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Jul 15, 2009 - 2 comments

Hepatitis B
Author: Nikolaos T Pyrsopoulos, MD, PhD, FACP, Chief of Hepatology, Medical Director of Liver Transplantation, Florida Hospital; Associate Professor of Medicine, University of Central Florida College of Medicine
Coauthor(s): K Rajender Reddy, MD, FACP, FACG, Professor, Department of Medicine, Division of Hepatology, University of Miami School of Medicine
Contributor Information and Disclosures

Updated: Jun 19, 2009

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Differential Diagnoses & Workup
Treatment & Medication
Further Reading
In 1965, Blumberg et al reported the discovery of the hepatitis B surface antigen (HBsAg), also known as Australia antigen, and its antibody, hepatitis B surface antibody (HBsAb). A few years later, in 1970, Dane visualized the hepatitis B virus (HBV) virion.1 Since then, considerable progress has been made regarding the epidemiology, virology, natural history, and treatment of this hepatotropic virus.

Hepatitis B is a worldwide healthcare problem, especially in developing areas. An estimated one third of the global population has been infected with the hepatitis B virus (HBV). Approximately 350 million people are lifelong carriers, and only 2% spontaneously seroconvert annually. Ongoing vaccination programs appear to be promising in the attempt to decrease the prevalence of hepatitis B virus (HBV) disease.

The hepatitis B virus (HBV) is transmitted hematogenously and sexually. The outcome of this infection is a complicated viral-host interaction that results in either an acute symptomatic disease or an asymptomatic disease. Patients may become immune to the hepatitis B virus (HBV), or they may develop a chronic carrier state. Later consequences are cirrhosis and the development of hepatocellular carcinoma (HCC).2,3,4,5 Antiviral treatment may be effective in approximately one third of the patients who receive it, and for selected candidates, liver transplantation currently seems to be the only viable treatment for the latest stages of hepatitis B.

Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.

Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.

Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.

Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.
For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Hepatitis B, Immunization Schedule, Adults, and Immunization Schedule, Children.

Hepatitis B virus (HBV) is a hepadnavirus.6,7,8,9,10 It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. Hepatitis B virus (HBV) can survive when stored for 15 years at –20°C, for 24 months at –80°C, for 6 months at room temperatures, and for 7 days at 44°C. The viral genome consists of a partially double-stranded circular DNA of 3.2 kilobase (kb) pairs that encodes 4 overlapping open reading frames, as follows:

S for the surface or envelope gene encoding the pre-S1, pre-S2, and the S protein
C for the core gene, encoding for the core nucleocapsid protein and the e antigen
X for the X gene encoding the X protein
P for the polymerase gene encoding a large protein promoting priming RNA-dependent and DNA-dependent DNA polymerase and RNase H activities
An upstream region for the S (pre-S) and C (pre-C,) genes has been found. The structure of this virion is a 42-nm spherical, double-shelled particle consisting of small spheres and rods, with an average width of 22 nm.

The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: a, common to all HBsAg, and d, y, w, and r, which are epidemiologically important. The core antigen, HBcAg, is the protein that encloses the viral DNA. It can also be expressed on the surface of the hepatocytes, initiating a cellular immune response. The e antigen, HBeAg, comes from the core gene and is a marker of active viral replication. Usually, HBeAg can be detected in patients with circulating serum hepatitis B virus (HBV) DNA.

The best indication of active viral replication is the presence of hepatitis B virus (HBV) DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) techniques are used to detect the viral genome in the serum.

The role of the X gene is to encode proteins that act as transcriptional transactivators that aid viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.

The production of antibodies against HBsAg confers protective immunity and can be detected in patients who have recovered from hepatitis B virus (HBV) infection or in those who have been vaccinated. Antibody to HBcAg is detected in almost every patient with previous exposure to hepatitis B virus (HBV). The immunoglobulin M (IgM) subtype is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. With this marker alone, one cannot understand the activity of the disease. Antibody to HBeAg is suggestive of a nonreplicative state and one in which the antigen has been cleared.

