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

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Zidovudine (ZDV)
Nevirapine (NVP): Antepartum Mothers
Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail
Lamivudine-Zidovudine (3TC-ZDV)
Lopinavir-ritonavir (LPV-RTV)
Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV])
Nevirapine (NVP): Infant short-course
Nevirapine (NVP): Infant extended
No Intervention
Discontinue triple ARVs
Continue triple ARVs
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for HIV Infections focused on measuring Mother to Child Transmission, HIV Infection, HAART, Maternal Health, Breastfeeding, Perinatal transmission

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Byramjee Jeejeebhoy Medical College (BJMC) CRS
  • Blantyre CRS
  • Malawi CRS
  • Soweto IMPAACT CRS
  • Shandukani Research CRS
  • Durban Paediatric HIV CRS
  • Umlazi CRS
  • Family Clinical Research Unit (FAM-CRU) CRS
  • Kilimanjaro Christian Medical Centre (KCMC)
  • MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
  • George CRS
  • Seke North CRS
  • St Mary's CRS
  • Harare Family Care CRS

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Active Comparator

Experimental

Experimental

Other

Experimental

Experimental

Experimental

Active Comparator

Arm Label

Antepartum Arm A

Antepartum Arm B

Antepartum Arm C

Late Presenters

Postpartum Arm A (Maternal Prophylaxis)

Postpartum Arm B (Infant Prophylaxis)

Maternal Health Arm A (Continue triple ARVs)

Maternal Health Arm B (Discontinue triple ARVs)

Arm Description

Mothers received ZDV + sdNVP + TRV Tail

Mothers received Triple ARV (3TC-ZDV + LPV-RTV)

Mothers received Triple ARV (TRV + LPV-RTV)

Registration to facilitate a structure to screen women and infants for randomization in the Postpartum Component.

Mothers received prophylaxis [preferred regimen: TRV + LPV-RTV]. Infants received short-course NVP.

Infants received extended NVP.

Mothers continued receiving triple ARV regimen [preferred regimen: TRV + LPV-RTV].

Mothers discontinued triple ARV regimen.

Outcomes

Primary Outcome Measures

Antepartum Component: Number of Confirmed Infant HIV Infections
Defined as HIV nucleic acid test (NAT) positivity of the specimen drawn at either the birth (Day 0-5) or Week 1 (Day 6-14) visit, confirmed by HIV NAT positivity of a second specimen collected at a different time point
Antepartum Component: Number of Mothers With Grade 3 or Higher Toxicities and Selected Grade 2 Hematologic, Renal, and Hepatic Adverse Events
These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
Antepartum Component: Number of Mothers With Obstetrical Complications
Complications included deaths, diagnoses, signs/symptoms, chemistry lab tests, or hematological lab tests, with grades of 3 (Severe) or worse. Obstetrical complications were those classified by the MedDra coding system as "Pregnancy, puerperium and perinatal conditions", except if the condition was the death of the fetus: "Abortions not specified as induced or spontaneous", "Abortions spontaneous", or "Stillbirth and foetal death."
Antepartum Component: Number of Mothers With Adverse Pregnancy Outcomes (e.g.,Stillbirth, Preterm Delivery (< 37 Weeks), Low Birth Weight (< 2,500 Grams), and Congenital Anomalies)
Composite outcome
Postpartum Component: Incidence of Confirmed Infant HIV Infection
Defined as infant HIV NAT positivity of a specimen drawn at any post-randomization visit (i.e., any visit after the Week 1 [Day 6-14] visit), confirmed by HIV NAT positivity of a second specimen drawn at a different time point. Analyses were conducted at the Mother-Infant (M-I) pair level, hence the worst outcome for multiple births was counted as a single event.
Postpartum Component: Incidence of Grade 3 or Higher Adverse Events and Selected Grade 2 Hematologic, Renal, and Hepatic Adverse Events
These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
Maternal Health Component: Incidence of Progression to AIDS-defining Illness or Death
AIDS-defining illness refers to the WHO Clinical Stage 4 illnesses in Appendix IV of the protocol. These events were reviewed and confirmed by an Endpoint review group.

