PROMISEIntroduction 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

AP (28 wks-term) IP PP

Antepartum Randomization: BF Settings(In Countries Where Short Course ARV Regimens Are Used for PMTCT)

MaternalHAART

MaternalHAART

MaternalZDV

MaternalZDV +

SD NVP+TRV

Infant SD NVP + ZDV x1 wk (7-12 d)

Infant SD NVP + ZDV x1 wk (7-12 d)

Randomize

At >28 wks gestation and

mother has CD4 >350

Breastfeedingmother-infant pair

eligible for Postpartum

Randomization

Maternal TRV x1 wk (7-12 d)

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

PP Until BF Cessation Or 18 Mos Postpartum

(Whichever Comes First)

Postpartum Randomization(Breastfeeding Mother-Infant Pairs)

Maternal HAART(start by day 7-12, for duration BF)

Infant NVP (start by day 7-12, for duration BF)

Randomize

If infant is uninfected on birth-72 hr sample

andmother has CD4 >350

and is breastfeeding

Mother-infants fromAntepartum Randomization

Mother-infants from women presenting in labor*

(mothers get ZDV + sdNVP/TRV + PP TRV to day 7-12, Infant sdNVP+ZDV to day 7-12)

Mother-infants from women presenting <72 hr postpartum*

(infant sdNVP + ZDV to day 7-12)(must have birth infant PCR result by 72 hours)

Populations to be Enrolled

* Late presenters:If CD4 subsequently found <350 -Mother referred for standard care

Infant get 6 weeks infant NVPthen both come off study

Day 7-12

Infantseligible for

Infant HealthRandomization

Mothereligible for

Maternal HealthRandomization

Potential Next Randomization

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