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

HIV Infections Clinical Trial

— PROMISE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01061151
• Other study ID #: 1077BF (PROMISE)
• Secondary ID: 10777IMPAACT 107
• Status: Completed
• Phase: Phase 3
• Start date: March 1, 2011
• Est. completion date: September 30, 2016

Study information

• Verified date: February 2022
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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

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

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

• Participants were randomly assigned to one of the following three arms:

• Maternal Regimens:

• Arm A : 1) Zidovudine (ZDV) from study entry through delivery, 2) single dose nevirapine (sdNVP) and emtricitabine-tenofovir disoproxil (TRV ) intrapartum, and 3) TRV postpartum for up to 14 days post-partum. Arm A is also labeled as ZDV+sdNVP+TRV tail.

• Arm B: Lamivudine (3TC)-zidovudine (ZDV) + lopinavir (LPV)-ritonavir (RTV) from study entry up to 14 days postpartum. Arm B is also labeled as 3TC-ZDV/LPV-RTV.

• Arm C: TRV/LPV-RTV from study entry up to 14 days postpartum. Arm C is also labeled as FTC-TDF/LPV-RTV.

• All infants born to women enrolled in this study were to receive NVP once a day as soon as possible after birth through 42 days of age or until the Week 6 study visit, whichever was later. Women switched or initiated HAART if it was needed for their own health.

• During pregnancy, participants attended study visits at study entry, 2 and 4 weeks after entry, and then every 4 weeks until labor and delivery. Women and infants were monitored during labor and delivery and attended a study visit 6 to 14 days after delivery. After delivery, eligibility criteria were assessed for subsequent randomizations (either Postpartum or Maternal Health). If they failed the entry criteria for the subsequent randomization, the mothers remained in follow-up for safety assessments and the infants were followed until the 104 week visit; otherwise they were followed under the subsequent component.

• All three antepartum arms were not available to all women throughout the PROMISE study. When the trial began, there were limited safety data on tenofovir in pregnancy, and randomization to tenofovir-based ART was limited to women coinfected with HIV and HBV, because benefit was felt to outweigh risk in that group. During period 1 (PROMISE protocol version 2.0 - April 2011 through September 2012), women without HBV coinfection were randomized to either Arm A or Arm B; and Hepatitis B (HBV) co-infected women were randomized to either Arm A, Arm B, or Arm C. However, in October 2012, with increased data on tenofovir in pregnancy, the protocol was modified to allow women regardless of HBV status to be assigned to any of the three regimens during period 2 (PROMISE protocol version 3.0 - October 2012 through the end of antepartum enrollment on October 1, 2014). By arm comparisons were restricted to times in which there were contemporaneous randomizations.

• Late Presenters: In addition the Antepartum Component, participants could enter PROMISE through the Late Presenters Registration (LP). Late presenters were identified in early or active labor or in the immediate postpartum period (up to 5 days postpartum). The Late Presenters Registration facilitated a structure to screen women and infants for randomization in the Postpartum Component. Women and infants not randomized in the Postpartum Component of PROMISE were followed through the Week 6 visit.

• There were 3543 mothers and 3407 live born infants enrolled in the Antepartum Component. There were 204 mothers and 204 live born infants in the Late Presenters Registration.

2. Postpartum Component: This PROMISE component compared the safety and efficacy of maternal triple ARV prophylaxis versus daily infant NVP prophylaxis for the prevention of mother-to-child transmission (PMTCT) through breastfeeding. The Postpartum Component consisted of mothers and infants from the Antepartum Component and the Late Presenters Registration who passed the Postpartum Component entry criteria.

• Participants were randomly assigned to one of two arms:

• Arm A: Women received LPV-RTV plus TRV from the Week 1 postpartum visit through the end of maternal follow-up (2 to 5 years). Infants received NVP once a day through 42 days of age or until the Week 6 study visit, whichever was later.

• Arm B: Infants received NVP once a day from the Week 1 postpartum visit until the end of risk for MTCT or until 18 months postpartum (104 weeks). Women did not receive antiretroviral drugs for MTCT prophylaxis.