Secondary Outcome Measures

Antepartum Component: Number of Infant HIV Infections
Detected by HIV NAT positivity
Antepartum Component: Probability of Overall and HIV-free Infant Survival Until 104 Weeks of Age, by Antepartum Arm (in Conjunction With Infants in the Postpartum Component)
For overall survival, failure was defined to be death. For HIV-free survival, failure was defined to be either death or developing HIV. The probability of living, or living without HIV infection, at 104 weeks was calculated by Kaplan-Meier estimation of the survival function.
Antepartum Component: Maternal HIV RNA Less Than 400 Copies/mL at Delivery
Analysis used the principle of intent to treat.
Postpartum Component: Proportion of Mother-Infant Pairs With no Death or HIV Diagnosis Through 24 Months Post-delivery
Defined as infant HIV NAT positivity of a specimen drawn at any post-randomization visit, confirmed by HIV NAT positivity of a second specimen drawn at a different time point, or infant death. Analyses (Kaplan-Meier probabilities) were conducted at the Mother-Infant (M-I) pair level, hence the worst outcome for multiple births was counted as a single event.
Postpartum Component: Proportion of Infants Alive Through 12 and 24 Months Post-delivery
Analyses (Kaplan-Meier probabilities) conducted for all individual infants (rather than M-I pair)
Maternal Health Component: Incidence of Death
Number of women who died during the maternal health component; that is, who had been randomized to either continue or discontinue ART after risk of HIV vertical transmission through breastfeeding was over.
Maternal Health Component: Incidence of AIDS-defining Illness
"AIDS-defining illness" refers to the WHO Clinical Stage 4 illnesses listed in Appendix IV. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
Maternal Health Component: Incidence of HIV/AIDS-related Events
"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
Maternal Health Component: Incidence Rate of Cardiovascular or Other Metabolic Events
Cardiovascular or metabolic events of particular concern were included in this analysis. A Poisson model with time to first event as an offset and an over-dispersion parameter was used to estimate incidence rates. Metabolic events considered were diabetes mellitus, lipodystrophy, or dyslipidemia. Cardiovascular events considered were hypertension, congestive heart failure, stroke, Transient Ischemia Event (TIA), pulmonary embolism, myocardial infarction (whether acute symptomatic or silent), coronary artery disease, deep vein thrombosis, peripheral vascular disease, or symptomatic HIV-associated cardiomyopathy.
Maternal Health Component: Other Targeted Medical Conditions
Other (non-cardiologic) medical conditions of particular concern were included in this outcome. A Poisson model with time to first event as an offset and an over-dispersion parameter was used to estimate incidence rates. Events included were metabolic events, hepatic events, renal events, infections such as pulmonary tuberculosis, malaria, or other serious bacterial infections, and others.
Maternal Health Component: Incidence of HIV/AIDS-related Event or Death
"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
Maternal Health Component: Incidence of HIV/AIDS-related Event or World Health Organization (WHO) Clinical Stage 2 or 3 Events
"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
Maternal Health Component: Incidence Rate of Death or Any Condition of Particular Concern
Particular events were targeted as those of particular concern. This outcome considered all such events: death, events defining WHO stages II, III, or IV, targeted cardiovascular adverse events, other targeted adverse events, or cancers which were not AIDS-defining. A complete list can be found in Appendix IV of the Protocol. A Poisson model with time to first event as an offset and an over-dispersion parameter was used to estimate incidence rates.
Maternal Health Component: Incidence of Tuberculosis
Incidence of tuberculosis.
Maternal Health Component: Toxicity: Incidence of Grade 3 or Greater Laboratory Results or Signs and Symptoms and Selected Grade 2 Hematologic, Renal, and Hepatic Laboratory Results
The maternal safety endpoints summarized include grade 2, 3 or 4 hematologies (hemoglobin (Hb), White Blood Cells (WBC), Absolute Neutrophil Count (ANC), platelet count), chemistries (Alanine Aminotransferase (ALT or SGPT), serum creatinine), and grade 3 or 4 signs and symptoms that occurred post-randomization. These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
Maternal Health Component: Incidence Rate of Progression to AIDS-defining Illness, Death, or a Serious Non-AIDS Cardiovascular, Hepatic, or Renal Event
This outcome included AIDS-defining illnesses or cardiovascular, hepatic, or renal adverse events of particular concern which were evaluated as serious. Serious outcomes were both those defined as serious according to the International Conference on Harmonization (ICH) definition, or outcomes with grades equal to or worse than 3 ("Severe"). A Poisson model with time to first event as an offset and an over-dispersion parameter was used to estimate incidence rates. Cardiovascular events considered were hypertension, congestive heart failure, stroke, Transient Ischemia Event (TIA), pulmonary embolism, myocardial infarction (whether acute symptomatic or silent), coronary artery disease, deep vein thrombosis, peripheral vascular disease, or symptomatic HIV-associated cardiomyopathy. Hepatic events considered were cirrhosis and idiopathic sclerosing cholangitis. Renal events considered were renal insufficiency, acute or chronic.

