A Safety and Tolerability Study of Nitazoxanide in HIV-HCV Treatment Failures

Chronic hepatitis C (CHC) viral infection is a major health problem affecting 130-170 million worldwide, and 2.7-3.9 million in the US, more than 3 times those with HIV infection. One-third of persons with HIV have CHC, a more rapid progression to cirrhosis and liver failure, with liver disease as one of the leading causes of mortality. Standard treatment, pegylated-interferon (IFN) alfa and ribavirin (RBV), has an efficacy, sustained virologic response (SVR), of less than 50% in those with HCV genotype 1 (GT 1); and only about 25% of those with HIV-HCV GT1 co-infection. SVR is even lower in those retreated, who were prior treatment relapsers or non-responders; few published studies exist, especially in those with HIV. Improved therapy is imperative given increasing morbidity and mortality and the proportion of persons who are relapsers or non-responders. Newer and promising anti-HCV therapies, directly acting antivirals (DAA), are in development. However, only 2 are in Phase 3 clinical trials and most remain far from FDA approval. An oral agent, nitazoxanide (NTZ), with broad in vitro anti-microbial activity and a good safety profile, has higher efficacy rates in treatment na ve participants mono-infected with HCV GT 1 or 4. There have not been studies in HIV co-infected persons, nor pharmacokinetic (PK) studies in liver or renal disease. In vitro studies suggest that NTZ has both a direct suppressive effect on HCV replication, as well as a sensitizing effect on IFN-mediated suppression of HCV replication, yet the exact mechanism of action giving rise to higher SVR rates is not well understood. This is an open-label study in 35 HIV-HCV GT 1 co infected persons, prior relapsers (n=25) or non-responders (n=10) after a full course of IFN and RBV therapy. Participants will receive 4 weeks of NTZ lead-in therapy, followed by NTZ/peg-IFN/RBV triple combination therapy for an additional 48 weeks. Slow responders will receive 72 weeks of triple therapy after the 4-week NTZ lead-in. The primary endpoint is safety and tolerability of NTZ. Secondary endpoints are exploratory: (1) efficacy rate estimation, (2) viral dynamics assessment, and determination of predictive response, (3) pharmacologic level assessment, (4) indirect mechanistic action evaluation of NTZ through virologic response, and, (5) IFN-stimulated genetic expression evaluation and determination of predictive response. There will be a sub-study evaluating the PK of NTZ in a group of 10 participants who are on a ritonavir-based HIV antiretroviral regimen.