Post on 23-Dec-2015
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
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
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)
Hypothesis
Will herpes suppressing agents improve maternal health among co-infected women in sub-Saharan Africa?
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
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
Study Design
• Double-blind, placebo-controlled, RCTIntervention: 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
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
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 randomizationViral loads and CD4 counts were compared using
multivariate linear regression controlling for baseline values
Daniel Matemo, VIP Lab
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 randomizedto valacyclovir
74 randomizedto placebo
2 women lost before delivery
Modified Intention-to-treat analysis 73 women 73 women
Baseline characteristics by study arm
Characteristic at baseline
Valacyclovirn=73
Placebon=73
Median (IQR)or n (%)
Median (IQR)or n (%)
Age (years) 25 (22-30) 25 (22-29)
No. of pregnancies 1 (1-3) 2 (1-2)
Education ≤ 8 years 43 (59%) 49 (67%)
Monthly rent (USD) 24 (19-33) 21 (13-33)
Employed 22 (30%) 18 (25%)
On ARVs for PMTCT 73 (100%) 68 (93%)
WHO Stage
Stage 1 68 (93%) 62 (85%)
Stage 2 5 (7%) 11 (15%)
CD4 count (cells/μL) 452 (351-560) 481 (340-598)
Log10 HIV-1 plasma RNA level (copies/ml)
3.99 (3.30-4.41) 3.84 (3.43-4.45)
Maternal Mortality and Morbidity
Number of cases
All women (n=146) Placebo (n=73) Valacyclovir (n=73)
Perinatal Complications
Stillbirth: 3 2 1
Cesarean section: 14 9 5
Maternal Morbidity
CD4 <250 cells/μl: 9 3 6
Tuberculosis: 6 4 2
Post-delivery hospitalization: 7 5 2
Malaria: 20 15 5
Diarrhea/colitis: 26 10 16
Maternal Mortality
Number of deaths: 3 2 1
Mean HIV-1 RNA(log10copies/ml)
Valacyclovir Placebo Difference P*
Enrollment 3.89 3.87 -0.01 0.95
6 months 3.98 4.39 -0.42 <0.001
12 months 4.10 4.53 -0.40 0.001
Effect of Valacyclovir on Plasma RNA
HIV-1 RNA differences at one year, by study arm
Effect of Valacyclovir on CD4 Count
Mean CD4 Count(cells/μl)
Valacyclovir Placebo Difference P*
Enrollment 484 487 -3 0.92
6 months 631 612 17 0.72
12 months 638 565 73 0.03
CD4 differences at one year, by study arm
Adherence to study drugs
• Average mean adherence was 86% overall
• no difference between study arms
• Adherence was measured by pill count
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
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)
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 )
AcknowledgementsResearch 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 GrantFogarty International Center International AIDS Research &
Training ProgramUniversity of Washington CFAR
Mathare North Health CenterVIP 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.