≥ 20% among the total HBV quasispecies pool are detectable using this technique.[32.] Fung and colleagues[33] presented data using a very sensitive line probe assay, which is more sensitive than direct sequencing (lower level of detection for antiviral-resistant variants at ≥ 5% of the total HBV quasispecies pool[34]) to screen for the presence of lamivudine mutations at codons180 and 204 in 146 nucleos(t)ide-naive patients. They found that preexisting mutations in thert180/204 pathway were relatively common, with M204V/I present in 13% of patients and L180M present in 7%. This was a cross-sectional analysis, so no data were available to demonstrate whether the presence of these mutations affected subsequent response to therapy. Nevertheless, it is plausible that baseline resistance testing might influence the choice of antiviral therapy in the future. For example, if a patient had the M204V/I mutation, one might avoid nucleoside analogues such as lamivudine or entecavir as first-line therapy and instead consider nucleotides such as adefovir or tenofovir. Because this concept is still emerging, it is not yet clear how to best use this type of information. Regardless, it is important to note that even patients with no previous drug exposure can have resistance mutations present in their viral quasispecies due to the error-prone replication of HBV.

Patrick Marcellin, MD: Longitudinal studies are necessary to determine the clinical relevance of these findings by assessing the influence of these minority HBV populations on the antiviral response and the incidence of resistance.

Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: These data are very interesting and warrant confirmation in subsequent studies. We currently have only 1 class of drugs for treatment of chronic HBV infection—nucleos(t)ide analogues—and there is a high frequency of cross-resistance with some of the available antiviral agents. Therefore, routine baseline testing for presence of treatment-associated mutations may become clinically useful and cost-effective in the future if such mutations are found at similar rates in other studies.
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Therapy of Chronic Hepatitis B: Who to Treat and When to Treat? A Case-Based Discussion , 2008

Introduction

Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Currently, there are 6 approved therapies, including 2 formulations of interferon alfa (standard interferon alfa and peginterferon alfa) and 4 nucleos(t)ide analogues (lamivudine, adefovir, entecavir, and telbivudine). It is anticipated that another nucleotide analogue, tenofovir, may be approved in the near future. Therefore, many treatment options are available that are effective in suppressing hepatitis B virus (HBV) replication, can be administered orally, and have excellent safety profiles. This has prompted some experts to recommend that all HBV carriers should receive treatment because chronic HBV infection can progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). However, current treatments do not eradicate HBV (see “Can Hepatitis B Be Cured?” by Marc G. Ghany, MD). Therefore, most patients require long durations of treatment, and in many instances, life-long treatment is required to maintain viral suppression. Sustained viral suppression, in turn, is required to achieve continued clinical benefit and to prevent hepatitis flares resulting from virologic relapse associated with the withdrawal of treatment. Not all HBV carriers will experience adverse consequences of chronic HBV infection, and for those individuals who do experience such complications, they may not occur until years or decades later. Furthermore, host immune response can result in spontaneous remission in some patients, which can at times be long lasting. Therefore, until a safe and affordable “cure” for hepatitis B is available, it is prudent to assess the long-term benefits vs long-term risks before recommending treatment (Figure 1).

When evaluating the benefits associated with treatment, one must take into consideration not only on-treatment viral suppression but also the durability of viral suppression after treatment is discontinued, the ability to maintain viral suppression during continued treatment, and most importantly, the impact on liver disease progression and HCC development. Risks associated with treatment include adverse effects, potential development of drug resistance, and costs. Interferon alfa is associated with a wide spectrum of adverse events.[1] Nucleos(t)ide analogues are generally well tolerated. However, adefovir has been associated with a low rate of nephrotoxicity,[2,3] and telbivudine has been reported to be associated with rare cases of myopathy and peripheral neuropathy.[4] Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 7 Recognition that the natural course of chronic HBV infection involves different phases with marked variations in HBV replication and activity of liver disease over time has shifted the paradigm in hepatitis B treatment from “who to treat” to “when to treat” (Figure 2). Therefore, all persons with chronic hepatitis B are potential treatment candidates. A patient who is not a treatment candidate at the time of presentation may become a treatment candidate during the course of follow-up if serum HBV DNA or alanine aminotransferase (ALT) levels increase or if there is clinical evidence of hepatic decompensation. For this reason, all patients who are not considered treatment candidates at presentation should be monitored and treatment initiated later if indications arise.

