Alison C. Roxby, MD, MSc. July 19, 2011 University of Washington / University of Nairobi

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 Daniel Matemo, VIP Lab 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

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

11. Baseline characteristics by study arm

12. Maternal Mortality and Morbidity

13. Effect of Valacyclovir on Plasma RNA

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

15. Effect of Valacyclovir on CD4 Count

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, withmean 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, WambuiKaruoya, Benetah Kendo, Jane Munuhe, and Samuel Kirichu We thank the women and children who participated and made this research possible.