What is chronic hepatitis C, and why is it a problem?
Hepatitis C is a virus that infects people’s liver. When an infection goes on for a long time, it is said to be ‘chronic’.
Hepatitis C is mainly transmitted between people through contact with infected blood (mostly through illegal drug use that involves needle-sharing, but possibly from mother to baby in the womb, or through having sex with an infected person).
Usually people infected with hepatitis C have no symptoms in the early stages of the infection; however, about 60% to 70% of them go on to develop severe liver-related problems which eventually lead to death. There are about 150 million people in the world with chronic hepatitis C infection and more than 350,000 of them die from this liver infection each year.
What are the treatments for chronic hepatitis C infection?
The current standard treatment for chronic hepatitis C is a combination of two medicines, pegylated interferon-alpha (interferon) and ribavirin. Interferon is not widely available globally and can have some adverse (harmful) effects. It works better on some types (genotypes) of the hepatitis C virus than others.
Nitazoxanide belongs to a class of antiviral medicines with activity against a broad range of viruses. It is the first medicine in this class to be investigated for its effect on chronic hepatitis C infection.
The purpose of this review
This Cochrane review tried to identify the benefits and harms of treating chronic hepatitis C infection with nitazoxanide.
Findings of this review
The review authors searched the medical literature up to April 2013, and identified seven relevant medical trials, with a total of 538 participants. The trials were performed in two countries, the USA and Egypt. All the trials had low numbers of participants, and the methods used in them were not of a high quality, which makes potential overestimation of benefits and underestimation of harms more likely. All the trials only included participants with chronic hepatitis C genotype (type) 1 or 4 infection.
Outcomes important to people who suffer from this infection include: death from all causes, death from chronic hepatitis C infection, how unwell you feel (morbidity), quality of life, and adverse events caused by the medicines. This review found no information, or very little low quality evidence, about the effects of nitazoxanide on any of these outcomes.
Nitazoxanide might have a beneficial effect on virus activity that can be monitored by analysis of blood samples (sustained virological response (SVR) and virological end-of-treatment response (ETR), but this is not certain. Indeed, the review authors could not draw any conclusions about the benefits or harms of nitazoxanide for people with chronic hepatitis C infection.
More randomised clinical trials of high methodological quality are needed to establish the effects of nitazoxanide in people with chronic hepatitis C.
We found very low quality, or no, evidence on nitazoxanide for clinically- or patient-relevant outcomes, such as all-cause mortality, chronic hepatitis C-related mortality, morbidity, and adverse events in participants with chronic hepatitis C genotype 1 or 4 infection. Our results of no improvement in alanine aminotransferase and aspartate aminotransferase serum levels were also uncertain. No conclusion could be drawn about liver histology because of a lack of data. Our results indicate that nitazoxanide might have an effect on sustained virological response and virological end-of-treatment response. However, both results could be influenced by systematic errors because all the trials included in the review had a high risk of bias. Furthermore, only the beneficial effect on number of participants achieving sustained virological response was supported when we applied trial sequential analysis. The results on virological end-of-treatment response might, therefore, be caused by a random error. We totally lack information on the effects of nitazoxanide in participants with chronic hepatitis C genotypes 2 or 3 infection. More randomised clinical trials with a low risk of bias are needed to assess the effects of nitazoxanide for chronic hepatitis C.
Hepatitis C infection is a disease of the liver caused by the hepatitis C virus. The estimated number of chronically infected people with hepatitis C virus worldwide is about 150 million people. Every year, another three to four million people acquire the infection. Chronic hepatitis C is a leading cause of liver-related mortality and morbidity. It is estimated that around 5% to 20% of people with the infection will develop liver cirrhosis, which increases the risk of hepatocellular carcinoma and liver failure. Until 2011, the combination therapy of pegylated interferon-alpha (peginterferon) and ribavirin was the approved standard treatment for chronic hepatitis C. In 2011, first-generation direct-acting antivirals have been licensed, for use in combination with peginterferon and ribavirin for treating hepatitis C virus genotype 1 infection. Nitazoxanide is another antiviral drug with broad antiviral activity and may have potential as an effective alternative, or an addition to standard treatment for the treatment of the hepatitis C virus.
To assess the benefits and harms of nitazoxanide in people with chronic hepatitis C virus infection.
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (last searched April 2013), The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 3), MEDLINE (Ovid SP, 1948 to April 2013), EMBASE (Ovid SP, 1980 to April 2013), LILACS (1983 to April 2013), and Science Citation Index EXPANDED (ISI Web of Knowledge, 1900 to April 2013), using the search strategies and the expected time spans. We also scanned reference lists of identified studies.
We also searched ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform search portal for registered trials, either completed or ongoing (April 2013).
We included randomised clinical trials that examined the effects of nitazoxanide versus placebo, no intervention, or any other intervention in patients with chronic hepatitis C. We considered any co-intervention, including standard treatment, if delivered to all intervention groups of the randomised trial concerned.
Two review authors extracted data independently. We assessed the risk of systematic errors ('bias') by evaluation of bias risk domains. We used Review Manager 5.2 for the statistical analyses of dichotomous outcome data with risk ratio (RR) and of continuous outcome data with mean difference (MD). For meta-analyses, we used a fixed-effect model and a random-effects model, along with an assessment of heterogeneity. We assessed risk of random errors ('play of chance') using trial sequential analysis. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to present review results in 'Summary of findings' tables.
We included seven randomised clinical trials with a total of 538 participants with chronic hepatitis C. Participants were 18 years of age or older, all diagnosed with chronic hepatitis C genotype 1 or 4. All of the trials had a high risk of bias. All of the trials compared nitazoxanide with placebo or no intervention, and six out of seven of the trials included different antiviral co-interventions administered equally to all intervention groups. Only one trial, comparing nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin, provided information that there were no deaths due to any cause or due to chronic hepatitis C (100 participants, very low quality evidence). The relative effect of nitazoxanide versus placebo or no intervention on adverse events was uncertain (37 out of 179 (21%) versus 30 out of 152 (20%); RR 1.10; 95% CI 0.71 to 1.71; I2 = 65%; four trials; very low quality evidence). Nitazoxanide decreased the risk of failure to achieve sustained virological response when compared with placebo or no intervention (159 out of 290 (55%) versus 133 out of 208 (64%); RR 0.85; 95% CI 0.75 to 0.97; I2 = 0%; seven trials; low quality evidence) and also the risk of failure to achieve virological end-of-treatment response (125 out of 290 (43%) versus 110 out of 208 (53%); RR 0.81; 95% CI 0.69 to 0.96; I2 = 46%; seven trials; low quality evidence). Trial sequential analysis supported the meta-analysis result for sustained virological response, but not the meta-analysis for virological end-of-treatment response. Meta-analysis also showed that nitazoxanide did not decrease the number of participants who showed no improvement in alanine aminotransferase and aspartate aminotransferase serum levels when compared with placebo or no intervention (52 out of 97 (54%) versus 47 out of 95 (49%); RR 1.09; 95% CI 0.84 to 1.42; I2 = 0%; three trials; very low quality evidence). None of the included trials assessed the effects of nitazoxanide on morbidity or on quality of life. Histological changes were only reported on a subset of three participants out of thirteen participants included in a long term-follow-up trial.