Clinical trial NCT01061151
Conditions: HIV Infections
Keywords: Mother to Child Transmission HIV Infection HAART Maternal Health Breastfeeding Perinatal transmission
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2011-03-01; Completion date: 2016-09-30
Enrollment: 3747 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to examine, in an integrated and comprehensive fashion, three critical questions currently facing HIV-infected pregnant and postpartum women and their infants:

1. What is the optimal intervention for the prevention of antepartum and intrapartum transmission of HIV?
2. What is the optimal intervention for the prevention of postpartum transmission in breastfeeding (BF) infants?
3. What is the optimal intervention for the preservation of maternal health after the risk period for prevention of mother-to-child-transmission ends (either at delivery or cessation of BF)?

The overall PROMISE protocol had three separate interventional components to address each of these three questions and was conducted at locations in Africa and other parts of the world. Due to variations in the standard of care for HIV-infected pregnant and postpartum women and their infants at different sites, not all of these questions were relevant. Therefore, two separate versions of the PROMISE protocol were developed, each containing only the relevant components. The 1077BF protocol was used at sites where the standard method of infant feeding was breastfeeding, whereas the 1077FF protocol was used at sites where the standard method of infant feeding was formula feeding. The analyses were collapsed across the two protocol versions, and therefore the summaries contain the results of the 1077BF and/or the 1077FF protocols.

Detailed description:
The incidence of mother-to-child transmission (MTCT) of HIV has decreased in recent years in the United States, Europe, and other resource-advantaged countries. Several factors have contributed to this decrease, including the administration of HAART during pregnancy, caesarean section delivery methods, and the use of formula instead of breastfeeding to feed infants. However, in resource-limited countries, the incidence of pediatric HIV infection remains high. Many pregnant women in these countries do not receive an adequate course of HAART, and the majority breastfeed their children.

This study was divided into three components (Antepartum, Postpartum, and Maternal Health Components). The following is a description of each of the three open label sequential randomization components, each designed to address one of the following three main objectives:

1. Antepartum Component: This PROMISE component compared the safety and efficacy of different HAART regimens for preventing the transmission of HIV during pregnancy, labor, and delivery.

   * Participants were randomly assigned to one of the following three arms:
   * Maternal Regimens:

     * Arm A : 1) Zidovudine (ZDV) from study entry through delivery, 2) single dose nevirapine (sdNVP) and emtricitabine-tenofovir disoproxil (TRV ) intrapartum, and 3) TRV postpartum for up to 14 days post-partum. Arm A is also labeled as ZDV+sdNVP+TRV tail.
     * Arm B: Lamivudine (3TC)-zidovudine (ZDV) + lopinavir (LPV)-ritonavir (RTV) from study entry up to 14 days postpartum. Arm B is also labeled as 3TC-ZDV/LPV-RTV.
     * Arm C: TRV/LPV-RTV from study entry up to 14 days postpartum. Arm C is also labeled as FTC-TDF/LPV-RTV.
   * All infants born to women enrolled in this study were to receive NVP once a day as soon as possible after birth through 42 days of age or until the Week 6 study visit, whichever was later. Women switched or initiated HAART if it was needed for their own health.
   * During pregnancy, participants attended study visits at study entry, 2 and 4 weeks after entry, and then every 4 weeks until labor and delivery. Women and infants were monitored during labor and delivery and attended a study visit 6 to 14 days after delivery. After delivery, eligibility criteria were assessed for subsequent randomizations (either Postpartum or Maternal Health). If they failed the entry criteria for the subsequent randomization, the mothers remained in follow-up for safety assessments and the infants were followed until the 104 week visit; otherwise they were followed under the subsequent component.
   * All three antepartum arms were not available to all women throughout the PROMISE study. When the trial began, there were limited safety data on tenofovir in pregnancy, and randomization to tenofovir-based ART was limited to women coinfected with HIV and HBV, because benefit was felt to outweigh risk in that group. During period 1 (PROMISE protocol version 2.0 - April 2011 through September 2012), women without HBV coinfection were randomized to either Arm A or Arm B; and Hepatitis B (HBV) co-infected women were randomized to either Arm A, Arm B, or Arm C. However, in October 2012, with increased data on tenofovir in pregnancy, the protocol was modified to allow women regardless of HBV status to be assigned to any of the three regimens during period 2 (PROMISE protocol version 3.0 - October 2012 through the end of antepartum enrollment on October 1, 2014). By arm comparisons were restricted to times in which there were contemporaneous randomizations.
   * Late Presenters: In addition the Antepartum Component, participants could enter PROMISE through the Late Presenters Registration (LP). Late presenters were identified in early or active labor or in the immediate postpartum period (up to 5 days postpartum). The Late Presenters Registration facilitated a structure to screen women and infants for randomization in the Postpartum Component. Women and infants not randomized in the Postpartum Component of PROMISE were followed through the Week 6 visit.
   * There were 3543 mothers and 3407 live born infants enrolled in the Antepartum Component. There were 204 mothers and 204 live born infants in the Late Presenters Registration.
2. Postpartum Component: This PROMISE component compared the safety and efficacy of maternal triple ARV prophylaxis versus daily infant NVP prophylaxis for the prevention of mother-to-child transmission (PMTCT) through breastfeeding. The Postpartum Component consisted of mothers and infants from the Antepartum Component and the Late Presenters Registration who passed the Postpartum Component entry criteria.