Full Information

First Posted
February 1, 2010
Last Updated
February 9, 2022
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01061151
Brief Title
Evaluating Strategies to Reduce Mother-to-Child Transmission of HIV Infection in Resource-Limited Countries
Acronym
PROMISE
Official Title
Breastfeeding Version of the PROMISE Study (Promoting Maternal and Infant Survival Everywhere)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
March 1, 2011 (Actual)
Primary Completion Date
September 30, 2016 (Actual)
Study Completion Date
September 30, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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: What is the optimal intervention for the prevention of antepartum and intrapartum transmission of HIV? What is the optimal intervention for the prevention of postpartum transmission in breastfeeding (BF) infants? 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: 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. 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
Mother to Child Transmission, HIV Infection, HAART, Maternal Health, Breastfeeding, Perinatal transmission

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
InvestigatorOutcomes Assessor
Masking Description
The investigators and outcomes assessor did not receive by-arm tabulations while the study was ongoing.
Allocation
Randomized
Enrollment
3747 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Antepartum Arm A
Arm Type
Active Comparator
Arm Description
Mothers received ZDV + sdNVP + TRV Tail
Arm Title
Antepartum Arm B
Arm Type
Experimental
Arm Description
Mothers received Triple ARV (3TC-ZDV + LPV-RTV)
Arm Title
Antepartum Arm C
Arm Type
Experimental
Arm Description
Mothers received Triple ARV (TRV + LPV-RTV)
Arm Title
Late Presenters
Arm Type
Other
Arm Description
Registration to facilitate a structure to screen women and infants for randomization in the Postpartum Component.
Arm Title
Postpartum Arm A (Maternal Prophylaxis)
Arm Type
Experimental
Arm Description
Mothers received prophylaxis [preferred regimen: TRV + LPV-RTV]. Infants received short-course NVP.
Arm Title
Postpartum Arm B (Infant Prophylaxis)
Arm Type
Experimental
Arm Description
Infants received extended NVP.
Arm Title
Maternal Health Arm A (Continue triple ARVs)
Arm Type
Experimental
Arm Description
Mothers continued receiving triple ARV regimen [preferred regimen: TRV + LPV-RTV].
Arm Title
Maternal Health Arm B (Discontinue triple ARVs)
Arm Type
Active Comparator
Arm Description
Mothers discontinued triple ARV regimen.
Intervention Type
Drug
Intervention Name(s)
Zidovudine (ZDV)
Intervention Description
300 mg twice daily
Intervention Type
Drug
Intervention Name(s)
Nevirapine (NVP): Antepartum Mothers
Intervention Description
200 mg at onset of labor
Intervention Type
Drug
Intervention Name(s)
Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail
Intervention Description
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 Type
Drug
Intervention Name(s)
Lamivudine-Zidovudine (3TC-ZDV)
Intervention Description
150 mg/300 mg twice daily
Intervention Type
Drug
Intervention Name(s)
Lopinavir-ritonavir (LPV-RTV)
Intervention Description
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 Type
Drug
Intervention Name(s)
Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV])
Intervention Description
200 mg/300 mg
Intervention Type
Drug
Intervention Name(s)
Nevirapine (NVP): Infant short-course
Intervention Description
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 Type
Drug
Intervention Name(s)
Nevirapine (NVP): Infant extended
Intervention Description
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 Type
Other
Intervention Name(s)
No Intervention
Intervention Description
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 Type
Other
Intervention Name(s)
Discontinue triple ARVs
Intervention Description
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 Type
Other
Intervention Name(s)
Continue triple ARVs
Intervention Description
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).
Primary Outcome Measure Information:
Title
Antepartum Component: Number of Confirmed Infant HIV Infections
Description
Defined as HIV nucleic acid test (NAT) positivity of the specimen drawn at either the birth (Day 0-5) or Week 1 (Day 6-14) visit, confirmed by HIV NAT positivity of a second specimen collected at a different time point
Time Frame
Measured at birth or Week 1 study visit
Title
Antepartum Component: Number of Mothers With Grade 3 or Higher Toxicities and Selected Grade 2 Hematologic, Renal, and Hepatic Adverse Events
Description
These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
Time Frame
Measured through the Week 1 postpartum study visit
Title
Antepartum Component: Number of Mothers With Obstetrical Complications
Description
Complications included deaths, diagnoses, signs/symptoms, chemistry lab tests, or hematological lab tests, with grades of 3 (Severe) or worse. Obstetrical complications were those classified by the MedDra coding system as "Pregnancy, puerperium and perinatal conditions", except if the condition was the death of the fetus: "Abortions not specified as induced or spontaneous", "Abortions spontaneous", or "Stillbirth and foetal death."
Time Frame
Measured through the Week 1 postpartum study visit
Title
Antepartum Component: Number of Mothers With Adverse Pregnancy Outcomes (e.g.,Stillbirth, Preterm Delivery (< 37 Weeks), Low Birth Weight (< 2,500 Grams), and Congenital Anomalies)
Description
Composite outcome
Time Frame
Measured at birth
Title
Postpartum Component: Incidence of Confirmed Infant HIV Infection
Description
Defined as infant HIV NAT positivity of a specimen drawn at any post-randomization visit (i.e., any visit after the Week 1 [Day 6-14] visit), confirmed by HIV NAT positivity of a second specimen drawn at a different time point. Analyses were conducted at the Mother-Infant (M-I) pair level, hence the worst outcome for multiple births was counted as a single event.
