Antiviral Therapy for Adults With Chronic Hepatitis B: A Systematic Review for a National Institutes of Health Consensus Development Conference

Tatyana A. Shamliyan; Roderick MacDonald; Aasma Shaukat; Brent C. Taylor; Jian-Min Yuan; James R. Johnson; James Tacklind; Indulis Rutks; Robert L. Kane; Timothy J. Wilt

doi:10.7326/0003-4819-150-2-200901200-00101

Conferences |20 January 2009

Antiviral Therapy for Adults With Chronic Hepatitis B: A Systematic Review for a National Institutes of Health Consensus Development Conference Free

Tatyana A. Shamliyan, MD, MS; Roderick MacDonald, MS; Aasma Shaukat, MD, MPH; Brent C. Taylor, PhD, MPH; Jian-Min Yuan, MD, PhD; James R. Johnson, MD; James Tacklind, BS; Indulis Rutks, BS; Robert L. Kane, MD; Timothy J. Wilt, MD, MPH

Tatyana A. Shamliyan, MD, MS

From the Minnesota Evidence-based Practice Center, University of Minnesota School of Public Health, Minneapolis Veterans Affairs Center for Chronic Disease Outcomes Research, and the University of Minnesota Medical School, Minneapolis, Minnesota.

Roderick MacDonald, MS

Aasma Shaukat, MD, MPH

Brent C. Taylor, PhD, MPH

Jian-Min Yuan, MD, PhD

James R. Johnson, MD

James Tacklind, BS

Indulis Rutks, BS

Robert L. Kane, MD

Timothy J. Wilt, MD, MPH

Article, Author, and Disclosure Information

From the Minnesota Evidence-based Practice Center, University of Minnesota School of Public Health, Minneapolis Veterans Affairs Center for Chronic Disease Outcomes Research, and the University of Minnesota Medical School, Minneapolis, Minnesota.
Disclaimer: The authors of this report are responsible for its content. Statements in the paper should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank the technical expert panel members Dr. Miriam Alter, Dr. Gary Davis, Dr. Daryl Lau, Dr. Michael Sorrell, and Dr. Myron Tong for their scientific and clinical input throughout this project; Shilpa Amin, MD, MBSC, AHRQ Task Order Officer, for her guidance throughout the project; and Dr. John Ward for reviewing and commenting on the draft. They also thank the librarians Judith Stanke and Dr. Del Reed for their contributions to the literature search; Maureen Carlyle and Marilyn Eells for their excellent technical assistance in preparation of the full evidence report and this manuscript; and Rebecca Schultz and Nancy Russell for their assistance with formatting the tables.
Grant Support: By Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services contract number 290-02-0009.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Tatyana A. Shamliyan, MD, MS, Division of Health Policy and Management, University of Minnesota School of Public Health, D351 Mayo (MMC 197), 420 Delaware Street SE, Minneapolis, MN 55455; e-mail, shaml005@umn.edu.
Current Author Addresses: Drs. Shamliyan and Kane: Division of Health Policy and Management, University of Minnesota School of Public Health, D351 Mayo (MMC 197), 420 Delaware Street SE, Minneapolis, MN.
Mr. MacDonald, Drs. Taylor and Wilt, and Mr. Rutks: Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.
Dr. Shaukat: Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, 420 Delaware Street SE (MMC 36), Minneapolis, MN 55455.
Dr. Yuan: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Room 300, West Bank Office Building, 1300 South Second Street, Minneapolis, MN 55454.
Dr. Johnson: Department of Infectious Diseases, Minneapolis Veterans Affairs Medical Center (111-F), 1 Veterans Drive, Minneapolis, MN 55417.
Mr. Tacklind: Agency for Healthcare Research and Quality Center for Chronic Disease Outcomes Research and the Cochrane Prostatic Diseases and Urologic Cancers Group, Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.
Author Contributions: Conception and design: T.A. Shamliyan, R.L. Kane, T.J. Wilt.
Analysis and interpretation of the data: T.A. Shamliyan, R. MacDonald, A. Shaukat, B.C. Taylor, J.R. Johnson, T.J. Wilt.
Drafting of the article: T.A. Shamliyan, R. MacDonald, A. Shaukat.
Critical revision of the article for important intellectual content: T.A. Shamliyan, A. Shaukat, B.C. Taylor, J.-M. Yuan, J.R. Johnson, R.L. Kane, T.J. Wilt.
Final approval of the article: T.A. Shamliyan, A. Shaukat, B.C. Taylor, J.-M. Yuan, J.R. Johnson, R.L. Kane, T.J. Wilt.
Provision of study materials or patients: I. Rutks.
Statistical expertise: R. MacDonald.
Obtaining of funding: R.L. Kane, T.J. Wilt.
Administrative, technical, or logistic support: R. MacDonald, J. Tacklind, I. Rutks, R.L. Kane, T.J. Wilt.
Collection and assembly of data: T.A. Shamliyan, R. MacDonald, A. Shaukat, J. Tacklind, I. Rutks.

Abstract

Background:

Chronic hepatitis B infection can lead to liver failure, hepatocellular carcinoma, and death.

Purpose:

To evaluate the effectiveness of antiviral therapy for adults with chronic hepatitis B infection.

Data Sources:

Randomized, controlled trials (RCTs) of interferon (α2b and pegylated α2a), lamivudine, adefovir, entecavir, and telbivudine published from 1990 to 2008.

Study Selection:

Randomized, controlled clinical trials of adults with chronic hepatitis B published in English after 1989 that reported death; incidence of hepatocellular carcinoma or liver failure; prevalence and incidence of cirrhosis; presence or seroconversion of hepatitis B e antigen (HBeAg) or surface antigen (HBsAg), viral load of hepatitis B virus DNA; aspartate aminotransferase and alanine aminotransferase (ALT) levels; or fibrosis scores after therapy with interferon-α2b, pegylated interferon-α2a, lamivudine, adefovir, entecavir, and telbivudine.

Data Extraction:

Data extracted with standard protocols to calculate risk difference for clinical outcomes, viral load, HBeAg and HBsAg, ALT, histologic scores, and adverse events.

Data Synthesis:

In 16 RCTs (4431 patients), drug treatment did not improve clinical outcomes of chronic hepatitis B infection, but the trials were underpowered. In 60 RCTs that examined intermediate outcomes, no single treatment improved all intermediate outcomes. Low-quality evidence suggested HBsAg clearance after interferon-α2b (2 RCTs; 211 patients). Moderate-quality evidence suggested ALT normalization at follow-up after treatment with adefovir (2 RCTs; 600 patients) and HBeAg loss with lamivudine (2 RCTs; 318 patients). With interferon-α2b, moderate-quality evidence suggested HBeAg loss (3 RCTs; 351 patients), seroconversion (2 RCTs; 304 patients), and ALT normalization (2 RCTs; 131 patients). Pegylated interferon-α2a versus lamivudine improved HBeAg seroconversion (1 RCT; 814 patients) and ALT normalization (2 RCTs; 905 patients) off treatment. Pegylated interferon-α2a combined with lamivudine versus lamivudine improved HBeAg loss (1 RCT; 543 patients) and ALT normalization (2 RCTs; 905 patients). Adverse events during antiretroviral therapy occurred in more than 50% of patients but were not associated with increased treatment discontinuation. However, most studies excluded patients with hepatic or renal insufficiency or other serious comorbid conditions.

Limitation:

Marked heterogeneity in study samples, interventions, and measured outcomes preclude definitive conclusions.

Conclusion:

Evidence was insufficient to assess treatment effect on clinical outcomes or determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. Future research is needed to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection.

Hepatitis B is highly prevalent, with 350 million chronic cases worldwide (1). Despite immunization efforts, 4713 incident cases of hepatitis B were diagnosed in the United States in 2006 (2). An estimated 2000 to 4000 deaths per year in the United States are related to chronic hepatitis B liver diseases (3), including liver cirrhosis and hepatocellular carcinoma (4).

Because most patients are asymptomatic, treatment goals of antiviral therapy include long-term prevention of progression, development of cirrhosis and liver failure, and hepatocellular carcinoma. Short-term intermediate laboratory responses have been proposed as potential surrogate measures of treatment effects on clinical outcomes (1). Normalization of liver enzyme levels, viral suppression and clearance, reduction in histologic scores of liver inflammation or fibrosis, and combinations of these outcomes have been used to measure response to antiviral drugs or development of antiviral resistance (1, 5).

Seven antiviral agents are approved to treat hepatitis B in the United States, including oral medications (lamivudine, telbuvidine, adefovir, tenofovir, and entecavir) and injected interferons (standard interferon-α2b and pegylated interferon-α2a). Other agents are under investigation. The U.S. Food and Drug Administration approved tenofovir for adults in August 2008 on the basis of ongoing, unpublished trials that compared tenofovir with adefovir on intermediate outcomes, the results of which were not available for our review (6).

This review was commissioned as background material for the National Institutes of Health Consensus Development Conference on Management of Chronic Hepatitis B in Adults to synthesize the published evidence about the effectiveness of interferon therapy, oral therapy, and various combinations with defined or continuous courses of treatment. The full report, including a detailed description of our methods, is available at www.ahrq.gov/downloads/pub/evidence/pdf/hepb/hepb.pdf (7).

