HLA-B57 does not fully explain the ability of HIV controllers to clear HCV infection Alice K. Asher 1, RN, MS; Glenn-Milo Santos 1, MPH; Jennifer Evans, MS 1 ; E. Kainne Dokubo 1, MD; Jeff Martin 1, MD; Steve Deeks 1, MD; MPH; Leslie Tobler 2, Dr.Ph; Mike Busch 2, MD, Ph.D.; Peter Hunt 1, MD; Kimberly Page 1, PhD, MPH 1 University of California, San Francisco 2 Blood Systems Research Institute, San Francisco, California

Spontaneous clearance of HCV 20-25% of HCV infected persons spontaneously clear the virus HIV co-infected: 10-20% Factors associated with spontaneous HCV clearance: –Sex (Micallef, et al., 2007; Page, et al., 2009) –IL-28B status (Thomas, et al., 2009) –HLA type (Thio, et al., 2002; Kim, et al., 2011) –T cell response (Osburn, et al., 2010) Micallef, 2007, J. Viral Hepatitis; Matthews, 2008, Gasterenterol Hepatol

HIV control in the absence of ART 1-5% of PLWHA are considered ‘HIV controllers’ Elite controllers: anti-HIV positive; no measurable HIV viremia (<75 copies/mL) Viremic controllers: anti-HIV positive; measurable low level viremia ( copies/mL) HIV controllers are more likely to spontaneously clear HCV Deeks, 2007, Immunity. Sadaji, 2010, AIDS; Salgado, 2011, AIDS; Kim, 2011, Gasteroenterology

Host genetic polymorphisms associated with HIV and HCV outcomes GeneHIV associationHCV association HLA-B*57Viral control (Migueles et al, PNAS 2000) Increased clearance (Thio et al, JV 2002) HLA-Cw*04More rapid HIV progression (Carrington et al, Science 1999) Decreased clearance (Thio et al, JV 2002) IL28B (CC)Association with higher all-cause mortality (Parczewski et al, AIDS Research and Human Retroviruses 2012) Increased clearance (Thomas et al, Nature 2009)

Objective 1)Assess relationship between spontaneous control of HIV and HCV clearance 2)Assess host genetic factors that may explain HCV clearance in HIV controllers

Methods Participants sampled from SCOPE cohort –>1600 chronically HIV+ patients –Enriched for HIV controllers –HLA typing available Included: HCV Ab+ (Ortho Clinical Diagnostics ® ) Excluded: HBsAg+, Hx of HCV treatment HCV RNA using discriminatory TMA (Novartis ® ) Spontaneous HCV clearance: HCVAb+/RNA- IL28B genotyping performed

Study population (N=279) Non-controllers N (%) N=231 HIV controllers† N (%) N=48 Sex Female (%)66 (29)14 (29) Age (Median IQR) 40 (36-46)41 (37-48) Race Caucasian (%)97 (42)18 (38) Elite controllers + HIV viremic controllers (<2000 copies/ML without ART for at least 12 months †

HCV clearance by HIV controller status 8

9 Differences significant when adjusted for sex, age & race (APR 1.44, p=0.026)

Genetic polymorphisms in HIV controllers and non-controllers HIV Non- controllers N (%) N=231 HIV controllers N (%) N=48 p-value HLA B*5724 (10)16 (33)<0.001* HLA Cw*0459 (26)8 (17)0.19 IL28B (CC)89 (39)12 (48)0.49

HCV clearance by HLA B*57 and HIV controller status 11 P=0.004

HCV clearance by HLA B*57 and HIV controller status 12 P for interaction =0.01 P=0.004

Conclusions HIV controllers are more likely to clear HCV infection than non-controllers While HLA B*57 predicts HCV clearance in HIV non-controllers, it does not fully explain HCV clearance in HIV controllers –>50% B*57- HIV controllers clear HCV Host factors other than HLA B*57 contribute to the control of HCV in HIV controllers Identifying these factors may support the development of novel vaccine strategies for HIV and HCV

Special Thanks SCOPE Study: –Peter Hunt, MD –Melissa Krone –Jeff Martin, MD –Steve Deeks, MD Kimberly Page, Ph.D., M.P.H. Milo Santos, M.P.H. Jennifer Evans, M.S. Meghan Morris, Ph.D. E. Kainne Dokubo, MD Blood Systems Research Institute: –Leslie Tobler, Dr.Ph –Mike Busch, MD, Ph.D. –Tzong-Hae Lee, MD, Ph.D.