Article

Thiazolides: a new class of antiviral drugs

The Romark Institute for Medical Research, Tampa, Florida 33607, USA.
Expert Opinion on Drug Metabolism &amp Toxicology (Impact Factor: 2.94). 06/2009; 5(6):667-74. DOI: 10.1517/17425250902988487
Source: PubMed

ABSTRACT Thiazolides have emerged as a new class of broad-spectrum antiviral drugs, and the first thiazolide, nitazoxanide, is in late-stage clinical trials for treating chronic hepatitis C.
To review the chemistry, pharmacology, toxicology and efficacy of thiazolides as antiviral agents with emphasis on clinical development of nitazoxanide in treating chronic hepatitis C.
Literature search, information from Romark Laboratories and my personal experience with the discovery and development of thiazolides serve as the sources for this review.
Thiazolides are metabolically stable, highly bound to plasma proteins and are associated with a favorable toxicology profile. Phase II clinical trials have demonstrated efficacy and safety of nitazoxanide added to peginterferon with or without ribavirin in treating patients with chronic hepatitis C. More limited clinical data indicated potential in treating chronic hepatitis B, and three randomized controlled trials have demonstrated efficacy in reducing the duration of viral gastroenteritis. New generation thiazolides with the nitro group of nitazoxanide replaced by a non-reducible group are not active against anaerobes but retain broad-spectrum activity against viruses. Further studies are needed. Research indicates that these drugs may play an important and complementary role in combination with other classes of antiviral drugs.

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We also scanned reference lists of identified studies.We also searched www.clinical trials.gov and the World Health Organisation's International Clinical Trials Registry Platform (ICTRP) search portal (WHO) at apps.who.int/trialsearch/Default.aspx 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 trials 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 with more than one trial, 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, in the review. 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 also assessed different antiviral co-interventions administered equally to all experimental groups. 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Trial sequential analysis supported the meta-analysis result for sustained virological response; however, it did not support 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 to 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. The included trials assessed only baseline data on morbidity. Histological changes were only reported on a subset of three participants out of thirteen participants included in a long term-follow-up trial. 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 on participants who showed 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 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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