   * Participants were randomly assigned to one of two arms:

     * Arm A: Women received LPV-RTV plus TRV from the Week 1 postpartum visit through the end of maternal follow-up (2 to 5 years). Infants received NVP once a day through 42 days of age or until the Week 6 study visit, whichever was later.
     * Arm B: Infants received NVP once a day from the Week 1 postpartum visit until the end of risk for MTCT or until 18 months postpartum (104 weeks). Women did not receive antiretroviral drugs for MTCT prophylaxis.
   * The maternal study visits were at entry, at postpartum weeks 6, 14, 26, and every 12 weeks thereafter. Infant study visits were at entry, every 4 weeks between postpartum weeks 6-26, every 12 weeks between postpartum week 38-98, and at postpartum week 104. At the end of risk for MTCT or 18 months postpartum, the mothers' eligibility criteria were assessed for a subsequent randomization in the Maternal Health Component. If they did not meet entry criteria for the Maternal Health randomization, they remained in follow-up for safety assessments; otherwise they were followed under the Maternal Health Component. Infants were followed until the 104 week visit.
   * Women switched or initiated HAART if it was needed for their own health. If a woman in Arm B initiated HAART then her infant discontinued NVP after 12 weeks of HAART or after her viral load was suppressed, whichever came first.
   * There were 2431 mothers and 2444 infants randomized as part of the Postpartum Component.
3. Maternal Health Component: This PROMISE component randomized women to continue or discontinue HAART after the end of risk for MTCT, either after delivery or after breastfeeding. Participants included women who were receiving the triple ARV regimen in the Postpartum Component; or receiving the triple ARV regimen in the Antepartum Component and were ineligible for the Postpartum Component.

   * Participants were randomly assigned to one of two study arms:

     * Arm A: Participants continued to receive the triple ARV regimen (preferred regimen was LPV-RTV plus TRV).
     * Arm B: Participants discontinued the triple ARV regimen.
   * Study visits occurred at Weeks 4 and 12 and then every 3 months thereafter. Study visits included a medical history review, questionnaires, physical exam, and blood collection. Women switched or initiated a triple ARV regimen if it was needed for their own health.
   * There were 875 mothers randomized as part of the Maternal Health Component.
   * The analyses for the Maternal Health Component we not solely based on the Maternal Health Randomization. Instead there were four prespecified comparison groups for the Maternal Health Component. The four comparison groups used the three randomizations as appropriate to answer the following questions:

     * Question 1: What is the effect on women of using a maternal triple ARV regimen to prevent MTCT during pregnancy, relative to using ZDV + sdNVP + TRV tail to prevent MTCT during pregnancy?
     * Question 2: What is the effect on women of using a maternal triple ARV regimen to prevent MTCT during breastfeeding, relative to using infant NVP to prevent MTCT during breastfeeding?
     * Question 3: What is the effect on women of extending versus discontinuing the antepartum/intrapartum maternal triple ARV regimen at the time of birth?
     * Question 4: What is the effect on women of extending versus discontinuing the postpartum maternal triple ARV regimen after the cessation of risk for MTCT during breastfeeding?
   * There were 1602 mothers included in the analyses for Question 2.

