Abstract: We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon-alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months. There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons. Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required.

Plain-language summary: We identified 10 randomised clinical trials which were eligible for our review. Nine randomised clinical trials (467 participants) provided information for one or more measures (outcomes). The main interventions compared included different forms of interferon (protein secreted in response to viral infection), namely, interferon-alpha alone, interferon-beta alone, pegylated interferon-alpha alone, pegylated interferon-alpha plus ribavirin (another antiviral drug), a vaccine called MTH-68/B made from a different virus, versus no intervention. None of the trials compared direct-acting antivirals (the latest option for treating HCV infection) versus placebo or other interventions. The average follow-up period in the trials ranged from six months to three years. Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. All the trials were at high risk of bias, and the overall quality of the evidence was very low. This means that there is a possibility of making wrong conclusions overestimating benefits or underestimating harms of one intervention or the other because of the way that the trials were conducted. No deaths occurred less than one year after treatment in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials in which participants were followed up beyond one year, there were no further deaths. The number of serious complications was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha. The percentage of people with any complications was higher with interferon-alpha and interferon-beta than with no intervention. None of the trials reported health-related quality of life, liver transplantation, liver failure, severe liver damage, or liver cancer. The percentage of people in whom the virus remained in the blood six months after the end of treatment was lower in the interferon-alpha than in the no intervention groups. There was no evidence of differences between the groups for all the remaining comparisons. There is significant uncertainty about the size and direction of the results and high quality randomised clinical trials are required.