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KSR Number: KSRA19928

Pharmacological interventions for acute hepatitis C infection

  • Cochrane Database Syst Rev 2017, 3, CD011644, 10.1002/14651858.CD011644.pub2
  • Full report

Risk of Bias Assessment

Overall summary: Risk of bias unclear

Bottom Line

Current evidence suggests that the progression of acute hepatitis C virus (HCV) infection to chronic HCV infection may decrease with the use of interferon-alpha or interferon-beta compared to no intervention. However, these results should be interpreted with caution, since reviewer error and bias cannot be ruled out during quality assessment, and the source of high heterogeneity in some analyses was not explored further. Further high-quality randomised controlled trials are required to assess how pharmaceutical treatments impact health-related quality of life, liver cirrhosis and liver transplantation in patients with acute HCV infection.

Risk of Bias Assessment

Overall summary Risk of bias unclear

Unclear

No information was provided regarding the number of reviewers involved in the risk of bias assessment, meaning reviewer error and bias cannot be ruled out. High heterogeneity in one outcome was not explored further.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably no
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review Unclear

Details of Review

Number of studies 10
Number of participants 488
Last search date 16th April 2016
Review type Intervention
Objective To compare the benefits and harms of different pharmacological interventions in the treatment of acute hepatitis C virus infection.
Population Participants with acute hepatitis C virus (HCV) infection, defined as the absence of HCV antibody and subsequent seroconversion (i.e. presence of HCV antibody in a person who was previously negative for HCV antibody or less than six months of HCV infection)), irrespective of the method of diagnosis of seroconversion or HCV genotype.

Participants who had other coexisting viral diseases such as HIV or hepatitis B virus coinfections or who had undergone previous liver transplantation were excluded.
Interventions Any pharmaceutical interventions primarily targeted at the treatment of acute hepatitis C virus infection, including: Interferon-alpha, pegylated interferon-alpha, interferon-beta, ribavirin, first-generation direct-acting antiviral agents (boceprevir and telaprevir) or second-generation direct-acting antiviral agents (other direct-acting antiviral agents); either alone or in combination.
Comparator A different pharmaceutical agent, placebo or no intervention.
Outcome Primary outcomes: mortality at maximal follow-up (time to death), short-term or medium-term mortality, adverse events, serious adverse events, health-related quality of life.

Secondary outcomes: liver transplantation, decompensated liver disease, cirrhosis, the proportion of participants with hepatocellular carcinoma, the proportion of participants with chronic HCV infection.
Study design Randomised controlled trials.

Results

In terms of mortality at maximum follow-up, eight studies reported no deaths across a mean period of follow-up of six to 36 months (8 studies, n = 337 participants).

In terms of short-term mortality (less than one year), eight out of nine studies reported no deaths (8 studies, n=342 patients), and one out of nine studies reported a single death for a patient treated with pegylated interferon-alpha plus ribavirin (1 study, n=95 participants).

In terms of medium-term mortality (between 1 to 5 years), three studies reported no deaths were observed in either interferon-beta or no intervention groups (three studies, n = 90 participants).

In terms of serious adverse events, pooled analysis reported no difference in the proportion of patients with serious adverse effects for pegylated interferon-alpha and ribavirin versus pegylated interferon-alpha (odds ratio [OR] 1.72, 95% confidence interval [CI] 0.70 to 4.21; 2 studies, n = 237 participants); however, the number of serious adverse events was reported to be higher for pegylated interferon-alpha plus ribavirin compared to pegylated interferon-alpha (rate ratio [RR] 2.74, 95% CI 1.40 to 5.33; 2 studies, n = 237 participants). No serious adverse events were reported for interferon-beta (one study) or MTH-68/B vaccination (one study) versus no intervention and the rate of serious adverse events for pegylated interferon-alpha plus ribavirin group (one study) and the pegylated interferon-alpha group (one study) was reported to be 25.1 per 100 participants and 9.2 per 100 participants respectively.

In terms of any adverse events, a single study reported an increase in the proportion of people with any type of adverse event for interferon-alpha (OR = 203.00, 95% CI 9.01 to 4574.81; 1 study, n = 33 participants) or interferon-beta (OR = 27.88, 95% CI 1.48 to 526.12; 1 study, n = 40 participants) compared to no intervention. However, a single study reported no difference in the number of adverse events recorded for interferon-beta compared to no intervention (OR 17.00, 95% CI 0.98 to 294.53; 1 study, n = 40 participants). The adverse event rate for the interferon-beta group was reported to be 14.7 per 100 participants. No adverse events were reported for MTH-68/B vaccination.

In terms of chronic Hepatitic C virus (HCV) infection, pooled analysis reported a lower proportion of patients with chronic HCV for interferon-alpha (OR 0.27, 95% CI 0.09 to 0.76; 3 studies, n = 90 participants) or interferon-beta (OR 0.07, 95% CI 0.00 to 1.24; 3 studies, n = 90 participants) compared with no intervention. A single study reported no difference in the proportion of participants with chronic HCV for MTH-68/B vaccination versus no intervention (OR 0.28, 95% CI 0.05 to 1.65; 1 study, n = 41 participants). Similarly, pooled analysis reported no difference in the proportion of participants with chronic HCV for pegylated interferon-alpha plus ribavirin versus pegylated interferon-alpha (OR 0.86, 95% CI 0.41 to 1.79; 2 studies, n = 237 participants).

Full Risk of Bias Assessment

The research objective was clearly stated. The eligibility criteria were explicitly defined. No restrictions were reported based on study characteristics or sources of information.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Probably yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably yes
Concerns regarding specification of study eligibility criteria Low

CENTRAL, MEDLINE, EMBASE, and Science Citation Index Expanded were searched for relevant studies. The World Health Organisation International Clinical Trials Registry Platform Search Portal and references of relevant articles were screened to identify further studies. A detailed search strategy was reported and was found appropriate. Searches were not restricted to the date, publication format or language. Two reviewers were independently involved in the study selection and any discrepancies were resolved by discussion or arbitration with other reviewers.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Yes
Concerns regarding methods used to identify and/or select studies Low

Two reviewers independently extracted the data and resolved discrepancies through discussion. Sufficient study characteristics were extracted for the interpretation of results. Relevant study results were appropriately collected for use in the synthesis. The methodological quality of included studies was assessed using the Cochrane risk of bias tool for randomised controlled trials. No information was provided regarding the number of reviewers involved in the risk of bias assessment.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Probably yes
3.5 Were efforts made to minimise error in risk of bias assessment? No information
Concerns regarding methods used to collect data and appraise studies Unclear

The synthesis appeared to include all eligible studies. The method of analysis was explained and appeared appropriate. Heterogeneity was assessed and was found to be high for one outcome (chronic HCV infection); this was not explored further. Publication bias was not assessed due to the limited number of trials; this was considered appropriate. The quality of individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably no
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Low

Abstract

Background: 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 (ra