Background: Nitazoxanide (NTZ)

ACTG 5269: The addition of Nitazoxanide to peginterferon alfa-2a and ribavirin does not significantly improve sustained virologic response in HCV treatment-naïve genotype 1 HIV-1/HCV co-infected subjects: Results of ACTG 5269 ValeriannaAmorosa, MD, TriinUmbleja, M Sc, Victoria Johnson, MD, Minhee Kang, PhD, Anne Luetkemeyer, MD, Matthew Bardin, PharmD, BCP, David Haas, MD, Ray Chung, MD, SuriaYesmin, Beverly Alston-Smith, MD, Pablo Tebas, MD, Marion Peters, MD On behalf of NIH/NIAID ACTG 5269 Study team

Background: Nitazoxanide (NTZ) • AIDS patients with Cryptosporidium • ALT levels decreased in some with viral hepatitis on NTZ • Higher SVR in Egyptian patients with HCV Genotype 4 monoinfection with addition of NTZ to PEG/RBV: SVR 80% vs 50% • HCV Genotype 1 addition of NTZ to PEG/RBV:SVR 44% vs. 32% • In HIV+, no major safety or drug interaction issues using NTZ for cryptosporidium Rossignol JF, et al, Gastroenterology, March, 2009; Bacon et al, EASL, 2010; LB2001

Study Objectives • Primary objective • Evaluate activity of NTZ added to PEG-IFN and weight-based RBV as determined by week 12: • cEVR: HCV RNA undetectable (<43 IU/ml) • EVR: HCV ≥ 2 log10 drop or undetectable • Secondary Objectives • Evaluate association between IL28B alleles and HCV response • Evaluate SVR rates Amorosa et al, Abstract TUPE176, IAS 2012, Luetkemeyer et al Abstract 758, CROI 2012

Study Design Week 4 to 52 Week 0 to 4 Follow Up Wk 76 NTZ 500 mg BID + PEG-IFN 180 µg qwk + RBV 1000 - 1200 mg/d 67 Subjects NTZ 500 mg BID cEVR & EVR ETR • Single arm, phase 2 pilot study • Powered to conclude cEVR >40% and EVR >50% • Historical control A5178 SLAM-C: Genotype 1 HCV/HIV treatment naïve participants, PEG/RBV x 72 weeks Chung RT HIV Clin Trial 2012

Study Populatoin • HIV +, CD4 > 200 cells/mm3on stable ARVs or no ARVs • ddI prohibited • No OIs within 24 months • Standard eligibility criteria

Treatment Stopping Rules • Failure to achieve EVR at week 12 triple therapy (study week 16) • Failure to achieve undetectable HCV RNA at week 24 of triple therapy (study week 28)

Methods • HCV RNA measurement: Roche TaqMan HCV, v1.0 with LLQ <43 IU/mL • A5178 : Roche CobasAmplicor Monitor, LLQ < 600 IU/ml • IL28B rs12979860 genotyping by ABI Taqman • A5178 - IL28B rs12979860 by MassARRAYiPLEX Gold

Safety Data

Virologic response with NTZ

Virologic response: Historical comparison * In A5269, at 12 weeks of triple therapy (study week 12); P-values are from one-sided Fisher’s exact tests.

Predicting SVR • Higher SVR rates: • <50 years - HCV GT 1b • Men - APRI ≤ 1.5 • Non-black - FIB-4 ≤3.25 • Baseline HCV RNA <800,000 IU/ml Predictors not statistically significant

SVR proportion by IL28B genotype

Summary • SVR rates on NTZ added to PEG-IFN+RBV not statistically greater than rates in historical controls treated with PEG-IFN+RBV • NTZ associated with better response in those with unfavorable IL28B genotype (T/T) • Clinical significance of this is unclear • Role of NTZ may depend upon the as yet undefined role of IL28b in IFN-free regimens • Further study ongoing regarding NTZ’s effect on IFN-responsiveness in context of IL28B genotype

Acknowledgements • Participating sites and Study patients: • SAN FRANCISCO GENERAL HOSPITAL • UNIVERSITY OF PENNSYLVANIA • UNIVERSITY OF ALABAMA AT BIRMINGHAM • UNIVERSITY OF PUERTO RICO • UNIVERSITY OF NORTH CAROLINA • NEW JERSEY MEDICAL SCHOOL • HARVARD • STANFORD • UCLA MEDICAL CENTER • UC SAN DIEGO MEDICAL CENTER • ROCHESTER • COMMUNITY HEALTH NETWORK INC • U. OF CINCINNATI COL. OF MED. • METROHEALTH MEDICAL CENTER, CLEVELAND • THE MIRIAM HOSPITAL RHODE ISLAND • CORNELL • HIV PREVENTION & TREATMENT CRS • VIRGINIA COMMONWEALTH UNIV. MEDICAL CTR. • ACTG • Romark • Roche • J. Darren Hazelwood – UAB Virology Specialty Laboratory 54

Background: Nitazoxanide (NTZ)