Background
Hepatitis B virus (HBV) is a virus that affects the liver. It is usually transmitted by injectable drug abuse, transfusion of infected blood, unhygienic tattooing practices, coming into contact with blood infected with HBV, or by unprotected sex. Acute HBV infection is the period that covers the period immediately after HBV infection. Most people are asymptomatic. About 5% to 40% of people with acute HBV develop symptoms such as jaundice (yellowish discolouration of the eyes and skin), tummy pain, tiredness, nausea, and vomiting. While most people clear the virus after acute HBV infection, the virus remains in others (chronic HBV infection) and causes major health problems (excessive tiredness and eventually may end with liver failure leading to vomiting blood, confusion, and death). Occasionally, people with acute HBV may develop immediate liver failure (fulminant HBV infection). The best way to treat acute HBV is not clear. We sought to resolve this issue by performing this review. We included all randomised clinical trials (RCTs) (clinical studies where people are randomly put into one of two or more treatment groups) published to August 2016. We included only trials in which participants with acute HBV infection had not undergone liver transplantation previously and did not have liver disease due to other viral infections. Apart from using standard Cochrane methods which allow comparison of only two treatments at a time (direct comparison), we planned to use an advanced method which allows comparison of the many different treatments individually which are compared in the trials (network meta-analysis). However, because of the nature of the information available, we could not determine whether the network meta-analysis results were reliable. So, we used standard Cochrane methodology.
Study characteristics
We identified seven RCTs. Trial authors included 592 (out of 597 randomised) participants in analyses. The trials included people with acute HBV infection of varying severity. The main interventions included hepatitis B immunoglobulin (a vaccine), interferon (protein secreted in response to viral infection), and lamivudine and entecavir (medicines) which are considered to have antiviral effects and were compared with placebo or no intervention. The trials' average follow-up period ranged from three months to one year in the six trials that reported this information.
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; two trials did not report the funding source.
Quality of evidence
The overall quality of evidence was low or very low, and all the trials were at high risk of bias (the likely possibility of making wrong conclusions overestimating benefits or underestimating harms because of the way the studies were conducted is high).
Key results
There was no evidence of differences in death at less than one year between any of the treated and untreated groups. The percentage of people who progressed to chronic HBV infection was higher in lamivudine versus placebo or no intervention and lamivudine versus entecavir groups. There was no evidence of difference in the proportion of people who progressed to chronic HBV infection between entecavir and no intervention. None of the trials reported progression to fulminant HBV infection. There were no serious adverse events in any of the treatment groups in the trials that reported this information. The percentage of people who developed adverse events was higher in the interferon group (100%) than in the placebo (dummy treatment) group (27%) in the trials that reported this information. There was no evidence of differences in the percentage of people who developed adverse events or the total number of adverse events in the comparison between lamivudine versus no treatment. One trial reported quality of life at one week; however, the information provided was insufficient to determine whether there was any difference between the interferon and placebo groups. None of the trials reported quality of life beyond one week or other important outcomes such as death beyond one year, severe progressive liver damage, liver failure, requirement for liver transplantation, or liver cancer. There is currently no evidence of benefit of any treatment in acute HBV infection. There is significant uncertainty in the results and high-quality RCTs are required.
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.
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.
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.
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.
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.
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.
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.