Methods

Data Sources and Study Selection

We searched MEDLINE, PubMed, the Cochrane Library (8), and other databases (9–11). We included randomized, controlled clinical trials (RCTs) of adults with chronic hepatitis B published in English after 1989 that reported death; incidence of hepatocellular carcinoma or liver failure; prevalence and incidence of cirrhosis; presence or seroconversion of hepatitis B e antigen (HBeAg) or surface antigen (HBsAg); viral load of hepatitis B virus (HBV) DNA; aspartate aminotransferase and alanine aminotransferase (ALT) levels; and histologic necroinflammatory or fibrosis scores after therapy with interferon-α2b, pegylated interferon-α2a, lamivudine, adefovir, entecavir, and telbivudine (12). Studies that enrolled at least 50 adults and provided treatment for 24 weeks or more were eligible for this review. Interferon studies of any size were eligible if participants were given treatment for at least 12 weeks. We excluded studies evaluating pregnant women, patients with hepatocellular carcinoma or HIV infection at baseline, patients undergoing chemotherapy or liver transplantation, or patients with several causes of hepatitis, unless outcomes for participants meeting our eligibility criteria were reported separately. The full report describes the search strategies (7). We included publications from the multinational HBV 99-01 Study Group assessing pegylated interferon-α2b, a treatment that has been intensively examined in patients with chronic hepatitis B but is not yet approved in the United States (13). Three investigators independently measured study eligibility (14).

Data Extraction and Quality Assessment

Three researchers independently evaluated the studies and extracted data to detect errors and discrepancies (14). We abstracted the number of events among treatment groups to calculate rates, relative risks (RRs), and absolute risk differences (15). We abstracted the number of patients randomly assigned to each treatment group as the denominator to calculate estimates, applying the intention-to-treat principle. We recorded intervals for outcome assessments in weeks from randomization for the active-treatment period and from the end of treatment for follow-up assessments. We prioritized clinical outcomes in the assessment of treatment benefits and harms. Sustained HBsAg loss or seroconversion was considered the criterion for resolution of hepatitis B viral infection and a major goal of antiviral therapy (1). Liver histologic outcomes included improved necroinflammatory and fibrosis scores. Sustained ALT normalization as diagnostic criteria of hepatocyte injury and sustained clearance of HBV DNA were assigned as secondary outcomes. Although positive associations with better clinical outcomes exist in observational studies, both outcomes may reverse after treatment. Because low levels of evidence from observational studies suggested that HBeAg-negative status was associated with worse clinical outcomes, we defined sustained HBeAg seroconversion as a desirable intermediate outcome.

We analyzed RCTs for participant selection, duration of and loss to follow-up, intention-to-treat principle, masking of treatment status, randomization scheme and its adequacy, allocation concealment, and justification of sample sizes (16). We assessed the level of evidence on the basis of the Grading of Recommendations Assessment, Development and Evaluation Working Group criteria (17, 18). We assigned a low level of evidence when data were from small RCTs or RCTs with flaws in design or analysis or were from post hoc subgroup analysis. We assigned a moderate level of evidence when a single, large multinational study or several small RCTs reported consistent associations between antiviral agents and outcomes and a high level of evidence when several high-quality studies in applicable patients reported consistent sustained effects at least 6 months after therapy.

Data Synthesis and Analysis

The full report includes evidence tables that summarize results of individual studies (7). We compared baseline data across the studies to test for differences in the target sample and to detect unusual patterns in the data (19–21). Analyses were conducted separately for clinical, biochemical, virologic, and histologic outcomes and for RRs and absolute risk differences. The protocol for meta-analyses was created according to recommendations (22, 23) to assess the consistency of the association between treatments and outcomes with random-effects models (24). Pooling criteria included the same operational definitions of outcomes and drug interventions (23). We used chi-square tests to assess heterogeneity (25, 26). Calculations used Stata statistical software, version 9.2 (StataCorp, College Station, Texas) (27). We assumed the presence of publication bias and did not use statistical tests for bias caused by sparse and heterogeneous data (14, 28–30).

Role of the Funding Source

The Agency for Healthcare Research and Quality suggested the initial questions and provided copyright release for this manuscript. The funding source had no role in the literature search, data analysis, conduct of the study, preparation of the review, or interpretation of the results. The funding source reviewed and approved the submitted manuscript without revisions.

Results

Ninety-three articles represented 60 unique RCTs (31–102). The full report contains the study flow diagram and the appendix with excluded studies (7). Studies enrolled 20 to 1367 patients who were predominately HBeAg-positive. Men constituted 78% of enrollees. Most enrollees were Asian (64%) or white (30%). The estimated duration of infection, reported in 8 studies, ranged from approximately 2 to 6 years. However, individual patient duration of infection ranged from 6 months to 20 years (31–40).

Clinical Outcomes

Studies that reported death, liver-related death, hepatocellular carcinoma, hepatic decompensation, or cirrhosis (Table) were not designed and did not have sufficient power to reliably assess drug effects on these clinical outcomes.

Table. Effects of Drug Therapies for Chronic Hepatitis B on Clinical Outcomes

Death was assessed in 13 studies, with very few deaths reported (36, 39–50). Low-level evidence suggested that lamivudine (41), entecavir (43–47), interferon-α2b (36, 39, 48), pegylated interferon-α2a (49), pegylated interferon-α2b (50), and adefovir (42) did not decrease mortality.

Two studies assessed cirrhosis with small sample size and relatively short-term treatment with interferon-α2b. Reduction in cirrhosis incidence (40) or prevalence (51) was not observed. Few events occurred, and the studies were not sufficiently powered to detect differences in cirrhosis (52).

Three studies reported hepatic decompensation with very few events (44, 47, 53). There was no significant difference in hepatic decompensation after administration of lamivudine versus placebo (55) or entecavir versus lamivudine (44, 47). A multicenter study involving 651 Asian patients (58% were HBeAg-positive) with confirmed cirrhosis (61%) or advanced fibrosis (41) reported a decrease in “disease progression” (7.8% vs. 17.7% [hazard ratio, 0.45; P = 0.001]) for lamivudine versus placebo. Disease progression was the first occurrence of an increase of at least 2 points in the Child–Pugh score, hepatic decompensation, bleeding varices, renal insufficiency, bleeding gastric or esophageal varices, spontaneous bacterial peritonitis with proven sepsis, hepatocellular carcinoma, or death related to liver disease.

Four studies reported hepatocellular carcinoma. None demonstrated a statistically significant difference compared with no treatment after lamivudine (41), interferon-α2b (54), prolonged adefovir therapy (42), or interferon monotherapy with and without corticosteroids (51). Incidence of hepatocellular carcinoma did not differ between lamivudine and placebo in the multicenter study of patients with confirmed cirrhosis or advanced fibrosis mentioned earlier (41). The author's primary analysis that adjusted for country, sex, baseline ALT level, Child–Pugh score, and Ishak fibrosis score found a borderline significant effect (hazard ratio, 0.49 [95% CI, 0.25 to 0.99]) (41). Results were not statistically significant when the authors excluded patients who developed hepatocellular carcinoma within 1 year of enrollment.

Intermediate Outcomes

Effects of Drugs on Markers of Resolved Hepatitis B

Four RCTs examined the effects of interferon-α2b on HBsAg loss (essential diagnostic criteria of chronic hepatitis B) (1) combined with other markers of resolved hepatitis B, including loss of HBV DNA, HBeAg seroconversion, and normalization of ALT (54–57), and did not find a significant increase in rates of complete response (Appendix Table 1). Compared with placebo, drugs did not increase HBsAg clearance at the end of the treatments. Only 1 RCT of 169 HBeAg-positive patients found a significant increase in HBsAg loss at the end of 24 weeks of interferon-α2b therapy (38) and interferon-α2b with corticosteroid therapy. Two RCTs (38, 48) found that steroid pretreatment followed by interferon-α2b compared with no antiviral drugs significantly increased HBsAg loss by 11% at the end of the treatments.

Eight RCTs (34, 38, 44, 47, 54, 58–60) investigated combined virologic and biochemical outcomes, including HBV DNA loss, HBeAg clearance and seroconversion, and ALT normalization (Appendix Table 1) at the end of treatment, and 13 RCTs (33–35, 44, 46, 50, 51, 54–57, 59, 60) examined the same outcomes at follow-up off interferon treatments. Interferon-α2b increased sustained rates of undetectable HBV DNA and HBeAg (33, 35, 54, 55), negative HBV DNA and HBeAg combined with normal ALT (57), and rates of undetectable HBV DNA combined with normalization of ALT (34, 54). Interferon-α2b combined with lamivudine compared with lamivudine alone increased HBV DNA loss and HBeAg clearance and seroconversion in 75 treatment-naive patients (59).

Histologic Outcomes

Histologic outcomes (Appendix Table 1) included improvement in total, fibrosis, or necroinflammatory scores as proposed surrogates to assess preventive effects of treatments on development of cirrhosis in individual patients (61, 62).

Effects of Drugs on Histologic Outcomes at the End of Treatment

Adefovir for 48 to 96 weeks improved necroinflammatory and fibrosis scores compared with placebo with no dose–response association (Appendix Table 1) (63–65). Lamivudine administration for 48 to 96 weeks improved necroinflammatory scores in all RCTs (60, 66–68). Entecavir compared with lamivudine improved necroinflammatory scores but without a dose–response association (44–46).

Effects of Drugs on Histologic Outcomes at Follow-up After Treatment

Only 1 RCT (69) reported histologic improvement in necroinflammatory scores at 24-week follow-up after completion of a 48-week administration of pegylated interferon-α2a compared with lamivudine in 552 HBeAg-negative patients (69) (Appendix Table 1).

