Pharmacological interventions for acute hepatitis C infection New search for studies and content updated (no change to conclusions)
Hepatitis C virus (HCV) is a single‐stranded RNA (ribonucleic acid) virus that has the potential to cause inflammation of the liver. The traditional definition of acute HCV infection is the first six months following infection with the virus. Another commonly used definition of acute HCV infection is the absence of HCV antibody and subsequent seroconversion (presence of HCV antibody in a person who was previously negative for HCV antibody). Approximately 40% to 95% of people with acute HCV infection develop chronic HCV infection, that is, have persistent HCV RNA in their blood. In 2010, an estimated 160 million people worldwide (2% to 3% of the world's population) had chronic HCV infection. The optimal pharmacological treatment of acute HCV remains controversial. Chronic HCV infection can damage the liver.Objectives
To assess the comparative benefits and harms of different pharmacological interventions in the treatment of acute HCV infection through a network meta‐analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta‐analysis and instead we assessed the comparative benefits and harms of different interventions versus each other or versus no intervention using standard Cochrane methodology.Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to April 2016 to identify randomised clinical trials on pharmacological interventions for acute HCV infection.Selection criteria
We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with acute HCV infection. We excluded trials which included previously liver transplanted participants and those with other coexisting viral diseases. We considered any of the various pharmacological interventions compared with placebo or each other.Data collection and analysis
We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed‐effect and random‐effects models based on the available‐participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.Main results
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.Authors' conclusions
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.
Maria Kalafateli, Elena Buzzetti, Douglas Thorburn, Brian R Davidson, Emmanuel Tsochatzis, Kurinchi Selvan Gurusamy
Plain language summary
Medical treatment of acute hepatitis C virus infection
Hepatitis C virus (HCV) 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 HCV, and unprotected sex. Acute HCV infection is the period that covers within six months of infection. While some people clear the virus after acute HCV infection, the virus remains in others. This is called chronic HCV infection and may cause major health problems such as excessive tiredness, and liver failure leading to vomiting blood, confusion, and death. Overall, an estimated 160 million people worldwide (2% to 3% of the world's population) have chronic HCV infection. A number of medical treatments have been used for acute HCV infection. The best way to treat acute HCV infection is not clear. We sought to resolve this issue by searching for existing studies on the topic. We included all randomised clinical trials (clinical studies where people are randomly put into one of two or more intervention groups) whose results were reported to April 2016. We included only trials in which participants had not undergone liver transplantation previously and those who did not have liver disease due to other viral infections. Apart from using standard Cochrane methods which allow comparison of only two interventions at a time (direct comparison), we planned to use advanced method which allows comparison of the many different interventions individually 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.
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.
Source of funding
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.
Quality of evidence
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.
Maria Kalafateli, Elena Buzzetti, Douglas Thorburn, Brian R Davidson, Emmanuel Tsochatzis, Kurinchi Selvan Gurusamy
Implications for practice
Very low quality evidence suggests that interferon‐alpha may decrease the incidence of chronic hepatitis C virus (HCV) infection as measured by lack of 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 did not find any evidence to support that pegylated interferons or ribavirin or both, are effective in people with acute HCV infection. We could find no randomised clinical trials comparing direct‐acting antivirals versus 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.
Implications for research
The trial design that is most likely to be accepted by hepatologists will probably involve direct‐acting antivirals and pegylated interferon. Researchers should use clinical outcomes for research on this topic. The ideal trial should include placebo as one of the intervention arms because there has been no evidence from randomised clinical trials that any of the interventions are effective in improving clinical outcomes. However, as many hepatologists and researchers believe that sustained virological response equates to cure of disease (although, this belief has been challenged (Gluud 2014; Koretz 2015)), it may be difficult to recruit into such a trial. The trials should be designed and reported using guidance from the SPIRIT statement (Standard Protocol Items: Recommendations for Interventional Trials; Chan 2013) and the CONSORT statement (Schulz 2010).Get full text at The Cochrane Library
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