• The maternal study visits were at entry, at postpartum weeks 6, 14, 26, and every 12 weeks thereafter. Infant study visits were at entry, every 4 weeks between postpartum weeks 6-26, every 12 weeks between postpartum week 38-98, and at postpartum week 104. At the end of risk for MTCT or 18 months postpartum, the mothers' eligibility criteria were assessed for a subsequent randomization in the Maternal Health Component. If they did not meet entry criteria for the Maternal Health randomization, they remained in follow-up for safety assessments; otherwise they were followed under the Maternal Health Component. Infants were followed until the 104 week visit.

• Women switched or initiated HAART if it was needed for their own health. If a woman in Arm B initiated HAART then her infant discontinued NVP after 12 weeks of HAART or after her viral load was suppressed, whichever came first.

• There were 2431 mothers and 2444 infants randomized as part of the Postpartum Component.

3. Maternal Health Component: This PROMISE component randomized women to continue or discontinue HAART after the end of risk for MTCT, either after delivery or after breastfeeding. Participants included women who were receiving the triple ARV regimen in the Postpartum Component; or receiving the triple ARV regimen in the Antepartum Component and were ineligible for the Postpartum Component.

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

• Arm A: Participants continued to receive the triple ARV regimen (preferred regimen was LPV-RTV plus TRV).

• Arm B: Participants discontinued the triple ARV regimen.

• Study visits occurred at Weeks 4 and 12 and then every 3 months thereafter. Study visits included a medical history review, questionnaires, physical exam, and blood collection. Women switched or initiated a triple ARV regimen if it was needed for their own health.

• There were 875 mothers randomized as part of the Maternal Health Component.

• The analyses for the Maternal Health Component we not solely based on the Maternal Health Randomization. Instead there were four prespecified comparison groups for the Maternal Health Component. The four comparison groups used the three randomizations as appropriate to answer the following questions:

• Question 1: What is the effect on women of using a maternal triple ARV regimen to prevent MTCT during pregnancy, relative to using ZDV + sdNVP + TRV tail to prevent MTCT during pregnancy?

• Question 2: What is the effect on women of using a maternal triple ARV regimen to prevent MTCT during breastfeeding, relative to using infant NVP to prevent MTCT during breastfeeding?

• Question 3: What is the effect on women of extending versus discontinuing the antepartum/intrapartum maternal triple ARV regimen at the time of birth?

• Question 4: What is the effect on women of extending versus discontinuing the postpartum maternal triple ARV regimen after the cessation of risk for MTCT during breastfeeding?

• There were 1602 mothers included in the analyses for Question 2.

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

Other known NCT identifiers

• NCT01253538

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3747
• Est. completion date: September 30, 2016
• Est. primary completion date: September 30, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Infections

Intervention

Drug:
• Zidovudine (ZDV)
300 mg twice daily
• Nevirapine (NVP): Antepartum Mothers
200 mg at onset of labor
• Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail
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.
• Lamivudine-Zidovudine (3TC-ZDV)
150 mg/300 mg twice daily
• Lopinavir-ritonavir (LPV-RTV)
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.
• Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV])
200 mg/300 mg
• Nevirapine (NVP): Infant short-course
Oral suspension (dosing according to birth weight) once a day through 42 days of age or through the week 6 visit, whichever is later.
• Nevirapine (NVP): Infant extended
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.

Other:
• No Intervention
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.
• Discontinue triple ARVs
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).
• Continue triple ARVs
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).

Locations

Country	Name	City	State
India	Byramjee Jeejeebhoy Medical College (BJMC) CRS	Pune	Maharashtra
Malawi	Blantyre CRS	Blantyre
Malawi	Malawi CRS	Lilongwe
South Africa	Family Clinical Research Unit (FAM-CRU) CRS	Cape Town	Western Cape
South Africa	Durban Paediatric HIV CRS	Durban	KwaZulu-Natal
South Africa	Umlazi CRS	Durban	KwaZulu-Natal
South Africa	Shandukani Research CRS	Johannesburg	Gauteng
South Africa	Soweto IMPAACT CRS	Johannesburg	Gauteng
Tanzania	Kilimanjaro Christian Medical Centre (KCMC)	Moshi
Uganda	MU-JHU Research Collaboration (MUJHU CARE LTD) CRS	Kampala
Zambia	George CRS	Lusaka
Zimbabwe	Seke North CRS	Chitungwiza
Zimbabwe	St Mary's CRS	Chitungwiza
Zimbabwe	Harare Family Care CRS	Harare

