Nitazoxanide plus Pegylated Interferon and Ribavirin Produces Virological Response in Some Prior Non-responders with Cirrhosis

		SUMMARY: According to interim results of a small study presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston last week, genotype 1 chronic hepatitis C patients with liver cirrhosis who did not respond to prior treatment with pegylated interferon alfa-2a (Pegasys) plus ribavirin experienced promising virological responses to triple combination therapy with pegylated interferon, ribavirin, and nitazoxanide. Nearly half (46%) of study participants achieved early virological response (EVR) at week 12 and 15% achieved undetectable viral load; however, only 1 out of 9 African-Americans achieved EVR.

Nitazoxanide -- a member of a class of small molecules known as thiazolides -- is a potent inhibitor of hepatitis C virus (HCV). Previous studies in HCV genotype 4 patients indicated that nitazoxanide may enhance sustained virological responses (SVR) with no serious adverse events.

Nitazoxanide is currently in Phase 2 clinical development for hepatitis C treatment. The pilot study presented at AASLD was conducted to assess the antiviral activity of lead-in nitazoxanide administered with pegylated interferon alfa-2a (Pegasys) plus ribavirin for treatment-experienced cirrhotic genotype 1 patients who experienced previous treatment failure.

The study included 14 participants (13 prior non-responders and 1 relapser). All but 1 were men, the average was 57 years, 9 were African-American, and 5 were white. Individuals with hepatitis A, B, or other forms of liver disease, hepatocellular carcinoma, HIV, pre-existing severe depression or other uncontrolled psychiatric disease, and significant kidney, cardiac, neurological, or other central nervous system disorders were excluded.

Participants received 500 mg twice-daily nitazoxanide for 4 weeks, followed by nitazoxanide plus 180 mcg/week pegylated interferon and weight-adjusted ribavirin for 48 weeks. Patients who did not achieve EVR (at least a 2 log decrease in HCV RNA) by week 12 and/or had detectable HCV RNA at 24 weeks discontinued the study.

Results

	Overall, 50% of participants achieved EVR at week 12 (see table).
	14.3% had undetectable HCV RNA at week 12 (see table).
	By week 48, all patients had undetectable viral load.
	Only 1 of 9 blacks achieved EVR, compared with all 5 whites.
	Overall, nitazoxanide combination therapy was well tolerated, without early discontinuation.
	No serious adverse events were reported throughout the study.
	Four patients developed adverse events including diarrhea (3), cellulitis (3), rash (2), and laryngitis (1).
	These events were mild-to-moderate and intermittent, with none leading to treatment discontinuation.
	Due to neutropenia and neutropenia, 3 patients required dose reductions for Peg-IFN/R.
	Five patients (without EVR) discontinued therapy due to lack of response.

Treatment	NTZ (N=14)	NTZ+PegIFN+R (N=14) (N=13) (N=7) (N=2)
Duration of Rx (weeks)	4	4+4	4+12	4+24	4+48
% EVR (>2 log decrease in HCV RNA)	0	14%	50%	60%	100%
% with undetectable HCV RNA	0	7%	14%	40%	100%
Average log decrease in HCV RNA	0.17	1.4	2.4	3.4	5.9

NTZ = nitazoxanide; PegIFN = pegylated interferon; R = ribavirin.

Based on these findings, the investigators concluded, "An interim analysis of this study indicates that treatment [of HCV genotype 1 patients] with lead-in nitazoxanide in combination with pegylated interferon and ribavirin has demonstrated promising results in these difficult to treat patients."

11/10/09

References
B Yoffe, K Gasitashvili, and V Khaoustov. Pilot study of lead-in nitazoxanide plus pegylated alpha-2a interferon and ribavirin in HCV-genotype 1 nonresponders with cirrhosis: interim results. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1580.