With the newest PCR techniques, scientists are able to identify variations in the hepatitis B virus (HBV) genome (variant strains). Mutations of various nucleotides such as the 1896 (precore/core region) processing the production of the HBeAg have been identified (HBeAg negative strain). The prevalence of the HBeAg negative virus varies among different areas. Estimates indicate that 50-60% of the patients from Southern Europe, the Middle East, Asia, and Africa as well as 10-30% of patients in the United States and Europe who have chronic hepatitis B virus (HBV) infection have been infected by this strain.

The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system. The latter attacks the hepatitis B virus (HBV) and causes liver injury. Activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides located on the surface of the hepatocytes, and an immunologic reaction occurs. Impaired immune reactions (eg, cytokine release, antibody production) or relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes.11,12

The final state of hepatitis B virus (HBV) disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop HCC.2,3,4 In the United States, the most common presentation is that of patients of Asian origin who acquired the disease as newborns (vertical transmission).

Four different stages have been identified in the viral life cycle of hepatitis B.

The first stage is immune tolerance. The duration of this stage for healthy adults is approximately 2-4 weeks and represents the incubation period. For newborns, the duration of this period is often decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness.

In the second stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline of the levels of hepatitis B virus (HBV) DNA is seen. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops.

In the third stage, the host can target the infected hepatocytes and the hepatitis B virus (HBV). Viral replication no longer occurs, and HBeAb can be detected. The HBV DNA levels are lower or undetectable, and aminotransferase levels are within the reference range. In this stage, an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present.

In the fourth stage, the virus cannot be detected and antibodies to various viral antigens have been produced. Different factors have been postulated to influence the evolution of these stages, including age, sex, immunosuppression, and coinfection with other viruses.

Eight different genotypes (A through H) representing a divergence of the viral DNA at around 8% have been identified.7 The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated, and the response to treatment with antiviral agents is less favorable for patients infected by genotype C compared with those infected by genotype B.

It is reported that the risk of HCC might be higher with an increasing level of hepatitis B virus (HBV) viral load and the presence of genotype C and common variants in the precore and basal core promoter regions.

**** et al studied an in vitro 1.5X hepatitis B virus (HBV) replication system that could generate high level of such viruses, which the investigators believed would help compare the replication capacity among the virus strains associated with high and low risk of HCC.13   Four strains of hepatitis B virus (HBV) were isolated from 2 patients with HCC and 2 hepatitis B virus (HBV) carriers; then, 4 corresponding constructs, HBV-1.5Xs, were generated after molecular cloning.

HepG2 cells were transfected with the HBV-1.5Xs, and the levels of HBsAg, HBeAg, and viral DNA were then detected in both the supernatant and the cells.13 After 24 and 48 hours of transfection, a high optical density value of HBsAg of 3.5 was observed in the supernatant as well as in some of the diluted cell lysate samples. The HBeAg level was relatively low in all strain samples of HBV. In addition, the log(10) values of viral loads were determined, with the cell lysate having a higher value (10-11 per mL) than that of the supernatant (6-7 per mL).13

**** et al determined that the novel HBV-1.5X system was capable of generating a high level of hepatitis B virus (HBV) in a consistent manner, but there was no significant difference in the replication capacities among these strains in vitro. The investigators concluded that the HBV-1.5X system may be a useful platform in helping to establish stable cell lines and transgenic mice for the investigation of viral pathogenesis, particularly for the various strains of hepatitis B virus (HBV).13

United States
An estimated 200,000 new cases of hepatitis B virus (HBV) occur annually, and 1-1.25 million people are carriers. The prevalence of the disease is higher among blacks and persons of Hispanic or Asian origin. In addition, a higher carrier rate exists among certain subpopulations such as the Alaskan Eskimos, Asian Pacific islanders, and Australian aborigines. Hepatitis B virus (HBV) accounts for 5-10% of cases of chronic end-stage liver disease and 10-15% of cases of HCC.

