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Background The PROMOTE study aims to measure long-term antiretroviral treatment (ART) safety and adherence; compare HIV disease progression; assess subsequent adverse pregnancy outcomes; evaluate effect of ART exposure on growth and development in HIV-exposed uninfected children; and assess long-term survival of mothers and children. This report primarily describes cohort characteristics at baseline to better understand long-term outcomes. Methods and findings This is a prospective study. HIV-infected mothers and their children originally recruited in a multisite randomized clinical trial for prevention of perinatal HIV transmission were re-enrolled in PROMOTE. A total of 1987 mothers and 1784 children were enrolled from eight sites in Uganda, Malawi, Zimbabwe and South Africa. Most women (75%) reported being married in Malawi and Zimbabwe compared to low proportions in South Africa (4.4% in Durban and 15% in Soweto), and 43.5% in Uganda (p<0.001). There were variabilities in contraceptive practices: injectable contraceptive was the commonest reported method (40.9% overall); implant was the second commonest (15.7% overall); oral contraceptives were common in Zimbabwe; and tubal ligation was common in Malawi and South Africa. At baseline, 97.8% of women reported currently using ART; 96.4% were in WHO clinical class 1 or 2; median CD4 cell count was 825 cells per uL; and viral load was undetectable in 1637 (~85%) of the women. Approximately, 14% of women did not inform their primary partners of their own HIV status, 18% reported that they knew their partners were not HIV tested, and 9% did not know if partner was tested. Overall mean age of children at enrollment was 3.5 years; and 5.7% and 25.0% had weight-for-age and height-for-age z-scores <2 standard deviations, respectively. Conclusions These baseline data show high adherence to ART use. However, issues of HIV disclosure and reproductive intentions remain important. In addition to ART and ensuring high adherence, other preventive measures should be included.
The PROMOTE study is an observational study to prospectively follow mothers and children who were originally recruited in the multi-country PROMISE randomized trial [1]. The PROMOTE enrollment started in December 2016—after termination and close-out of the PROMISE trial in 2015 (Fig 1). PROMOTE enrollment was completed in June 2017 and follow-up is planned to continue up to 2021. The PROMOTE study is conducted at eight research sites in four African countries: Makerere University Johns Hopkins University (MUJHU)/Kampala (Uganda), Blantyre and Lilongwe (Malawi), Harare, Seke North and St. Mary’s (Zimbabwe), Perinatal Health Research Unit (PHRU)/Johannesburg and uMlazi/Durban (South Africa). Fig 1 shows the study cohorts and the timing of their enrollment: 1) HIV-infected women who previously enrolled in the PROMISE trial from the eight African sites are enrolled and followed in the PROMOTE study; 2) The first born infants in PROMISE are enrolled in PROMOTE and followed with their mothers; 3) All children born during the PROMOTE follow-up as a result of a subsequent (repeat) pregnancy are enrolled and followed with their mothers. In addition to these distinct three cohorts, a small group of infants were born after closure of the PROMISE study and prior to start of the PROMOTE study. These “Gap” children were not formally enrolled; however, mothers were interviewed at PROMOTE baseline about the date of birth and survival status of these children. Women and children enrolled in the PROMISE trial (and children born subsequently in PROMOTE) from one of eight African sites in Uganda, Malawi, Zimbabwe and South Africa; mothers willing to provide informed consent to enroll and continue follow-up in the PROMOTE study for herself and for her children); lives within the study catchment area; and has no plans to move during the study period. If a mother died, a caregiver can sign the informed consent to continue follow-up of the child who enrolled originally in PROMISE. If the child died, the mother can consent to be followed without her child. Mother not able or willing to provide informed consent to continue follow-up in the PROMOTE study; plans to relocate permanently out of the catchment area during the cohort study period; judged by the site team and protocol chairs as having social or other reasons which would make it difficult for the mother/child pair to comply with study requirements. HIV-infected women previously enrolled in the PROMISE study were enrolled after appropriate counseling and consenting in the PROMOTE study. New study visits, schedule of evaluations, procedures, and study forms were implemented. The maternal screening and enrollment evaluations included: eligibility evaluations (e.g., obtaining written informed consent to participate in follow-up and collection of study samples), administration of sociodemographic questionnaires, medical history, physical examinations (e.g., WHO clinical staging and comorbid conditions such as TB), and provision of ART adherence counseling. ART is supplied per national guidelines as the prevailing standard of care in each country (efavirenz [EFV]-based regimen in Malawi, Zimbabwe and South Africa, and protease inhibitor [PI]-based regimen in Uganda). Enrollment laboratory evaluations included: complete blood count (CBC) with differential, CD4+ cell count, viral load, and serum chemistries (alanine aminotransferase, creatinine and creatinine clearance). Additional procedures included dual-energy X-ray absorptiometry (DXA scan), and storage of samples (blood samples for resistance testing and hair for cumulative