Viral (HBV DNA) Clearance

Viral (HBV DNA) clearance was associated with a favorable prognosis in observational longitudinal studies, although few data are available that are adjusted for baseline HBV DNA levels (1, 4) (Appendix Table 1). The studies used assays with different sensitivity to detect HBV DNA, including polymerase chain reaction assay (31, 33, 36, 44, 45, 47, 58, 60, 63, 70–77), reverse transcription polymerase chain reaction assay (43, 78), or solution hybridization assay (32, 37–39, 51, 59, 67, 68, 79–84).

Effects of Drugs on Viral Clearance at Follow-up After Treatment

Limited low to moderate evidence suggested that antiviral drugs and their combinations resulted in HBV DNA clearance at follow-up after therapy, ranging from 18 to 24 weeks. Interferon-α2b at 8- to 24-week follow-up increased HBV DNA loss compared with placebo or no antiviral therapy (33, 37); however, the effects were attenuated at longer follow-up (33, 37, 38). Limited, low-level evidence from 1 RCT suggested effects of lamivudine on HBV DNA loss at 24-week follow-up after 96 weeks of drug administration (60). One large RCT reported a significant benefit from adefovir administration in HBeAg-negative patients that was maintained at 18 weeks after treatment (64). Entecavir provided similar HBV DNA loss compared with lamivudine at 24-week follow-up (44) (Appendix Table 1).

Effects of Drugs on ALT Normalization at Follow-up Off Treatment

Alanine aminotransferase normalization at follow-up off treatment was greater after adefovir compared with placebo in HBeAg-negative (64) as well as -positive patients (74). Lamivudine compared with placebo increased rates of ALT at 24-week follow-up off treatment in 139 HBeAg-negative patients (60). Interferon-α2b at doses of 35 million units per week but not 7 million units per week compared with no antiviral treatment increased rates of ALT normalization at 8- to 24-week follow-up (33, 38). In contrast with the superior effectiveness of lamivudine at the end of the treatment, ALT normalization at 24- week follow-up after treatment was greater after pegylated interferon-α2a compared with lamivudine, and after combined therapy of pegylated interferon-α2a with lamivudine compared with lamivudine alone (49, 69).

Effects of Drugs on HBeAg Clearance or Seroconversion at Follow-up Off Treatment

A moderate amount of evidence demonstrated a significant sustained HBeAg clearance at follow-up off treatment for interferon-α2b (33, 40, 85). In patients receiving 52 weeks of lamivudine, HBeAg loss was greater at 16 weeks after therapy than in patients receiving placebo (68, 80). Interferon-α2b (40, 85) increased rates of HBeAg seroconversion versus placebo at 28- to 64-week follow-up. Pooled analysis of individual patient data from 4 RCTs found a significant increase in HBeAg seroconversion after combined therapy with interferon-α2b and lamivudine (85). Telbivudine compared with adefovir for 24 to 52 weeks increased HBeAg seroconversion in relative terms without significant differences in absolute rates (76). Pegylated interferon-α2a increased HBeAg seroconversion at 24-week follow-up compared with lamivudine (49). Pegylated interferon-α2a combined with lamivudine resulted in greater HBeAg seroconversion compared with lamivudine alone but not pegylated interferon-α2a alone (49). Combined treatments of pegylated interferon-α2b with lamivudine for 60 weeks increased HBeAg seroconversion compared with lamivudine alone (48). All other comparisons demonstrated random differences between compared drugs.

Relapse was reappearance of HBV DNA (31, 45, 47, 58, 73, 74, 82, 86–88) or increase in viral load and ALT levels (78) at the end of active treatments or at follow-up after therapies (34, 35, 38, 44, 50, 51, 54, 59, 83) (Appendix Table 1). Lamivudine administration for 60 weeks compared with 48 weeks increased rates of virologic relapse in 1 RCT of HBeAg-positive patients (88). Entecavir administration for 52 weeks resulted in lower rates of viral relapse at 24-week follow-up after treatment compared with lamivudine in HBeAg-positive, treatment-naive patients (44).

Drug-Specific Mutations

Drug-specific mutation (Appendix Table 1) was detected by the development of resistant HBV YMDD mutations (mutation in amino acid sequence tyrosine, methionine, aspartate, aspartate) at the end of lamivudine treatments (31, 41, 42, 49, 59, 63, 71, 73, 78, 80, 86–90) or at follow-up after the therapies (64, 79) (Appendix Table 1). Lamivudine administration increased the rates of YMDD mutation compared with placebo by 43% (41, 80). Longer treatments for 60 weeks versus 48 weeks resulted in larger rates of mixed and pure YMDD mutations (88). Adefovir versus placebo increased rates of emerging amino acid substitutions in the HBV-RT domain and rates of rt221Y amino acid substitution but not rt134D, rt219A, rt91I, rt134N, rt54H, and rt145M substitutions (63, 86). Longer treatments for 240 versus 114 weeks increased rates of adefovir-resistant mutations (42). However, combined therapy with adefovir plus lamivudine reduced the rates of YMDD compared with lamivudine monotherapy in patients with chronic hepatitis B and YMDD mutant HBV (71), with random differences in wild-type mutations. Interferon-α2b combined with lamivudine reduced rates of mutation compared with lamivudine alone, but with inconsistent effect sizes across 6 studies (31, 59, 73, 80, 87, 89). Pegylated interferon-α2a with lamivudine compared with pegylated interferon-α2a alone increased mutation in HBeAg-positive patients (49). The same study reported reduced rates of mutations with pegylated interferon-α2a or peginterferon-α2a combined with lamivudine than with lamivudine monotherapy (49). At follow-up after treatments, interferon-α2b alone or combined with lamivudine resulted in lower rates of mutations compared with lamivudine alone (79).

Baseline HBeAg status has been used for treatment decision making. However, the association between changes in HBeAg and clinical outcomes has not been tested in RCTs. Low-quality evidence indicates that treatment effects may vary by baseline HBeAg status.

Evidence From Trials That Combined Patients With HBeAg-Negative and -Positive Baseline Status

Lamivudine decreased disease progression (defined by hepatic decompensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease) compared with placebo among patients who were HBeAg-positive at baseline but did not decrease disease progression among those who were HBeAg-negative (41). Telbivudine compared with lamivudine reduced the rates of detectable HBV DNA and improved necroinflammatory scores, with no worsening in the Knodell fibrosis score among HBeAg-positive patients, and random differences occurred in HBeAg-negative patients (77). Telbivudine compared with lamivudine in patients with compensated hepatitis B resulted in better outcomes in HBeAg-positive patients with no difference in a small subsample of HBeAg-negative patients (91). In contrast, only entecavir compared with lamivudine resulted in higher rates of undetectable HBV DNA and normal ALT levels among patients with an HBeAg-negative baseline status, and random differences occurred in HBeAg-positive patients (43).

Evidence from trials that included only HBeAg-negative patients (11 studies) suggested no effects on clinical outcomes or resolved hepatitis and inconsistent effects on intermediate measures. Adefovir improved biochemical, virologic, and histologic outcomes at the end of treatment and at follow-up after the treatment without development of genetic mutations (63, 64). Interferon-α2b combined with lamivudine was not more effective than lamivudine alone on combined (virologic with biochemical) (82) or virologic (73, 82, 89) outcomes but lowered the rates of reappearance of detectable serum HBV DNA (71) and genetic viral mutations (89). Pegylated interferon-α2a compared with lamivudine improved off-treatment biochemical and virologic outcomes and necroinflammatory scores but did not improve fibrosis scores (69). Pegylated interferon-α2a combined with lamivudine compared with lamivudine improved biochemical and virologic outcomes, with no differences in liver histology, after treatment (69).

Applicability of the Results to Patient Subsamples

The results from published RCTs can be generalized to adults with chronic hepatitis B without hepatic decompensation and serious confounding illnesses, predominately Asian or white men. Low-level evidence from RCTs suggested moderate differences in treatment effects among patient subsamples with different baseline characteristics (www.ahrq.gov/clinic/epcindex.htm). Younger patient age was associated with enhanced HBV DNA clearance and ALT normalization in patients treated with pegylated interferon versus lamivudine (92, 93). Disease progression or treatment induced sustained ALT normalization, and HBV DNA clearance did not vary by sex (41, 53, 83, 92, 93) or baseline body weight (92). Patients with longer duration of hepatitis responded to therapy 2.5 times less frequently than those with shorter duration of the disease. Sustained virologic response (HBeAg and HBV DNA loss) at 48 weeks off therapy with interferon-α2b combined with lamivudine compared with lamivudine monotherapy was greater in patients with an estimated duration of hepatitis of 10 years or less after adjustment for sex and age (31).

Treatment-induced follow-up histology, HBeAg or DNA clearance, and ALT normalization did not clearly vary by baseline histology severity (31, 58, 85, 94). However, individual RCTs reported that HBeAg loss was higher per 1-unit increase in baseline histologic activity index score (85). Lamivudine improved histology more than placebo among patients with moderate or severe hepatitis but failed in those with mild hepatitis (67). Virologic response to interferon-α2b plus lamivudine after treatment increased in those with a baseline inflammation score of 7 or more, independent of sex and age (31). Presence of steatosis did not modify the effect of pegylated interferon-α2a combined with lamivudine on posttreatment response (HBV DNA disappearance and ALT normalization) in both HBeAg-positive and -negative patients (94). Adjusted rates of posttreatment response were greater per 1-unit increase in baseline Knodell histologic activity index (94).

