HepB Forum : Unofficial Research Thread (URT) Tx info

[stevenNYer]

I am reposting articles / summaries on the treatment management of chronic HepB.  "cajim" located these articles which are quite informative.  I thought about putting them on a seaprate Health Page but didn't think it was appropriate since we didn't write them.

Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information.  Let's keep this URT free of comments.  For comments, start a new thread indicating that it's in reference to URT.

We'll see how it goes.

[cajim]

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.

[cajim]

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.

[cajim]

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.

[cajim]

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.

[cajim]

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].

[cajim]

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