PROMISE mothers were followed for 2 to 5 years, depending on when they enrolled. Infants were followed up to 104 weeks of age. Infant and maternal follow-up ended in September 2016. PROMISE randomizations were halted in the summer of 2014 due to slow accrual to the Later Presenters Registration and the Formula Feeding protocol. Due to the results of an external study, on July 7th 2015 the PROMISE interventions were halted and ART was offered to all participants. Per recommendation from the Data and Safety and Monitoring Board on November 4th 2014, the primary analyses for the Antepartum Component include follow-up through September 10th, 2014. Per recommendation from the Data and Safety and Monitoring Board on November 12th 2015, the primary analyses for the Postpartum Component include follow-up through July 7th, 2015. The Adverse Events in the Reported Adverse Event section include all study follow-up.

Arms: arm 1: Mothers received ZDV + sdNVP + TRV Tail arm 2: Mothers received Triple ARV (3TC-ZDV + LPV-RTV) arm 3: Mothers received Triple ARV (TRV + LPV-RTV) arm 4: Registration to facilitate a structure to screen women and infants for randomization in the Postpartum Component. arm 5: Mothers received prophylaxis \[preferred regimen: TRV + LPV-RTV\]. Infants received short-course NVP. arm 6: Infants received extended NVP. arm 7: Mothers continued receiving triple ARV regimen \[preferred regimen: TRV + LPV-RTV\]. arm 8: Mothers discontinued triple ARV regimen.
Interventions: intervention 1: Zidovudine (ZDV) intervention 2: Nevirapine (NVP): Antepartum Mothers intervention 3: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail intervention 4: Lamivudine-Zidovudine (3TC-ZDV) intervention 5: Lopinavir-ritonavir (LPV-RTV) intervention 6: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) intervention 7: Nevirapine (NVP): Infant short-course intervention 8: Nevirapine (NVP): Infant extended intervention 9: No Intervention intervention 10: Discontinue triple ARVs intervention 11: Continue triple ARVs
Intervention descriptions: intervention 1: 300 mg twice daily intervention 2: 200 mg at onset of labor intervention 3: 200 mg/300 mg x 2 tablets at onset of labor or as soon as possible thereafter; 200 mg/300 mg orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later. intervention 4: 150 mg/300 mg twice daily intervention 5: 400 mg/100 mg twice daily beginning at \>= 14 weeks gestation; 600 mg/150 mg twice daily beginning at \>= 28 weeks gestation or at next visit (during third trimester) through delivery; 400 mg/100 mg twice daily after delivery up to 14 days postpartum. intervention 6: 200 mg/300 mg intervention 7: Oral suspension (dosing according to birth weight) once a day through 42 days of age or through the week 6 visit, whichever is later. intervention 8: Oral suspension (dosing according to birth weight) once a day from 6 (up to 14) days of age until there was no longer any risk of MTCT or until the end of follow-up (104 weeks), whichever came first. intervention 9: Women registered before/during labor received the full Antepartum Arm A regimen.

Women registered after labor, and who received nevirapine outside of the study, received the Emtricitabine-tenofovir disoproxil fumarate (Truvada \[TRV\]) tail. intervention 10: ARVs were discontinued. When protocol specified criteria were met, mothers could be prescribed any licensed antiretroviral medication, as long as the treatment met the definition of HAART (three ARV drugs from two or more drug classes). intervention 11: Mothers could be prescribed any licensed antiretroviral medication, as long as the treatment met the definition of HAART (three ARV drugs from two or more drug classes).

Protocol documents: