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.