Alison Murphy Princeton University

1. Twice Weekly Peg-IFN-alpha-2a with Ribavirin Improves Early Viral Kinetics over Standard Therapy Among HIV/HCV Co-Infected African American Patients Alison MurphyPrinceton University

2. Introduction Co-infection with Hepatitis C virus (HCV) is seen in approximately one-third of all HIV-infected persons in the US due to shared routes of transmission. HCV/HIV co-infected patients have a more rapid rate of progression of liver fibrosis when compared to that of HCV mono-infected individuals. Finally, co-infection with HIV decreases the rates of sustained virological response (SVR) to combination therapy.

3. Clinical Definition Lower limit of detection Peg-Interferon- + Ribavirin

4. Non-responder Viral Breakthrough Relapser Sustained Responder Relationship Between Early Viral Kinetics and Therapeutic Response Neumann et al. 3rd IAS abstract (2005)

5. Study rationale Studies have shown that early HCV viral kinetics can predict SVR in HIV/HCV co-infected individuals. These studies have suggested that twice weekly dosing of pegylated interferon may: Prevent end of week rebound Improve early viral response Potentially increase SVR among HIV/HCV co-infected individuals.

6. Study Design

7. Primary Endpoint Change in log HCV viral levels on day 7.

8. Secondary Endpoints Log change in HCV response on days 14, 21 and 28 of treatment. • Change in pharmacokinetics of peginterferon.Safety and tolerability of twice weekly peginterferon. Change in end of treatment response Change in sustained viral response Change in liver fibrosis score per liver biopsy results. Change in liver enzymes at all time points.

9. Study Subjects Eligibility Criteria included: 18 years of age or older, CD4+ T cell counts > 100 cells/mm3, absolute neutrophil counts >1000 cells/mm3, HCV viral load >2000 IU/mL, histologic evidence of chronic hepatitis C and stable HIV disease with or without ART.

10. Laboratory Studies HCV and HIV RNA concentration in plasma were measured by VERSANT RNA 3.0 Assay during all study visits. The assay has a lower limit of detection for HCV of 615 IU/mL. HCV RNA concentration was measured in plasma on day 0, 3, 5, 6, 7, 10, 14, 21, 28, 42, 56 and then every 4 weeks for 72 weeks. Liver chemistry and safety laboratory tests were performed prior to the treatment and during each study visit. Liver biopsy was obtained prior to initiation of therapy and at week 72 visit.

11. Statistical Analysis The non-parametric Mann-Whitney U test was used to test the significance of differences in distribution of continuous variables. Non-parametric Spearman test was used to test the significance of correlation between variables. Significance was assumed at p<0.05.

12. Baseline characteristics of patients • Genotype 1a • Male • African American • 10 patients received standard therapy • 9 patients received investigational therapy

13. Patients on investigational arm had better early virologic response P=0.04

14. Patients on investigational arm had better early virologic response P=0.04

15. Patients on investigational arm had better clinically relevant early virologic end points EVR2, EVR4 and EVR12 (2 logs or more drop in HCV VL) RVR4, EVR24 and ETR (less than 615 IU/mL of HCV VL)

16. Biweekly Peg-IFN Dosing Improves HCV Viral Kinetics in African Americans QW median BW median P<0.04

17. Patients receiving investigational therapy achieved normalization of ALT and AST earlier than patients receiving standard therapy. P=0.04 P=0.03 ALT AST

18. Adverse Event Profiles were similar among both groups P>0.05 No significantly higher number of adverse events in investigational over standard therapy.

19. Most patients experienced hematologic toxicities P>0.05 P>0.05 No significantly higher number of more common adverse events in investigational over standard therapy

20. Conclusions (1) Twice weekly Peg IFN-alpha 2a therapy yields higher rate of early virological response when compared to standard treatment. Twice weekly Peg IFN-alpha 2a treatment is safe and is tolerated to the same extent as standard IFN treatment. Twice weekly Peg IFN-alpha 2a treatment is associated with rapid normalization of hepatic enzymes. Twice weekly Peg IFN-alpha 2a treatment may be a viable therapeutic option for African American patients who are also infected with HIV.

21. Conclusions (2) All patients who had sustained virologic response had improvement in hepatic histology at week 72 irrespective of therapeutic regimen Future studies are warranted to validate the clinical utility of using twice weekly Peg IFN treatment to improve SVR in HCV and HIV co-infected patients.

22. NIAID, LIR/BRB/CCMD Shyam Kottilil MD. Michael A. Polis MD. William Sachau Marie Angeline O’Shea Lynne Wu MD. Catherine A. Rehm Michael Proschan Ph.D. Henry Masur MD. OP8 Clinic Staff H. Clifford Lane MD. Anthony S. Fauci MD. NIMH, NIH Donald Rosenstein MD. Haniya Raza MD. Joseph J. Rasimas MD. Bar-Ilan University, Israel Avidan U. Neumann Ph.D. Lynne Rozenberg MSc NCI, NIH David E. Kleiner MD. Erasmus University, The Netherlands Bart Haagmans Ph.D. Acknowledgments HIV/HCV Co-infected Patients

23. Both Groups Experienced a decline in CD4 counts but not percentage Comparable CD4 levels throughout Standard and Investigational therapy