drug levels). The maternal follow-up evaluations are conducted every six months and include: medical history, physical examination, adherence questionnaire (and counseling), and child neurodevelopmental questionnaire (every 12 months). Participants are allowed to attend interim visits for health conditions or issues pertaining to ART. Women who miss their scheduled visit during a certain window period or with abnormal laboratory results (e.g., high viral load) are actively followed at the location they provided and advised to return to the clinic for follow-up. Transportation costs are provided for follow-up visits. Data are collected at scheduled and interim visits as appropriate. The laboratory follow-up procedures were similar to the enrollment procedures. Women who enrolled in PROMOTE and subsequently had a repeat pregnancy followed a specific initial schedule that included pregnancy registration, confirmation of pregnancy, medical history and physical examination, and laboratory tests which included hepatitis B surface antigen test. Antenatal (monthly) and delivery evaluations and laboratory tests were also conducted similar to enrollment visits. At all scheduled and unscheduled visits evaluation of adverse events and classification was based on the DAIDS toxicity table (Version 2 [9]). Two cohorts of children are part of the PROMOTE study: those born during the PROMISE trial and those born subsequently during the PROMOTE study. The enrollment evaluations for Children born in the PROMISE trial included eligibility evaluations, clinical evaluations (medical history, physical examination [including neurological], documentation of the child’s HIV status, survival status and anthropometric measures). The enrollment evaluations also included laboratory tests (CBC with differential, HIV status), DXA scan, developmental testing, and Disability/ Child Behavior questionnaires. Follow-up evaluations for first born PROMISE and repeat pregnancy children included clinical and laboratory evaluations every 6 months. The PROMOTE study is managed by a Coordinating Center at the Johns Hopkins University in Baltimore, Maryland, and data management and statistical support is provided by a Data Management Center (DMC) at the Centre for the AIDS Programme of Research in South Africa (CAPRISA) in Durban, South Africa. PROMOTE study data are completed on designated case report forms (CRFs) by trained study workers. At the outset, research teams at all sites received training on the protocol, manual of operations, and quality control (QC)/quality assurance (QA) procedures. Regular monitoring of the study is provided by two designated scientists. Data QC/QA is conducted at the clinical sites, data are entered locally, and securely transferred to the DMC in South Africa. The DMC monitors site data entry of CRFs, data completion and provides refresher training whenever needed. A unique data sharing feature of the PROMOTE study is use of the same participant identification as in the PROMISE randomized clinical trial to allow data access from time of birth of the first child in PROMISE providing a follow-up opportunity of approximately 11 years for mothers and children from time of enrollment in PROMISE to completion of PROMOTE (this plan has been approved and included in the consent form). For the baseline data included in this report, we present descriptive and stratified analyses by research site and country. Current analyses are restricted to summaries of enrolled cohorts of women and children, and description of factors related to socioeconomic, reproductive, ART, and adverse events at the time of enrollment (baseline). Even though site specific data will be presented, data for few selected variables (marital status, socioeconomic status indicated by availability of water and electricity, travel time to the clinic, HIV status disclosure and CD4 cell count) were included by country for statistical testing purposes. Fisher-Freeman-Halton test and Kruskal-Wallis test were used to determine if there was an association between countries and few selected categorical and continuous variables, respectively. The PROMOTE study was approved by all relevant institutional review boards (IRBs) in the U.S. and collaborating African research sites/countries. These are: MUJHU/Kampala, Uganda: The Joint Clinical Research Centre (JCRC) IRB in Uganda and The Johns Hopkins Medical Institutions (JHMI) IRB in the U.S.; Blantyre, Malawi: College of Medicine Research and Ethics Committee (COMREC) in Malawi and Johns Hopkins Medical Institutions (JHMI) IRB in the U.S.; Lilongwe, Malawi: National Health Sciences Research Committee (NHSRC) in Malawi and University of North Carolina, Chapel Hill (UNC-CH) Office of Human Research Ethics IRB in the U.S.; Harare, Seke North and St. Mary’s sites, Zimbabwe: Medical Research Council of Zimbabwe (MRCZ) National Ethics Committee; PHRU, Johannesburg, South Africa: University of Witwatersrand Human Research Ethics Committee (Medical); and uMlazi, Durban, South Africa: Biomedical Research Ethics Committee and Kwazulu-Natal Department of Health. All women signed a written informed consent form to enroll and be followed with their children for the duration of the study and to provide study samples. All women are on ART regimens provided as the standard of care in each country. The PROMOTE study provides at no cost laboratory testing and clinical management as necessary. Children found HIV-infected are started on ART per country-specific regimens and guidelines. Maternal counseling on antiretroviral adherence and other health issues are also provided at the clinics.
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