Hepatitis B virus (HBV) is blamed for 5000 deaths annually. The prevalence is low in persons younger than 12 years, but it increases in those older than 12 years—associated with the initiation of sexual contact (the major mode of transmission), the number of sexual partners, and an early age of first intercourse. Additional risk factors identified in the National Health and Nutrition Examination Survey III survey are non-Hispanic black ethnicity, cocaine use, high number of sexual partners, divorced or separated marital status, foreign birth, and low educational level.

Because of the implementation of routine vaccinations of infants in 1992 and adolescents in 1995, the prevalence of hepatitis B virus (HBV) is expected to decline further.

The hepatitis B virus (HBV) carrier rate variation is 1-20% worldwide. This variation is related to differences in the mode of transmission and the patient's age at infection. The prevalence of the disease in different geographic areas can be characterized as follows:

Low-prevalence areas (rate of 0.1-2%) include Canada, Western Europe, Australia, and New Zealand. In the areas of low prevalence, sexual transmission and percutaneous transmission during adulthood are the main modes of transmission.
Intermediate-prevalence areas (rate of 3-5%) include Eastern and Northern Europe, Japan, the Mediterranean basin, the Middle East, Latin and South America, and Central Asia. In areas of intermediate prevalence, sexual and percutaneous transmission and transmission during delivery are the major routes.
High-prevalence areas (rate of 10-20%) include China, Indonesia, sub-Saharan Africa, the Pacific Islands, and Southeast Asia. In areas of high prevalence, the predominant mode of transmission is perinatal, and the disease is transmitted vertically during early childhood from the mother to the infant. Vaccination programs implemented in highly endemic areas such as Taiwan seem to change the prevalence of hepatitis B virus (HBV) infection. In Taiwan, seroprevalence declined from 10% in 1984 (before vaccination programs) to less than 1% in 1994 after the implementation of vaccination programs, and the incidence of HCC declined from 0.52% to 0.13%.3

An estimated 250,000 persons per year globally and 5000 persons per year in the United States die from chronic hepatitis B virus (HBV) infection.

Black individuals have a higher prevalence of hepatitis B virus (HBV) disease than persons of Hispanic origin or white persons.

More cases of hepatitis B virus (HBV) disease occur in males than in females.

The earlier the disease is acquired, the greater the chance of developing chronic hepatitis B infection. Infants (mainly infected through vertical transmission) have a 90% chance, children have a 25-50% chance, adults have an approximately 5% chance, and elderly persons have an approximately 20-30% chance of developing chronic disease.

The spectrum of the symptomatology of hepatitis B disease varies from subclinical hepatitis to icteric hepatitis to hyperacute, acute, and subacute hepatitis during the acute phase, and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and HCC during the chronic phase.

Acute phase
The incubation period is 1-6 months.
Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis. Patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis.
Icteric hepatitis is associated with a prodromal period, during which a serum sickness –like syndrome can occur. The symptomatology is more constitutional and includes the following:
Low-grade fever
Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)
Right upper quadrant and epigastric pain (intermittent, mild to moderate)
Patients with hyperacute, acute, and subacute hepatitis may present with the following:
Hepatic encephalopathy
Disturbances in sleep pattern
Mental confusion
Chronic phase
Patients with chronic hepatitis can be healthy carriers without any evidence of active disease, and they also are asymptomatic.
Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:
Symptoms similar to those of acute hepatitis
Mild upper quadrant pain or discomfort
Hepatic decompensation

The physical examination findings vary from minimal to impressive (patients with hepatic decompensation) according to the stage of disease.

Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:
Low-grade fever
Jaundice (10 d after the appearance of constitutional symptomatology and lasting for 1-3 mo)
Hepatomegaly (mildly enlarged soft liver)
Splenomegaly (5-15%)
Palmar erythema (rarely)
Spider nevi (rarely)
The physical examination of patients with chronic hepatitis B virus (HBV) infection can reveal stigmata of chronic liver disease such as the following:
Palmar erythema
Spider angioma
Patients with cirrhosis may have the following symptoms:
History of variceal bleeding
Peripheral edema
Testicular atrophy
Abdominal collateral veins (caput medusa)