The decision of whether to treat now or to defer treatment hinges on 3 key questions: 1) How active or advanced is the liver disease now? 2) What is the risk of progression to cirrhosis, hepatic decompensation, or HCC in the next 10-20 years? 3) What is the likelihood that clinical benefit can be maintained after a finite course of treatment, for example, 3-5 years? In this review, examples are presented of clear-cut scenarios in which treatment should be initiated, clear-cut scenarios in which treatment can be deferred, and debatable scenarios in which the decision to treat should be individualized. Moreover, the rationale for recommending immediate treatment vs deferral of treatment is discussed for each case. The choice of treatment and the endpoints of therapy are covered in “Therapy of Chronic Hepatitis B: What to Choose, When to Stop, and When to Change” by Ira M. Jacobson, MD.

Clear-cut Cases in Which Treatment Should Be Initiated

Patients With Detectable Serum HBV DNA and Hepatic Decompensation
Case 1
A 58-year-old white man presented with jaundice and ascites for 2 weeks. Blood test results showed HBV DNA 7000 IU/mL, ALT 38 IU/L (normal < 40 IU/L), total bilirubin 3.1 mg/dL, and international normalized ratio (INR) of prothrombin time of 1.6.
Discussion
Although the serum HBV DNA level is not very high in this patient, nucleos(t)ide therapy should be initiated in this case. Interferon alfa–based treatment is contraindicated in patients with decompensated cirrhosis because of high rates of treatment-associated adverse events.[5,6] However, several studies have shown that lamivudine is effective in stabilizing the liver disease in these patients.[7-9] This may allow patients to undergo liver transplantation,[10,11] or in some cases reversal of liver failure may allow patients to be removed from the transplant waiting list.[12,13] It should be emphasized that although viral suppression can be evident within 4 weeks of antiviral therapy, clinical benefit takes 3-6 months to be apparent. Therefore, all patients who present with hepatic decompensation should be evaluated for liver transplantation.[11] Furthermore, HCC surveillance should be continued as HCC has been reported even in patients in whom HBV DNA had been suppressed.[8,14] For patients who proceed to transplantation, viral suppression before transplantation can decrease the risk of HBV reinfection after transplantation. In addition, antiviral therapy should be continued posttransplantation, and the combination of hepatitis B immune globulin and nucleos(t)ide analogues such as lamivudine and adefovir have significantly improved patient outcomes.[15] Although most of these data are based on studies of lamivudine therapy, it is reasonable to assume that other nucleos(t)ide analogues will provide the same benefits.

