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Management of chronic hepatitis B |
Wilt TJ, Shamliyan T, Shaukat A, Taylor BC, MacDonald R, Yuan JM, Johnson JR, Tacklind J, Rutks I, Kane RL |
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CRD summary This review evaluated the effectiveness of antiviral therapy for adults with chronic hepatitis B infection. The authors concluded that evidence was insufficient to assess the effect of treatment on clinical outcomes or to determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. The authors' conclusions are appropriate and are likely to be reliable. Authors' objectives To evaluate the effectiveness of antiviral therapy for adults with chronic hepatitis B infection. In addition, the authors assessed whether there are differences in effectiveness for treatment naive versus drug-resistant patients or for other sub-populations (these are not summarised here). Searching MEDLINE, PUBMED and the Cochrane Library were searched for English language articles published between 1990 and December 2007 (search terms were provided). The websites of MedWatch (US), Medicines and Healthcare Products Regulatory Agency (UK, MHRA) and the European Agency for the Evaluation of Medicinal Products were also searched. The search strategy was reported. Study selection Randomised controlled trials (RCTs) of adults with chronic hepatitis B that assessed treatments approved by the US Food and Drug Administration (FDA), as of June 2008, were eligible for inclusion. Trials were required to have at least 50 participants and treatment duration of at least 24 weeks, with the exception trials of interferon therapy which had to have treatment duration of at least 12 weeks, but could be of any size.
The main outcomes of interest were clinical outcomes (mortality, hepatocellular carcinoma, hepatic decompensation and cirrhosis). Intermediate outcomes including markers of resolved hepatitis B, biochemical, virological and histological outcomes were also included. Sustained resolved hepatitis B was considered the most relevant intermediate outcome. It was defined as hepatitis B surface antigen loss or seroconversion in combination with loss of hepatitis B virus DNA, hepatitis B e antigen seroconversion, and normalisation of aspartate aminotransferase and alanine aminotransferase levels. Adverse effects were also reported. A sustained response was defined as six months or more following the end of therapy. Only clinical outcomes, adverse events and resolved hepatitis B are summarised in this abstract.
The interventions assessed in the included trials were interferon (alpha-2b and pegylated alpha-2a), lamivudine, adefovir, entecavir and telbivudine (pegylated alpha-2a was not licensed in US at the time of the review), alone or in combination with another treatment. The comparators were placebo, or two of the interventions of interest were compared. Participants in the included trials were predominantly male (78%) and hepatitis B e antigen positive. Most participants were Asian (64%) or white (30%). Most trials excluded patients with hepatic decompensation, renal insufficiency and serious co-morbid conditions. Where reported, the duration of infection varied from six months to 20 years amongst individual patients.
Three researchers independently assessed studies for inclusion. Assessment of study quality Three researchers independently assessed trials for selection of participants, duration of and loss to follow-up, intention-to-treat analysis, blinding, adequacy of randomisation, allocation concealment, and justification of sample size. Data extraction The number of events and number randomised to each group and rates, relative risks (RR) and absolute risk differences (RD) and 95% confidence intervals (CI) were calculated based on intention-to-treat data.
Three researchers independently extracted data. Methods of synthesis Trials were discussed in a narrative synthesis, with accompanying tables, and the evidence was rated using GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group criteria. Where trials were similar enough, they were pooled in a meta-analysis using a random-effects model. χ2 tests were used to assess heterogeneity. Results of the review Sixty RCTs were included, ranging in size from 20 to 1,367 patients.