Time Frame
Measured through site recommended duration of breastfeeding, complete cessation of breastfeeding or 18 months of age, whichever comes first
Title
Postpartum Component: Incidence of Grade 3 or Higher Adverse Events and Selected Grade 2 Hematologic, Renal, and Hepatic Adverse Events
Description
These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
Time Frame
Measured through site recommended duration of breastfeeding, complete cessation of breastfeeding or 18 months of age, whichever comes first
Title
Maternal Health Component: Incidence of Progression to AIDS-defining Illness or Death
Description
AIDS-defining illness refers to the WHO Clinical Stage 4 illnesses in Appendix IV of the protocol. These events were reviewed and confirmed by an Endpoint review group.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary Outcome Measure Information:
Title
Antepartum Component: Number of Infant HIV Infections
Description
Detected by HIV NAT positivity
Time Frame
Measured at the birth (<= 3 days postpartum) visit
Title
Antepartum Component: Probability of Overall and HIV-free Infant Survival Until 104 Weeks of Age, by Antepartum Arm (in Conjunction With Infants in the Postpartum Component)
Description
For overall survival, failure was defined to be death. For HIV-free survival, failure was defined to be either death or developing HIV. The probability of living, or living without HIV infection, at 104 weeks was calculated by Kaplan-Meier estimation of the survival function.
Time Frame
Measured from birth through 104 weeks of age
Title
Antepartum Component: Maternal HIV RNA Less Than 400 Copies/mL at Delivery
Description
Analysis used the principle of intent to treat.
Time Frame
Measured at the time of delivery
Title
Postpartum Component: Proportion of Mother-Infant Pairs With no Death or HIV Diagnosis Through 24 Months Post-delivery
Description
Defined as infant HIV NAT positivity of a specimen drawn at any post-randomization visit, confirmed by HIV NAT positivity of a second specimen drawn at a different time point, or infant death. Analyses (Kaplan-Meier probabilities) were conducted at the Mother-Infant (M-I) pair level, hence the worst outcome for multiple births was counted as a single event.
Time Frame
Measured through 24 months post-delivery
Title
Postpartum Component: Proportion of Infants Alive Through 12 and 24 Months Post-delivery
Description
Analyses (Kaplan-Meier probabilities) conducted for all individual infants (rather than M-I pair)
Time Frame
Measured at 12 and 24 months post-delivery
Title
Maternal Health Component: Incidence of Death
Description
Number of women who died during the maternal health component; that is, who had been randomized to either continue or discontinue ART after risk of HIV vertical transmission through breastfeeding was over.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Incidence of AIDS-defining Illness
Description
"AIDS-defining illness" refers to the WHO Clinical Stage 4 illnesses listed in Appendix IV. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Incidence of HIV/AIDS-related Events
Description
"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Incidence Rate of Cardiovascular or Other Metabolic Events
Description
Cardiovascular or metabolic events of particular concern were included in this analysis. A Poisson model with time to first event as an offset and an over-dispersion parameter was used to estimate incidence rates. Metabolic events considered were diabetes mellitus, lipodystrophy, or dyslipidemia. Cardiovascular events considered were hypertension, congestive heart failure, stroke, Transient Ischemia Event (TIA), pulmonary embolism, myocardial infarction (whether acute symptomatic or silent), coronary artery disease, deep vein thrombosis, peripheral vascular disease, or symptomatic HIV-associated cardiomyopathy.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Other Targeted Medical Conditions
Description
Other (non-cardiologic) medical conditions of particular concern were included in this outcome. A Poisson model with time to first event as an offset and an over-dispersion parameter was used to estimate incidence rates. Events included were metabolic events, hepatic events, renal events, infections such as pulmonary tuberculosis, malaria, or other serious bacterial infections, and others.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Incidence of HIV/AIDS-related Event or Death
Description
"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Incidence of HIV/AIDS-related Event or World Health Organization (WHO) Clinical Stage 2 or 3 Events
Description
"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Incidence Rate of Death or Any Condition of Particular Concern
Description
Particular events were targeted as those of particular concern. This outcome considered all such events: death, events defining WHO stages II, III, or IV, targeted cardiovascular adverse events, other targeted adverse events, or cancers which were not AIDS-defining. A complete list can be found in Appendix IV of the Protocol. A Poisson model with time to first event as an offset and an over-dispersion parameter was used to estimate incidence rates.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Incidence of Tuberculosis
Description
Incidence of tuberculosis.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Toxicity: Incidence of Grade 3 or Greater Laboratory Results or Signs and Symptoms and Selected Grade 2 Hematologic, Renal, and Hepatic Laboratory Results
Description
The maternal safety endpoints summarized include grade 2, 3 or 4 hematologies (hemoglobin (Hb), White Blood Cells (WBC), Absolute Neutrophil Count (ANC), platelet count), chemistries (Alanine Aminotransferase (ALT or SGPT), serum creatinine), and grade 3 or 4 signs and symptoms that occurred post-randomization. These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Title