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948882 tn?1270557407
by bram44, Oct 04, 2009

Hepatitis B: Treatment & Medication
Author: Nikolaos T Pyrsopoulos, MD, PhD, FACP, Chief of Hepatology, Medical Director of Liver Transplantation, Florida Hospital; Associate Professor of Medicine, University of Central Florida College of Medicine
Coauthor(s): K Rajender Reddy, MD, FACP, FACG, Professor, Department of Medicine, Division of Hepatology, University of Miami School of Medicine
Contributor Information and Disclosures

Updated: Jun 19, 2009

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Differential Diagnoses & Workup
Treatment & Medication
Further Reading
Medical Care
Therapy is currently recommended for patients with evidence of chronic active hepatitis B disease (ie, high aminotransferase levels, positive HBV DNA findings, HBeAg). Various algorithms have been proposed, such as that by Keeffe and colleagues14 and the American Association for the Study of Liver Diseases (AASLD).15 In general, for the HBeAg-positive patient population that is identified with evidence of chronic hepatitis B virus (HBV) disease, treatment is advised to be administered when the HBV DNA level is ≥20,000 IU/mL (105 copies/mL) and when serum ALT is elevated for 3-6 months.

For the HBeAg-negative chronic population with hepatitis B disease, treatment can be administered when the HBV DNA is ≥ 2000 IU/mL (104 copies/mL) and serum ALT is elevated (ALT levels >20 U/L for females and 30 U/L for males) for 3-6 months.

Medication (see also Medication, below)

Currently, interferon alfa (IFN-a), lamivudine, telbivudine, adefovir, entecavir, and tenofovir are the main treatment drugs approved globally, although ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine, clevudine (l-FMAU), and therapeutic vaccines. It appears that lamivudine and telbivudine are not recommended as first-line agents in the treatment of hepatitis B disease.16

Patients who have lost HBeAg and in whom HBV DNA is undetectable have an improved clinical outcome (ie, slower rate of disease progression, prolonged survival without complications, reduced rate of HCC, and clinical and biochemical improvement after decompensation).

Special attention must be given to patients on liver transplantation lists. Initiation of treatment with adefovir or entecavir or tenofovir or in combination with lamivudine is of cardinal importance before and after liver transplantation to achieve viral suppression and to prevent recurrence of the disease after the procedure.