Clinical outcomes: Only 16 RCTs reported clinical outcomes. The authors stated that none of the RCTs were of sufficient size or duration to assess the effect of the different treatments; the majority reported zero or a small number of outcomes. All RCTs were classified as providing a low level of evidence. None of the 13 trials reporting mortality reported a statistically significant improvement in mortality due to treatment; neither did the two studies reporting cirrhosis; nor any of the four studies reporting hepatocellular carcinoma. Two trials reporting hepatic decompensation did not report a statistically significant benefit with any treatment and one trial (of 651 Asian patients) reported a decrease in 'disease progression' for lamivudine versus placebo (hazard ratio 0.45, p=0.001)
Markers of resolved hepatitis B: The trials were classified as providing low to moderate level of evidence. None of the ten trials assessing sustained hepatitis B surface antigen clearance (eight to 48 weeks post-treatment) with active therapy compared to placebo reported a statistically significant improvement with active treatment. Six trials compared active treatment to placebo at end of treatment; one reported a statistically significant increase hepatitis B surface antigen loss at the end of 24 weeks of alpha-2b interferon therapy and after alpha-2b interferon therapy in combination with corticosteroid. A pooled analysis of two trials comparing alpha-2b interferon therapy (with steroid pre-treatment) to no antiviral treatment found a significant increase in hepatitis B surface antigen loss at the end of treatment. Amongst ten trials comparing two active interventions (interferon and reverse transcriptase inhibitors) there was no statistically significant difference in sustained hepatitis B surface antigen clearance.
Adverse events: Adverse events were reported for more than 50% of patients, but were not associated with increased discontinuation of treatment. The frequency and severity of adverse events were similar for oral antiviral drugs and placebo. Interferon-based therapies were not as well tolerated as oral drugs. Authors' conclusions The evidence was insufficient to assess the effect of treatment on clinical outcomes or to determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. CRD commentary The review had a clearly stated review question and inclusion criteria. A number of relevant databases were searched for studies. Relevant studies may have been missed due to the language restrictions, but given the number of included studies reporting no statistically significant effect of treatment on clinical outcomes, it is unlikely that the inclusion of unpublished studies would have changed the conclusions of the review. Appropriate methods were used to reduce error and bias in study selection, quality assessment and data extraction. The use of predominantly narrative synthesis seemed appropriate given the diversity of the included trials. The authors' conclusions are appropriate and are likely to be reliable. Implications of the review for practice and research Practice: The authors stated that the data were insufficient for decision-making about the long-term effects of treatment for chronic hepatitis B on long-term outcomes.
Research: The authors stated that further research, assessing sustained benefits at six months or later, is required to identify optimal therapies for adults with chronic hepatitis B infection. In addition, consensus is required about whether currently used intermediate markers are true surrogates for clinical outcomes and further work is required on standardisation of outcome measures. Funding Agency for Healthcare Research and Quality, US Department of Health and Human Services, contract number 290-02-0009. Bibliographic details Wilt TJ, Shamliyan T, Shaukat A, Taylor BC, MacDonald R, Yuan JM, Johnson JR, Tacklind J, Rutks I, Kane RL. Management of chronic hepatitis B. Rockville, MD, USA: Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment Number 174. 2008 Other publications of related interest Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan JM, Johnson JR, Tacklind J, Rutks I, Kane RL, Wilt TJ. Antiviral therapy for adults with chronic hepatitis B: a systematic review for a National Institutes of Health consensus development conference. Annals of Internal Medicine 2009; 150(2):111-124.
Shamliyan TA, Johnson JR, MacDonald R, Shaukat A, Yuan JM, Kane RL, Wilt TJ. Systematic review of the literature on comparative effectiveness of antiviral treatments for chronic hepatitis B infection. Journal of General Internal Medicine 2011; 26(3):326-339. Indexing Status Subject indexing assigned by NLM MeSH Antiviral Agents /adverse effects /therapeutic use; Carcinoma, Hepatocellular /etiology; Chronic Disease; Female; Hepatitis B /complications /mortality /therapy; Hepatitis B virus /metabolism; Humans; Interferon-alpha /adverse effects /therapeutic use; Liver Neoplasms /etiology; Liver Transplantation /adverse effects; Male; Recombinant Proteins; Treatment Outcome; Viral Load AccessionNumber 12009105007 Date bibliographic record published 17/06/2009 Date abstract record published 02/12/2009 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. |
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