Maternal Health Component: Incidence Rate of Progression to AIDS-defining Illness, Death, or a Serious Non-AIDS Cardiovascular, Hepatic, or Renal Event
Description
This outcome included AIDS-defining illnesses or cardiovascular, hepatic, or renal adverse events of particular concern which were evaluated as serious. Serious outcomes were both those defined as serious according to the International Conference on Harmonization (ICH) definition, or outcomes with grades equal to or worse than 3 ("Severe"). A Poisson model with time to first event as an offset and an over-dispersion parameter was used to estimate incidence rates. Cardiovascular events considered were hypertension, congestive heart failure, stroke, Transient Ischemia Event (TIA), pulmonary embolism, myocardial infarction (whether acute symptomatic or silent), coronary artery disease, deep vein thrombosis, peripheral vascular disease, or symptomatic HIV-associated cardiomyopathy. Hepatic events considered were cirrhosis and idiopathic sclerosing cholangitis. Renal events considered were renal insufficiency, acute or chronic.
Time Frame
From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Other Pre-specified Outcome Measures:
Title
Maternal Health Component: Cost-effectiveness
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since cost-effectiveness was not a focus of the study.
Time Frame
From study entry until July 7, 2015.
Title
Maternal Health Component: Changes in Plasma Concentrations of Inflammatory and Thrombogenic Markers
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since inflammation and thrombogenic markers were not a focus of the study.
Time Frame
From study entry until July 7, 2015.
Title
Maternal Health Component: Quality of Life
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since quality of life was not a focus of the study.
Time Frame
From study entry until July 7, 2015.
Title
Maternal Health Component: Self-reported Adherence
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since adherence was not a focus of the study.
Time Frame
From study entry until July 7, 2015.
Title
Maternal Health Component: Viral Resistance
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since viral resistance was not a focus of the study.
Time Frame
From study entry until July 7, 2015.
Title
Postpartum Component: Functional Maternal Antibody and HIV-envelope Binding Responses in Breast Milk and Plasma, Until Cessation of Breastfeeding or 18 Months Postpartum, Whichever Comes First
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since functional maternal antibody and HIV-envelope binding responses were not a focus of the study.
Time Frame
Measured through the time of cessation of breastfeeding or 18 months postpartum, whichever comes first
Title
Postpartum Component: Pharmacokinetic Parameters of ARV Drugs Measured in Maternal Plasma, Hair, Breast Milk, and Infant Blood (Plasma or Dried Blood Spot) Samples Collected at Birth; Weeks 1, 6, 14, and 26; and Subsequent Visits During Breastfeeding
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since pharmacokinetics was not a focus of the study.
Time Frame
Measured through the last study visit during breastfeeding, or 18 months postpartum, whichever comes first
Title
Postpartum Component: Cost-effectiveness and Feasibility of the Study ARV Prophylaxis Regimens
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since cost-effectiveness was not a focus of the study.
Time Frame
Measured at the end of the 5-year study period
Title
Postpartum Component: Rates and Patterns of Maternal and Infant Resistance to the Maternal and Infant ARV Regimens
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since viral resistance was not a focus of the study.
Time Frame
Measured at the end of the 5-year study period
Title
Postpartum Component: Adherence to the Maternal and/or Infant ARV Regimens, as Measured by Maternal Report and Hair Measures
Description
Adherence is by maternal report; adherence through hair analysis is not included here. The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome since adherence was not a focus of the study.
Time Frame
Week 6 visit (14 days - 9 weeks postpartum); Week 14 visit (10-19 weeks postpartum); Week 26 visit (20 to 31 weeks postpartum); Week 50 visit (44 to 55 weeks postpartum); and Week 74 visit (68 to 80 weeks postpartum).
Title
Antepartum Component: Antepartum Change in HBV DNA Viral Load Between Week 8 and Baseline Levels (Using Log HBV DNA) Among Women With Detectable HBV DNA Viral Loads at Baseline and Other HBV Outcome Measures
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome measure since changes in HBV DNA Viral Load was not a focus of the study.
Time Frame
Measured at Week 8
Title
Antepartum Component: Cost Effectiveness and Feasibility of the Trial ARV Regimens
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome measure since cost effectiveness was not a focus of the study.
Time Frame
Measured at the end of the 5-year study period
Title
Antepartum Component: Maternal and Infant Viral Resistance to the Maternal and Infant ARV Strategies
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome measure since viral resistance was not a focus of the study.
Time Frame
Measured at the end of the 5-year study period
Title
Antepartum Component: Adherence to the Maternal Antiretroviral (ARV) Regimen, as Measured by Maternal Report
Description
The protocol did not distinguish between outcomes essential to the primary publication and outcomes for subsequent publications of lesser priority. This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome measure since adherence was not a focus of the study.
Time Frame
Measured through the Week 1 postpartum study visit