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

India,  Malawi,  South Africa,  Tanzania,  Uganda,  Zambia,  Zimbabwe, 

References & Publications (4)

Becquet R, Ekouevi DK, Arrive E, Stringer JS, Meda N, Chaix ML, Treluyer JM, Leroy V, Rouzioux C, Blanche S, Dabis F. Universal antiretroviral therapy for pregnant and breast-feeding HIV-1-infected women: towards the elimination of mother-to-child transmission of HIV-1 in resource-limited settings. Clin Infect Dis. 2009 Dec 15;49(12):1936-45. doi: 10.1086/648446. Review. — View Citation

Taha T, Nour S, Li Q, Kumwenda N, Kafulafula G, Nkhoma C, Broadhead R. The effect of human immunodeficiency virus and breastfeeding on the nutritional status of African children. Pediatr Infect Dis J. 2010 Jun;29(6):514-8. doi: 10.1097/INF.0b013e3181cda531. — View Citation

U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0. [Upda

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Maternal Health Component: Cost-effectiveness	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.	From study entry until July 7, 2015.
Other	Maternal Health Component: Changes in Plasma Concentrations of Inflammatory and Thrombogenic Markers	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.	From study entry until July 7, 2015.
Other	Maternal Health Component: Quality of Life	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.	From study entry until July 7, 2015.
Other	Maternal Health Component: Self-reported Adherence	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.	From study entry until July 7, 2015.
Other	Maternal Health Component: Viral Resistance	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.	From study entry until July 7, 2015.
Other	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	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.	Measured through the time of cessation of breastfeeding or 18 months postpartum, whichever comes first
Other	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	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.	Measured through the last study visit during breastfeeding, or 18 months postpartum, whichever comes first
Other	Postpartum Component: Cost-effectiveness and Feasibility of the Study ARV Prophylaxis Regimens	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.	Measured at the end of the 5-year study period
Other	Postpartum Component: Rates and Patterns of Maternal and Infant Resistance to the Maternal and Infant ARV Regimens	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.	Measured at the end of the 5-year study period
Other	Postpartum Component: Adherence to the Maternal and/or Infant ARV Regimens, as Measured by Maternal Report and Hair Measures	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.	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).
Other	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	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.	Measured at Week 8
Other	Antepartum Component: Cost Effectiveness and Feasibility of the Trial ARV Regimens	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.	Measured at the end of the 5-year study period
Other	Antepartum Component: Maternal and Infant Viral Resistance to the Maternal and Infant ARV Strategies	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.	Measured at the end of the 5-year study period
Other	Antepartum Component: Adherence to the Maternal Antiretroviral (ARV) Regimen, as Measured by Maternal Report	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.	Measured through the Week 1 postpartum study visit
Primary	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	Measured at birth or Week 1 study visit
Primary	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).	Measured through the Week 1 postpartum study visit
Primary	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."	Measured through the Week 1 postpartum study visit
Primary	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	Measured at birth
Primary	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.	Measured through site recommended duration of breastfeeding, complete cessation of breastfeeding or 18 months of age, whichever comes first
Primary	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).	Measured through site recommended duration of breastfeeding, complete cessation of breastfeeding or 18 months of age, whichever comes first
Primary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	Antepartum Component: Number of Infant HIV Infections	Detected by HIV NAT positivity	Measured at the birth (<= 3 days postpartum) visit
Secondary	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.	Measured from birth through 104 weeks of age
Secondary	Antepartum Component: Maternal HIV RNA Less Than 400 Copies/mL at Delivery	Analysis used the principle of intent to treat.	Measured at the time of delivery
Secondary	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.	Measured through 24 months post-delivery
Secondary	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)	Measured at 12 and 24 months post-delivery
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	Maternal Health Component: Incidence of Tuberculosis	Incidence of tuberculosis.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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).	From study entry until July 7, 2015, an average of 94 weeks of follow-up.
Secondary	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.	From study entry until July 7, 2015, an average of 94 weeks of follow-up.

External Links

•   IMPAACT Study 1077BF
•   MedDra coding of complications