Tenofovir and Entecavir Are the Most Effective Antiviral Agents for Chronic Hepatitis B: A Systematic Review and Bayesian Meta-analyses

doi:10.1053/j.gastro.2010.06.042

Gastroenterology

Volume 139, Issue 4, October 2010, Pages 1218-1229.e5

https://doi.org/10.1053/j.gastro.2010.06.042 Get rights and content

Background & Aims

The relative efficacies of licensed antiviral therapies for treatment-naive chronic hepatitis B (CHB) infection in randomized controlled trials have not been determined. We evaluated the relative efficacies of the first 12 months of CHB treatments.

Methods

Drugs evaluated were lamivudine, pegylated interferon, adefovir, entecavir, telbivudine, and tenofovir, as monotherapies and combination therapies, in treatment-naive individuals. Databases were searched for randomized controlled trials of the first 12 months of therapy in hepatitis B e antigen (HBeAg)-positive and/or HBeAg-negative patients with CHB published in English before October 31, 2009. Bayesian mixed treatment comparisons were used to calculate the odds ratios, including 95% credible intervals and predicted probabilities of surrogate outcomes to determine the relative effects of each treatment.

Results

In HBeAg-positive patients, tenofovir was most effective in inducing undetectable levels of HBV DNA (predicted probability, 88%), normalization of alanine aminotransferase (ALT) levels (66%), HBeAg seroconversion (20%), and hepatitis B surface antigen loss (5%); it ranked third in histologic improvement of the liver (53%). Entecavir was most effective in improving liver histology (56%), second for inducing undetectable levels of HBV DNA (61%) and normalization of ALT levels (70%), and third in loss of hepatitis B surface antigen (1%). In HBeAg-negative patients, tenofovir was the most effective in inducing undetectable levels of HBV DNA (94%) and improving liver histology (65%); it ranked second for normalization of ALT levels (73%).

Conclusions

In the first year of treatment for CHB, tenofovir and entecavir are the most potent oral antiviral agents for HBeAg-positive patients; tenofovir is most effective for HBeAg-negative patients.

Section snippets

Eligibility Criteria

To be included, studies must have examined adults with HBeAg-positive and/or HBeAg-negative CHB in randomized, phase 3, controlled trials comparing new drug treatments with either placebo or already licensed drugs. The drugs evaluated included pegylated interferon, lamivudine, adefovir, entecavir, telbivudine, or tenofovir as monotherapy or combination therapy administered for a 1-year period (48–52 wk). Trials that used standard interferon therapy were not included in the analysis. The trials

Search Results and Study Characteristics

We initially identified 3338 potentially eligible citations. After evaluating these citations and their bibliographies, we included 20 trials9, 10, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 (Figure 2); 15 in HBeAg-positive patients, 8 in HBeAg-negative patients. Three of these studies evaluated both HBeAg-positive and HBeAg-negative patients.

Table 1 provides a summary of the characteristics of the 20 studies that met our inclusion criteria. Double-blinding was described

Discussion

Many new antiviral treatments for CHB have become available within the past 2 decades. The first drug approved was interferon, an immune modulator and antiviral. After its inception, there has been a shift toward focusing on oral antiviral drugs, nucleos(t)ide analogues. RCTs comparing these treatments have been limited to comparing 2–3 drugs or drug combinations at a time whereas traditional meta-analytic techniques are limited to comparing 2 interventions. This has left clinicians to make

Conclusions

Our systematic review and Bayesian MTC analysis shows that for patients with HBeAg-positive CHB, entecavir and tenofovir are the most effective treatments, whereas for HBeAg-negative patients, tenofovir is the most effective treatment as measured by our defined surrogate clinical outcomes. (Supplementary Table 1, Supplementary Table 2).

Acknowledgments

The authors thank Elizabeth Uleryk for her assistance with our systematic search of the literature. The authors would like to recognize Karen Liu for aiding in the collection of articles.

