Nitazoxanide for chronic hepatitis C - PubMed (original) (raw)

Review

Nitazoxanide for chronic hepatitis C

Kristiana Nikolova et al. Cochrane Database Syst Rev. 2014.

Abstract

Background: 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.

Objectives: To assess the benefits and harms of nitazoxanide in people with chronic hepatitis C virus infection.

Search methods: 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).

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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; I(2) = 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; I(2) = 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; I(2) = 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; I(2) = 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.

Authors' conclusions: 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.

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Conflict of interest statement

Kristiana Nikolova: nothing to declare. Christian Gluud: nothing to declare. Berit Grevstad: nothing to declare. Janus C Jakobsen: nothing to declare.

Figures

1

1

Study flow diagram

2

2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

3

3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

4

4

Figure 4 Trial sequential analysis of the fixed‐effect meta‐analysis of the effect of nitazoxanide versus placebo or no intervention on adverse events in chronic hepatitis C infected patients. The trial sequential analysis is performed with a type 1 error of 5% (two sided), a power of 80%, an assumed control proportion of number of patients with adverse events of 20%, and an anticipated relative risk reduction (RRR) of 40%. The diversity‐adjusted required information size (DARIS) to detect or reject a RRR of 40% with a between trial heterogeneity in the meta‐analysis is estimated to 1946 participants. The actually accrued number of participants is 331, which is only 17% of the required information size. The blue cumulative Z‐curve does not cross the conventional statistical boundaries or the red inward sloping trial sequential monitoring boundaries for benefit or harm. Not even with a large RRR of 40% is there evidence to support that nitazoxanide has any effect on adverse events. The cumulative Z‐curve does not reach the futility area, demonstrating that further trials may be needed.

5

5

Figure 5 Trial sequential analysis of the fixed‐effect meta‐analysis of the effect of nitazoxanide versus placebo or no intervention on risk of failure of sustained virological response in patients with chronic hepatitis C virus infection. The trial sequential analysis is performed with a type 1 error of 5% (two sided), a power of 80%, an assumed control proportion of number of participants with failure of sustained virological response of 64%, and an anticipated relative risk reduction (RRR) of 20%. The diversity‐adjusted required information size (DARIS) to detect or reject a RRR of 20% with a between trial heterogeneity in the meta‐analysis is estimated to 419 participants. The actually accrued number of participants is 498. The blue cumulative Z‐curve crosses the red inward sloping trial sequential monitoring boundaries for benefit. This implies that there is no risk of random error in the estimate of a beneficial effect of nitazoxanide versus placebo or no intervention.

6

6

Figure 6 Trial sequential analysis of the fixed‐effect meta‐analysis of the effect of nitazoxanide versus placebo or no intervention on risk of failure of virological end‐of‐treatment response in patients with chronic hepatitis C virus infection. The trial sequential analysis is performed with a type 1 error of 5% (two sided), a power of 80%, an assumed control proportion of number of patients who failed to achieve a virological end‐of‐treatment response of 53%, and an anticipated relative risk reduction (RRR) of 20%. The diversity‐adjusted required information size (DARIS) to detect or reject a RRR of 20% with a between trial heterogeneity in the meta‐analysis is estimated to 2263 participants. The actually accrued number of participants is 498, which is 22% of the required information size. The blue cumulative Z‐curve does not cross the red inward sloping trial sequential monitoring boundaries for benefit or harm. Therefore, there is no evidence to support that nitazoxanide influences number of patients who failed (which is not even drawn by the programme) to achieve virological end‐of‐treatment response. The cumulative Z‐curve does not reach the futility area, demonstrating that further trials may be needed.

7

7

Figure 7 Trial sequential analysis of the fixed‐effect meta‐analysis of the effect of nitazoxanide versus placebo or no intervention on number of participants with chronic hepatitis C virus infection without improvement in alanine aminotransferase or aspartate aminotransferase serum levels. The trial sequential analysis is performed with a type 1 error of 5% (two sided), a power of 80%, an assumed control proportion of number of patients with morbidity of 49%, and an anticipated relative risk reduction (RRR) of 20%. The diversity‐adjusted required information size (DARIS) to detect or reject a RRR of 20% with a between trial heterogeneity in the meta‐analysis is estimated to 806 participants. The actually accrued number of participants is 192, which is 24% of the required information size. The blue cumulative Z‐curve does not cross the red inward sloping trial sequential monitoring boundaries for benefit or harm. Therefore, there is no evidence to support that nitazoxanide has any effect on number of participants without change in alanine aminotransferase or aspartate aminotransferase serum levels. The cumulative Z‐curve does not reach the futility area (which is not even drawn by the programme), demonstrating that further trials may be needed.

1.1

1.1. Analysis

Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 1 All‐cause mortality.

1.2

1.2. Analysis

Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 2 Chronic hepatitis C‐related mortality.

1.4

1.4. Analysis

Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 4 Adverse events.

1.6

1.6. Analysis

Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 6 Failure of sustained virological response.

1.7

1.7. Analysis

Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 7 Failure of virological end‐of‐treatment response.

1.8

1.8. Analysis

Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 8 Participants without improvement in ALT and/or AST serum levels.

2.1

2.1. Analysis

Comparison 2 Subgroup: treatment‐naives, relapsers and non‐responders, Outcome 1 All‐cause mortality.

2.2

2.2. Analysis

Comparison 2 Subgroup: treatment‐naives, relapsers and non‐responders, Outcome 2 Chronic hepatitis C‐related mortality.

2.4

2.4. Analysis

Comparison 2 Subgroup: treatment‐naives, relapsers and non‐responders, Outcome 4 Adverse events.

2.6

2.6. Analysis

Comparison 2 Subgroup: treatment‐naives, relapsers and non‐responders, Outcome 6 Failure of sustained virological response.

2.7

2.7. Analysis

Comparison 2 Subgroup: treatment‐naives, relapsers and non‐responders, Outcome 7 Failure of virological end‐of‐treatment response.

2.8

2.8. Analysis

Comparison 2 Subgroup: treatment‐naives, relapsers and non‐responders, Outcome 8 Participants without improvement in ALT and/or AST serum levels.

3.1

3.1. Analysis

Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 1 All‐cause mortality.

3.2

3.2. Analysis

Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 2 Chronic hepatitis C‐related mortality.

3.4

3.4. Analysis

Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 4 Adverse events.

3.6

3.6. Analysis

Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 6 Failure of sustained virological response.

3.7

3.7. Analysis

Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 7 Failure of virological end‐of‐treatment response.

3.8

3.8. Analysis

Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 8 Participants without improvement in ALT and/or AST serum levels.

4.1

4.1. Analysis

Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 1 All‐cause mortality.

4.2

4.2. Analysis

Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 2 Chronic hepatitis C‐related mortality.

4.4

4.4. Analysis

Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 4 Adverse events.

4.6

4.6. Analysis

Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 6 Failure of sustained virological response.

4.7

4.7. Analysis

Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 7 Failure of virological end‐of‐treatment response.

4.8

4.8. Analysis

Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 8 Participants without improvement in ALT and/or AST serum levels.

5.1

5.1. Analysis

Comparison 5 Best‐worst case scenario analysis, Outcome 1 Failure of sustained virological response.

6.1

6.1. Analysis

Comparison 6 Worst‐best case scenario analysis, Outcome 1 Failure of sustained virological response.

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