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PROMISE

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)

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PROMISE

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  1. PROMISE Introduction to PROMISE Protocol May 6, 2009

  2. 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)

  3. 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

  4. 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

  5. Formula feeding, mother eligible for Maternal Health Randomization

  6. 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).

  7. 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

  8. 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

  9. 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

  10. 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)

  11. 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)

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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.

  20. 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 %

  21. 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.

  22. 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

  23. 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

  24. 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

  25. 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

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