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
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: Hemoglobin greater than or equal to 7.5 g/dL White blood cell count (WBC) greater than or equal to 1,500 cells/mm^3 Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3 Platelets greater than or equal to 50,000 cells/mm^3 Alanine aminotransferase (ALT) less than or equal to 2.5 times the upper limit of normal (ULN) 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: Hemoglobin greater than or equal to 7.0 g/dL WBC greater than or equal to 1,500 cells/mm^3 ANC greater than or equal to 750 cells/mm^3 Platelets greater than or equal to 50,000 cells/mm^3 ALT less than or equal to 2.5 times the upper limit of normal (ULN) 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): Hemoglobin greater than or equal to 10 g/dL WBC greater than or equal to 1,500 cells/mm^3 ANC greater than or equal to 750 cells/mm^3 Platelets greater than or equal to 50,000 cells/mm^3 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: ANC greater than or equal to 750 cells/mm^3 Hemoglobin greater than or equal to 7.0 gm/dL Platelet count greater than or equal to 50,000 cells/mm^3 ALT (SGPT) less than or equal to 2.5 times the ULN 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mary Glenn Fowler, MD, MPH
Organizational Affiliation
Johns Hopkins Medical Institute, Makerere U.-JHU Research Collaboration
Official's Role
Study Chair
Facility Information:
Facility Name
Byramjee Jeejeebhoy Medical College (BJMC) CRS
City
Pune
State/Province
Maharashtra
ZIP/Postal Code
411001
Country
India
Facility Name
Blantyre CRS
City
Blantyre
Country
Malawi
Facility Name
Malawi CRS
City
Lilongwe
Country
Malawi
Facility Name
Soweto IMPAACT CRS
City
Johannesburg
State/Province
Gauteng
ZIP/Postal Code
1862
Country
South Africa
Facility Name
Shandukani Research CRS
City
Johannesburg
State/Province
Gauteng
ZIP/Postal Code
2001
Country
South Africa
Facility Name
Durban Paediatric HIV CRS
City
Durban
State/Province
KwaZulu-Natal
ZIP/Postal Code
4001
Country
South Africa
Facility Name
Umlazi CRS
City
Durban
State/Province
KwaZulu-Natal
ZIP/Postal Code
4001
Country
South Africa
Facility Name
Family Clinical Research Unit (FAM-CRU) CRS
City
Cape Town
State/Province
Western Cape
ZIP/Postal Code
7505
Country
South Africa
Facility Name
Kilimanjaro Christian Medical Centre (KCMC)
City
Moshi
Country
Tanzania
Facility Name
MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
City
Kampala
Country
Uganda
Facility Name
George CRS
City
Lusaka
Country
Zambia
Facility Name
Seke North CRS
City
Chitungwiza
Country
Zimbabwe
Facility Name
St Mary's CRS
City
Chitungwiza
Country
Zimbabwe
Facility Name
Harare Family Care CRS
City
Harare
Country
Zimbabwe

