By Liz Highleyman

Researchers are studying a variety of approaches to improve response to interferon-based therapy for hepatitis C virus (HCV) infection, including extended duration therapy and addition of new drugs.

Studies presented at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco looked at adding nitazoxanide (Alinia) to pegylated interferon and to novel directly-targeted "STAT-C" agents in the development pipeline.

Jean-Francois Rossignol of Romark Laboratories and colleagues presented results from a study evaluating a 4 week lead-in period using nitazoxanide alone, before continuing with nitazoxanide plus pegylated interferon in patients with HCV genotype 4, which is considered difficult to treat (lower response rates than genotypes 2 or 3, slightly higher than genotype 1).

Nitazoxanide is a thiazolide anti-infective agent with activity against several protozoa, bacteria, and viruses. It is FDA approved for treatment of Cryptosporidium and Giardia. Laboratory studies have shown that nitazoxanide and its active metabolite, tizoxanide, inhibit HCV replication in vitro.

As background, the investigators noted that in their previous STEALTH-C1 trial, genotype 4 patients who received nitazoxanide monotherapy for 12 weeks followed by nitazoxanide plus pegylated interferon alfa, with or without ribavirin, for 36 weeks responded more rapidly and achieved a higher sustained virological response (SVR) rate than those receiving standard therapy using pegylated interferon plus ribavirin for 48 weeks.

The present study sought to determine whether similar improvement in outcomes could be obtained with a shorter 4 week nitazoxanide lead-in. The trial was designed to use data from STEALTH C-1 as a historical control.

This study included 44 patients enrolled at the University of Tanta in Egypt, where genotype 4 is the predominant HCV type. Almost all (40 patients) had genotype 4, but 3 had genotype 1, and 1 had genotype 2. Baseline characteristics, including age, sex, body mass index (BMI), fibrosis stage, and other demographic and disease-related characteristics were similar to those of patients enrolled in STEALTH C-1.

All participants received 500 mg twice-daily nitazoxanide monotherapy for 4 weeks, followed by 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus nitazoxanide for 36 more weeks (total 48 weeks of treatment); patients did not receive ribavirin.

The primary endpoint was SVR, defined as HCV RNA < 10 IU/mL 24 weeks after completion of treatment. Secondary endpoints included undetectable HCV RNA (< 10 IU/mL) at week 4 (rapid virological response or RVR) and week 12 (complete early virological response or cEVR) after starting combination therapy, as well as end of treatment response (ETR).

Results

• In an intent-to-treat analysis, week 4 RVR rates were as follows:

• 4 week nitazoxanide lead-in + pegylated interferon: 59%;

• 12 week nitazoxanide lead-in + pegylated interferon (STEALTH-C1): 54%;

• 12 week nitazoxanide lead-in + pegylated interferon + ribavirin (STEALTH-C1): 64%;

• 48 week pegylated interferon + ribavirin (standard therapy): 38%.

• Week 12 complete EVR rates were as follows:

• 4 week nitazoxanide lead-in + pegylated interferon: 82%;

• 12 week nitazoxanide lead-in + pegylated interferon: 68%;

• 12 week nitazoxanide lead-in + pegylated interferon + ribavirin: 86%;

• 48 week pegylated interferon + ribavirin: 70%.

• ETR rates were as follows:

• 4 week nitazoxanide lead-in + pegylated interferon: 86%;

• 12 week nitazoxanide lead-in + pegylated interferon: 71%;

• 12 week nitazoxanide lead-in + pegylated interferon + ribavirin: 82%;

• 48 week pegylated interferon + ribavirin: 75%.

• SVR rates were as follows:

• 4 week nitazoxanide lead-in + pegylated interferon: 80%;

• 12 week nitazoxanide lead-in + pegylated interferon: 61%;

• 12 week nitazoxanide lead-in + pegylated interferon + ribavirin: 79%;

• 48 week pegylated interferon + ribavirin: 50%.

• 2 of the 3 genotype 1 patients experienced RVR.

• All genotype 1 and 2 patients experienced cEVR, ETR, and SVR.

• SVR rates were 78% for genotype 4, 100% for genotype 1, and 100% for genotype 2.

• Adverse events were similar to those observed in STEALTH C-1.

• Frequency of side effects was similar in the nitazoxanide and standard therapy arms.

• Only 1 patient discontinued therapy, due to non-compliance.

"The nitazoxanide lead-in phase used in the STEALTH C-1 trial can be reduced from 12 weeks to 4 weeks without compromising RVR, cEVR, ETR, and SVR rates," the investigators concluded.

"Results support the need for further studies of the efficacy of dual therapy with [pegylated interferon] plus nitazoxanide without ribavirin and suggest similar efficacy of [pegylated interferon] plus nitazoxanide in patients with genotypes other than genotype 4," they added.

In another AASLD presentation, Brent Korba of Georgetown University Medical Center and colleagues described preclinical studies demonstrating synergistic interactions between nitazoxanide and STAT-C antiviral drugs targeting the HCV NS5B polymerase (2'C methylcytidine and HCV-796) and NS3 protease (telaprevir and BILN-2061) in HCV replicon models.

Nitazoxanide was also active against replicons with mutations conferring resistance to telaprevir- and 2'C methylcytidine. (Development of HCV-796 and BILN-2061 has been discontinued).

The authors concluded that nitazoxanide is a good candidate for combination therapies with STAT-C agents in the absence of interferon or ribavirin.

"These new studies confirm earlier data suggesting synergistic activity between nitazoxanide and [pegylated interferon] in genotype 4 patients and provide a first look at sustained virologic response in a limited number of genotype 1 patients," Dr. Rossignol said in a press release issued by Romark. "These data also provide interesting insights into the mechanism of action of nitazoxanide, including a potential role for its combination with STAT-C drugs, and confirm previous findings related to its safety."

These data indicate that when using nitazoxanide, ribavirin (which helps prevent relapse) may not be needed to maintain a sustained response, suggested Romark Chief Medical Officer and study co-investigator Emmet Keeffe.

In late October, Romark announced completion of enrollment of a U.S. Phase II trial -- dubbed STEALTH-C3 -- evaluating nitazoxanide with a 4 week lead-in plus pegylated interferon plus ribavirin in treatment-naive patients with HCV genotype 1, the most common type in this country. The study includes more than 100 participants, and data from a planned interim analysis are expected in early 2009.

12/2/08

References

J Rossignol, A Elfert, EB Keeffe. Evaluation of a 4 Week Lead-In Phase with Nitazoxanide (NTZ) Prior to Peginterferon (PegIFN) Plus NTZ for Treatment of Chronic Hepatitis C: Final Report. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 87/1848.

B Korba, M Elazar, P Liu, and others. Potential Role for Nitazoxanide in Combination with STAT-C Agents for the Inhibition of HCV Replication without the Development of Resistance. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 115.

T Schaninger, J Hong, GG Luo. Nitazoxanide Inhibits Hepatitis C Virus Replication In Vitro. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1000.

Other source
Romark Laboratories. Romark Announces Presentation of New Data for Nitazoxanide in Chronic Hepatitis C at AASLD 2008. Press release. November 4, 2008.