The effect of viral load on outcomes after therapy was difficult to interpret because of varying assays and cutoffs of baseline DNA. Inconsistent effects yielded no dose–response relationship. No studies reported subgroups with very low viral load. Combined administration of interferon-α2b with lamivudine resulted in greater HBV DNA clearance and HBeAg seroconversion after treatment in patients with baseline HBV DNA greater than 10⁷ copies/mL (59). Pegylated interferon-α2a provided greater sustained response than did lamivudine in patients with baseline HBV DNA in the 25th to 75th percentile range (49, 92), with random differences at other percentiles. Treatment-induced ALT normalization and HBV DNA clearance or HBeAg seroconversion varied by HBV DNA genotype. Patients with genotypes B and C versus patients with genotype D had better responses at the end of treatments (92) and at follow-up after therapy (49, 90, 92, 93, 95–97). Patients with genotype A had lower adjusted odds of response than did patients with genotype C (92).

Baseline ALT Levels

Treatment-induced improvement in intermediate outcomes varied by baseline ALT levels, with inconsistent low-level evidence of a better response among patients with elevated baseline ALT levels (31, 49, 85, 94, 95). Hepatitis B virus DNA loss was more frequent among patients with elevated baseline ALT levels at follow-up after interferon-α2b administration with corticosteroid pretreatment than after interferon-α2b alone (95). Adjusted odds of sustained virologic response to interferon-α2b combined with lamivudine compared with lamivudine alone were higher in patients with baseline ALT levels of 150 U/L or more versus less than 150 U/L (RR, 3.12 [CI, 1.43 to 6.82]) (31). Sustained response to pegylated interferon-α2a combined with lamivudine compared with lamivudine alone was greater per 1-U/L increase in baseline ALT levels (RR, 10.32 [CI, 9.71 to 10.97]) (94). However, several studies reported no association between dose–response increase in baseline ALT levels and sustained response to pegylated interferon-α2a versus lamivudine (49) or pegylated interferon-α2b combined with lamivudine versus lamivudine (96).

Pretreatment Status

Seroconversion of HBeAg after pegylated interferon-α2a (alone or with lamivudine) was higher than that after lamivudine among lamivudine-naive patients (49), but not among previous lamivudine recipients. Five RCTs enrolled lamivudine-resistant patients (43, 46, 53, 72, 98). Among patients who did not respond to lamivudine, adefovir plus lamivudine versus lamivudine increased ALT normalization and HBV DNA clearance but not HBeAg clearance or seroconversion (72) without improving outcomes compared with adefovir monotherapy (72). Entecavir increased HBV DNA and HBeAg clearance and normalization of ALT in HBeAg-positive patients compared with lamivudine (43, 46) and improved necroinflammatory and fibrosis scores (46). Patients whose previous interferon therapy failed did not benefit from the addition of lamivudine (99).

Adverse Events

Investigators assessed adverse events to decide whether a change in dose or discontinuation of therapy was needed because of severity of events or laboratory abnormalities (Figure; Appendix Table 2). Duration of the assessed events and treatment utilization for adverse events was not reported. Variability of the reported adverse events and the definitions of severity and seriousness preclude pooling of harms. We could not detect obvious reasons for such variability because no validated questionnaire exists to assess adverse events after antiviral drugs. Studies did not report run-in periods of drug therapy to identify and exclude patients with adverse events before randomization. Almost all studies excluded patients with hepatic decompensation or renal insufficiency. Many studies excluded patients with serious comorbid conditions (31, 41, 49, 51, 53, 58, 65, 68–70, 72, 78, 80, 90, 100, 101) or nonviral chronic liver diseases (31, 41, 43, 44, 46, 59, 67, 68, 75, 79–81, 89, 98, 102). Randomization still resulted in valid comparisons of adverse events in the active treatment group versus control group, and absolute rates of adverse events compared with the odds of positive effects on various outcomes permit an estimate of the balance between benefits and harms in clinical settings (Figure).

Figure.

Absolute rates of the frequent (>40%) adverse effects after interferon therapy, by baseline HBeAg status.

HBeAg = hepatitis B e antigen.

Adverse events during antiviral therapy were reported for more than 50% of patients. Forty-four publications reported withdrawal from treatment and adverse effects categorized as “serious” by the investigators. No study assessed treatment adherence. Withdrawal rates and frequency and severity of adverse events after oral antiviral drugs were similar to those with placebo. The general exceptions included increases in ALT levels with adefovir and lamivudine and an added black-box warning that participants with or at risk for impaired renal function may develop nephrotoxicity with long-term administration of adefovir. Other reported adverse events were usually mild, including fatigue, headache, abdominal pain, nausea, and diarrhea. Entecavir was better tolerated than lamivudine (44, 46, 47).

Interferon-based therapies were not as well tolerated as oral drugs. Dose modifications, primarily because of neutropenia and thrombocytopenia, were required for nearly 50% of individuals receiving interferon-based therapies. An initial influenza-like illness was commonly associated with pegylated interferon-α2a treatment, noted by pyrexia, fatigue, myalgia, and headache. Withdrawal rates were 24% higher after interferon-α2b than with no treatment (54). Pegylated interferon-α2a combined with lamivudine resulted in greater discontinuation versus placebo or lamivudine alone (69). Patients had serious adverse events more often after combined therapy of lamivudine with interferon-α2b (89) or pegylated interferon-α2a (49) than after lamivudine alone.

Discussion

We restricted our review to publications in English, but conducted an additional MEDLINE search for RCTs of eligible antiviral drugs that were published in other languages. We reviewed the abstracts of 10 publications published in Chinese that examined adefovir (103), entecavir (104, 105), interferon-α2b or pegylated interferon-α2b (106, 107), and lamivudine (108–112). We concluded that language bias, if present, would not change our overall conclusions about the efficacy of the evaluated antiviral drugs in adults with chronic hepatitis B.

We did not evaluate antiviral drugs that have not been approved by the U.S. Food and Drug Administration for chronic hepatitis B, including emtricitabine, clevudine, pradefovir, valtorcitabine, and thymosin-α1 (113). These drugs did not prevent liver cancer or decompensation but resulted in viral loss and normalization of ALT levels (114–117), HBeAg seroconversion and improved histology (118), antiviral mutations, and immunologic biomarkers (119) in patients with chronic hepatitis B or coinfection with HIV (120, 121).

Data available from RCTs are insufficient to provide patients, clinicians, researchers, and policymakers with high-quality information needed for decision making about the long-term effects of chronic hepatitis B treatments on clinical outcomes. None of the RCTs demonstrated an effect on death, hepatocellular carcinoma, liver decompensation, cirrhosis, or resolved hepatitis. However, none were of sufficient size or duration or were designed to assess clinical outcomes. Individual studies reported very few events and compared different drugs and patients, generally precluding pooling. Therefore, we cannot exclude the possibility that antiviral agents might improve clinical outcomes.

A single study found a significant reduction in hepatocellular carcinoma due to lamivudine in 651 adults (98% were Asian; 85% were men) with baseline cirrhosis or fibrosis after adjustment for baseline variables (hazard ratio, 0.49 [CI, 0.25 to 0.99]; absolute risk reduction, 4%). The results were not significant after exclusion of patients who developed hepatocellular carcinoma within 1 year of randomization, and the risk for death increased, although not significantly (RR, 2.47 [CI, 0.12 to 51.25]) (41). Disease progression, defined by a 2-point increase in Child–Pugh score comprised nearly half of the events. The Child–Pugh score assesses severity of liver disease on the basis of components that include biochemical measures (serum bilirubin and albumin levels and prothrombin) in addition to clinical measurements (ascites, encephalopathy, and sepsis).

For most outcomes, most conclusions about changes in intermediate outcomes were based on low levels of evidence from a single study or inconsistent results from several studies; therefore, our confidence in the effect size estimate is generally low. The role of intermediate markers or their combinations as surrogates for effects of treatment on clinical outcomes in chronic hepatitis B has never been adequately tested. Trial authors did not justify selection of intermediate markers by the clinical or prognostic importance of the expected changes. Anticipated odds of improved intermediate outcomes should be compared with odds of adverse effects.

Consensus among investigators and regulatory agencies is needed about whether currently used intermediate markers are true surrogates for treatment effects on mortality, morbidity, and quality of life in adults with chronic hepatitis B. Standardization of the measurements of viral load and hepatic aminotransferase in relation to patient age, race, and sex, and a uniform scoring system for liver biopsies with a single definition of what constitutes a clinically meaningful change in score, are essential for synthesis of the results from different studies. Future clinical trials should assess sustained benefits for 6 or more months after the active treatments.