Patients With Severe Hepatitis Flare
Case 2
A 41-year-old Chinese man presented with a 3-week history of fatigue. Blood test results showed ALT 725 IU/L, total bilirubin 1.7 mg/dL, INR 1.2, platelet count 145,000/mm3, HBeAgpositive, and HBV DNA 64,000 IU/mL. Repeat blood tests 1 week later showed ALT 650 IU/L, total bilirubin 2.1 mg/dL, INR 1.3, and IgM antibodies to hepatitis B core antigen (anti-HBc) positive.
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Discussion
It is important to determine if this patient is experiencing acute hepatitis B or an exacerbation of chronic hepatitis B. Antiviral treatment is not necessary and provides no clinical benefit in the vast majority of patients with acute hepatitis B infection; > 95% of immunocompetent adults with acute hepatitis B recover spontaneously.[1,16] Differentiating severe exacerbation of chronic hepatitis B from acute hepatitis B can be difficult in persons who are not known to be carriers because IgM anti-HBc can be positive during severe exacerbations. Although ALT flares are frequently observed in patients with chronic HBV infection and may be a sign of a vigorous host immune response that may result in successful HBeAg seroconversion, ALT flares associated with an increase in bilirubin or INR are ominous. Serum HBV DNA levels are often low and may at times be undetectable in patients presenting with ALT flares, particularly in patients who present after the peak of the ALT flare. Several case series have Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 9 found that antiviral therapy in patients with severe exacerbation of chronic hepatitis B improves survival compared with untreated historical controls.[17,18] Although data from randomized controlled trials are not available, antiviral therapy should be instituted for patients with icteric ALT flares or those resulting in derangements in liver synthetic function to prevent progression to hepatic failure and to minimize irreversible liver damage.[1] Patients with mild exacerbations—defined as normal bilirubin and INR, ALT  700,000 Eq/mL.[14] In this trial, the impact of antiviral therapy on HCC alone was only marginally significant (hazard ratio: 0.49; P = .047). Whether antiviral therapy will prevent disease progression in patients with advanced fibrosis or cirrhosis and lower serum HBV DNA levels is unclear. The American Association for the Study of Liver Diseases (AASLD) Practice Guidelines recommended an HBV DNA cutoff of > 2000 IU/mL for initiating treatment in patients with compensated cirrhosis and close monitoring of those with HBV DNA levels  20,000 IU/mL and ALT > 2 x ULN followed by treatment if no spontaneous HBeAg loss occurs.[1] The guidelines also suggest that a pretreatment liver biopsy in compensated patients is useful in assessing the degree of inflammation and the extent of fibrosis but is not a prerequisite for initiating treatment.

Patients With HBeAg-Negative Chronic Hepatitis
Case 5
A 62-year-old Greek woman presented during routine examination with abnormal liver enzymes. Blood test results showed ALT 83 IU/L, and upon further testing, the patient was found to be HBeAg negative with HBV DNA 69,000 IU/mL. Liver biopsy showed mild inflammation with a histologic activity index of 5 and early bridging indicated by an Ishak fibrosis score of 3.
Discussion
This patient meets AASLD Practice Guidelines criteria for initiation of treatment for HBeAgnegative chronic hepatitis.[1] Contrary to HBeAg-positive patients, spontaneous sustained remission is extremely rare among HBeAg-negative patients; therefore, a short period of observation before initiating treatment is not required when there is biochemical and histologic evidence of significant liver injury.[1]

