Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial

Objectives We set out to evaluate the effect of postnatal exposure to tenofovir-containing antiretroviral therapy on bone mineral density among breastfeeding women living with HIV. Design IMPAACT P1084s is a sub-study of the PROMISE randomized trial conducted in four African countries (ClinicalTrials.gov number NCT01066858). Methods IMPAACT P1084s enrolled eligible mother-infant pairs previously randomised in the PROMISE trial at one week after delivery to receive either maternal antiretroviral therapy (Tenofovir disoproxil fumarate / Emtricitabine + Lopinavir/ritonavir-maternal TDF-ART) or administer infant nevirapine, with no maternal antiretroviral therapy, to prevent breastmilk HIV transmission. Maternal lumbar spine and hip bone mineral density were measured using dual-energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74. We studied the effect of the postpartum randomization on percent change in maternal bone mineral density in an intention-to-treat analysis with a t-test; mean and 95% confidence interval (95%CI) are presented. Results Among 398/400 women included in this analysis, baseline age, body-mass index, CD4 count, mean bone mineral density and alcohol use were comparable between study arms. On average, maternal lumbar spine bone mineral density declined significantly through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference (95%CI) -2.86 (-4.03, -1.70) percentage points (p-value <0.001). Similarly, maternal hip bone mineral density declined significantly more through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference -2.29% (-3.20, -1.39) (p-value <0.001). Adjusting for covariates did not change the treatment effect. Conclusions Bone mineral density decline through week 74 postpartum was greater among breastfeeding HIV-infected women randomized to receive maternal TDF-ART during breastfeeding compared to those mothers whose infants received nevirapine prophylaxis. The PROMISE trial enrolled 3747 pregnant women living with HIV along with their infants to determine the optimal antiretroviral strategy to prevent perinatal and postpartum transmission of HIV from mother to child and preserve maternal health and infant survival in 15 countries across different health settings [38–41]. The PROMISE Antepartum randomization was to open-label Zidovudine mono-drug prophylaxis or Zidovudine/Lamivudine/Lopinavir/ritonavir ART (see S1 Fig–PROMISE study design). The PROMISE Postpartum Component randomized healthy women with HIV and high CD4 counts intending to breast feed and their uninfected, healthy infants weighing at least 2kg one week after delivery to receive either open-label maternal ART (Tenofovir disoproxil fumarate/Emtricitabine + Lopinavir/ritonavir–‘TDF-ART’) or administer infant nevirapine prophylaxis without maternal ART (iNVP) throughout the period of breastfeeding to prevent breastmilk transmission. At the time PROMISE was conducted, enrolled women did not meet the criteria to initiate ART for their own health and life-long ART was not yet standard for pregnant women. The Bone and Kidney Health sub-study offered postpartum co-enrolment to a sub-set of women enrolled in PROMISE with no prior TDF exposure during pregnancy in four African countries with capacity for BMD evaluation; Malawi, South Africa, Uganda and Zimbabwe; with a target sample size of 400. On July 6, 2015 PROMISE sites were notified that all participants should be offered ART based on the results of the Strategic Timing of AntiRetroviral Treatment (START) study [42] which demonstrated a significant benefit to beginning ART, including in patients with high CD4 counts. Analyses for P1084s are thus based on data collected at visits through the date of notification. After obtaining maternal consent, P1084s sub-study entry occurred immediately (same day) after PROMISE Postpartum randomization on postpartum day 6–14. Participants were followed at 6, 26 and 74 postpartum weeks. Data collected throughout follow-up included socio-demographic information, medical history, HIV-related medical information including viral load, ART adherence assessment, smoking status, alcohol intake status, physical activity level, dietary intake, renal function, concomitant medications including contraceptive use and breastfeeding status. The protocol did not specify nutritional supplements. Weight and height measurements were conducted by trained study staff according to standardized measurement guidance. Maternal participants randomized to iNVP (no ART) who subsequently met immunological or clinical criteria to initiate ART for their own health were immediately started on ART and remained in observational follow-up. Maternal BMD was measured at the lumbar spine and hip by dual-energy x-ray absorptiometry (DXA). The baseline measurement was scheduled at postpartum week one (day 5–21) and repeated at postpartum week 74 (+/-6 weeks), unless the participant was