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HIV and Hepatitis.com Coverage of the
45th Annual Meeting of the European
Association for the Study of the Liver (EASL 2010)

April 14 - 18, 2010, Vienna, Austria

Nitazoxanide Increases Response to Pegylated Interferon plus Ribavirin in Treatment-naive and Non-responder Hepatitis C Patients

SUMMARY: Adding nitazoxanide (Alinia) to standard hepatitis C therapy using pegylated interferon plus ribavirin led to higher sustained response rates for both previously untreated patients and those who were not cured with prior interferon-based therapy, according to studies presented recently at the Digestive Disease Week conference in May and the annual meeting of the European Association for the Study of the Liver (EASL 2010) in April.

By Liz Highleyman

Nitazoxanide is a broad-spectrum thiazolide drug being developed by Romark Laboratories that has demonstrated activity against a variety of micro-organisms including protozoa, hepatitis B virus (HBV), and hepatitis C virus (HCV).

Treatment-naive Patients

Investigators at both conferences presented final data from STEALTH C-3, a Phase 2 clinical trial of nitazoxanide in previously untreated patients with genotype 1 chronic hepatitis C.

The study included 112 participants at 13 U.S. centers who were randomly assigned (2:1) to receive either 500 mg twice-daily nitazoxanide or placebo along with pegylated interferon alfa-2a (Pegasys) plus ribavirin for 48 weeks. About one-third of patients had advanced liver fibrosis or cirrhosis (stage F3-F4).

The primary study endpoint was sustained virological response (SVR), or continued undetectable HCV viral load 24 weeks after completing treatment. The researchers also looked at rapid virological response (RVR), or undetectable (< 10 IU/mL) HCV RNA at week 4; complete early virological response (EVR), or undetectable HCV RNA at week 12; partial EVR, at least a 2 log drop in viral load at week 12, and end-of-treatment response (ETR), or undetectable viral load at completion of therapy.

Results

Patients receiving nitazoxanide had higher response rates than those taking placebo by 12 weeks, but not at 4 weeks:
 
RVR: 12% in nitazoxanide arm vs 19% in placebo arm;
Complete EVR: 62% vs 49%, respectively;
ETR: 63% vs 46%, respectively;
SVR: 44% vs 32%, respectively.
SVR rates were consistently higher for nitazoxanide recipients in difficult-to-treat patient sub-groups:
 
High baseline viral load (> 800,000 IU/mL): 41% vs 29% respectively;
African-Americans: 38% vs 20%, respectively.
Nitazoxanide was generally well-tolerated
Rates of serious adverse events were similar in the nitazoxanide and placebo arms.
The only adverse events significantly associated with nitazoxanide were mild-to-moderate diarrhea and urine discoloration.

"Consistent with previously reported results in naive genotype 4 patients, the addition of nitazoxanide increased the SVR rate in genotype 1 naive patients by more than one-third," the investigators concluded.

Treatment-experienced Patients


The Phase 2 STEALTH C-2 trial evaluated nitazoxanide in combination with pegylated interferon plus ribavirin in genotype 1 chronic hepatitis C patients who previously failed to achieve a sustained response with standard therapy alone.

This study, conducted at 10 U.S. centers, included 64 participants. About 60% were null responders to prior treatment (< 2 log drop in HCV RNA after 12 weeks), while 20% were partial responders (> 2 log drop after 12 weeks but never undetectable) and 20% had insufficient date. About 7% were black and 40% had stage F3-F4 fibrosis or cirrhosis.

Participants were randomly assigned (2:1) to receive 500 mg twice-daily nitazoxanide or placebo for a 4-week lead-in period, followed by nitazoxanide or placebo plus pegylated interferon/ribavirin for 48 weeks.

Patients discontinued the study if they did not achieve at least 1 log drop in HCV RNA after 4 weeks of combination therapy, at least 2 log drop after 12 weeks of combination therapy, or undetectable HCV RNA after 28 weeks of combination therapy.

Again, the primary endpoint was SVR, with secondary endpoints including RVR, complete and partial EVR, and ETR.