Clear-cut Cases in Which Treatment Can Be Deferred
Inactive HBV Carriers
Case 6
A 38-year-old Vietnamese woman was found to be hepatitis B surface antigen (HBsAg) positive during routine checkup. She has no previous history of hepatitis or jaundice. Blood test results showed serum ALT 20 IU/L, HBeAg-negative disease, and HBV DNA 50 IU/mL.
Discussion
After spontaneous HBeAg seroconversion, 67% to 80% of patients become inactive carriers.[20-22] This patient meets the criteria of an inactive carrier; therefore, treatment is not indicated at this time.[1] However, given the fluctuating nature of HBeAg-negative chronic hepatitis, follow-up testing of ALT and HBV DNA levels at 1- to 3-month intervals during the first year and at 6-month intervals thereafter is needed to ascertain that this patient is indeed in the inactive carrier state.[23,24] Most inactive carriers have persistent or intermittent detection of serum HBV DNA, albeit at low levels.[25] Nonetheless, studies are lacking to show that antiviral treatment during this period will improve outcome or prevent subsequent HBV reactivation. Several long-term follow-up studies showed that the prognosis of inactive carriers is favorable, especially if the inactive carrier state is reached early. One study of 296 Italian HBsAg-positive blood donors reported no increase in mortality and no hepatic decompensation after 23 years.[26] All inactive carriers should continue to be monitored because reactivation of HBV replication can occur after varying durations in the inactive carrier state. Longitudinal studies of adult inactive carriers reported that 15% to 24% developed HBeAg-negative chronic hepatitis and 1% to 17% had sustained reversion back to HBeAg positivity.[21]
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Patients in the Immune-Tolerance Phase Who Are Younger Than 30 Years Case 7
A 27-year-old Chinese woman was found to be HBsAg positive during a checkup. Subsequent tests showed ALT 18 IU/L, HBeAg-positive disease, and HBV DNA 5.6 x 109 IU/mL. Her mother and 1 brother also tested positive for HBsAg.
Discussion
This patient fits the profile of a patient in the immune-tolerance phase of HBV infection, and treatment is not recommended by the AASLD Practice Guidelines at this time because the likelihood of significant liver injury at this stage is low.[1] An additional reason for not recommending treatment is the low rate of treatment-related HBeAg seroconversion among patients with normal pretreatment ALT.[27] Recent studies showed that up to 50% of HBV carriers with normal ALT had significant liver disease on biopsies and HBV carriers with ALT 0.5-1.0 x ULN had higher rates of liver-related deaths than those with ALT  40 years.[30,31] Similarly, studies reporting abnormal liver histology in patients with normal ALT found that moderate to severe inflammation or fibrosis was mainly observed in patients older than 40 years of age.[33] Studies that focused on patients in the immune-tolerance phase showed that 33% to 49% had stage 0 fibrosis whereas the remainder had stage I fibrosis.[34,35] In one study, follow-up biopsies after a mean of 5 years revealed no change in fibrosis score in 41 out of 48 patients who remained in the immune-tolerance phase.[35] Another study found that only 5% of patients progressed to cirrhosis and none to HCC during a follow-up period of 10.5 years.[36] Finally, available treatments have not been shown to increase the rate of HBeAg seroconversion in patients with normal ALT, based on cutoffs established by diagnostic laboratories.[27] Given the need for long durations of therapy, the benign outcome in the shortterm future for the vast majority of patients in the immune-tolerance phase, and the possibility of a benign long-term outcome in those patients who achieve HBeAg seroconversion early in life, treatment is not recommended for young patients (younger than 35 years of age) in the immune-tolerance phase.

Cases Where The Treatment Decision Must Be Individualized
Patients in the Immune-Tolerance Phase Who Are Older Than 40 Years
Case 8
A 45-year-old Korean man was found to be HBsAg positive. Blood test results revealed ALT 29 IU/L at initial testing, and he was HBeAg positive with an HBV DNA level of 5.4 x 107 IU/mL. Subsequent testing revealed ALT 24 IU/L 6 months later
Discussion
This patient fits the profile of a patient in the immune-tolerance phase as defined by the AASLD Practice Guidelines.[1] Although this patient had a lower serum HBV DNA level than the patient in Case 7, treatment should be considered because of this patient’s older age. Recent studies showed that although significant liver disease is rarely found among young patients in the immune-tolerance phase, delayed HBeAg seroconversion after the age of 40 years and persistently high serum HBV DNA levels after 4 decades of infection are Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 12 associated with increased risks of adverse outcomes.[37] A liver biopsy may help in determining the urgency of treatment.
Patients With a Strong Family History of HCC
Case 9
A 30-year-old Korean woman was found to be HBsAg positive after her 37-year-old brother was recently diagnosed with HCC. Her mother and all her siblings were HBV carriers and 1 of her maternal uncles also had HCC that was diagnosed when he was 58 years of age. Blood test results showed the patient to be HBeAg positive with serum ALT IU/L and HBV DNA 7.4 x 107 IU/mL. Repeat tests after 4 and 12 months showed ALT 15 IU/L and 20 IU/L, respectively.
Discussion
Based on AASLD Practice Guideline definitions, this patient is in the immune-tolerance phase.[1] As a result and given her young age, treatment is not indicated at this time. There have been several reports of familial clustering of HCC, but it is unclear whether this is related to genetic or environmental factors or a more virulent strain of HBV.[38] It is understandable that this patient would be very concerned about her risk of HCC. Some experts advocate treating all chronic hepatitis B patients with a strong family history of HCC, regardless of their clinical and virological profile. However, it must be emphasized that there are no data to support the hypothesis that antiviral therapy can completely prevent HCC and there is no model to predict the risk of HCC in this patient. The potential benefits of antiviral therapy must be balanced against the risks of years of antiviral therapy that may indeed be lifelong, and those potential risks must be weighed particularly carefully for a young woman who might be planning to start a family in the near future.
Patients With Borderline High or Fluctuating Serum HBV DNA and/or ALT
Case 10
A 45-year-old black man was found to have mildly elevated ALT. Serial test results showed ALT 25 IU/L, 64 IU/L, and 43 IU/L. Other test results showed HBeAg-negative, HBV DNA 4500 IU/mL in an initial test, and HBV DNA 31,000 IU/mL in a repeat test.
Discussion
This patient appeared to be in the inactive carrier state at initial presentation, but subsequent tests showed continued mildly elevated ALT and increasing serum HBV DNA. Because of the need for many years—if not lifelong—treatment, the AASLD Practice Guidelines recommend liver biopsy to ascertain the presence of histologic damage, with treatment recommended for those with moderate to severe inflammation and/or significant fibrosis.[1] A longer period of observation before biopsy might be appropriate if the patient was younger (younger than 30 years of age) with similar characteristics and history, particularly if the patient is reluctant to undergo liver biopsy.

