PROMISE Introduction to PROMISE Protocol May 6, 2009

PROMISE – Addresses 4 Questions in an Integrated and Comprehensive Fashion What is the optimal intervention for the prevention of antepartum and intrapartum transmission of HIV? (Antepartum Component) What is the optimal intervention for the prevention of postpartum transmission in breast feeding (BF) infants? (Postpartum Component) What is the optimal intervention for the preservation of maternal health after the risk period for MTCT ends (either at delivery or cessation of BF)? (Maternal Health Component) What is the optimal intervention for the prevention of the infant morbidity and mortality associated with BF cessation? (Infant Health Component)

Antepartum Component - Background and Rationale  In women with higher CD4+ counts, HAART or ZDV started at 28 weeks plus sdNVP reduce MTCT of HIV  Rates of MTCT HAART in resource rich countries - < 2% ZDV + sdNVP in resource limited countries – 1.1 – 3.9% HAART in resource limited countries – 1.2 – 4.1%  In resource limited countries, rates of transmission are similar  However, no randomized trials comparing the two strategies  Question is important in both breast feeding and formula feeding areas of the world

Antepartum Component - Equipoise  HAART-related toxicities in women who do not require HAART for their own health and their ARV exposed infants are a concern  HAART may increase pregnancy complications, including pre-term births  Stopping HAART after delivery may have detrimental effects on maternal health  Development of viral resistance  Cost of HAART greater than ZDV + sdNVP

Formula feeding, mother eligible for Maternal Health Randomization

Primary Objectives  In mothers with CD4 >350 starting PMTCT at 28 weeks gestation and prior to active labor who plan to breast or formula feed: Evaluate the comparative efficacy of maternal antepartum HAART versus antepartum short course ZDV + sdNVP/TRV in reducing antepartum and intrapartum MTCT through 1 week of age (7-12 days) Assess and compare the safety and tolerance of these ARV regimens, including adverse pregnancy outcomes (stillbirths, prematurity and low birth weight).

Targeted Accrual  4,400 women 3,400 from breastfeeding areas 1,000 from formula feeding areas  Efficacy - Provides 90% power to detect a difference of 4% vs. 2.2% in MTCT between the randomization groups, based on a 2-sided Type I error of 5%  Safety – Would also provide greater than 90% power to detect differences in low-birth weight and pre- term delivery between the two groups

Secondary Objectives  HIV infection at birth (to 72 hrs)  Adherence to maternal regimens  ARV Resistance (mother and infant, if infected)  Cost effectiveness and feasibility  Rates of maternal RNA <400 by time of ARV start before delivery

Hepatitis B Sub-Study  Hepatitis B sub-study To compare the anti-HBV efficacy of antepartum HAART regimens, assessed as change in hepatitis B viral load during the antepartum period. To describe vertical transmission of HBV and its characteristics in infants To evaluate and compare maternal HBV DNA viral load levels and presence of HBV drug resistance at delivery and through up to four years postpartum. To estimate HBV virologic, safety outcomes (LFT) and HBV serologic changes over time following anti-HBV ARV regimen cessation. To estimate and compare maternal anemia at delivery

Study Design  Women who are not HBV co-infected are randomized to one of 2 Arms Arm A: ZDV + sdNVP Arm B: ZDV/3TC/LPV-RTV  Women who are HBV co-infected are randomized to one of 3 Arms Arm A: ZDV + sdNVP Arm B: ZDV/3TC/LPV-RTV (single HBV active agent) Arm C: TRV/LPV-RTV (dual HBV active agent, TRV=Truvada= Tenofovir DF + FTC)

Primary Endpoints  Confirmed presence of infant HIV infection detected by HIV NAT positivity of the specimen drawn at either the birth (day 0-3) or week 1 (day 7-12) visit.  Grade 3 or higher toxicity, obstetrical complications, and adverse pregnancy outcomes (including stillbirth, preterm delivery at <37 weeks of age, and low birth weight <2500 grams)

Flow of Patients to Other Components of PROMISE  Breastfeeding enrollees who give consent and are eligible: Mom/infants go to Postpartum Component Mothers, if got HAART, eligible for Maternal Health Component Infants eligible for Infant Health randomization if uninfected when wean  Formula feeding enrollees who give consent and are eligible : Mothers, ff got HAART, eligible for Maternal Health Component Mothers, if got ZDV/sdNVP, is followed to provide control group for maternal health comparisons