Results

HCV viral load did not change significantly during the 4-week nitazoxanide monotherapy lead-in period.
Patients receiving nitazoxanide had higher response rates than those taking placebo, but rates were low overall and differences did not reach statistical significance:
 
RVR: 5% in nitazoxanide arm vs 0 in placebo arm;
Complete EVR: 7% vs 0, respectively;
Partial EVR: 38% vs 29%, respectively;
ETR: 14% vs 0, respectively;
SVR: 7% vs 0.
The 3 patients who achieved SVR were white and had high baseline viral load (> 800,000 IU/mL), 2 of the 3 were partial responders to prior treatment, and 1 had advanced fibrosis.
2 sustained responders achieved RVR and all 3 had complete EVR.
3 late responders who achieved ETR but not EVR relapsed during post-treatment follow-up.
Again, nitazoxanide was generally well-tolerated.
The only adverse event attributed to nitazoxanide was mild-to-moderate diarrhea.
No serious adverse events attributable to nitazoxanide were reported.

"This was a particularly difficult-to-treat patient population," said Romark Chairman and Chief Science Office (and nitazoxanide discoverer) Jean-Francois Rossignol, MD. "The data suggests that nitazoxanide will be most relevant in patients with partial response to prior therapy or in prior relapsers."

Based on studies to date, Romark has decided on a nitazoxanide dose of 675 mg using a controlled-release tablets to achieve better bioavailability. This formulation will be further evaluated in Phase 3 trials. Researchers plan to test nitazoxanide with a shorter 24-week duration of pegylated interferon, with and without ribavirin (which helps prevent post-treatment relapse), and in combination with new direct-acting anti-HCV agents. In addition, the AIDS Clinical Trials Group (ACTG) is studying nitazoxanide plus pegylated interferon/ribavirin in HIV/HCV coinfected patients.

Investigator affiliations:

DDW Bacon abstract: Romark Institute for Medical Research, Romark Laboratories, Tampa, FL; Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA; Division of Gastroenterology and Hepatology, St. Louis University Medical Center, St. Louis, MO; Liver Institute of Virginia, Bon Secours Health System, Newport News, VA; Section of Digestive Diseases, Yale University, New Haven, CT; Florida Center for Gastroenterology, Largo, FL; Georgetown University Medical Center, Fairfax, VA.

EASL Shiffman abstract: Liver Institute of Virginia, Bon Secours Health System, Newport News, VA; Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA; Division of Gastroenterology, Weill Cornell Medical College, New York, NY; Nashville Gastrointestinal Specialists, Inc., Nashville, TN; The Romark Institute for Medical Research, Romark Laboratories, Sausalito, CA.

EASL Bacon abstract: Division of Gastroenterology and Hepatology, St Louis University Medical Center, St Louis, MO; Liver Institute of Virginia, Bon Secours Health System, Newport News, VA; Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT; Florida Center for Gastroenterology, Largo, FL; Georgetown University Medical Center, Washington, DC; The Romark Institute for Medical Research, Romark Laboratories, Sausalito, CA; Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA.


5/28/10

References

BR Bacon, ML Shiffman, JK Lim, and others. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide plus peginterferon and ribavirin in naive patients with chronic hepatitis C genotype 1 infection: final report. Digestive Disease Week. New Orleans. May 1-5, 2010. Abstract 711b.

ML Shiffman, A Ahmed, IM Jacobson, and others. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide with peginterferon alfa-2a and ribavirin in nonresponders (NR) with chronic hepatitis C genotype 1: final report. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. Abstract.

BR Bacon, ML Shiffman, JK Lim, and others. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide plus peginterferon and ribavirin in HCV genotype 1 naive patients: week 12 sustained virologic response rate. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. Abstract.

Other sources

Romark Labratories. Romark Announces Final Data from Clinical Trial of Nitazoxanide in Treatment-naïve Patients with Genotype 1 Chronic Hepatitis C. Press release. May 4, 2010.

Romark Labratories. Romark Announces Data from Clinical Trial of Nitazoxanide in Patients with Genotype 1 Chronic Hepatitis C Who Previously Failed Treatment with Peginterferon Plus Ribavirin. Press release. April 19, 2010.

Romark Labratories. Romark Announces Data from Clinical Trial of Nitazoxanide in Treatment-naive Patients with Genotype 1 Chronic Hepatitis C. Press release. April 15, 2010.


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



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