12. IPD Sharing Statement

Citations:
PubMed Identifier
20054287
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Citation
WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-related Disease in Adults and Children, World Health Organization, 2007. Available: http://apps.who.int/iris/handle/10665/43699
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Stranix-Chibanda L, Tierney C, Pinilla M, George K, Aizire J, Chipoka G, Mallewa M, Naidoo M, Nematadzira T, Kusakara B, Violari A, Mbengeranwa T, Njau B, Fairlie L, Theron G, Mubiana-Mbewe M, Khadse S, Browning R, Fowler MG, Siberry GK; PROMISE Study Team. Effect on growth of exposure to maternal antiretroviral therapy in breastmilk versus extended infant nevirapine prophylaxis among HIV-exposed perinatally uninfected infants in the PROMISE randomized trial. PLoS One. 2021 Aug 20;16(8):e0255250. doi: 10.1371/journal.pone.0255250. eCollection 2021.
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Theron G, Brummel S, Fairlie L, Pinilla M, McCarthy K, Owor M, Chinula L, Makanani B, Violari A, Moodley D, Chakhtoura N, Browning R, Hoffman R, Fowler MG. Pregnancy Outcomes of Women Conceiving on Antiretroviral Therapy (ART) Compared to Those Commenced on ART During Pregnancy. Clin Infect Dis. 2021 Jul 15;73(2):e312-e320. doi: 10.1093/cid/ciaa805.
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Aizire J, Sikorskii A, Ogwang LW, Kawalazira R, Mutebe A, Familiar-Lopez I, Mallewa M, Taha T, Boivin MJ, Fowler MG; PROMISE-NEURODEV study team. Decreased growth among antiretroviral drug and HIV-exposed uninfected versus unexposed children in Malawi and Uganda. AIDS. 2020 Feb 1;34(2):215-225. doi: 10.1097/QAD.0000000000002405.
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Links:
URL
http://www.impaactnetwork.org/studies/1077BF.asp
Description
IMPAACT Study 1077BF
URL
https://www.meddra.org/
Description
MedDra coding of complications

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

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