References

Lok
AS
,
McMahon
BJ
.
Chronic hepatitis B.
Hepatology
2007
45
507
39
PubMed
CrossRef

PubMed
National Center for Health Statistics. Health, United States, 2006, with Chartbook on Trends in the Health of Americans. National Center for Health Statistics. Hyattsville, MD: National Center for Health Statistics; 2006. DHHS publication no. 20402.
Miniño
AM
,
Heron
MP
,
Murphy
SL
,
Kochanek
KD
.
Centers for Disease Control and Prevention National Center for Health Statistics National Vital Statistics System
Deaths: final data for 2004.
Natl Vital Stat Rep
2007
55
1
119
PubMed
PubMed
Pungpapong
S
,
Kim
WR
,
Poterucha
JJ
.
Natural history of hepatitis B virus infection: an update for clinicians.
Mayo Clin Proc
2007
82
967
75
PubMed
CrossRef

PubMed
Hoofnagle
JH
,
Doo
E
,
Liang
TJ
,
Fleischer
R
,
Lok
AS
.
Management of hepatitis B: summary of a clinical research workshop.
Hepatology
2007
45
1056
75
PubMed
CrossRef

PubMed
Birnkrant D. Approval letter for Viread (tenofovir disoproxil fumarate) Tablets. Letter to Gilead Sciences, Inc., from Debra Birnkrant, MD, Director of the Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research. NDA 21-356/S-025. 11 August 2008. Accessed at www.fda.gov/cder/foi/appletter/2008/021356s025ltr.pdf on 19 November 2008.
Wilt TJ, Shamliyan T, Shaukat A, Taylor BC, MacDonald R, Yuan J-M, et al. Management of Chronic Hepatitis B. Evidence Report/Technology Assessment No. 174. (Prepared by the Minnesota Evidence-based Practice Center under contract no. 290-02-0009.) Rockville, MD: Agency for Healthcare Research and Quality; 2008. AHRQ publication no. 09-E002.
The Cochrane Library. Chichester, UK: J Wiley; 2008. Accessed at www.cochrane.org on 25 November 2008.
U.S. Food and Drug Administration
MedWatch
MedWatch online voluntary reporting form (3500)
Rockville, MD
U.S. Food and Drug Administration, MedWatch
2002
Great Britain Committee on Safety of Medicines. Great Britain Medicines Control Agency, Great Britain Medicines and Healthcare products Regulatory Agency. Current Problems in Pharmacovigilance. Accessed at www.mhra.gov.uk/Publications/Safetyguidance/CurrentProblemsinPharmacovigilance/index.htm on 25 November 2008.
European Agency for the Evaluation of Medicinal Products
European Public Assessment Reports (EPARs).
London
European Agency for the Evaluation of Medicinal Products
2837
U.S. Food and Drug Administration (FDA). Center for Drug Evaluation and Research (CDER). Accessed at www.fda.gov/cder/ on 19 November 2008.
ClinicalTrials.gov Information about Federally and Privately Supported Clinical Research in Human Volunteers. Bethesda, MD: U.S. National Library of Medicine; 2002.
Higgins
J
,
Green
S
.
The Cochrane Collaboration
The Cochrane handbook for systematic reviews of interventions.
2006
Chichester, UK
J Wiley
2005
Dawson
B
,
Trapp
RG
.
Basic & Clinical Biostatistics (LANGE Basic Science). 3rd ed.
New York
McGraw-Hill
2004
West
S
,
King
V
,
Carey
TS
,
Lohr
KN
,
McKoy
N
,
Sutton
SF
,
et al
Systems to rate the strength of scientific evidence.
Evid Rep Technol Assess (Summ)
2002
1
11
PubMed
Atkins
D
,
Briss
PA
,
Eccles
M
,
Flottorp
S
,
Guyatt
GH
,
Harbour
RT
,
et al
GRADE Working Group
Systems for grading the quality of evidence and the strength of recommendations II: pilot study of a new system.
BMC Health Serv Res
2005
5
25
PubMed
CrossRef

PubMed
Atkins
D
,
Eccles
M
,
Flottorp
S
,
Guyatt
GH
,
Henry
D
,
Hill
S
,
et al
GRADE Working Group
Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches The GRADE Working Group.
BMC Health Serv Res
2004
4
38
PubMed
CrossRef

PubMed
Al-Marzouki
S
,
Evans
S
,
Marshall
T
,
Roberts
I
.
Are these data real? Statistical methods for the detection of data fabrication in clinical trials.
BMJ
2005
331
267
70
PubMed
CrossRef

PubMed
Buyse
M
,
George
SL
,
Evans
S
,
Geller
NL
,
Ranstam
J
,
Scherrer
B
,
et al
The role of biostatistics in the prevention, detection and treatment of fraud in clinical trials.
Stat Med
1999
18
3435
51
PubMed
CrossRef

PubMed
Kahn
HA
,
Sempos
CT
.
Statistical Methods in Epidemiology (Monographs in Epidemiology and Biostatistics).
New York
Oxford Univ Pr
1989
Moher
D
,
Cook
DJ
,
Eastwood
S
,
Olkin
I
,
Rennie
D
,
Stroup
DF
.
Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses.
Lancet
1999
354
1896
900
PubMed
CrossRef

PubMed
Whitehead
A
.
Meta-analysis of controlled clinical trials.
Chichester, UK
J Wiley
2002
DerSimonian
R
,
Laird
N
.
Meta-analysis in clinical trials.
Control Clin Trials
1986
7
177
88
PubMed
CrossRef

PubMed
Viechtbauer
W
.
Confidence intervals for the amount of heterogeneity in meta-analysis.
Stat Med
2007
26
37
52
PubMed
CrossRef

PubMed
Knapp
G
,
Biggerstaff
BJ
,
Hartung
J
.
Assessing the amount of heterogeneity in random-effects meta-analysis.
Biom J
2006
48
271
85
PubMed
CrossRef

PubMed
Egger
M
,
Smith
GD
,
Altman
DG
.
Systematic Reviews in Health Care
London
BMJ Books
2001
Egger
M
,
Smith
GD
.
Bias in location and selection of studies.
BMJ
1998
316
61
6
PubMed
CrossRef

PubMed
Dickersin K, Min YI. NIH clinical trials and publication bias. Online J Curr Clin Trials. 1993;Doc No 50:[4967 words; 53 paragraphs]. [PMID: 8306005]
Thornton
A
,
Lee
P
.
Publication bias in meta-analysis: its causes and consequences.
J Clin Epidemiol
2000
53
207
16
PubMed
CrossRef

PubMed
Barbaro
G
,
Zechini
F
,
Pellicelli
AM
,
Francavilla
R
,
Scotto
G
,
Bacca
D
,
et al
Lamivudine Italian Study Group Investigators
Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial.
J Hepatol
2001
35
406
11
PubMed
CrossRef

PubMed
Chung
YH
,
Song
BC
,
Lee
GC
,
Shin
JW
,
Ryu
SH
,
Jung
SA
,
et al
Individualization of interferon therapy using serum hepatitis B virus DNA to reduce viral relapse in patients with chronic hepatitis B: a randomized, controlled trial.
Eur J Gastroenterol Hepatol
2003
15
489
93
PubMed
PubMed
Di Bisceglie
AM
,
Fong
TL
,
Fried
MW
,
Swain
MG
,
Baker
B
,
Korenman
J
,
et al
A randomized, controlled trial of recombinant alpha-interferon therapy for chronic hepatitis B.
Am J Gastroenterol
1993
88
1887
92
PubMed
PubMed
Hadziyannis
S
,
Bramou
T
,
Makris
A
,
Moussoulis
G
,
Zignego
L
,
Papaioannou
C
.
Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B.
J Hepatol
1990
11
S133
6
PubMed
CrossRef

PubMed
Janssen
HL
,
Gerken
G
,
Carreño
V
,
Marcellin
P
,
Naoumov
NV
,
Craxi
A
,
et al
Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP).
Hepatology
1999
30
238
43
PubMed
CrossRef

PubMed
Lopez-Alcorocho
JM
,
Bartolome
J
,
Cotonat
T
,
Carreño
V
.
Efficacy of prolonged interferon-alpha treatment in chronic hepatitis B patients with HBeAb: comparison between 6 and 12 months of therapy.
J Viral Hepat
1997
4
27
32
PubMed
CrossRef

PubMed
Niederau
C
,
Heintges
T
,
Niederau
M
,
Stremmel
W
,
Strohmeyer
G
.
Prospective randomized, controlled trial of sequential treatment with corticoids and alpha-interferon versus treatment with interferon alone in patients with chronic active hepatitis B.
Eur J Med
1992
1
396
402
PubMed
PubMed
Perrillo
RP
,
Schiff
ER
,
Davis
GL
,
Bodenheimer
HC
Jr
,
Lindsay
K
,
Payne
J
,
et al
A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group.
N Engl J Med
1990
323
295
301
PubMed
CrossRef

PubMed
Reichen
J
,
Bianchi
L
,
Frei
PC
,
Malé
PJ
,
Lavanchy
D
,
Schmid
M
.
Efficacy of steroid withdrawal and low-dose interferon treatment in chronic active hepatitis B. Results of a randomized multicenter trial. Swiss Association for the Study of the Liver.
J Hepatol
1994
20
168
74
PubMed
CrossRef

PubMed
Waked
I
,
Amin
M
,
Abd el Fattah
S
,
Osman
LM
,
Sabbour
MS
.
Experience with interferon in chronic hepatitis B in Egypt.
J Chemother
1990
2
310
8
PubMed
CrossRef

PubMed
Liaw
YF
,
Sung
JJ
,
Chow
WC
,
Farrell
G
,
Lee
CZ
,
Yuen
H
,
et al
Cirrhosis Asian Lamivudine Multicentre Study Group
Lamivudine for patients with chronic hepatitis B and advanced liver disease.
N Engl J Med
2004
351
1521
31
PubMed
CrossRef

PubMed
Hadziyannis
SJ
,
Tassopoulos
NC
,
Heathcote
EJ
,
Chang
TT
,
Kitis
G
,
Rizzetto
M
,
et al
Adefovir Dipivoxil 438 Study Group
Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.
Gastroenterology
2006
131
1743
51
PubMed
CrossRef