Summary: Implications for Clinical Practice
• Currently available HBV treatments suppress but do not eradicate HBV.
• Most patients require long durations of treatment to derive continued clinical benefit.
• Treatment may be required for years, decades, or the duration of the patient’s life. Therefore, the decision to initiate treatment must balance the long-term benefits vs the long-term risks.
• Treatment is indicated if the risk of liver-related morbidity and mortality in the near future (within 5-10 years) and the likelihood of achieving maintained viral suppression during continued treatment are both high.
• Treatment is also indicated if the risk of liver-related morbidity and mortality in the foreseeable future of 10-20 years and the likelihood of achieving sustained viral suppression after a defined course of treatment are both high (Table).
• Treatment is not indicated if the risk of liver-related morbidity and mortality in the next 20 years and/or the likelihood of achieving sustained viral suppression after a defined course of treatment are low.
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thank u very much...it is very educational..you did a great job...kudos
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Resistance Through 6 Years of Entecavir Treatment
Anna S. F. Lok, MD: To start our discussion, several studies presented at the 2009 European Association for the Study of the Liver (EASL) meeting focused on patients who had received multiple years of nucleos(t)ide analogue therapy, one of which provided an update on long-term resistance data for patients treated with entecavir. ETV-901 is a nonrandomized rollover followup study designed to evaluate long-term entecavir treatment of patients from 6 phase II and III clinical studies. Nucleos(t)ide-naive and lamivudine-refractory patients (those with continued viremia or confirmed resistance while on lamivudine) with chronic hepatitis B virus (HBV) infection who received > 12 weeks of continuous entecavir therapy in the previous trials were eligible for inclusion in ETV-901. Tenney and colleagues[1] reported on the cumulative probability of entecavir resistance through Year 6, identified by sequencing annually or at withdrawal from study or at any time if the patient had HBV DNA ≥ 300 copies/mL (~ 59 IU/mL) or virologic breakthrough (≥ 1 log10 IU/mL increase in HBV DNA from nadir) (Entecavir Resistance Rare in Nucleoside-Naive HBV Patients Through 6 Years). During the first year of ETV-901, 663 nucleoside-naive patients and 187 lamivudine-refractory patients were evaluable, but during the course of the follow-up, as with any long-term study of this kind, many patients discontinued treatment after achieving hepatitis B e antigen (HBeAg) seroconversion or failing to achieve a study-defined treatment response, in which case they were eligible to receive alternative therapies. As a result, only 99 patients who were nucleoside naive and 29 who were lamivudine refractory at initial enrollment were still being monitored on entecavir therapy in the ETV-901 study 6 years later. The cumulative rate of genotypic resistance to entecavir remained very low at 1.2% among nucleoside-naive patients by Year 6 of treatment. These results are extremely encouraging; this study represents the longest follow-up data available on nucleos(t)ide analogue therapy, and the initial very low rate of resistance has been maintained during a long-term treatment course.
Patrick Marcellin, MD: Results at 4 and 5 years have been presented previously and are now confirmed at 6 years. However, the number of patients is becoming ever smaller, so there is some limitation to the conclusions that can be drawn.
Anna S. F. Lok, MD: Indeed, one shortcoming of this study is the fact that only 99 of the
original 663 patients were still in the study at the time of the Year 6 analysis. The patients who withdrew because of failure to achieve an adequate response may have been those at the greatest risk of developing drug resistance, so the rate of resistance reported here may underestimate the rate that would be seen on an intent-to-treat basis. Moreover, a higher resistance rate could be seen in clinical practice than was reported in this study because patients are typically not monitored as closely in the clinic as in a clinical trial such as this, and some patients may be less motivated to adhere to treatment, resulting in higher resistance rates. Nonetheless, these data are very encouraging compared with the resistance data that have been reported for some of the other oral agents, such as lamivudine, adefovir, and telbivudine.
