Peripartum Valacyclovir Improves Markers of HIV-1 Disease Progression in Women Co-Infected with HSV-2:

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, 2011University of Washington / University of Nairobi 1Good afternoon. I would like to thank the organizers for inviting me to speak today. I am presenting research done in Nairobi Kenya in collaboration with researchers at the Unversity of Nairobi. I have no outside disclosures.The Problem:15.7 million women of reproductive age are HIV-infected4 9 lifetime pregnancies per womanLifetime risk of maternal mortality: 1 in 22 womenWorldwide, HIV is the leading cause of death among women of reproductive ageInterventions are needed to improve the health of mothers with HIV

2There are 15.7 million women of reproductive age in the developing world infected with HIV. Women in the developing world have high rates of pregnancy, both intended and unintended, and are therefore at risk for pregnancy-related morbidity and mortality. HIV is the leading cause of death globally among women of reproductive age.Our project sought to design an intervention to improve the health of HIV positive mothers. Research Rationale: Effect of HSV-2 suppression on HIV-1 progressionUse 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)

3It has been clearly shown that treatment of HSV-2 with acyclovir or valacyclovir can reduce HIV plasma RNA levels. The average reduction seen ranges from 0.25 0.4 log copies/ml.In a recently concluded study of serodiscordant couples, HSV-2 positive, HIV positive partners randomized to daily acyclovir had a 16% reduction in risk of HIV disease progression. The disease progression endpoint was defined as death, CD4 count below 200, or initiation of anti-retroviral therapy.HypothesisWill herpes suppressing agents improve maternal health among co-infected women in sub-Saharan Africa?

4Our study was designed to see if some of the benefits of herpes suppressing drugs could be seen in pregnant and postpartum women, who have been excluded from prior trials. We hypothesized that herpes-suppressing agents could improve maternal health and reduce disease progression among co-infected women in sub-Saharan Africa. This study is part of a larger trial to determine effects of herpes suppressive therapy on women who were pregnant and breastfeeding

Valacyclovir in Pregnancy StudyAim 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

5Our first aim, XXXThe antivirals used by women in this population are AZT monotherapy starting at 28 weeks gestation, and single dose nevirapine for the mother at delivery. Some mothers also received an AZT/3TC tail for one week following administration of single dose nevirapine.We chose valacyclovir instead of acyclovir because it is easier to adhere to, longer acting, more potent, and as of 2009 is available as a generic medication.Valacyclovir in Pregnancy StudyAim 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

6Our second aim, XXXThis aim attempted to replicate the results of the Partners in Prevention trial, in the setting of pregnant women.

Study DesignDouble-blind, placebo-controlled, RCTIntervention: 500 mg valacyclovir or placebo BIDPregnant women seeking antenatal careAll women both HIV-1/HSV-2 seropositiveAll women with CD4 >250 cells/l

Enrolled/randomized to valacyclovir at 34 weeks gestationFollowed for 1 year postpartum

Clinicaltrials.gov identifier: NCT00530777

7This study was a double-blind, placebo-controlled randomized clinical trial. The intervention was 500 mg of valacyclovir twice daily or matched placebo. We enrolled pregnant women seeking antenatal care who were seropositive for both HIV and HSV-2. Women also had to have CD4 count greater than 250 cells and be WHO clinical stage 1 or 2.

Women were enrolled and randomized at 34 weeks gestation and were followed for one year postpartum. HIV levels were measured in the genital tract, breast milk and plasma. Other trial results, including the effect of valacyclovir on breast milk RNA levels, were presented yesterday by my co-investigator Alison Drake.Study LocationWomen 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 positiveMathare North VCT

8Women were recruited and followed at the 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. Most women live in extreme economic precarity and live on less than $1 USD per day.300 women initiate antenatal care here each month, and about 10% are HIV positive. This clinic has an active PMTCT program, provides universal HIV screening of pregnant women, has an on-site clinic for women who need combination antiretrovirals, and also is a site for the mother to mother support group program for pregnant women with HIV.

MethodsLaboratory: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 9Laboratory studies included HIV RNA levels collected at enrollment and at 6 and 12 months postpartum. CD4 counts were assessed in the 3rd trimester and again at 6 and 12 months postpartum. Patients were assessed clinically by the study physician monthly, or if ill. Statistical methods included chi squared and t tests to compare adequacy of randomization, and VL and CD4 were compared using multivariate linear regression controlling for baseline values.

149 ineligible HSV-2 negative: 85 (24%)CD4 < 250: 67 (19%)WHO stage: 57 (16%)Nairobi delivery/residence: 35 (10%)62 not enrolled359 screened210 eligible148 enrolled74 randomizedto valacyclovir74 randomizedto placebo2 women lost before deliveryModified Intention-to-treat analysis73 women73 women10We screened 359 pregnant, HIV-1 infected women and ultimately enrolled our target of 148. The main reasons for not enrolling included being HSV-2 negative (24%) and having low CD4 counts (19%). We had information from delivery for 146 women and therefore the results I am presenting are for these women, in a modified intention to treat analysis.10Baseline characteristics by study armCharacteristic at baseline Valacyclovirn=73Placebon=73Median (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 StageStage 168 (93%)62 (85%)Stage 25 (7%)11 (15%)CD4 count (cells/L)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)11These are the baseline characteristics of our participants. Our randomization was adequate and the groups had no significant demographic or clinical differences. The average age of women in our study was 25 and most had 1 or 2 prior pregnancies. As expected, they were mainly poor women. Only one-third were employed; average rent was $20/month, most women had no plumbing or electricity in their home. Most women WHO stage 1, and were asymptomatic from HIV. Almost everyone had initiated AZT for PMTCT by the time they enrolled in the study. The median CD4 count in the valacyclovir arm was 452 and was 481 in the placebo arm, and baseline HIV-1 viral loads were similar about 3.9 log copies/ml.

Maternal Mortality and MorbidityNumber of casesAll women (n=146)Placebo (n=73)Valacyclovir (n=73)Perinatal Complications Stillbirth: 321Cesarean section: 1495Maternal MorbidityCD4