PubMed
Chang
TT
,
Gish
RG
,
Hadziyannis
SJ
,
Cianciara
J
,
Rizzetto
M
,
Schiff
ER
,
et al
BEHoLD Study Group
A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients.
Gastroenterology
2005
129
1198
209
PubMed
CrossRef

PubMed
Chang
TT
,
Gish
RG
,
de Man
R
,
Gadano
A
,
Sollano
J
,
Chao
YC
,
et al
BEHoLD AI463022 Study Group
A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
N Engl J Med
2006
354
1001
10
PubMed
CrossRef

PubMed
Lai
CL
,
Shouval
D
,
Lok
AS
,
Chang
TT
,
Cheinquer
H
,
Goodman
Z
,
et al
BEHoLD AI463027 Study Group
Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.
N Engl J Med
2006
354
1011
20
PubMed
CrossRef

PubMed
Sherman
M
,
Yurdaydin
C
,
Sollano
J
,
Silva
M
,
Liaw
YF
,
Cianciara
J
,
et al
AI463026 BEHoLD Study Group
Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B.
Gastroenterology
2006
130
2039
49
PubMed
CrossRef

PubMed
Gish
RG
,
Lok
AS
,
Chang
TT
,
de Man
RA
,
Gadano
A
,
Sollano
J
,
et al
Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B.
Gastroenterology
2007
133
1437
44
PubMed
CrossRef

PubMed
Robson
SC
,
Brice
E
,
van Rensburg
C
,
Kannemeyer
J
,
Hift
RJ
,
Kirsch
RE
.
Safety and efficacy of interferon alpha-2b following prednisone withdrawal in the treatment of chronic viral hepatitis B. A case–controlled, randomised study.
S Afr Med J
1992
82
317
20
PubMed
PubMed
Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group
Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
N Engl J Med
2005
352
2682
95
PubMed
CrossRef

PubMed
Chan
HL
,
Hui
AY
,
Wong
VW
,
Chim
AM
,
Wong
ML
,
Sung
JJ
.
Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B.
Hepatology
2005
41
1357
64
PubMed
CrossRef

PubMed
Zarski
JP
,
Causse
X
,
Cohard
M
,
Cougnard
J
,
Trepo
C
.
A randomized, controlled trial of interferon alfa-2b alone and with simultaneous prednisone for the treatment of chronic hepatitis B. French Multicenter Group.
J Hepatol
1994
20
735
41
PubMed
CrossRef

PubMed
Wong
JB
,
Koff
RS
,
Tinè
F
,
Pauker
SG
.
Cost-effectiveness of interferon-alpha 2b treatment for hepatitis B e antigen-positive chronic hepatitis B.
Ann Intern Med
2837
122
664
75
CrossRef
Kim
YJ
,
Kim
BG
,
Jung
JO
,
Yoon
JH
,
Lee
HS
.
High rates of progressive hepatic functional deterioration whether lamivudine therapy is continued or discontinued after emergence of a lamivudine-resistant mutant: a prospective randomized, controlled study.
J Gastroenterol
2006
41
240
9
PubMed
CrossRef

PubMed
Lampertico
P
,
Del Ninno
E
,
Manzin
A
,
Donato
MF
,
Rumi
MG
,
Lunghi
G
,
et al
A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.
Hepatology
1997
26
1621
5
PubMed
CrossRef

PubMed
Lok
AS
,
Wu
PC
,
Lai
CL
,
Lau
JY
,
Leung
EK
,
Wong
LS
,
et al
A controlled trial of interferon with or without prednisone priming for chronic hepatitis B.
Gastroenterology
1992
102
2091
7
PubMed
CrossRef

PubMed
Müller
R
,
Baumgarten
R
,
Markus
R
,
Schulz
M
,
Wittenberg
H
,
Hintsche-Kilger
B
,
et al
Low dose alpha interferon treatment in chronic hepatitis B virus infection.
Gut
1993
34
S97
8
PubMed
CrossRef

PubMed
Müller
R
,
Baumgarten
R
,
Markus
R
,
Schulz
M
,
Wittenberg
H
,
Hintsche-Kilger
B
,
et al
Treatment of chronic hepatitis B with interferon alfa-2b.
J Hepatol
1990
11
S137
40
PubMed
CrossRef

PubMed
Lai
CL
,
Leung
N
,
Teo
EK
,
Tong
M
,
Wong
F
,
Hann
HW
,
et al
Telbivudine Phase II Investigator Group
A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B.
Gastroenterology
2005
129
528
36
PubMed
CrossRef

PubMed
Sarin
SK
,
Kumar
M
,
Kumar
R
,
Kazim
SN
,
Guptan
RC
,
Sakhuja
P
,
et al
Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients.
Am J Gastroenterol
2005
100
2463
71
PubMed
CrossRef

PubMed
Chan
HL
,
Wang
H
,
Niu
J
,
Chim
AM
,
Sung
JJ
.
Two-year lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B: a double-blind, placebo-controlled trial.
Antivir Ther
2007
12
345
53
PubMed
PubMed
Poynard
T
,
Zoulim
F
,
Ratziu
V
,
Degos
F
,
Imbert-Bismut
F
,
Deny
P
,
et al
Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) during lamivudine therapy in patients with chronic hepatitis B infection.
Am J Gastroenterol
2005
100
1970
80
PubMed
CrossRef

PubMed
Hui
CK
,
Leung
N
,
Shek
WH
,
Zhang
HY
,
Luk
JM
,
Poon
RT
,
et al
Hong Kong Liver Fibrosis Study Group
Changes in liver histology as a “surrogate” end point of antiviral therapy for chronic HBV can predict progression to liver complications.
J Clin Gastroenterol
2008
42
533
8
PubMed
CrossRef

PubMed
Hadziyannis
SJ
,
Tassopoulos
NC
,
Heathcote
EJ
,
Chang
TT
,
Kitis
G
,
Rizzetto
M
,
et al
Adefovir Dipivoxil 438 Study Group
Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.
N Engl J Med
2003
348
800
7
PubMed
CrossRef

PubMed
Hadziyannis
SJ
,
Tassopoulos
NC
,
Heathcote
EJ
,
Chang
TT
,
Kitis
G
,
Rizzetto
M
,
et al
Adefovir Dipivoxil 438 Study Group
Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.
N Engl J Med
2005
352
2673
81
PubMed
CrossRef

PubMed
Marcellin
P
,
Chang
TT
,
Lim
SG
,
Tong
MJ
,
Sievert
W
,
Shiffman
ML
,
et al
Adefovir Dipivoxil 437 Study Group
Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.
N Engl J Med
2003
348
808
16
PubMed
CrossRef

PubMed
Yuen
MF
,
Chow
DH
,
Tsui
K
,
Wong
BC
,
Yuen
JC
,
Wong
DK
,
et al
Liver histology of Asian patients with chronic hepatitis B on prolonged lamivudine therapy.
Aliment Pharmacol Ther
2005
21
841
9
PubMed
CrossRef

PubMed
Lai
CL
,
Chien
RN
,
Leung
NW
,
Chang
TT
,
Guan
R
,
Tai
DI
,
et al
A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.
N Engl J Med
1998
339
61
8
PubMed
CrossRef

PubMed
Dienstag
JL
,
Schiff
ER
,
Wright
TL
,
Perrillo
RP
,
Hann
HW
,
Goodman
Z
,
et al
Lamivudine as initial treatment for chronic hepatitis B in the United States.
N Engl J Med
1999
341
1256
63
PubMed
CrossRef

PubMed
Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group
Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.
N Engl J Med
2004
351
1206
17
PubMed
CrossRef

PubMed
Lai
CL
,
Rosmawati
M
,
Lao
J
,
Van Vlierberghe
H
,
Anderson
FH
,
Thomas
N
,
et al
Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection.
Gastroenterology
2002
123
1831
8
PubMed
CrossRef

PubMed
Perrillo
R
,
Hann
HW
,
Mutimer
D
,
Willems
B
,
Leung
N
,
Lee
WM
,
et al
Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus.
Gastroenterology
2004
126
81
90
PubMed
CrossRef

PubMed
Peters
MG
,
Hann
HW
,
Martin
P
,
Heathcote
EJ
,
Buggisch
P
,
Rubin
R
,
et al
Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B.
Gastroenterology
2004
126
91
101
PubMed
CrossRef

PubMed
Economou
M
,
Manolakopoulos
S
,
Trikalinos
TA
,
Filis
S
,
Bethanis
S
,
Tzourmakliotis
D
,
et al
Interferon-alpha plus lamivudine vs lamivudine reduces breakthroughs, but does not affect sustained response in HBeAg negative chronic hepatitis B.
World J Gastroenterol
2005
11
5882
7
PubMed
CrossRef

PubMed
Zeng
M
,
Mao
Y
,
Yao
G
,
Wang
H
,
Hou
J
,
Wang
Y
,
et al
A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B.
Hepatology
2006
44
108
16
PubMed
CrossRef

PubMed
Ke
CZ
,
Chen
Y
,
Gong
ZJ
,
Meng
ZJ
,
Liu
L
,
Ren
ZJ
,
et al
Dynamic changes of HBV DNA in serum and peripheral blood mononuclear cells of chronic hepatitis patients after lamivudine treatment.
World J Gastroenterol
2006
12
4061
3
PubMed
CrossRef