Published reports indicate that after IFN-a treatment with 5 million U/d or 10 million U 3 times per week subcutaneously (SC) for 4 months, the HBV DNA levels and HBeAg become undetectable in 30-40% of patients. In addition, 10% of patients seroconvert from HBsAg to HBsAb. Unfortunately, 5-10% of patients' disease relapses after completion of treatment. A transient "flare" (ie, increased aminotransferase levels during the beginning of treatment) can be identified, and this represents the impact of the activated cytolytic T cells on the infected hepatocytes.
High levels of aminotransferases, a low viral load, and infection with the wild type are good prognostic factors for response to IFN-a treatment.
Asian patients and patients with the precore mutant virus tend to not have a clinical response to IFN-a treatment.
Special attention must be given to patients with HBV-decompensated cirrhosis (eg, ascites, encephalopathy) who are taking IFN-a because of the fact that, although they occasionally may have a treatment response, they can also deteriorate further.
The adverse effects of IFN-a treatment can sometimes be severe, even devastating. Some patients cannot complete treatment. A flulike syndrome, myelosuppression (eg, leukopenia, thrombocytopenia), nausea, diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia are among the adverse effects that may occur.
Pegylated IFN-a 2a
A 48-week regimen of pegylated IFN-a 2a might induce a 27% rate of HBeAg seroconversion and a 25% rate of loss of HBV DNA.18 Extension to treatment for 48 weeks resulted in an HBeAg seroconversion of 32%.
Placing patients that have HBeAg-negative chronic hepatitis B disease on 48 weeks of a pegylated IFN-a 2a regimen resulted in a significantly greater percentage of patients with a viral load that was nondetectable 24 weeks after the end of treatment (19%) compared with lamivudine monotherapy (7%).16
It appears that patients infected by hepatitis B virus (HBV) genotype A or B have a better response to IFN treatment compared with patients infected by genotype C or D, and this kind of treatment appears to be more appealing, especially for patients with increased ALT levels.
A nucleoside analogue that inhibits the viral polymerase, lamivudine has been associated with a 4-log reduction of the viral load. Lamivudine treatment (100 mg/d) has been associated with a 16-18% seroconversion rate from HBeAg to HBeAb, a 30-33% rate of HBeAg loss, a 40-50% normalization of the value of the aminotransferases, and a 1-2% HBsAg seroconversion rate.
Histologic improvement (ie, reduction of histologic activity index of >2 points) has been noticed in approximately 50% of patients taking this medication. The adverse effects are negligible.
Lamivudine appears to be effective for patients who do not have a treatment response to IFN-a (eg, patients infected by the precore mutant virus). A transient elevation of aminotransferases can be noticed shortly after starting treatment.
The HBeAg seroconversion rate has been shown to possibly increase to 27% after 2 years, 40% after 3 years, and 47% after 4 years of treatment in patients with a viral load of less than 104 pg/mL.
Lamivudine treatment has also been shown to dramatically improve the condition of patients with decompensated disease due to hepatitis B virus (HBV) reactivation.
The emergence of viral variants is the major complication in hepatitis B disease.22,23 Approximately 15-30% of patients develop a mutation of the viral polymerase gene (the YMDD variants) after 12 months of treatment, and approximately 50% develop a mutation after 3 years of treatment. However, continued treatment after the breakthrough with the variant type has been associated with lower HBV DNA levels, less aminotransferase activity, and histologic improvement. For these patients, discontinuation of treatment is accompanied by a reversion to a wild type of hepatitis B virus (HBV) and a flare of the disease.
Adefovir dipivoxil
This agent is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of adefovir dipivoxil has been tested in HBeAg-positive, HBeAg-negative, and lamivudine-resistant patients with encouraging results.
The estimated rate of resistance to adefovir and the development of mutations (rtN236T and rtA181V) are approximately 4-6% after 3 years and approximately 30% after 5 years of treatment.24,25,26,27
The optimal dose seems to be 10 mg/d.28,29 Higher doses are nephrotoxic.
The results of 2 multicenter trials that used adefovir for 48 weeks were published. In HBeAg-positive patients who received 10 mg of adefovir daily, a median 3.52 log reduction of the viral load (HBV DNA) level was noted. In 48% of the patients, normalized aminotransferase levels were reported. Histologic improvement was noticed in 53% of the patients who received this regimen.28 The HBeAg seroconversion rate was 12%. Of the HBeAg-negative population, 64% experienced histologic improvement after receiving 10 mg of adefovir for 48 weeks, and 72% had normalized aminotransferase levels. The serum HBV DNA level was decreased in 51% of subjects.28,29 The outcomes were maintained if treatment was continued for 144 weeks, but the benefits were lost if treatment was discontinued at 44 weeks. The development of resistant mutations (rtN236T and rtA181V) has been estimated to be around 6%.29
Entecavir is a potent guanosine analogue inhibitor of the viral polymerase with no resistance developed as of this writing, so far after 2 years of use, in patients who have no history of previous treatment with nucleoside analogues.
With regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who are naive to nucleoside analogues relative to patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 72% of the entecavir group versus 62% of the lamivudine group (P = 0.009). Undetectable serum HBV DNA levels were reported in 67% of entecavir-treated patients compared with 36% of lamivudine-treated patients (P <0.001). Normalized ALT levels were achieved in 68% of the entecavir group versus 60% of the lamivudine group (P = 0.02). The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log copies/mL (on a base-10 scale) in the entecavir-treated patients relative to 5.4 log copies/mL in the lamivudine-treated patients (P <0.001). HBeAg seroconversion occurred in 21% of patients treated with entecavir and 18% of patients treated with lamivudine (P = 0.33).
With regard to the HBeAg-negative population, administration of 0.5 mg of entecavir in patients who are naive to nucleoside analogues compared with patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 71% of the entecavir group versus 61% of the lamivudine group (P = 0.01). Undetectable serum HBV DNA levels were found in 90% of the entecavir-treated patients versus 72% of the lamivudine-treated patients (P <0.001). Normalized ALT levels were achieved in 78% of the entecavir group compared with 71% of the lamivudine group (P = 0.045).30 The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log copies/mL (on a base-10 scale) in the entecavir-treated patients versus 4.5 log copies/mL in the lamivudine-treated patients (P <0.001).30
Telbivudine, a cytosine nucleoside analogue, is a potent inhibitor of the HBV DNA polymerase.
The results of the GLOBE Trial, a phase III study, that tested the administration of 600 mg of telbivudine versus 100 mg of lamivudine over a 2-year period were announced.31,32 In the HBeAg-positive population, therapeutic response (defined as HBV DNA 2 points without worsening fibrosis) at week 48. The investigators included secondary end points such as viral suppression (HBV DNA level <400 copies/mL), histologic improvement, serologic response, normalization of ALT levels, and development of resistance mutations.35 At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir than of those receiving adefovir had reached the primary end point (P <0.001), and viral suppression occurred in more HBeAg-negative patients in the tenofovir group (93%) than patients in the adefovir group (63%) (P <0.001), as well as in more HBeAg-positive patients receiving tenofovir (76%) than those receiving adefovir (13%) (P <0.001).35 In addition, significantly more HBeAg-positive patients in the tenofovir group (68%) not only had normalized ALT levels relative to those in the adefovir group (54%) (P = 0.03) but also loss of HBsAg (3% tenofovir group vs 0% adefovir group) (P = 0.02).35 At the end of 48 weeks, none the patients had developed the amino acid substitutions within HBV DNA polymerase that are associated with phenotypic resistance to tenofovir or other drugs used to treat hepatitis B virus (HBV) infection; tenofovir  produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not; and the 2 treatments in both studies had similar safety profiles.35 Marcellin et al concluded that among patients with chronic hepatitis B virus (HBV) infection, tenofovir at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir at a daily dose of 10 mg through week 48.35

