Alison Drake International AIDS Society Conference July 18, 2011 Valacyclovir suppression reduces breast milk and plasma HIV-1 RNA postpartum: results of a randomized clinical trial

Abstracts at IAS 2011 Oral Abstract Session Maternal Health and Paediatric Outcomes TUAB0202: Tuesday 2:30 – 4:00, MR 4 Poster Exhibitions MOPE174: Monday 12:30 – 2:30 TUPE268: Tuesday 12:30 – 2:30

MTCT in non-breastfeeding populations Pregnancy DeliveryPostpartum ZDV sdNVP Maternal ZDV + 3TC (1 wk) Maternal HAART Postnatal Tx rate (6 mo) 1 - 2% Maternal HAART

MTCT in breastfeeding populations Pregnancy DeliveryPostpartum ZDV sdNVP Maternal ZDV + 3TC (1 wk) Maternal HAART or Infant NVP Postnatal Tx rate (6 mo) % 3 - 5%Maternal HAART Cessation of BF

MTCT in breastfeeding populations Access to ARVs for PMTCT not universal 53% coverage in low- and middle- income countries (WHO 2010) Alternative strategies needed to reduce postnatal transmission Pregnancy DeliveryPostpartum ZDV sdNVP Maternal ZDV + 3TC (1 wk) Maternal HAART or Infant NVP Postnatal Tx rate (6 mo) % 3 - 5%Maternal HAART Cessation of BF

HSV-2 infection in HIV-1 infected women Prevalence 75% to > 95% Suppressive therapy Reduces plasma HIV-1 RNA log 0.18 log greater reduction with valacyclovir (Ludema 2011) Effect on breast milk HIV-1 RNA or MTCT unknown

Aims To evaluate the effect of valacyclovir suppressive therapy administered during late pregnancy and for 12 months postpartum on: Plasma HIV-1 RNA levels Breast milk HIV-1 RNA detection and levels

Study design Inclusion criteria Procedures HIV-1/HSV-2 seropositive ≥ 18 years of age HAART ineligible CD4 > 250 cells/mm 3 Seeking ANC in Nairobi, Kenya Deliver and remain in Nairobi 12 months postpartum Double blind RCT 500 mg valacyclovir or placebo bid PMTCT ARVs ZDV + sdNVP

28-32wk 34wk 38wk 2wk 6wk 14wk 6mo12mo Study design Pregnancy Delivery Postpartum Screen Enroll & Randomize Inclusion criteria Procedures HIV-1/HSV-2 seropositive ≥ 18 years of age HAART ineligible CD4 > 250 cells/mm 3 Seeking ANC in Nairobi, Kenya Deliver and remain in Nairobi 12 months postpartum Blood & breast milk Double blind RCT 500 mg valacyclovir or placebo bid PMTCT ARVs ZDV + sdNVP

74 valacyclovir 74 placebo 73 included in analysis 1 LTFU April 2008 – June screened 211 eligible 148 enrolled Screening, enrollment, and follow-up * not mutually exclusive Ineligible * 85 HSV-2 67 CD4 70 HAART 24 Residence

Baseline and infant characteristics Median (IQR) or Mean* (95% CI) or n (%) CharacteristicValacyclovir (n=73)Placebo (n=73) Age (years)25 ( )25 ( ) Reported history of GUD10 (14)13 (18) CD4 count (cells/mm 3 )452 ( )481 ( ) WHO stage 168 (93)62 (85) Plasma HIV-1 RNA (log 10 copies/mL)*3.89 ( )3.87 ( ) Initiated ZDV by enrollment73 (100)68 (93) Infant received sdNVP67/72 (93)70/71 (96) Breastfeeding (reported at 2 weeks)67/72 (93)66/66 (100)

Postpartum plasma HIV-1 RNA levels Placebo Valacyclovir

Postpartum plasma HIV-1 RNA levels Placebo Valacyclovir

Postpartum plasma HIV-1 RNA levels Placebo Valacyclovir

Postpartum plasma HIV-1 RNA levels Placebo Valacyclovir p 2wk PVL 2- 6 wk rate of ∆ < lower (95% CI 0.92 – 0.28 )

Postpartum plasma HIV-1 RNA levels Placebo Valacyclovir p 6 wk – 12 mo rate of ∆Mean (95% CI) difference lower (0.73 – 0.30) 0.3<0.001

HIV-1 RNA detection in breast milk

Breast milk HIV-1 RNA levels Placebo Valacyclovir Breast milk Plasma Median (IQR) 6 wk 14 wk 2.42 (1.70 – 3.35)1.70 (1.70 – 2.96) 1.70 (1.70 – 2.57)1.70 (1.70 – 1.70)

Breast milk and plasma HIV-1 RNA levels Placebo Valacyclovir Median (IQR) 6 wk 14 wk 2.42 (1.70 – 3.35)1.70 (1.70 – 2.96) 1.70 (1.70 – 2.57)1.70 (1.70 – 1.70) Breast milk Plasma

Risk of infant HIV-1 transmission n = 6 n = 4

Conclusions Valacyclovir reduced Early breast milk HIV-1 RNA detection Plasma HIV-1 RNA 0.51 log Plasma results consistent with other trials Impact of valacyclovir on MTCT may differ from heterosexual transmission Prolonged exposure to bodily fluids 0.4 log lower viral load associated with reduced risk of postnatal MTCT (Neveu 2011)

Implications Valacyclovir is an appealing intervention Valacyclovir suppressive therapy, in conjunction with PMTCT ARVs, should be evaluated as an intervention to reduce postnatal MTCT and improve maternal health

Acknowledgments University of Washington Carey Farquhar Alison Roxby Anna Wald Grace John-Stewart Barbra Richardson Julie Overbaugh Jane Hitti Sandy Emery University of Nairobi James Kiarie Francisca Ongecha-Owuor Funding NIH R03 5R03HD NIH ARRA 5R03HD S1 University of Washington CFAR P30 AI CFAR STD Pre-doctoral Training Grant 5T32AI Puget Sound Partners for Global Health UW Royalty Research Fund Study participants Mathare staff DSMB GlaxoSmithKline