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Currently, oral NA antiviral therapy is recommended by international guidelines for patients with CHB who have treatment indications.9–11 Among the available NAs, entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both recommended as first-line NAs in most practice guidelines because of their superior potency, favorable safety profiles, and high genetic barriers to drug resistance.12,13 There is accumulated evidence indicating that long-term ETV and TDF treatment can improve liver histology, resolve fibrosis, and reduce the risk of HCC, liver-related complications, and mortality.14–17
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From January 2008 to December 2013, a total of 12,388 consecutive adult patients with CHB who received a finite course of TDF treatment (n = 1250) or ETV treatment (n = 11,138) were analyzed through screening for study eligibility followed by the 1:4 propensity score matching method.
In the entire cohort, the annual incidence and survival between the ETV and TDF groups were not significantly different regarding HCC occurrence (2.05 vs 2.74 per 100 patient-years [PY]; P = 0.055; hazard ratio [HR], 0.975; log-rank, P = 0.966), cirrhosis-related complications (1.9 vs 2.4 per 100 PY; P = 0.149; HR, 0.869; log-rank, P = 0.388), or all-cause mortality (2.16 vs 1.6 per 100 PY; P = 0.119; HR, 0.831; log-rank, P = 0.342), respectively. Propensity score matching analyses yielded similar results regarding HCC occurrence, cirrhosis-related complications, and all-cause mortality. In addition, these findings were consistently reproduced in the subgroups of patients with chronic hepatitis and cirrhosis that developed before antiviral treatment.
ETV and TDF did not significantly differ in prevention of HCC occurrence or reduction of cirrhosis-related complications and all-cause mortality in patients with CHB receiving a finite period of treatment.
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: Conflicts of interest These authors disclose the following: Ms Woo is supported by the Canadian Liver Foundation (graduate studentship); Dr Sherman reported honoraria (<$10,000 each) for consulting to and speaking on behalf of Gilead, Bristol-Myers Squibb, Glaxo, Hoffmann-LaRoche, and compensation for being an expert witness (<$2000); Dr Wong conducts educational rounds that are sponsored by Axcan, Bristol Myers Squibb, Gilead, Novartis, Roche, and Schering-Plough, whose content is not related to the subject area; Dr Einarson has received consulting fees and grant support from Biogen, Amgen, GlaxoSmithKline, Schering–Plough, Hoffmann–La Roche, Novartis, and Bristol–Meyers Squibb; Dr Heathcote has received consulting fees and/or grant support from Axcan, Gilead Sciences, GlaxoSmithKline, Debio, Schering–Plough, Vertex Tibotec, Boehringer Ingelheim, Bristol–Myers Squibb, and Hoffmann–La Roche; Dr Krahn has received a grant to fund this study from Gilead Sciences. The remaining authors disclose no conflicts.

Funding This study was supported by Gilead Sciences. The design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript were performed independently of Gilead Sciences.

None of the funding organizations or sponsors had any role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript.

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Clinical—Liver, Pancreas, and Biliary TractTenofovir and Entecavir Are the Most Effective Antiviral Agents for Chronic Hepatitis B: A Systematic Review and Bayesian Meta-analyses

Background & Aims

Methods

Results

Conclusions

Section snippets

Eligibility Criteria

Search Results and Study Characteristics

Discussion

Conclusions

Acknowledgments

J Hepatol

Gastroenterology

Hepatology

J Clin Epidemiol

Lancet

Gastroenterology

J Hepatol

J Hepatol

Gastroenterology

Epidemiology and natural history of hepatitis B

Semin Liver Dis

Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients

Hepatology

A cost-effectiveness analysis of currently approved treatments for HBeAg-positive chronic hepatitis B

Pharmacoeconomics

Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks

Hepatology

[AASLD practice guidelines. Chronic hepatitis B: update of therapeutic guidelines]

Rom J Gastroenterol

EASL practice guidelines: management of chronic hepatitis B

J Hepatol

A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B

N Engl J Med

Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B

N Engl J Med

Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses

BMJ

Bayesian methods for evidence synthesis in cost-effectiveness analysis

Pharmacoeconomics

Alternative methods for monitoring convergence of iterative simulations

J Comput Graph Stat

Bayesian approaches to clinical trials and health-care evaluations

Clinical—Liver, Pancreas, and Biliary Tract
Tenofovir and Entecavir Are the Most Effective Antiviral Agents for Chronic Hepatitis B: A Systematic Review and Bayesian Meta-analyses