1. Peripartum Valacyclovir Improves Markers of HIV-1 Disease Progression in Women Co-Infected with HSV-2: A Randomized Trial Alison C. Roxby, MD, MSc. July 19, 2011 University of Washington / University of Nairobi

2. The Problem: 15.7 million women of reproductive age are HIV-infected 4 – 9 lifetime pregnancies per woman Lifetime risk of maternal mortality: 1 in 22 women Worldwide, HIV is the leading cause of death among women of reproductive age Interventions are needed to improve the health of mothers with HIV

3. Research Rationale: Effect of HSV-2 suppression on HIV-1 progression Use of acyclovir or valacyclovir to suppress HSV-2 is associated with 0.25-0.40 log copies/ml reduction in HIV-1 plasma RNA One trial of long-term acyclovir in co-infected patients reduced HIV-1 disease progression by 16% (Lingappa et al 2010 – Partners In Prevention)

4. Hypothesis Will herpes suppressing agents improve maternal health among co-infected women in sub-Saharan Africa?

5. Valacyclovir in Pregnancy Study Aim 1: To determine whether herpes suppression with valacyclovir will reduce HIV-1 RNA levels in pregnant and postpartum women receiving antiretrovirals for prevention of mother to child transmission (PMTCT) of HIV-1

6. Valacyclovir in Pregnancy Study Aim 2: To determine whether herpes suppression with valacyclovir is associated with improved CD4 counts and reductions in HIV-1 disease progression in women followed for 12 months postpartum Mathare North Health Centre, Nairobi

7. Study Design Double-blind, placebo-controlled, RCT Intervention: 500 mg valacyclovir or placebo BID Pregnant women seeking antenatal care All women both HIV-1/HSV-2 seropositive All women with CD4 >250 cells/μl Enrolled/randomized to valacyclovir at 34 weeks gestation Followed for 1 year postpartum Clinicaltrials.gov identifier: NCT00530777

8. Study Location Women were recruited and followed at Mathare North Health Center in Nairobi This clinic provides primary health care and maternity services on the edge of the Mathare slum, home to 1,000,000 people About 300 women initiate antenatal care each month, and about 10% are HIV positive Mathare North VCT

9. Methods Laboratory: HIV-1 RNA and CD4 were measured at or before 34 weeks gestation, 6 months postpartum and 12 months postpartum Clinical: Clinical assessment of WHO stage was done monthly Statistical: Study arms were compared using chi-squared and t-tests to determine adequacy of randomization Viral loads and CD4 counts were compared using multivariate linear regression controlling for baseline values Daniel Matemo, VIP Lab

10. 149 ineligible HSV-2 negative: 85 (24%) CD4 < 250: 67 (19%) WHO stage: 57 (16%) Nairobi delivery/residence: 35 (10%) 62 not enrolled 359 screened 210 eligible 148 enrolled 74 randomized to valacyclovir 74 randomized to placebo 2 women lost before delivery Modified Intention-to-treat analysis 73 women

11. Baseline characteristics by study arm Characteristic at baseline Valacyclovir n=73 Placebo n=73 Median (IQR) or n (%) Median (IQR) or n (%) Age (years)25 (22-30)25 (22-29) No. of pregnancies1 (1-3)2 (1-2) Education ≤ 8 years43 (59%)49 (67%) Monthly rent (USD)24 (19-33)21 (13-33) Employed22 (30%)18 (25%) On ARVs for PMTCT73 (100%)68 (93%) WHO Stage Stage 168 (93%)62 (85%) Stage 25 (7%)11 (15%) CD4 count (cells/μL)452 (351-560)481 (340-598) Log 10 HIV-1 plasma RNA level (copies/ml) 3.99 (3.30-4.41)3.84 (3.43-4.45)

12. Maternal Mortality and Morbidity Number of cases All women (n=146)Placebo (n=73)Valacyclovir (n=73) Perinatal Complications Stillbirth: 321 Cesarean section: 1495 Maternal Morbidity CD4 <250 cells/μl: 936 Tuberculosis: 642 Post-delivery hospitalization: 752 Malaria: 20155 Diarrhea/colitis: 261016 Maternal Mortality Number of deaths: 321

13. Mean HIV-1 RNA (log 10 copies/ml) ValacyclovirPlaceboDifferenceP* Enrollment3.893.87-0.010.95 6 months3.984.39-0.42<0.001 12 months4.104.53-0.400.001 Effect of Valacyclovir on Plasma RNA

14. HIV-1 RNA differences at one year, by study arm

15. Effect of Valacyclovir on CD4 Count Mean CD4 Count (cells/μl) ValacyclovirPlaceboDifferenceP* Enrollment484487-30.92 6 months631612170.72 12 months638565730.03

16. CD4 differences at one year, by study arm

17. Adherence to study drugs Average mean adherence was 86% overall no difference between study arms Adherence was measured by pill count

18. Conclusions Valacyclovir consistently reduced HIV-1 RNA levels by 0.40 log copies/ml in pregnant and postpartum women –This effect was noted despite short-courses of antiretroviral therapy for PMTCT CD4 count was significantly different at 12 months between study arms, with mean CD4 73 cells/μl higher in the valacyclovir arm

19. Significance Valacyclovir may be an additional tool to improve outcomes among pregnant and postpartum women Modeling suggests that HIV viral load reductions of this nature could lengthen time to development of AIDS by 1.9 years in similar asymptomatic patients (Baggaley 2009, Modjarrad 2008) Use of valacyclovir may be cost-effective in African settings where access to ART continues to be limited (Vickerman 2011)

20. Significance Safety data are conclusive that valacyclovir requires no laboratory monitoring in pregnant or postpartum women (IAS poster MOPE174) Consistent lowering of maternal HIV-1 plasma viral load could reduce HIV-1 transmission to infants during the breastfeeding period (IAS oral MOAC0201 )

21. Acknowledgements Research Team: PIs: Carey Farquhar (UW), James Kiarie (UoN) Alison Drake, Daniel Matemo, Francisca Ongecha-Owuor, Barbra Richardson, Anna Wald, Julie Overbaugh, Sandra Emery, Grace John-Stewart Funders: National Institutes of Health (R03 HD 057773, R03 HD 057773-02S1, R01 AI076105) Fogarty International Clinical Research Fellowship (Roxby, Ongecha-Owuor) UW Royalty Research Fund & Puget Sound Partners Grant Fogarty International Center International AIDS Research & Training Program University of Washington CFAR Mathare North Health Center VIP Study Staff: Sarah Githuku, Jane Waithira, Winnie Nekesa, Wambui Karuoya, Benetah Kendo, Jane Munuhe, and Samuel Kirichu We thank the women and children who participated and made this research possible.