pregnant. Standardized procedures for obtaining the scan were followed to minimize differences between the study sites–all scanners were Hologic models that were cross-calibrated with a phantom, each technician underwent webinar training and quality review of their first scan, and DXA scans were centrally analyzed at the University of California San Francisco Department of Radiology and Biomedical Imaging. DXA operators and readers were blinded to study treatment assignment. The study was funded by the National Institutes of Health (ClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT01066858","term_id":"NCT01066858"}}NCT01066858). Written informed consent was obtained from each sub-study participant. Study conduct adhered to international guidelines, and the sub-study was approved by an institutional review board or ethics committee at each site and corresponding collaborating institutions in the United States. Ethics committees and institutional review boards that approved this study include—MUJHU/Kampala, Uganda: The Joint Clinical Research Centre (JCRC) IRB, the National Drug Authority in Uganda and the Johns Hopkins Medical Institutions (JHMI) IRB in the U.S.; Wits RHI Shandukani CRS and Soweto IMPAACT CRS, Johannesburg, South Africa: University of Witwatersrand Human Ethics Research Committee (Medical), Medicines Control Council (South African Health Products Regulatory Authority in February 2018); FAM-CRU CRS, Cape town, South Africa: Health Research Ethics Committee (HREC), Faculty of Health Sciences, Stellenbosch University and Medicines Control Council (South African Health Products Regulatory Authority in February 2018); Durban Paediatric HIV CRS, Durban, South Africa: University of KwaZulu-Natal (UKZN) Biomedical Research Ethics Committee, Medicines Control Council (South African Health Products Regulatory Authority in February 2018);George CRS, Lusaka, Zambia: University of North Carolina (UNC) at Chapel Hill Biomedical IRB and University of Zambia Biomedical Research Ethics Committee (UNZABREC); Harare, Seke North and St. Mary’s sites, Zimbabwe: Medical Research Council of Zimbabwe(MRCZ), Research Council of Zimbabwe (RCZ), Medicine Control Authority of Zimbabwe (MCAZ), Joint Parirenyatwa group of Hospitals/University of Zimbabwe College of Health Sciences Research Ethics Committee(JREC); Byramjee Jeejeebhoy Medical College (BJMC) CRS, Pune, India: BJ Government College CTU Ethics Committee and Johns Hopkins IRB; Blantyre, Malawi: College of Medicine Research and Ethics Committee (COMREC) in Malawi, Pharmacy, Medicines and Poisons Board and Johns Hopkins Medical Institutions (JHMI) IRB in the U.S.; Lilongwe, Malawi: National Health Sciences Research Committee (NHSRC) in Malawi Pharmacy, Medicines and Poisons Board, and University of North Carolina, Chapel Hill (UNC-CH) Office of Human Research Ethics IRB in the U.S and Kilimanjaro Christian Medical Centre (KCMC), Moshi, Tanzania: Kilimanjaro Christian Medical College Ethics Committee, National Health Research Ethics Committee and Tanzania Medicines and Medical Devices Authority. The primary outcome measure was percent change in lumbar spine (LS) BMD assessed by DXA between baseline and week 74. A secondary outcome measure was percent change in hip BMD from baseline to week 74. Primary analyses were carried out by randomized assignment for the mothers included in the analysis, as were secondary analyses on additional DXA outcome measures. Selected subgroup and restricted/as-treated analyses were performed as secondary analyses. Percent change in maternal LS BMD and hip BMD were analyzed with Student t-tests (two-sided) to compare the maternal TDF-ART and iNVP arms. The TDF-ART versus iNVP effect was adjusted for covariates and effect modification by subgroups (interaction tests) was assessed via linear regression. Covariates included at postpartum randomization (baseline): age, weight, parity at PROMISE entry, HIV RNA level, country, and antepartum randomization assignment. Additional comparisons applied Wilcoxon/Kruskal-Wallis test for continuous data, and χ2/exact tests for categorical data, as appropriate. Analyses were performed using SAS v9.4 (Cary, NC). Statistical significance was set at the 0.05 level, with no adjustment for multiple comparisons. The data cannot be made publicly available due to the ethical restrictions in the study’s informed consent documents and in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network’s approved human subjects protection plan; public availability may compromise participant confidentiality. However, data are available to all interested researchers upon request to the IMPAACT Statistical and Data Management Centre’s data access committee by email to [email protected] or [email protected]. This committee reviews and responds to requests for data, obtains necessary approvals from IMPAACT leadership and the NIH, arranges for signature of a Data Use Agreement, and releases the requested data.