Evaluating Strategies to Reduce Mother-to-Child Transmission of HIV Infection in Resource-Limited Countries

Breastfeeding Version of the PROMISE Study (Promoting Maternal and Infant Survival Everywhere)

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.

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.

Antepartum Component Inclusion Criteria:

• Confirmed HIV-1 infection, defined as documented positive results from two samples collected at different time points prior to study entry. More information on this criterion can be found in the protocol.

• Currently pregnant and greater than or equal to 14 weeks gestation based on clinical or other obstetrical measurements

• CD4 count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), on a specimen obtained within 30 days prior to study entry

• Results of HBV screening (HBsAg testing) available from specimen obtained within 30 days prior to study entry

• The following laboratory values from a specimen obtained within 30 days prior to study entry:

  1. Hemoglobin greater than or equal to 7.5 g/dL
  2. White blood cell count (WBC) greater than or equal to 1,500 cells/mm^3
  3. Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3
  4. Platelets greater than or equal to 50,000 cells/mm^3
  5. Alanine aminotransferase (ALT) less than or equal to 2.5 times the upper limit of normal (ULN)
  6. Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

• Plans to deliver in the study-affiliated clinic or hospital

• Has no plans to move outside of the study site area during the 24 months following delivery

• Age of legal majority for the respective country and willing and able to provide written informed consent

Antepartum Component Exclusion Criteria:

• Participation in PROMISE for a prior pregnancy
• Ingestion of any antiretroviral (ARV) regimen with three or more drugs (regardless of duration) or more than 30 days of a single or dual ARV regimen during current pregnancy, according to self report or available medical records
• Requires triple ARV therapy (HAART) for own health based on local standard guidelines
• World Health Organization (WHO) stage 4 disease
• Prior receipt of HAART for maternal treatment indications (e.g., CD4 less than 350 cells/mm^3 or clinical indications); however, could have received ARVs for the sole purpose of prevention of mother-to-child transmission (PMTCT) in previous pregnancies (prior PMTCT regimens could have included a triple ARV regimen, ZDV, 3TC-ZDV, and/or sdNVP for PMTCT, as well as use of a short dual nucleoside reverse transcriptase inhibitor [NRTI] "tail" to reduce risk of NVP resistance.)
• In labor - at onset or beyond (may be eligible for the Late Presenter registration)
• Clinically significant illness or condition requiring systemic treatment and/or hospitalization within 30 days prior to study entry
• Current or history of tuberculosis (TB) disease (positive PPD without TB disease is not exclusionary)
• Use of prohibited medications within 14 days prior to study entry (refer to the protocol for a list of prohibited medications)
• Fetus detected to have serious congenital malformation (ultrasound not required to rule out this condition)
• Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)
• Known to meet the local standard criteria for treatment of HBV (Note: HBV DNA testing or other specialized assessments are not expected to be performed as part of this study. A woman would be excluded only if this information is documented from other sources and she meets the local standard criteria for HBV treatment based on those assessments.)
• Social or other circumstances that would hinder long-term follow-up, in the opinion of the site investigator
• Currently incarcerated

Late Presenter Inclusion Criteria:

• Age of legal majority for the respective country
• HIV-1 infection, defined as documented positive results from tests performed on one sample at any time prior to Late Presenter Registration
• In labor (from onset/early labor or beyond) or within 5 days after delivery (with day of delivery considered day 0)
• Has provided written informed consent
• Has no plans to move outside of the study site area during the 24 months following delivery
• If delivered, infant alive and healthy (In the case of a multiple birth, a mother-infant pair will be included in the Late Presenter registration only if both/all infants and the mother meet the eligibility criteria. If only one infant of a multiple birth is alive, the M-I pair may be registered if the infant and the mother otherwise meet all of the eligibility criteria.)

Late Presenter Exclusion Criteria:

• Participation in PROMISE in prior pregnancy
• Ingestion of any antiretroviral regimen during current pregnancy (including for solely for PMTCT), according to self report and available medical records (Note: Use of ARVs provided as standard of care for PMTCT during labor/delivery or postpartum prior to Late Presenter registration is not exclusionary.)
• If known: CD4 count < 350 cells/mm3 or below the country-specific threshold for initiation of treatment, if that threshold is > 350 cells/mm3, on specimen obtained within 30 days prior to study entry (result not required prior to registration)
• Requires triple ARV therapy (HAART) for own health according to local standard guidelines
• WHO Stage 4 disease
• Prior receipt of HAART for maternal treatment indications (e.g., CD4 < 350 cells/mm3 or clinical indications); however, could have received ARVs for the sole purpose of PMTCT in previous pregnancies. (Prior PMTCT regimens could have included a triple ARV regimen, ZDV, 3TCZDV and/or sdNVP for PMTCT, as well as use of a short dual NRTI "tail" to reduce risk of NVP resistance.)
• Current or history of TB disease (positive PPD without TB disease is not exclusionary)
• Known positive infant HIV nucleic acid test (NAT) result (result not required prior to registration)
• Fetal demise or early neonatal death (prior to enrollment/registration)
• Fetus detected with serious congenital malformation (ultrasound not required to rule out this condition)
• Life threatening infant illness or birth condition incompatible with life
• If delivered, infant birth weight < 2.0 kg
• Social or other circumstances which would hinder long-term follow-up, in the opinion of the site investigator
• Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block (also known as Mobitz I or Wenckebach) is not considered exclusionary)

Postpartum Component Inclusion Criteria:

• Participation in the Antepartum Component or registered as a Late Presenter

• Provided written informed consent

• Has no plans to move outside of the study site area during the 24 months following delivery

• Maternal CD4 count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), from a specimen obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol.

