1. 1 Effect of Maternal HAART on Postnatal HIV-1 Transmission after Cessation of Extended Infant Antiretroviral Prophylaxis Taha Taha 1, Johnstone Kumwenda 2, Stephen Cole 3, Donald Hoover 4, George Kafulafula 2, Qing Li 1, Michael Thigpen 5, Mary Glenn Fowler 1, Newton Kumwenda 1, Lynne Mofenson 6 1 Johns Hopkins University, Baltimore, MD, USA 2 University of Malawi, Blantyre, Malawi 3 University of North Carolina, Chapel Hill, NC, USA 4 Rutgers University, Piscataway, NJ, USA 5 Centers for Disease Control and Prevention, Atlanta, GA, USA 6 Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USA

2. 2 Background: PEPI Malawi Trial  The PEPI (Post-Exposure Prophylaxis of Infants) - Malawi trial, conducted between 2004-2007, demonstrated that – daily extended infant antiretroviral prophylaxis through age 14 weeks significantly reduced postnatal HIV- 1 transmission by >65% during the period of prophylaxis.

3. 3 BACKGROUND: PEPI-Malawi Rate of HIV-1 Infection in Infants HIV-1 Uninfected at Birth by Treatment Arm Age 1 wk 6 wks 14 Wks 6 mos 9 mos 12 mos 15 mos 18 mos 24 mos Estimates (%) Control0.24.9 8.2 10.41111.813 14.615.3 Extended NVP0.11.7 2.7 4.05.26.57.39.511.0 Extended NVP+ZDV0.21.5 2.7 5.36.47.88.510.011.6

4. 4 Background: PEPI Malawi Trial  In PEPI, mother/infant pairs were enrolled within 72 hours of birth, and breastfeeding, uninfected infants were randomized to receive: –Control regimen of sd-NVP+ZDV for 1 week; –Control + daily NVP to age 14 weeks; or –Control + daily NVP+ZDV to age 14 weeks.  Information on breastfeeding and maternal HAART use collected at each visit.  Blood samples collected to test for infant HIV infection and maternal CD4 counts.

5. 5 Background  Maternal HAART during breastfeeding is another potential strategy to reduce HIV postnatal transmission.  The complementary effect of antiretroviral infant prophylaxis and maternal HAART is unknown.  We examined the association of maternal HAART use with postnatal HIV transmission in the PEPI study after cessation of extended infant prophylaxis.

6. 6 Background: HAART Availability  When the PEPI trial started in 2004, HAART was not available in Malawi.  During the conduct of the PEPI trial, in 2006 HAART became available through a Malawi government treatment program.  Eligible women (clinical and/or CD4 <250/mm 3 ) were referred to government ART clinic.

7. 7 Background: HAART Availability  The ability to initiate maternal HAART was influenced by logistical considerations. –Some eligible women did not receive HAART due to clinic waiting time; missed visits; drug availability delay; partner consent; refusals, etc. –Coverage was limited; overall, 13% of women received HAART during follow-up. –Most women (>80%) who received HAART initiated it after 14 weeks postpartum.

8. 8 Methods  Three maternal groups defined based on eligibility for and receipt of HAART: –HAART-Eligible-Treated: person-time (P-T) contributed by infants of women with CD4<250/mm 3 who received HAART. –HAART-Eligible-Untreated: P-T contributed by infants of women with CD4<250/mm 3 who did not receive HAART. –HAART-Ineligible: P-T contributed by infants of women with CD4≥250/mm 3 for entire study who were not eligible for HAART.

9. 9 Methods  Infant HIV-1 infection rates between 14 weeks & 24 months was estimated using Kaplan-Meier curves and person-time, stratified by maternal HAART category.  Cox proportional hazards models were used to estimate the association of maternal HAART use (time-varying) with infant HIV-1 infection between 14 weeks & 24 months, adjusting for infant antiretroviral prophylaxis treatment arm.