Surgical Care
Orthotopic liver transplantation (OLT) is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease. The implementation of hepatitis B immunoglobulin (HBIG) during and after the OLT period, and of lamivudine or adefovir in the pre-and post-OLT periods, dramatically improves the recurrence rate of hepatitis B virus (HBV) infection.

Acute and chronic hepatitis (patients without cirrhosis): No dietary restrictions
Decompensated cirrhosis (prominent signs of portal hypertension or encephalopathy): Low-sodium diet (1.5 g/d), high-protein diet (ie, white-meat protein [eg, pork, turkey, fish]), and, in cases of hyponatremia, fluid restriction (1.5 L/d)
The goals of pharmacotherapy in patients with hepatitis B disease are to reduce morbidity and to prevent complications.

Antiviral agents interfere with viral replication and weaken or abolish viral activity.

Tenofovir disoproxil fumarate (Viread)
Nucleotide analogue (adenosine monophosphate) reverse transcriptase and HBV polymerase inhibitor.

300 mg PO qd

For patients with renal impairment adjust dose as follows:

CrCl 30-49 mL/min: Administer q48h.
CrCl 10-29 mL/min Administer twice weekly.
CrCL 50 mL/min: 10 mg PO qd
CrCl 20-49 mL/min: 10 mg PO q48h
CrCl 10-19 mL/min: 10 mg PO q72h

Hemodialysis: 10 mg PO qwk following hemodialysis

Not established

DosingInteractionsContraindicationsPrecautionsCoadministration with ibuprofen increases the bioavailability of adefovir; drugs that alter renal tubular secretion may affect adefovir renal elimination.

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Hepatitis exacerbation may occur following drug discontinuation; may increase the risk of renal dysfunction; HIV resistance may emerge in patients with untreated or unrecognized HIV; lactic acidosis and hepatomegaly with steatosis have been reported with other nucleoside analogues

Entecavir (Baraclude)
Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate (dGTP) to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic HBV infection. Available as a tablet and as oral solution (0.05 mg/mL; 0.5 mg = 10 mL).