If…Then…  Mothers and infants who do not meet MATERNAL eligibility criteria for post partum component Mothers participate in observational follow-up.  Infants who do not meet INFANT eligibility criteria for post partum component or who experience fetal demise If mother on HAART, evaluate for Maternal Health component. If mother not on HAART, participates in observational follow-up.  Mothers who decline randomization but agree to continue follow up Mothers participate in observational follow-up.  Mothers who decline randomization and observational follow-up Off study at week 6.  Regardless of mother status, infants followed through 104 weeks of age, if allowed  Infected infants continue to be followed with limited evaluations, but includes CD4+ count every 12 weeks

Late-Presenters – Background and Rationale  Many HIV-infected pregnant women in resource- limited settings miss the opportunity for HIV testing, ARV for prevention of MTCT, and ARV treatment for their own health due to the late antenatal presentation and/or limited delivery of counseling and testing services  Depending on the clinical center, up to 30% of HIV- infected women in resource-limited countries may present late in pregnancy or in active labor  These women and their infants may benefit from participation in the Postpartum component

Late-Presenters Design  May enroll in the late-presenters administrative component during active labor up to 3 days postpartum  Provide the structure to administer intrapartum and/or immediate postpartum care  Provides structure to complete the necessary screening evaluations for women and infants for randomization in the Postpartum component.

Late-Presenters  Intrapartum and immediate postpartum management of LPs will mirror that of the women and infants randomized to the antepartum short course ZDV(IP ZDV + sdNVP, TRV and TRV tail)  If women and infants meet eligibility criteria, will enroll in Postpartum component  If not, Off study at Week 6  Infants provided with 6 weeks of NVP

Postpartum Component - Background and Rationale  Avoidance of breastfeeding results in reduced MTCT but increased infant mortality  Two general strategies have been proposed to reduce the risk of postpartum BF HIV transmission: Use of infant ARV prophylaxis during BF Use of maternal HAART during BF

Postpartum Component - Equipoise  HAART-related toxicities in women who do not require HAART for their own health and their ARV exposed infants are a concern  Development of viral resistance  Cost of maternal HAART greater than infant NVP

Primary Objectives  Evaluate the comparative efficacy of giving daily maternal HAART versus daily infant NVP prophylaxis during BF to reduce cumulative HIV transmission from BF.  Assess the safety and tolerance of these ARV regimens for mother and infant.

Targeted Accrual  4,650 women 3,100 from Antenatal randomization in breastfeeding mothers 1,550 late-presenters  Efficacy – Provides 90% power to detect a difference of 5% vs. 3% in postnatal MTCT at BF cessation between the randomization groups, based on a 2-sided Type I error of 5 %

Secondary Objectives  Time to postnatal HIV transmission  Assess if MTCT differs Early-presenting versus late-presenting mothers Mothers who received HAART versus ZDV + sdNVP/TRV during pregnancy  Compare HIV-free survival and overall infant mortality rates among infants  Adherence to maternal and infant regimens  ARV Resistance (mother and infant, if infected)  Cost effectiveness and feasibility  Assess MTCT according to mode of infant feeding and other risk factors.

Study Design  Drug Regimens Arm A - Maternal HAART prophylaxis: TRV/LPV-RTV Arm B – Infant prophylaxis: NVP  All infants receive CTX prophylaxis from 6 weeks through cessation of BF

Primary Endpoints  Infant HIV infection detected by HIV NAT positivity of a specimen drawn at any post- randomization visit (i.e.,. any visit after the week 1 (day 7-12) visit)  Grade 3 or higher toxicity

Flow of Patients to Other Components of PROMISE After Breastfeeding Cessation  Mothers, if got HAART, eligible for Maternal Health Component  Mothers of infants who received NVP enter observational follow-up  Infants eligible for Infant Health randomization if uninfected

If…Then…  Mothers who are ineligible for Maternal Health Component Mothers participate in observational follow-up.  Mothers who decline randomization but agree to continue follow up Mothers participate in observational follow-up.  Mothers who decline randomization and observational follow-up Off study at completion of Postpartum component