Clinical trial NCT01185028
Conditions: Hepatitis C Infection HIV Infection
Keywords: Chronic HCV HCV Treatment Nonresponders HCV Treatment Relapsers HIV-HCV Co-Infection Nitazoxanide Hepatitis C
Sponsor: National Institutes of Health Clinical Center (CC)
Start date: 2010-08-01; Completion date: 2011-10-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Chronic hepatitis C (CHC) is a major health problem that particularly affects individuals with human immunodeficiency virus (HIV) infection, and can lead to cirrhosis and liver failure. Standard treatment for people with HIV and CHC is a 48-week course of pegylated-interferon alfa 2a (peg-IFN) and ribavirin (RBV), but better treatments are needed for those who either do not respond to the drugs or who relapse after treatment.
* Nitazoxanide has been approved by the Food and Drug Administration primarily to treat diarrhea caused by parasites, and it has been studied in the treatment of CHC infection. However, it has not been tested in persons infected with HIV and CHC co-infection. Researchers are interested in determining whether nitazoxanide is a safe and tolerable treatment for CHC in individuals with HIV.

Objectives:

\- To assess the safety and tolerability of using nitazoxanide to treat chronic hepatitis C infection in individuals with HIV who have not responded to standard treatment for hepatitis C.

Eligibility:

\- Individuals at least 18 years of age who have been diagnosed with both HIV and chronic hepatitis C, and who have either not responded to or relapsed after previous hepatitis C treatment.

Design:

* Participants will be screened with a physical examination and medical history; blood and urine tests; imaging studies; possible heart, lung, and psychological tests; and a liver biopsy if one has not been done in the past 3 years.
* Participants will receive nitazoxanide, the medication being studied, to take by mouth for 4 weeks, and will provide blood samples during this time.
* After 4 weeks, participants will receive the first dose of peg-IFN and RBV. Participants will have weekly injections of peg-IFN and continue to take nitazoxanide and RBV by mouth for 48 weeks. Individuals who are slow to respond to this combined CHC treatment (nitazoxanide, peg-IFN, and RBV) by week 12 will continue to have the combined treatment for an extended period, a total of 72 weeks.
* Participants will have study visits to provide blood samples and have other tests two times in the first month of combined treatment, and then at months 2, 3, 4, 7, 10, 13, 19; and month 25 only in participants slow to respond to combined treatment.
* Some participants who are on specific HIV treatment regimens may enroll in a substudy that will require three separate 12-hour visits for repeated blood samples and other tests during the initial 4-week nitazoxanide treatment.

Detailed description:
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.

Arms: arm 1: Nitazoxanide 500mg po bid for 4 wks followed by peg-IFN/Ribavirin/nitazoxanide for 48 weeks
Interventions: intervention 1: Nitazoxanide With Pegylated Interferon And Ribavirin
Intervention descriptions: intervention 1: Nitazoxanide 500mg po bid for 4 wks followed by peg-IFN/Ribavirin/nitazoxanide for 48 weeks

Protocol documents: