Effect of High-Dose HSV-2 Suppressive Therapy on Plasma HIV-1 RNA levels: a randomized, cross over trial 6 th IAS conference, Rome, Italy th July, 2011 Kenneth K. Mugwanya Co-Investigators: Jared Baeten, MD, PhD Nelly Mugo, MBChB, M.Med., MPH Elizabeth Irungu, MBChB Kenneth Ngure, BSN, MPH Connie Celum, MD, MPH

 Standard-dose HSV-2 suppressive therapy (acyclovir 400 mg twice daily) reduces plasma HIV-1 levels by log 10 copies/mL.  If greater HIV suppression can be achieved with higher dose HSV-2 suppression, there may be a role for HSV-2 suppression to delay HIV disease progression and/or reduce HIV transmission.Methods  Randomized, open label, crossover trial, 32 HIV-1/HSV-2 dually-infected  Not on ART, CD4 >250, detectable PVL: Kenya  HSV-2 suppression regimens: valacyclovir 1.5 gm Vs. acyclovir 400 mg both twice daily for 12 wks, then a 2 wk wash-out, and then the alternative for 12 wks.  PVL were measured weekly, with additional time points at day 1,2,& 3 post- drug initiation, and at day 3 post-drug termination.  Safety: AST, ALT, Creatinine, CBC, CD4 at screening and end of each drug period  Participants provided written informed consent. ( ClinicalTrials.gov number NCT )Background

At Enrollment:  17 (53%) were women  Median age was 37 years (range 23-60)  Median CD4 count: 441 cells/ µL (range )  Mean plasma HIV levels: 4.10 log 10 copies/mL (SD: 0.75). Follow-up: mean plasma HIV-1 levels  Valacyclovir arm: 2.94 log 10 copies/mL, (95% CI: 2.65, 3.24)  Acyclovir arm: 3.56 log 10 copies/mL, (95% CI: 3.26, 3.85)  Mean difference between the study arms: 0.62 log 10 copies/mL lower in VAL. arm (95% CI -0.68, -0.55; p<0.001)  Valacyclovir Vs. Baseline PVL levels prior to HSV-2 suppression: 1.23 log 10 copies/mL decrease (95% CI, -1.38, -1.07; p <0.001) Drug adherence and safety:  Participants took a median of 99.4% of tablets dispensed  lab. safety profiles were similar in both arms Results

Plasma HIV-1 levels by treatment arm

 High dose valacyclovir was safe and significantly reduced plasma HIV-1 levels by an average of 0.6 log 10 copies/mL compared to standard dose acyclovir, and a net >1 log 10 copies/mL decrease compared to baseline HIV-1 levels prior to HSV-2 suppression.  Given the constraints on ART programs and preference of some HIV-1 infected individuals to delay ART initiation, the potential for high dose HSV-2 suppression to delay ART initiation warrants further evaluation. Conclusions

 Study participants  The Bill and Melinda Gates Foundation (grant 26469)  US National Institutes of Health (grant R01 AI083034)  GlaxoSmithKline for study drug donation  Dr Ruth Wamae, and the staff at the Thika Partners Clinic  The Immunology Lab. at the University of Nairobi for HIV-1 PCR testing  The Clinical Trials Lab. University of Nairobi for additional lab. Testing  Dr. Larry Corey, University of Washington  Dr. Anna Wald, University of Washington  Dr. Meredith Potochnic, University of WashingtonAcknowledgements