Background
Hepatitis C virus is mainly transmitted by contact to infected blood. Chronic hepatitis C infection affects around 3% of the world population and progresses slowly. Most patients present without symptoms, or with symptoms like fatigue or liver-related morbidity. Frequently, the disease is discovered by coincidence because of abnormal laboratory results. Around 5% to 40% of all infected patients will develop severe liver damage which can cause severe liver-related morbidities and eventually death. Current treatment consists of pegylated interferon-alpha plus ribavirin and in some subgroups of patients these agents are combined with telaprevir or boceprevir, or other direct acting antivirals. In about 70% of patients with chronic hepatitis C, it is possible to eradicate the virus from the blood, but the clinical effects are not known. Aminoadamantanes (another group of antiviral drugs), mostly amantadine, have been tested in several clinical trials. The authors have previously systematically reviewed amantadine versus placebo or no intervention and found no significant effects of amantadine.
Review questions and study characteristics
Only amantadine has been tested in randomised clinical trials including participants with chronic hepatitis C. The main goal of these trials was to investigate whether amantadine as a single therapy or amantadine in combination with other antiviral therapies, compared with placebo or no intervention (with or without antiviral therapy), could increase the proportion of patients with virus eradication from the blood. This review evaluates whether amantadine versus other antiviral drugs has any beneficial or harmful effect in patients with chronic hepatitis C. The trials compared amantadine with ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. The primary outcomes were the composite of all-cause mortality or liver-related morbidity and adverse events. This review includes six randomised clinical trials with a total of 581 patients.
Key results and quality of evidence
All the included trials were with high risk of bias. This review did not demonstrate any benefits or harms of amantadine on all-cause mortality or liver-related morbidity and on adverse events, but data were sparse. Compared with ribavirin, amantadine seemed to lead to more participants who fail to achieve sustained virological response (that is, undetectable hepatitis C virus RNA in serum by sensitivity testing six months after the end of treatment). This may be real or due to bias (systematic errors), but it does not seem to be due to play of chance (random errors), as trial sequential analysis confirmed the result. Compared with mycophenolate mofetil, amantadine seemed less effective in achieving end-of-treatment virological response. Compared with interferon-alpha or interferon-gamma, amantadine did not seem to offer benefits. Accordingly, the evidence from this review does not support the routine clinical use of amantadine. Therefore, it is probably better to examine the effects of other direct acting antivirals in the hepatitis C field than to conduct more randomised clinical trials on amantadine. We found no randomised clinical trials assessing other aminoadamantanes, for example rimantadine.
This systematic review has identified evidence of very low quality for the key outcomes of all-cause mortality or liver-related morbidity and adverse events in people with chronic hepatitis C when treated with amantadine compared with ribavirin, mycophenolate, interferon-alpha, or interferon-gamma. The timeframe for measuring the composite outcome was insufficient in the included trials. There was low quality evidence that amantadine led to more participants who failed to achieve sustained virological response compared with ribavirin. This observation may be real or caused by systematic errors (bias), but it does not seem to be caused by random error (play of chance). Due to the low quality of the evidence, we are unable to determine definitively whether amantadine is less effective than other antivirals in patients with chronic hepatitis C. As it appears less likely that future trials assessing amantadine or potentially other aminoadamantanes for patients with chronic hepatitis C would show strong benefits, it is probably better to focus on the assessments of other direct acting antiviral drugs. We found no evidence assessing other aminoadamantanes in randomised clinical trials in order to recommend or refute their use.
Hepatitis C virus infection affects around 3% of the world population or approximately 160 million people. A variable proportion (5% to 40%) of the infected people develop clinical symptoms. Hence, hepatitis C virus is a leading cause of liver-related morbidity and mortality with hepatic fibrosis, end-stage liver cirrhosis, and hepatocellular carcinoma as the dominant clinical sequelae. Combination therapy with pegylated (peg) interferon-alpha and ribavirin achieves sustained virological response (that is, undetectable hepatitis C virus RNA in serum by sensitivity testing six months after the end of treatment) in approximately 40% to 80% of treated patients, depending on viral genotype. Recently, a new class of drugs have emerged for hepatitis C infection, the direct acting antivirals, which in combination with standard therapy or alone can lead to sustained virological response in 80% or more of treated patients. Aminoadamantanes, mostly amantadine, are antiviral drugs used for the treatment of patients with chronic hepatitis C. We have previously systematically reviewed amantadine versus placebo or no intervention and found no significant effects of the amantadine on all-cause mortality or liver-related morbidity and on adverse events in patients with hepatitis C. Overall, we did not observe a significant effect of amantadine on sustained virological response. In this review, we systematically review aminoadamantanes versus other antiviral drugs.
To assess the beneficial and harmful effects of aminoadamantanes versus other antiviral drugs for patients with chronic hepatitis C virus infection by conducting a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.
The Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11 of 12, 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), Science Citation Index EXPANDED (1900 to December 2013), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm up to December 2013. Furthermore, full text searches were conducted until December 2013.
Randomised clinical trials assessing aminoadamantanes in participants with chronic hepatitis C virus infection.
Two authors independently extracted data. RevMan Analysis was used for statistical analysis of dichotomous data using risk ratio (RR) with 95% confidence intervals (CI). Methodological domains were used to assess the risk of systematic errors ('bias'). We used trial sequential analysis to assess risk of random errors ('play of chance').
Six randomised clinical trials with 581 participants with chronic hepatitis C were included. All trials had high risk of bias. The included trials compared amantadine versus other antiviral drugs: ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. Standard antiviral therapy (interferon-alpha, interferon-alpha plus ribavirin, or peg interferon alpha) was administered equally to the intervention and the control groups in five trials, depending on when the trial was conducted. Four trials compared amantadine versus ribavirin. There were no deaths or liver-related morbidity in the two intervention groups (0/216 (0%) versus 0/211 (0%); 4 trials; very low quality of the evidence). The lower estimated risk for (serious) adverse events leading to treatment discontinuation with amantadine was imprecise (RR 0.56, 95% CI 0.27 to 1.16; based on 10/216 (5%) versus 18/211 (9%) participants in 4 trials; very low quality of the evidence). There were more participants with failure of sustained virological response in the amantadine group than in the ribavirin group (206/216 (96%) versus 176/211 (84%); RR 1.14, 95% CI 1.07 to 1.22, 4 trials; low quality of the evidence). Amantadine versus ribavirin more often failed to achieve end-of follow-up biochemical response (41/46 (89%) versus 31/46 (67%); RR 1.31, 95% CI 1.05 to 1.63; 2 trials; very low quality of the evidence). One trial compared amantadine versus mycophenolate mofetil. There were no significant differences between the two treatment groups, except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response (low quality of evidence). One trial each compared amantadine versus interferon-alpha or interferon-gamma. Both comparisons showed no significant differences in the treatment outcomes (very low quality of the evidence). The observed effects could be due to real effects, systematic errors (bias), or random errors (play of chance). This possible influence on the observed effect by play of chance is due to the fact that trial sequential analyses could not confirm our findings. We were not able to perform meta-analyses on failure of histological improvement and quality of life due to lack of valid data in all trial comparisons.