Treatment for nucleoside naive: 0.5 mg PO qd 2 h ac or 2 h pc

CrCl 30-49 mL/min: 0.25 mg PO qd
CrCl 10-29 mL/min: 0.15 mg PO qd
CrCl <10 mL/min: 0.05 mg PO qd

Receiving lamivudine or lamivudine resistance: 1 mg PO qd 2 h ac or 2 h pc

CrCl 30-49 mL/min: 0.5 mg PO qd
CrCl 10-29 mL/min: 0.3 mg PO qd
CrCl 50 mL/min: 600 mg PO qd
CrCl 30-49 mL/min: 600 mg PO q48h or 400 mg PO qd
CrCl <30 mL/min (not requiring dialysis): 600 mg PO q72h or 200 mg PO qd

ESRD: 600 mg PO q96h

Optimal treatment duration not established

16 years: Administer as in adults.

DosingInteractionsContraindicationsPrecautionsToxicity may increase when administered concurrently with drugs that decrease renal excretion (eg, acyclovir, aminoglycosides, amphotericin B, cisplatin, cyclosporine, metformin, tacrolimus); may increase the risk of myopathy when coadministered with HMG-CoA reductase inhibitors (statins)

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals; severe acute hepatitis B exacerbations have been reported when anti-hepatitis B therapy (including telbivudine) is discontinued (closely monitor hepatic function with both clinical and laboratory follow-up for at least several months following discontinuation of anti-hepatitis B therapy, and resume therapy, if necessary); myopathy has been reported; common adverse effects include upper respiratory tract infection, fatigue, malaise, abdominal pain, nasopharyngitis, headache, increased CK level, cough, nausea, vomiting, flulike symptoms, diarrhea, pyrexia, arthralgia, rash, back pain, dizziness, and dyspepsia.

Interferon agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions.

Peginterferon alfa 2a (Pegasys)
Binds to cell surface receptors in a cascade of protein interactions resulting in gene transcription. These stimulated genes inhibit viral replication in infected cells, cell proliferation, and immunomodulation. Indicated for adults with HBeAg-positive and HBeAg-negative chronic hepatitis B disease with compensated liver disease and evidence of viral replication and liver inflammation.

180 mcg SC once weekly for 48 wk; administer in abdomen or thigh

Not established

DosingInteractionsContraindicationsPrecautionsTheophylline may increase toxicity by reducing clearance; cimetidine may increase the antitumor effects; zidovudine and vinblastine may increase toxicity.

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; ongoing or recent alcohol use; platelet count <70,000/mm3

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

X - Contraindicated; benefit does not outweigh risk

Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis, aggressive behavior, hallucinations, violent behavior, suicidal ideation, suicide attempt, suicide, homicidal ideation [rare]), even without previous history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia; neutropenia; thrombocytopenia; thyroid dysfunction; retinal abnormalities

Interferon alfa-2b (Intron A) or alfa-2a (Roferon-A)
Protein product manufactured by recombinant DNA technology. Mechanism of antiviral activity is not clearly understood. However, modulation of host immune responses enhances cytolytic T-cell activity; stimulates natural killer cell activity and amplifies HLA class I protein on infected cells. Direct antiviral activity activates viral ribonucleases, inhibits viral entry to cells, and inhibits viral replication. Direct antifibrotic effect has been postulated.

Before initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if patient's condition does not respond within 4 months, discontinue treatment. If a response occurs, continue treatment until no further improvement is observed. Whether continued treatment is beneficial after that time remains unknown.

5 million U IM/SC qd for 16 wk; alternatively, 10 million U IM/SC 3 times per wk for 16 wk

Reduce dose by 50% if severe reactions occur or temporarily discontinue therapy until symptoms from adverse reactions improve.

Not established

1024307 tn?1292002086
by April63, Oct 05, 2009
Great information. Please keep doing your wonderful work. Thank you!

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