10. 10 Results  2318 infants HIV uninfected at age 14 weeks were included. Of these: –73% (1694) had mothers with high CD4 count during entire follow-up. –27% (624) had mothers with low CD4 count:  5.7% (133) had high maternal CD4 count early but declined to <250 cells during follow-up;  21% (491) had low CD4 count throughout follow-up.  Overall, 310 women received HAART at some time postpartum: 45% (279/624) with low CD4 count and ~2% (31/1694) with clinical indications).

11. 11 Results  These 2318 infants contributed a total of 2750 person-years (p-yr) of follow-up.  130 (5.6%) became HIV infected: –5 infections among HAART-Eligible-Treated with 279 p-yrs of follow-up. –53 infections among HAART-Eligible-Untreated with 502 p-yrs of follow-up. –72 infections among HAART-Ineligible with 1969 p-yrs of follow-up.

12. 12 Cumulative HIV-1 Infections (Between 14 Weeks & 24 Months) among Infants HIV-1 Uninfected at Age 14 Weeks (April 2004-Dec 2007) Age(Months) Control % (95% CI) N=722 Ext. NVP % (95% CI) N=804 Ext. NVP+ZDV % (95% CI) N=792 6 1.3 (0.7, 2.5) 0.9 (0.4-1.9) 1.8 (1.1-3.1) 9 2.1 (1.2-3.4) 2.0 (1.2-3.3) 3.0 (2.0-4.5) 12 2.9 (1.8-4.5) 3.4 (2.3-5.1) 4.3 (3.1-6.1) 15 4.3 (2.9-6.3) 4.3 (3.0-6.2) 5.1 (3.7-7.0) 18 6.1 (4.4-8.5) 6.6 (4.9-9.0) 6.7 (5.0-9.0) 24 6.9 (5.0-9.4) 8.2 (6.1-11.1) 7.9 (5.9-10.4)

13. 13 Postnatal HIV Transmission (Between 14 Weeks and 24 Months) and Association with Maternal HAART Use Rate/100 p-yrs (95% CI) Rate Ratio Adjusted Rate Ratio * 95% CI HAART-Eligible- Untreated 10.6(7.9-13.8)1.001.00--- HAART-Eligible- Treated 1.8(0.6-4.2)0.180.18 0. 07-0.44 HAART-Ineligible3.7(2.9-4.6)0.350.350.25-0.50 * Adjusted for infant prophylaxis study arm

14. 14Conclusions  Transmission of HIV-1 through breast milk continued after completion of infant extended antiretroviral prophylaxis (even in mothers who received HAART).  Among HAART-Eligible-Treated mothers, maternal HAART significantly reduced infant HIV transmission between 14 weeks and 24 months compared to mothers who were HAART-Eligible but did not receive HAART.

15. 15Conclusions  The magnitude of transmission reduction with HAART in HAART-Eligible-Treated mothers, compared to HAART-Eligible mothers who were untreated, was substantial (82%).  Provision of HAART to eligible breastfeeding women has dual benefits: – it improves their own health, and – it also decreases postnatal HIV transmission.

16. 16Conclusions  Postnatal transmission among the 73% of mothers with persistently high CD4 count (HAART-Ineligible) was: –significantly lower than HAART-Eligible Untreated mothers (10.6 vs 3.7/100 p- yrs), and –was not significantly different from HAART-Eligible-Treated mothers (1.8 vs 3.7/100 p-yrs, with overlapping 95% CI).

17. 17Conclusions  For late-presenting women such as in the PEPI-Malawi trial: –Starting extended infant prophylaxis at birth, –Rapid identification of women with low CD4 cell counts with initiation of HAART as soon as possible postpartum, –and continuing infant prophylaxis for infants of women who do not need HAART, Could provide an effective strategy to allow prolonged safe breastfeeding in RLC. Could provide an effective strategy to allow prolonged safe breastfeeding in RLC.

18. 18 Acknowledgments  Funding source: This study was supported by a Cooperative Agreement (# 5 U50 PS022061-05; Award # U50/CC0222061) from the Centers for Disease Control and Prevention and Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.  We are indebted to the mothers and children who participated in the PEPI-Malawi study. We are grateful to the nursing and technical staff in Malawi and to several scientists in both the US and Malawi for their excellent collaboration and help throughout this study.