• The following maternal laboratory values within 30 days prior to entry:

  1. Hemoglobin greater than or equal to 7.0 g/dL
  2. WBC greater than or equal to 1,500 cells/mm^3
  3. ANC greater than or equal to 750 cells/mm^3
  4. Platelets greater than or equal to 50,000 cells/mm^3
  5. ALT less than or equal to 2.5 times the upper limit of normal (ULN)
  6. Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

• Infant alive, healthy, less than or equal to 14 days of age, and uninfected (negative HIV NAT result on specimen drawn prior to study entry)

• The following infant lab values on specimen obtained prior to study entry (within 14 days of birth):

  1. Hemoglobin greater than or equal to 10 g/dL
  2. WBC greater than or equal to 1,500 cells/mm^3
  3. ANC greater than or equal to 750 cells/mm^3
  4. Platelets greater than or equal to 50,000 cells/mm^3
  5. ALT less than or equal to 2.5 times the ULN

• For Registered Late Presenters: Confirmed maternal HIV-1 infection, defined as documented positive results from two samples collected at different time points at any time prior to entry. More information on this criterion can be found in the protocol.

Postpartum Component Exclusion Criteria:

• Positive infant HIV NAT result on specimen drawn prior to entry or no infant HIV NAT result on specimen drawn prior to entry
• Life-threatening infant illness or birth condition incompatible with life
• Infant birth weight less than 2.0 kg
• Social or other circumstances that would hinder long-term follow-up, as judged by the site investigator
• Current or history of TB disease (positive PPD without TB disease is not exclusionary)
• Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)
• Requires triple ARV therapy (HAART) for own health

Maternal Health Component Inclusion Criteria:

• Randomly assigned to triple ARV prophylaxis as part of the Postpartum Component and has continued triple ARV prophylaxis until the current randomization without treatment interruption (defined as more than 14 consecutive days of missed dosing) within the previous 30 days; OR randomly assigned to triple ARV prophylaxis in the Antepartum Component but ineligible for the Postpartum Component and has continued triple ARV prophylaxis until the current randomization without treatment interruption (defined as more than 7 consecutive days of missed dosing) within the previous 30 days

• Within two weeks after complete breastfeeding cessation is achieved (defined as completely stopping all exposure to breast milk for greater than or equal to 28 days); i.e., within 29 to 42 days of last breast milk exposure, or reached 18 months postpartum (whichever comes first). Women who reach 18 months postpartum while still breastfeeding will be eligible for entry within 2 weeks before and 4 weeks after the Week 74 visit (Week 72-78); OR if the woman was randomized to triple ARV prophylaxis in the Postpartum Component and her infant is infected and still breastfeeding, she will be eligible for the Maternal Health Component within 42 days of specimen collection for the confirmatory infant HIV NAT; OR if the woman was randomized to triple ARV prophylaxis in the Antepartum Component but mother-infant pair was ineligible for the Postpartum Component she will be eligible for the Maternal Health Component beginning at the Week 1 visit (6-14 days postpartum) through 28 days after delivery; these women should be randomized as soon as possible, ideally within 6-14 days after delivery; OR if the woman was randomized to triple ARV prophylaxis in the Postpartum Component and breastfeeding risk for MTCT ceases for other reasons (e.g., infant death or permanent removal from home through legal services or adoption) within 28 days of event. More information on this criterion can be found in the protocol.

• Provided written informed consent

• CD4 cell count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), on a specimen obtained within 30 days prior to study entry

• The following laboratory values on a specimen obtained within 30 days prior to study entry:

  1. ANC greater than or equal to 750 cells/mm^3
  2. Hemoglobin greater than or equal to 7.0 gm/dL
  3. Platelet count greater than or equal to 50,000 cells/mm^3
  4. ALT (SGPT) less than or equal to 2.5 times the ULN
  5. Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

• Intend to remain in current geographical area of residence for the duration of study

Maternal Health Component Exclusion Criteria:

• WHO Stage 4 disease
• Clinically significant illness or condition requiring systemic treatment and/or hospitalization within 30 days prior to study entry
• Current or history of TB disease (positive PPD without TB disease is not exclusionary)
• Use of prohibited medications within 14 days prior to study entry
• Social or other circumstances that would hinder long term follow-up as judged by the site investigator
• Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)
• Requires a triple ARV regimen for own health