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

Abstract

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.

Bone and Renal Health in Infants With or Without Breastmilk Exposure to Tenofovir-Based Maternal Antiretroviral Treatment in the PROMISE Randomized Trial

“…Seven infants had a positive HIV test (defined as infected by at least 2 positive HIV-1 nucleic acid tests or probably infected based on an independent committee determination), 3 infants in the mART arm, and 4 in the iNVP arm. The median infant age at the first positive HIV test was 9 months (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Treatment for HIV-infected infants was provided from their respective national programs and they continued in follow-up through scheduled exit.…”

“…[3][4][5] The effect on infant health of antiretroviral agents (ARVs) secreted in breastmilk on infant health should be considered when selecting regimens, 6,7 yet rigorous trial data are lacking. In particular, although it is well-established in adults that tenofovir disoproxil fumarate (TDF) is associated with 1%-3% greater loss in bone mineral density [8][9][10] and increased renal tubular dysfunction compared with non-TDF-containing ARV regimens, [11][12][13][14] scant experience of TDF use or exposure in infants limits the ability to estimate the likelihood of TDFrelated bone and renal toxicity in infants. 15,16 Although breastfeeding infants are exposed to only 0.01%-0.04% of the recommended weight-adjusted therapeutic TDF dose, 8,17 the possibility of infant toxicity through direct exposure in breastmilk or mediated by potential TDF-related alterations in breastmilk 18 deserves evaluation given the wide use of TDF for HIV treatment and prevention.…”

Impact of Tenofovir Disoproxil Fumarate Use During Pregnancy on Maternal Bone Mineral Density

“…This is the first randomized controlled trial among pregnant women with HIV/HBV coinfection to evaluate maternal BMD changes after initiation during pregnancy of a regimen containing TDF vs a regimen without TDF. Five studies in the literature (two presented as conference abstracts only) have reported on bone mineral indices of women with HIV [6][7][8][9] or HBV 10 infection treated with TDF-containing regimens during pregnancy or breastfeeding. In an observational study of breastfeeding women with HIV in Uganda, no significant difference was found between TDF-containing ART (N = 161) vs no ART (N = 57) in spine and hip BMD T-scores at 2 weeks and 9 months postpartum.…”

Gender and sex considerations in HIV and bone health

“…Women with no prior TDF exposure during pregnancy were randomized to receive TDF-ART or their infant received nevirapine for prevention of HIV transmission via breastfeeding. The mothers on maternal ART experienced greater decline in BMD at the spine (−2%) and total hip (−5.3%) compared with mothers whose infants received nevirapine [7].…”