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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Lamivudine plus adefovir combination therapy versus entecavir monotherapy for lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis

YJ Sheng, JY Liu, SW Tong, HD Hu, DZ Zhang, P Hu, and H Ren.

Review published: 2011.

CRD summary

The review concluded that lamivudine plus adefovir was more effective and longer lasting than entecavir monotherapy in the treatment of lamivudine-resistant patients with chronic hepatitis B. The limited number patients and poor quality studies, along with no significant benefit shown in the analyses for virological response (the primary outcome), mean that the authors' conclusions may not be reliable.

Authors' objectives

To determine the efficacy of lamivudine plus adefovir compared with entecavir monotherapy in the treatment of chronic hepatitis B patients with lamivudine resistance.


PubMed, EMBASE, Web of Knowledge, and The Cochrane Library were searched with no language restriction up to March 2011. Search terms were reported. Authors were contacted when insufficient information was presented in the full article. Reference lists of retrieved articles were also checked.

Study selection

Randomised controlled trials (RCTs), cohort or case-control studies that compared lamivudine plus adefovir with entecavir monotherapy in adult patients with chronic hepatitis B with lamivudine resistance were eligible for inclusion. Excluded patients were: pregnant women; those infected with hepatitis B strains resistant to drugs other than lamivudine; those co-infected with hepatitis C virus, hepatitis D virus, or HIV; those who presented with serious concurrent medical illness including concomitant renal failure, evidence of hepatocellular carcinoma or organ transplantation history; those who used immunodeficiency drugs within the last six months. Cohort and case-control studies were required to match cases and controls by patient characteristics. Eligible studies were required to have well-defined inclusion and exclusion criteria, and clear definitions of treatment response.

In all included studies, the regimen for the combined therapy was 100mg/daily of lamivudine and 10mg/daily of adefovir, and the dosage of entecavir monotherapy was 1.0mg/daily. Treatment duration ranged from 48 weeks to 24 months (where reported). The mean age of participants ranged from 46.8 to 53.7 years (where reported). The primary outcome of interest was virological response (defined as the proportion of patients with undetectable hepatitis B DNA levels). Most studies were conducted in Korea, with one RCT conducted in Italy and another in China.

The authors did not state how many reviewers were involved in the study selection process.

Assessment of study quality

RCTs were assessed using QUORUM guidelines as well as the Jadad scale.

At least two reviewers assessed study quality and discrepancies were resolved with the assistance of another reviewer.

Data extraction

Two reviewers independently extracted data on the primary outcome (virological response) and secondary outcomes (mean hepatitis B virus infection, DNA reduction, virological breakthrough, biochemical response (alanine aminotransferase normalisation and hepatitis B e antigen seroconversion). For the primary outcome, numbers of events in treatment and control groups were extracted. For continuous outcomes the mean value and its standard deviation in both groups were extracted. Data were extracted on an intention-to-treat basis. Discrepancies were resolved by an arbitrator.

Methods of synthesis

Pooled relative risks (RRs) or standardised mean differences (SMDs) with their associated 95% confidence intervals (CIs) were calculated. A fixed-effect model was used; if significant statistical heterogeneity (p<0.1) was found, a random-effects model was used. Statistical heterogeneity was assessed using the Χ² and Ι².

Results of the review

Six studies were included in the review; three were RCTs (214 patients) and three were cohort studies (237 patients). All three included RCTs received a Jadad score of 2, none described method of randomisation in detail, but all appeared to report drop-outs/withdrawals.

No significant difference was shown for the primary outcome of virological response (RR 1.11, 95% CI 0.89 to 1.37; Ι²=0%; five studies). A significant mean reduction in hepatitis B virus DNA at 48 weeks after treatment (SMD 0.44, 95% CI 0.18 to 0.71; Ι²=53%; three studies) and virological breakthrough at 48 weeks (RR 0.16, 95% CI 0.06 to 0.39; Ι²=0%; six studies) was found for lamivudine with adefovir compared with entecavir monotherapy, but no significant difference was shown at 24 weeks or 12 weeks after treatment.

No statistically significant between group differences were found for alanine aminotransferase normalisation and hepatitis B e antigen seroconversion at 48 weeks after treatment.

Two studies reported on the safety of treatments, but neither found any differences safety; both treatments appeared to be tolerated.

Authors' conclusions

Combination therapy (lamivudine plus adefovir) was more effective than switching to entecavir monotherapy and had longer lasting effects in the treatment of lamivudine-resistant patients with chronic hepatitis B.

CRD commentary

The review question was supported by clear inclusion and exclusion criteria. Attempts were made to identify relevant evidence from a number of sources with no language restriction. Appropriate steps were made to minimise the possibility of errors and bias in the extraction of data and quality assessment, but it was not clear if similar steps were taken in the selection of studies.

Relevant criteria were considered in the assessment of study quality. There was limited reporting of the quality results, but the three randomised trials included were considered to be of poor quality (Jadad score of 2). Of the six studies included in the review, half were observational and all included small sample sizes. Most analyses were based on only three studies. There was evidence of significant heterogeneity between studies. The authors base their conclusions of a benefit of combination therapy on secondary outcomes; the primary outcome (virological response) showed no significant benefit.

Given these considerations, the authors' conclusions may not be reliable.

Implications of the review for practice and research

Practice: The authors recommended, due to the benefits and limitations of treatment with adevfovir, individualised treatment regimens in treating patients with a history of previous lamivudine resistance.

Research: The authors stated that further sufficiently powered, high-quality, multi-centre RCTs were needed to guide standards of care for treating patients with chronic hepatitis B with lamivudine resistance.


National Natural Science Foundation of China; National Science and Technology Major Project of China; Program for Changjiang Scholars and Innovative Research Team in University, China.

Bibliographic details

Sheng YJ, Liu JY, Tong SW, Hu HD, Zhang DZ, Hu P, Ren H. Lamivudine plus adefovir combination therapy versus entecavir monotherapy for lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. Virology Journal 2011; 8:393. [PMC free article: PMC3173393] [PubMed: 21824397]

Indexing Status

Subject indexing assigned by NLM


Adenine /administration & dosage /analogs & derivatives; Antiviral Agents /administration & dosage; Drug Resistance, Viral; Drug Therapy, Combination /methods; Guanine /administration & dosage /analogs & derivatives; Hepatitis B, Chronic /drug therapy; Humans; Lamivudine /administration & dosage; Liver Function Tests; Organophosphonates /administration & dosage; Salvage Therapy /methods; Time Factors; Treatment Outcome; Viral Load



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 21824397

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