PubMed
Chan
HL
,
Heathcote
EJ
,
Marcellin
P
,
Lai
CL
,
Cho
M
,
Moon
YM
,
et al
018 Study Group
Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial.
Ann Intern Med
2007
147
745
54
CrossRef

PubMed
Lai
CL
,
Gane
E
,
Liaw
YF
,
Hsu
CW
,
Thongsawat
S
,
Wang
Y
,
et al
Globe Study Group
Telbivudine versus lamivudine in patients with chronic hepatitis B.
N Engl J Med
2007
357
2576
88
PubMed
CrossRef

PubMed
Chan
HL
,
Leung
NW
,
Hui
AY
,
Wong
VW
,
Liew
CT
,
Chim
AM
,
et al
A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone.
Ann Intern Med
2005
142
240
50
CrossRef

PubMed
Schalm
SW
,
Heathcote
J
,
Cianciara
J
,
Farrell
G
,
Sherman
M
,
Willems
B
,
et al
Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.
Gut
2000
46
562
8
PubMed
CrossRef

PubMed
Schiff
ER
,
Dienstag
JL
,
Karayalcin
S
,
Grimm
IS
,
Perrillo
RP
,
Husa
P
,
et al
International Lamivudine Investigator Group
Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders.
J Hepatol
2003
38
818
26
PubMed
CrossRef

PubMed
Yalcin
K
,
Degertekin
H
,
Yildiz
F
,
Celik
Y
.
Comparison of 12-month courses of interferon-alpha-2b-lamivudine combination therapy and interferon-alpha-2b monotherapy among patients with untreated chronic hepatitis B.
Clin Infect Dis
2003
36
1516
22
PubMed
CrossRef

PubMed
Akarca
US
,
Ersoz
G
,
Gunsar
F
,
Karasu
Z
,
Saritas
E
,
Yuce
G
,
et al
Interferon-lamivudine combination is no better than lamivudine alone in anti-HBe-positive chronic hepatitis B.
Antivir Ther
2004
9
325
34
PubMed
PubMed
Jang
MK
,
Chung
YH
,
Choi
MH
,
Kim
JA
,
Ryu
SH
,
Shin
JW
,
et al
Combination of alpha-interferon with lamivudine reduces viral breakthrough during long-term therapy.
J Gastroenterol Hepatol
2004
19
1363
8
PubMed
CrossRef

PubMed
Scotto
G
,
Palumbo
E
,
Fazio
V
,
Cibelli
DC
,
Saracino
A
,
Angarano
G
.
Efficacy and tolerability of lamivudine alone versus lamivudine plus alpha-interferon for treatment of chronic active hepatitis B in patients with a precore-mutant variant.
Infez Med
2006
14
145
51
PubMed
PubMed
Perrillo
RP
,
Lai
CL
,
Liaw
YF
,
Dienstag
JL
,
Schiff
ER
,
Schalm
SW
,
et al
Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.
Hepatology
2002
36
186
94
PubMed
CrossRef

PubMed
Westland CE, Yang H, Delaney WE 4th, Gibbs CS, Miller MD, Wulfsohn M, et al. 437 and 438 Study Teams. Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology. 2003;38:96-103. [PMID: 12829991]
Akyuz
F
,
Kaymakoglu
S
,
Demir
K
,
Aksoy
N
,
Karaca
C
,
Danalioglu
A
,
et al
Lamivudine monotherapy and lamivudine plus interferon alpha combination therapy in HBeAg negative chronic hepatitis B not responding to previous interferon alpha monotherapy.
Acta Gastroenterol Belg
2007
70
20
4
PubMed
PubMed
Yao
GB
.
Management of hepatitis B in China.
J Med Virol
2000
61
392
7
PubMed
CrossRef

PubMed
Shi
M
,
Wang
RS
,
Zhang
H
,
Zhu
YF
,
Han
B
,
Zhang
Y
,
et al
Sequential treatment with lamivudine and interferon-alpha monotherapies in hepatitis B e antigen-negative Chinese patients and its suppression of lamivudine-resistant mutations.
J Antimicrob Chemother
2006
58
1031
5
PubMed
CrossRef

PubMed
Janssen
HL
,
van Zonneveld
M
,
Senturk
H
,
Zeuzem
S
,
Akarca
US
,
Cakaloglu
Y
,
et al
HBV 99-01 Study Group
Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.
Lancet
2005
365
123
9
PubMed
CrossRef

PubMed
Chou
YC
,
Yu
MW
,
Wu
CF
,
Yang
SY
,
Lin
CL
,
Liu
CJ
,
et al
Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma.
Gut
2008
57
91
7
PubMed
CrossRef

PubMed
Bonino
F
,
Marcellin
P
,
Lau
GK
,
Hadziyannis
S
,
Jin
R
,
Piratvisuth
T
,
et al
Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group
Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B.
Gut
2007
56
699
705
PubMed
CrossRef

PubMed
Zhao
H
,
Kurbanov
F
,
Wan
MB
,
Yin
YK
,
Niu
JQ
,
Hou
JL
,
et al
Genotype B and younger patient age associated with better response to low-dose therapy: a trial with pegylated/nonpegylated interferon-alpha-2b for hepatitis B e antigen-positive patients with chronic hepatitis B in China.
Clin Infect Dis
2007
44
541
8
PubMed
CrossRef

PubMed
Cindoruk
M
,
Karakan
T
,
Unal
S
.
Hepatic steatosis has no impact on the outcome of treatment in patients with chronic hepatitis B infection.
J Clin Gastroenterol
2007
41
513
7
PubMed
CrossRef

PubMed
Wai
CT
,
Chu
CJ
,
Hussain
M
,
Lok
AS
.
HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C.
Hepatology
2002
36
1425
30
PubMed
PubMed
Chan
HL
,
Tse
AM
,
Zhang
MD
,
Wong
VW
,
Chim
AM
,
Hui
AY
,
et al
Genetic polymorphisms of interleukin-1-beta in association with sustained response to anti-viral treatment in chronic hepatitis B in Chinese.
Aliment Pharmacol Ther
2006
23
1703
11
PubMed
CrossRef

PubMed
Buster
EH
,
Hansen
BE
,
Buti
M
,
Delwaide
J
,
Niederau
C
,
Michielsen
PP
,
et al
HBV 99-01 Study Group
Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis.
Hepatology
2007
46
388
94
PubMed
CrossRef

PubMed
Akyildiz
M
,
Gunsar
F
,
Ersoz
G
,
Karasu
Z
,
Ilter
T
,
Batur
Y
,
et al
Adefovir dipivoxil alone or in combination with lamivudine for three months in patients with lamivudine resistant compensated chronic hepatitis B.
Dig Dis Sci
2007
52
3444
7
PubMed
CrossRef

PubMed
Mutimer
D
,
Naoumov
N
,
Honkoop
P
,
Marinos
G
,
Ahmed
M
,
de Man
R
,
et al
Combination alpha-interferon and lamivudine therapy for alpha-interferon-resistant chronic hepatitis B infection: results of a pilot study.
J Hepatol
1998
28
923
9
PubMed
CrossRef

PubMed
Jang
JW
,
Choi
JY
,
Bae
SH
,
Yoon
SK
,
Chang
UI
,
Kim
CW
,
et al
A randomized, controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization.
Hepatology
2006
43
233
40
PubMed
CrossRef

PubMed
Lu
HY
,
Zhuang
LW
,
Yu
YY
,
Ivan
H
,
Si
CW
,
Zeng
Z
,
et al
Intrahepatic HBV DNA as a predictor of antivirus treatment efficacy in HBeAg-positive chronic hepatitis B patients.
World J Gastroenterol
2007
13
2878
82
PubMed
CrossRef

PubMed
Santantonio
T
,
Niro
GA
,
Sinisi
E
,
Leandro
G
,
Insalata
M
,
Guastadisegni
A
,
et al
Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B patients: a controlled pilot study.
J Hepatol
2002
36
799
804
PubMed
CrossRef

