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. 2017 Mar 21;3(3):CD011645.
doi: 10.1002/14651858.CD011645.pub2.

Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis

Konstantinos Mantzoukis  1 , Manuel Rodríguez-Perálvarez  2 , Elena Buzzetti  3 , Douglas Thorburn  3 , Brian R Davidson  4 , Emmanuel Tsochatzis  3 , Kurinchi Selvan Gurusamy  4
Affiliations

Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis

Konstantinos Mantzoukis et al. Cochrane Database Syst Rev. .

Abstract

Background: Infection with hepatitis B virus (HBV) can be symptomatic or asymptomatic. Apart from chronic HBV infection, the complications related to acute HBV infection are severe acute viral hepatitis and fulminant hepatitis characterised by liver failure. The optimal pharmacological treatment of acute HBV infection remains controversial.

Objectives: To assess the benefits and harms of pharmacological interventions in the treatment of acute HBV infection through a network meta-analysis and to generate rankings of the available treatments according to their safety and efficacy. As it was not possible to assess whether the potential effect modifiers were similar across different comparisons, we did not perform the network meta-analysis, and instead, assessed the benefits and harms of different interventions using standard Cochrane methodological procedures.

Search methods: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, WHO International Clinical Trials Registry Platform, and randomised clinical trials (RCTs) registers to August 2016 to identify RCTs on pharmacological interventions for acute HBV infection.

Selection criteria: RCTs, irrespective of language, blinding, or publication status in participants with acute HBV infection. We excluded trials if participants had previously undergone liver transplantation and had other coexisting viral diseases such as hepatitis C virus and HIV. We considered any of the various pharmacological interventions compared with each other or with placebo, or no intervention.

Data collection and analysis: We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.

Main results: Seven trials (597 participants) met our review inclusion criteria. All trials provided information for one or more outcomes; however, five participants were excluded from analysis by study authors. All the trials were at high risk of bias. Overall, all the evidence was low or very low quality evidence because of risk of bias (downgraded one level for risk of bias), small sample size (downgraded one level for imprecision), and wide CIs (downgraded one more level for imprecision in some comparisons). Of the seven trials, six were two-armed trials, while one trial was a three-armed trial. The comparisons included hepatitis B immunoglobulin (HBIG) versus placebo (one trial; 55 participants); interferon versus placebo (two trials; 200 participants); lamivudine versus placebo or no intervention (four trials; 316 participants); lamivudine versus entecavir (one trial; 90 participants); and entecavir versus no intervention (one trial; 131 participants). One trial included only people with acute HBV with hepatic encephalopathy (i.e. people with fulminant liver failure); one trial included only people with severe acute HBV, but it did not state whether any of the people also had fulminant HBV infection; three trials excluded fulminant HBV infection; and two trials did not report the severity of acute HBV infection. The mean or median follow-up period in the trials ranged from three to 12 months in the trials that provided this information.There was no evidence of any differences in short-term mortality (less than one year) in any of the comparisons: HBIG versus placebo (OR 1.13, 95% CI 0.36 to 3.54; participants = 55; 1 trial), lamivudine versus placebo or no intervention (OR 1.29, 95% CI 0.33 to 4.99; participants = 250; 2 trials); lamivudine versus entecavir (OR 1.23, 95% CI 0.13 to 11.65; participants = 90; 1 trial), or entecavir versus no intervention (OR 1.05, 95% CI 0.12 to 9.47; participants = 131; 1 trial). The proportion of people who progressed to chronic HBV infection was higher in the lamivudine group than the placebo or no intervention group (OR 1.99, 95% CI 1.05 to 3.77; participants = 285; 3 trials) and in the lamivudine group versus entecavir group (OR 3.64, 95% CI 1.31 to 10.13; participants = 90; 1 trial). There was no evidence of a difference in the proportion of people who progressed to chronic HBV infection between the entecavir and the no intervention groups (OR 0.58, 95% CI 0.23 to 1.49; participants = 131; 1 trial). None of the trials reported progression to fulminant HBV infection. Three trials with 371 participants reported serious adverse events. There were no serious adverse events in any of the groups (no intervention: 0/183 (0%), interferon: 0/67 (0%), lamivudine: 0/100 (0%), and entecavir: 0/21 (0%)). The proportion of people with adverse events was higher in the interferon group than the placebo group (OR 348.16, 95% CI 45.39 to 2670.26; participants = 200; 2 trials). There was no evidence of a difference in the proportion of people with adverse events between the lamivudine group and the placebo or no intervention group (OR 1.42, 95% CI 0.34 to 5.94; participants = 35; 1 trial) or number of adverse events between the lamivudine group and the placebo or no intervention group (rate ratio 1.72, 95% CI 1.01 to 2.91; participants = 35; 1 trial). One trial with 100 participants reported quality of life at one week. The scale used to report the health-related quality of life was not stated and lacked information on whether higher score meant better or worse, making it difficult to interpret the results. None of the trials reported quality of life beyond one week or other clinical outcomes such as mortality beyond one year, liver transplantation, cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma.Two trials received funding from pharmaceutical companies; three trials were funded by parties without any vested interest in the results or did not receive any special funding; the source of funding was not available in the remaining two trials.

Authors' conclusions: Low or very low quality evidence suggests that progression to chronic HBV infection was higher in people receiving lamivudine compared with placebo, no intervention, or entecavir. Low quality evidence suggests that interferon may increase the adverse events after treatment for acute HBV infection. Based on a very low quality evidence, there is currently no evidence of benefit of any intervention in acute HBV infection. There is significant uncertainty in the results and further RCTs are required.

PubMed Disclaimer

Conflict of interest statement

This report is independent research funded by the National Institute for Health Research (NIHR Cochrane Programme Grants, 13/89/03 ‐ evidence‐based diagnosis and management of upper digestive, hepato‐biliary, and pancreatic disorders). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health.

KM: no financial disclosures. MRP: acted as advisory for Astellas and has received educational grants from Astellas and Novartis. EB: no financial disclosures. DT: funded by Astellas for his attendance at the International Liver Transplantation Society meeting in 2014; received GBP 25,000 from Boston Scientific to fund a clinical research fellow in 2013. BD: no financial disclosures. ET: no financial disclosures. KG: no financial disclosures.

Figures

1
1
Study flow diagram. HBV: hepatitis B virus; RCT: randomised clinical trial.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Trial sequential analysis of progression to chronic hepatitis B virus infection (lamivudine versus placebo or no treatment) and adverse events (proportion) (interferon versus placebo): Using the control group proportion observed in the trials (Pc = 41.3% and 34.9% respectively), alpha error of 2%, beta error of 90%, relative risk reduction (RRR) of 20%, and diversity observed in the analysis (0%), the accrued sample sizes (285 and 200 respectively) were only small proportions of the diversity‐adjusted required information sizes (DARIS) (progression to chronic hepatitis B = 1783; adverse events (proportion) = 2303). While the Z‐curve (blue lines) crossed the conventional boundary of P = 0.05 (dotted green lines) favouring placebo or no treatment, it did not cross any of the trial sequential monitoring boundaries (dotted red lines). There was a high risk of random errors.
1.1
1.1. Analysis
Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 2 Chronic hepatitis B virus infection.
1.4
1.4. Analysis
Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 4 Adverse events proportion.
1.5
1.5. Analysis
Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 5 Adverse events number.
1.7
1.7. Analysis
Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 7 Seroconversion.
1.8
1.8. Analysis
Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 8 Time to seroconversion.
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