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Background: 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., Objectives: 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., Search Methods: 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., Selection Criteria: Randomised clinical trials assessing aminoadamantanes in participants with chronic hepatitis C virus infection., Data Collection and Analysis: 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')., Main Results: 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., Authors' Conclusions: 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.

Background: Around 3% of the world's population (approximately 160 million people) are chronically infected with hepatitis C virus. The proportion of infected people who develop clinical symptoms varies between 5% and 40%. Combination therapy with pegylated interferon-alpha plus ribavirin eradicates the virus from the blood six months after treatment (sustained virological response) in approximately 40% to 80% of infected patients, depending on the viral genotype. New antiviral agents, such as boceprevir and telaprevir, in combination with standard therapy, can increase sustained virological response in genotype 1 infected patients to at least 70%. There is therefore an unmet need for drugs that can achieve a higher proportion of sustained virological response. Aminoadamantanes are antiviral drugs used for treatment of patients with chronic hepatitis C., Objectives: To assess the beneficial and harmful effects of aminoadamantanes for patients with chronic hepatitis C infection by conducting a systematic review with meta-analyses of randomised clinical trials, as well as trial sequential analyses., Search Methods: We conducted electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 11 of 12 (1995 to December 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 and checked the reference lists of identified publications., Selection Criteria: Randomised clinical trials assessing aminoadamantanes in patients with chronic hepatitis C infection., Data Collection and Analysis: Two authors independently extracted data. We assessed for risks of systematic errors ('bias') using the 'Risk of bias' tool. We analysed dichotomous data with risk ratio (RR) and continuous data with mean difference (MD) or standardised mean difference (SMD), both with 95% confidence intervals (CI). We used trial sequential analysis to assess the risk of random errors ('play of chance'). We assessed quality using the GRADE system., Main Results: We included 41 randomised clinical trials with 6193 patients with chronic hepatitis C. All trials had high risk of bias. All included trials compared amantadine versus placebo or no intervention. Standard antiviral therapy was administered equally to the intervention and the control groups in 40 trials. The standard antiviral therapy, which was administered to both intervention groups, was interferon-alpha, interferon-alpha plus ribavirin, and peg interferon-alpha plus ribavirin, depending on the time when the trial was conducted.When we meta-analysed all trials together, the overall results demonstrated no significant effects of amantadine, when compared with placebo or no intervention, on our all-cause mortality or liver-related morbidity composite outcome (5/2353 (0.2%) versus 6/2264 (0.3%); RR 0.90, 95% CI 0.38 to 2.17; I² = 0%; 32 trials; very low quality). There was also no significant effect on adverse events (288/2869 (10%) versus 293/2777 (11%); RR 0.98, 95% CI 0.84 to 1.14; I² = 0%; 35 trials; moderate quality). We used both fixed-effect and random-effects meta-analyses. Amantadine, when compared with placebo or no intervention, did not significantly influence the number of patients who failed to achieve a sustained virological response (1821/2861 (64%) versus 1737/2721 (64%); RR 0.98, 95% CI 0.95 to 1.02; I² = 35%; 35 trials; moderate quality). However, in the subgroup using interferon plus ribavirin, amantadine decreased the number of patients who failed to achieve a sustained virological response (422/666 (63%) versus 447/628 (71%); RR 0.89, 95% CI 0.83 to 0.96; I² = 41%; 11 trials; low quality). Similar results were found for failure to achieve an end of treatment virological response. Amantadine, when compared with placebo or no intervention, significantly decreased the number of patients without normalisation of alanine aminotransferase (ALT) serum levels at the end of treatment (671/1141 (59%) versus 732/1100 (67%); RR 0.88, 95% CI 0.83 to 0.94; I² = 47%; 19 trials; low quality). Amantadine, when compared with placebo or no intervention, did not significantly influence the end of follow-up biochemical response (1133/1896 (60%) versus 1151/1848 (62%); RR 0.95, 95% CI 0.91 to 1.00; I² = 49%; 21 trials; low quality).The observed beneficial effects could be true effects but could also be due to both systematic errors (bias) and random errors (play of chance). The latter is due to the fact that trial sequential analyses could not confirm or refute our findings. We were not able to perform meta-analyses for failure of histological improvement or quality of life due to a lack of valid data., Authors' Conclusions: This systematic review does not demonstrate any significant effects of amantadine on all-cause mortality or liver-related morbidity composite outcome and on adverse events in patients with hepatitis C; however, the median trial duration was 12 months, with a median follow-up of six months, which is not long enough to assess the composite outcome sufficiently. Overall, we did not see an effect of amantadine on failure to achieve a sustained virological response. Subgroup analyses demonstrated that the combination of amantadine plus interferon-alpha and ribavirin seems to increase the number of patients achieving a sustained virological response. This finding may be caused by both systematic errors (bias) and risks of random errors (play of chance), but it could also be real. Based on the results of the overall evidence, it appears less likely that future trials assessing amantadine for patients with chronic hepatitis C will show strong benefits. Therefore, it is probably advisable to wait for the results of trials assessing other direct-acting antiviral drugs. In the absence of convincing evidence of benefit, the use of amantadine is justified in the context of randomised clinical trials assessing the effects of combination therapy. We found a lack of evidence on other aminoadamantanes than amantadine.

In this new Dutch guideline for hepatitis C virus infection we provide recommendations for the management of hepatitis C infection. Until 2012 the standard for treatment consisted of pegylated interferon alpha (peg-IFNa) and ribavirin. The advent of first-generation direct antiviral agents such as boceprevir and telaprevir has changed the concept of treatment of adult chronic hepatitis C genotype 1 infected patients. There are three benefits of boceprevir and telaprevir. They increase the likelihood of cure in 1) naive genotype 1 patients and 2) in patients who did not respond to earlier treatment with peg-IFNa and ribavirin, while 3) allowing shortening of treatment duration from 48 weeks to 24 or 28 weeks, which is possible in 40-60% of non-cirrhotic naive (boceprevir and telaprevir) and relapsing patients (telaprevir). The use of boceprevir and telaprevir is associated with multiple side effects and awareness of these side effects is needed to guide the patient through the treatment process. This guideline, formulated on behalf of The Netherlands Association of Hepato-gastroenterologists, The Netherlands Association of Internal Medicine, and The Dutch Association for the Study of Liver Disease, serves as a manual for physicians for the management and treatment of acute and chronic hepatitis C virus monoinfection in adults.

Hepatitis C virus (HCV) is the most common infectious cause of chronic liver disease in Europe. With the introduction of interferon based therapy in combination with ribavirin treatment of chronic HCV has become feasible. This therapy has become the standard of care for patients with HCV and depending on the HCV genotype treatment is successful in 40-70% of patients. In the recent years a new class of drugs have emerged that changed the landscape of HCV treatment. These direct antiviral agents inhibit the NS3/N4A serine protease of HCV. Prototypes are telaprevir and boceprevir and they specifically exert antiviral activity against genotype 1 HCV. A series of landmark trials has paved the way for introduction of these agents, and they have documented a great improvement in the care of genotype 1 HCV patients. Telaprevir and boceprevir are given in combination with pegylated interferon and ribavirin and are useful for treatment naive as well as treatment experienced patients. The clinician should be aware of these developments as they have implications for side effect management, and drug-drug interactions. Finally, strategic use of these agents comes with stopping rules and require close monitoring of the HCV viral load.