Maria Buti, MD: When assessing the extrapolation of these data to clinical practice, it is also important to note that the study population only includes patients who achieved undetectable HBV DNA (< 0.7 mEq/mL [~ 1.2 x 105 IU/mL]) at Year 2 but did not achieve HBeAg loss (for HBeAg-positive patients) or normalized alanine aminotransferase (ALT) (for HBeAg-negative patients). Patients who achieved HBV DNA suppression < 1.2 x 105 IU/mL and HBeAg loss (or ALT normalization) at Year 1 were allowed to discontinue therapy and were not included in this analysis. In addition, patients who were rolled over could have had up to a 35-day gap in treatment when transitioning to ETV-901. Because the ETV-901 study was blinded and included patients rolling over from both the entecavir and the lamivudine arms of the previous studies in treatment-naive and lamivudine-refractory patients, all patients initially received a combination of 100-mg lamivudine and 1-mg entecavir for up to 18-20 weeks before the protocol was amended and lamivudine was discontinued while entecavir was continued at 1 mg/day. In clinical practice, the approved dose for treatment-naive patients is 0.5 mg/day. It is not clear whether these factors might have influenced the resistance rates seen in the study population.
Anna S. F. Lok, MD: I agree that this study presents a best-case scenario and in clinical
practice it may be less likely that such a low resistance rate will be achieved. Nonetheless, the results are still very encouraging. Nearly all clinical studies have provided patients the option to modify therapy after some point, so unfortunately only some of the original lamivudine studies are providing a pure perspective on long-term outcomes with monotherapy in every single patient. For example, the ongoing long-term tenofovir trials Study 102 [2] and Study 103[3] permit the addition of emtricitabine at Week 72 for patients with detectable viremia, so the long-term results will not reflect strict
monotherapy.
Maria Buti, MD: Although these aspects of study design may hamper the generation of pure data sets, they also reflect the reality that optimal management of patients at high risk of resistance may require special approaches such as combination therapy, rather than continued treatment with a single agent that is not achieving optimal suppression.
Patrick Marcellin, MD: In summary, although it is important to note the limitations of this study, the key conclusion remains that entecavir is a highly effective drug with a very low resistance rate in treatment-naive patients.
Anna S. F. Lok, MD: Turning to the patients who were lamivudine refractory when they started entecavir, the resistance rate in these patients rose from 6% at the end of Year 1 to 57% at the end of Year 6. We should note that there was a much smaller number of lamivudine-refractory patients and of the 187 patients at Year 1, only 29 remained on study at the end of Year 6, so these resistance data are based on a very small number of patients. Nonetheless, the data are strong enough to indicate that entecavir monotherapy is not an optimal option for patients who failed to respond to previous lamivudine treatment. The investigators also reported on the patterns of entecavir-associated resistance mutations found over time in ETV-901. In previous studies, the mutations associated with entecavir resistance were located at amino acid positions 184, 202, and 250. No new mutations were identified at any other amino acid positions during 6 years. As a reminder, mutations at those 3 positions only confer entecavir resistance in the presence of the M204I/V ± L180M mutations.
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thanks for all the info.
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Thank you for posting so much information
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