PubMed
Zhao
H
,
Zhang
YX
,
Chen
XY
,
Wang
L
,
Tang
XP
,
Si
CW
.
[A clinical study of adefovir dipivoxil in treating lamivudine refractory HBeAg-positive chronic hepatitis B].
Zhonghua Nei Ke Za Zhi
2007
46
294
7
PubMed
PubMed
Yao
GB
,
Zhu
M
,
Wang
YM
,
Xu
DZ
,
Tan
DM
,
Chen
CW
,
et al
[A double-blind, double-dummy, randomized, controlled study of entecavir versus lamivudine for treatment of chronic hepatitis B].
Zhonghua Nei Ke Za Zhi
2006
45
891
5
PubMed
PubMed
Yao
GB
,
Zhang
DF
,
Wang
BE
,
Xu
DZ
,
Zhou
XQ
,
Lei
BJ
.
[A study of the dosage and efficacy of entecavir for treating hepatitis B virus].
Zhonghua Gan Zang Bing Za Zhi
2005
13
484
7
PubMed
PubMed
Zhao
H
,
Si
CW
,
Wei
L
,
Wan
MB
,
Ying
YK
,
Hou
JL
,
et al
[A multicenter, randomized, open-label study of the safety and effectiveness of pegylated interferon alpha 2b and interferon alpha 2b in treating HBeAg positive chronic hepatitis B patients].
Zhonghua Gan Zang Bing Za Zhi
2006
14
323
6
PubMed
PubMed
Liu
G
,
Hu
G
,
Tan
D
,
Zhang
Z
.
[A prospective investigation on interferon treatment of chronic hepatitis B].
Hunan Yi Ke Da Xue Xue Bao
1998
23
400
2
PubMed
PubMed
Zhu
M
,
Xu
B
,
Yao
GB
.
[Durability of HBeAg seroconversion in lamivudine treatment of chronic hepatitis B patients].
Zhonghua Gan Zang Bing Za Zhi
2005
13
534
6
PubMed
PubMed
Song
JW
,
Zhang
G
,
Lin
JG
,
Tang
WX
,
Lin
JS
.
[Clinical study of lamivudine and interferon combinate administration to inhibit hepatitis B virus replication].
Zhonghua Gan Zang Bing Za Zhi
2004
12
593
6
PubMed
PubMed
Yao
GB
,
Wang
BE
,
Cui
ZY
,
Yao
JL
,
Zeng
MD
.
[The long-term efficacy of lamivudine in chronic hepatitis B: interim analysis of 3-year's clinical course].
Zhonghua Nei Ke Za Zhi
2003
42
382
7
PubMed
PubMed
Ma
H
,
You
H
,
Yin
S
.
[Clinical efficacy of lamivudine in the treatment of chronic hepatitis B].
Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi
2001
15
147
9
PubMed
PubMed
Yao
G
,
Wang
B
,
Cui
Z
.
[Long-term effect of lamivudine treatment in chronic hepatitis B virus infection].
Zhonghua Gan Zang Bing Za Zhi
1999
7
80
3
PubMed
PubMed
Ghany
M
,
Liang
TJ
.
Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B.
Gastroenterology
2007
132
1574
85
PubMed
CrossRef

PubMed
Lim
SG
,
Krastev
Z
,
Ng
TM
,
Mechkov
G
,
Kotzev
IA
,
Chan
S
,
et al
Randomized, double-blind study of emtricitabine (FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B.
Antimicrob Agents Chemother
2006
50
1642
8
PubMed
CrossRef

PubMed
Lee
HS
,
Chung
YH
,
Lee
K
,
Byun
KS
,
Paik
SW
,
Han
JY
,
et al
A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B.
Hepatology
2006
43
982
8
PubMed
CrossRef

PubMed
Yoo
BC
,
Kim
JH
,
Chung
YH
,
Lee
KS
,
Paik
SW
,
Ryu
SH
,
et al
Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B.
Hepatology
2007
45
1172
8
PubMed
CrossRef

PubMed
Yoo
BC
,
Kim
JH
,
Kim
TH
,
Koh
KC
,
Um
SH
,
Kim
YS
,
et al
Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression.
Hepatology
2007
46
1041
8
PubMed
CrossRef

PubMed
Lim
SG
,
Ng
TM
,
Kung
N
,
Krastev
Z
,
Volfova
M
,
Husa
P
,
et al
Emtricitabine FTCB-301 Study Group
A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B.
Arch Intern Med
2006
166
49
56
PubMed
CrossRef

PubMed
Gish
RG
,
Trinh
H
,
Leung
N
,
Chan
FK
,
Fried
MW
,
Wright
TL
,
et al
Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study.
J Hepatol
2005
43
60
6
PubMed
CrossRef

PubMed
Peters
MG
,
Andersen
J
,
Lynch
P
,
Liu
T
,
Alston-Smith
B
,
Brosgart
CL
,
et al
ACTG Protocol A5127 Team
Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127.
Hepatology
2006
44
1110
6
PubMed
CrossRef

PubMed
Dore
GJ
,
Cooper
DA
,
Pozniak
AL
,
DeJesus
E
,
Zhong
L
,
Miller
MD
,
et al
903 Study Team
Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus.
J Infect Dis
2004
189
1185
92
PubMed
CrossRef

PubMed
Yao
G
,
Wang
B
,
Cui
Z
,
Yao
J
,
Zeng
M
.
A randomized double-blind placebo-controlled study of lamivudine in the treatment of patients with chronic hepatitis B virus infection.
Chin Med J (Engl)
1999
112
387
91
PubMed
PubMed
Perez
V
,
Tanno
H
,
Villamil
F
,
Fay
O
.
Recombinant interferon alfa-2b following prednisone withdrawal in the treatment of chronic type B hepatitis.
J Hepatol
1990
11
S113
7
PubMed
CrossRef

PubMed
Perez
V
,
Findor
J
,
Tanno
H
,
Sordá
J
.
A controlled trial of high dose interferon, alone and after prednisone withdrawal, in the treatment of chronic hepatitis B: long term follow up.
Gut
1993
34
S91
4
PubMed
CrossRef

PubMed
Cooksley
WG
,
Piratvisuth
T
,
Lee
SD
,
Mahachai
V
,
Chao
YC
,
Tanwandee
T
,
et al
Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B.
J Viral Hepat
2003
10
298
305
PubMed
CrossRef

PubMed
Flink
HJ
,
van Zonneveld
M
,
Hansen
BE
,
de Man
RA
,
Schalm
SW
,
Janssen
HL
.
HBV 99-01 Study Group
Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype.
Am J Gastroenterol
2006
101
297
303
PubMed
CrossRef

PubMed
Liaw
YF
,
Leung
NW
,
Chang
TT
,
Guan
R
,
Tai
DI
,
Ng
KY
,
et al
Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.
Gastroenterology
2000
119
172
80
PubMed
CrossRef

PubMed
Honkoop
P
,
de Man
RA
,
Niesters
HG
,
Main
J
,
Nevens
F
,
Thomas
HC
,
et al
Quantitative hepatitis B virus DNA assessment by the limiting-dilution polymerase chain reaction in chronic hepatitis B patients: evidence of continuing viral suppression with longer duration and higher dose of lamivudine therapy.
J Viral Hepat
1998
5
307
12
PubMed
CrossRef

PubMed
Dienstag
JL
,
Goldin
RD
,
Heathcote
EJ
,
Hann
HW
,
Woessner
M
,
Stephenson
SL
,
et al
Histological outcome during long-term lamivudine therapy.
Gastroenterology
2003
124
105
17
PubMed
CrossRef

PubMed
Nevens
F
,
Main
J
,
Honkoop
P
,
Tyrrell
DL
,
Barber
J
,
Sullivan
MT
,
et al
Lamivudine therapy for chronic hepatitis B: a six-month randomized dose-ranging study.
Gastroenterology
1997
113
1258
63
PubMed
CrossRef

PubMed

This feature is available only to Registered Users

Subscribe/Learn More

PDF

Not Available

Citations

2009 American College of Physicians

Conferences |20 January 2009

Antiviral Therapy for Adults With Chronic Hepatitis B: A Systematic Review for a National Institutes of Health Consensus Development Conference Free

Abstract

Methods

Data Sources and Study Selection

Data Extraction and Quality Assessment

Data Synthesis and Analysis

Role of the Funding Source

Results

Clinical Outcomes

Table. Effects of Drug Therapies for Chronic Hepatitis B on Clinical Outcomes

Intermediate Outcomes

Effects of Drugs on Markers of Resolved Hepatitis B

Histologic Outcomes

Effects of Drugs on Histologic Outcomes at the End of Treatment

Effects of Drugs on Histologic Outcomes at Follow-up After Treatment

Viral (HBV DNA) Clearance

Effects of Drugs on Viral Clearance at Follow-up After Treatment

Effects of Drugs on ALT Normalization at Follow-up Off Treatment

Effects of Drugs on HBeAg Clearance or Seroconversion at Follow-up Off Treatment

Drug-Specific Mutations

Evidence From Trials That Combined Patients With HBeAg-Negative and -Positive Baseline Status

Applicability of the Results to Patient Subsamples

Baseline ALT Levels

Pretreatment Status

Adverse Events

Figure.

Discussion

References

Figure.

Table. Effects of Drug Therapies for Chronic Hepatitis B on Clinical Outcomes

This feature is available only to Registered Users

0 Comments

See Also

Content

Information For

Services

Awards and Cover

Other Resources

Follow Annals On

Conferences |20 January 2009

Antiviral Therapy for Adults With Chronic Hepatitis B: A Systematic Review for a National Institutes of Health Consensus Development Conference Free

Abstract

Methods

Data Sources and Study Selection

Data Extraction and Quality Assessment

Data Synthesis and Analysis

Role of the Funding Source

Results

Clinical Outcomes

Table. Effects of Drug Therapies for Chronic Hepatitis B on Clinical Outcomes

Intermediate Outcomes

Effects of Drugs on Markers of Resolved Hepatitis B

Histologic Outcomes

Effects of Drugs on Histologic Outcomes at the End of Treatment

Effects of Drugs on Histologic Outcomes at Follow-up After Treatment

Viral (HBV DNA) Clearance

Effects of Drugs on Viral Clearance at Follow-up After Treatment

Effects of Drugs on ALT Normalization at Follow-up Off Treatment

Effects of Drugs on HBeAg Clearance or Seroconversion at Follow-up Off Treatment

Drug-Specific Mutations

Evidence From Trials That Combined Patients With HBeAg-Negative and -Positive Baseline Status

Applicability of the Results to Patient Subsamples

Baseline ALT Levels

Pretreatment Status

Adverse Events

Figure.

Discussion

References

Figure.

Table. Effects of Drug Therapies for Chronic Hepatitis B on Clinical Outcomes

This feature is available only to Registered Users

0 Comments

See Also

Content

Information For

Services

Awards and Cover

Other Resources

Follow Annals On

You need a subscription to this content to use this feature.