Evaluating Strategies to Reduce Mother-to-Child Transmission of HIV Infection in Resource-Limited Countries
Condition: HIV Infections
MeSH terms: Infections; HIV Infections; Acquired Immunodeficiency Syndrome
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
Intervention description: 300 mg twice daily; 200 mg at onset of labor; 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.; 150 mg/300 mg twice daily; 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.; 200 mg/300 mg; Oral suspension (dosing according to birth weight) once a day through 42 days of age or through the week 6 visit, whichever is later.; 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.; 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.; 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).; 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 MeSH terms: Ritonavir; Lopinavir; Tenofovir; Lamivudine; Emtricitabine; Zidovudine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Nevirapine; Lamivudine, zidovudine drug combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Masking description: The investigators and outcomes assessor did not receive by-arm tabulations while the study was ongoing.
Enrollment: 3747.0
Sex: All
Healthy volunteers: No
Keywords: Mother to Child Transmission; HIV Infection; HAART; Maternal Health; Breastfeeding; Perinatal transmission

Summary:

      The purpose of this study was to examine, in an integrated and comprehensive fashion, three
      critical questions currently facing HIV-infected pregnant and postpartum women and their
      infants:

        1. What is the optimal intervention for the prevention of antepartum and intrapartum
           transmission of HIV?

        2. What is the optimal intervention for the prevention of postpartum transmission in
           breastfeeding (BF) infants?

        3. What is the optimal intervention for the preservation of maternal health after the risk
           period for prevention of mother-to-child-transmission ends (either at delivery or
           cessation of BF)?

      The overall PROMISE protocol had three separate interventional components to address each of
      these three questions and was conducted at locations in Africa and other parts of the world.
      Due to variations in the standard of care for HIV-infected pregnant and postpartum women and
      their infants at different sites, not all of these questions were relevant. Therefore, two
      separate versions of the PROMISE protocol were developed, each containing only the relevant
      components. The 1077BF protocol was used at sites where the standard method of infant feeding
      was breastfeeding, whereas the 1077FF protocol was used at sites where the standard method of
      infant feeding was formula feeding. The analyses were collapsed across the two protocol
      versions, and therefore the summaries contain the results of the 1077BF and/or the 1077FF
      protocols.
    

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:

               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