1. Impact of HSV-2 suppressive therapy with daily acyclovir on HIV-1 disease progression: a randomized placebo- controlled trial in Rakai, Uganda Steven J. Reynolds, MD, MPH National Institute of Allergy and Infectious Diseases U.S. National Institutes of Health Rakai Health Sciences Program Johns Hopkins University School of Medicine

2. Background Despite the enormous success of ART scale up, of 22.5 million HIV infected individuals in sub-Saharan Africa, >85% are NOT yet on treatment 3.4 million do not have access 15.7 million are not yet eligible (pre-ART stage) Strategies to delay HIV disease progression could offset some of the burden faced by countries continuing to scale up treatment with limited resources

3. Background: HSV-2 & HIV HSV-2 most common cause of GUD, seroprevalence rates 70-90% among HIV-1 infected, HSV-2 reactivation common and known to increase HIV-1 replication Results of 7 RCTs: daily acyclovir or valacyclovir reduced plasma HIV-1 by 0.33 (95% CI; -0.56, -0.10) log 10 copies/ml (AIDS, 2011; 25) Valacyclovir has an even greater impact on HIV VL (IAS abstract B0106) One study revealed a modest impact of daily suppressive acyclovir on disease progression, 16% reduction (J. Lingappa, Lancet 2010; 375)

4. Objective To assess the impact of Acyclovir 400mg twice daily over 24 months versus placebo on: Progression to CD4<250 cells/ul or WHO IV (primary endpoint) Impact on HIV VL, GUD incidence, HSV-2 shedding (secondary endpoints)

5. Entebbe Airport Rakai District

6. Methods: Study Design 440 HIV/HSV-2 co-infected participants with CD4 between 300-400 cells/ul randomized to either ACV 400mg twice daily or placebo 24 months follow-up, participants seen monthly for adherence assessment (pill-counts), examination for GUD if symptomatic, women provided self- administered vaginal swabs Every 6 months, laboratory visit (CBC, CD4, HIV VL), quality of life survey and full physical examination

7. Methods: Analysis Survival analysis used to measure the impact of ACV on HIV disease progression Cox proportional hazards models adjusted for baseline VL, CD4 and gender Mixed linear effects model used to measure the impact of ACV on HIV viral load trajectories Secondary post-hoc analysis examined impact of ACV on disease progression among participants with low ( =50000 copies/ml) baseline HIV VL

8. Results 440 participants randomized between May 2007 and Nov 2008 14 (3.1%) subjects lost to follow-up during study 12 (2.7%) subjects died on study Excellent follow-up, of those participants remaining on study, 99% of expected study visits completed SAFE: No SAEs related to study treatment

9. Results: Baseline Characteristics CharacteristicPlacebo n=220Treatment n=220 Gender (female)161 (73%)150 (68%) Age 20-2944 (20%)46 (21%) 30-3993 (42%) 40-4953 (24%)54 (25%) 50+30 (14%)26 (12%) Median CD4 cells/ul350 (321-372)350 (373-375) Log 10 VL (IQR)4.44 (3.80, 5.05)4.43 (3.85, 5.07)

10. Results 205 (46.7%) participants reached primary endpoint, (95 treatment and 110 placebo) 45 participants censored during follow-up due to: LTFU (14) ART initiation (17) death (12) missed last study visit (2) Adherence, calculated in 3 month blocks, was high in both study arms ranging from 81%-95% participants achieving >90% study drug coverage

11. 0.00 0.20 0.40 0.60 090180270360450540630720 Probability of ART Eligibility Based on CD4 count and WHO Clinical staging Figure 1 Cumulative probability of ART Eligibility Total follow-up time (days) Treatment Placebo AHR 0.73 (95% CI 0.56-0.97, p=0.029)

12. 0.00 0.10 0.20 0.30 0.40 0.50 090180270360450540630720 Placebo Treatment Probability of ART Eligibility Total follow-up time (days) Enrolment viral load <50 000 copies/ml Figure 2 Cumulative probability of ART Eligibility AHR 0.90 (95% CI 0.54-1.5, p=0.688)

13. 0.00 0.15 0.30 0.45 0.60 0.75 090180270360450540630720 Placebo Treatment Probability of ART Eligibility Total follow-up time (days) Enrolment viral load 50000+ copies/ml Figure 3 Cumulative probability of ART Eligibility AHR 0.62 (95% CI 0.43-0.96, p=0.03)

14. Results Overall 27% reduction in HIV disease progression among participants treated with ACV 400mg twice daily versus placebo (AHR 0.73, 95% CI 0.56-0.97, p=0.029) Greater impact observed among participants with higher baseline HIV VL, particularly among those with >50000 copies/ml (AHR 0.62; 95% CI 0.43-0.96, p=0.03)

15. Results: Impact on HIV VL Annual rate of change of log 10 VL copies/ml overall 0.169 (95% CI 0.032-0.305) Placebo 0.402 (95% CI 0.212-0.592) ACV -0.061 (95% CI -0.250-0.129) Difference: -0.463 (95% CI -0.731 -0.194, p=0.001) log 10 VL copies/ml

16. Conclusion Acyclovir 400mg twice daily delayed disease progression among HIV/HSV-2 co-infected individuals Acyclovir reduced HIV VL by 0.463 log 10 copies/ml consistent with earlier randomized trials Treatment of chronic HSV-2 infection may be warranted in HIV infected individuals Future studies of Valacyclovir (better bioavailability) are warranted and may have an even greater impact on HIV disease progression

17. Acknowledgments NIAID/NIH Tom Quinn Kevin Newell Oliver Laeyendecker Johns Hopkins Ron Gray Maria Wawer Rakai Health Sciences Program David Serwadda Fred Makumbi Iga Boaz Gertrude Nakigozi George Mundo Godfrey Kigozi Nelson Sewankambo Dennis Buwembo Tom Lutalo Francis Bbosa Fred Nalugoda Noah Kiwanuka Pascal Ssebowa Victor Ssempijja Rakai Health Sciences Program Community Participants Division of Intramural Research NIAID/NIH & PEPFAR