CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

780 MITOCHONDRIAL DNA CONTENT IN HIV-EXPOSED UNINFECTED INFANTS IN CAMEROON

Jennifer Jao 1 , Kathleen M. Powis 2 , Brian Kirmse 3 , Chunli Yu 1 , Fanny Epie 4 , Elaine J. Abrams 5 , Derek LeRoith 1 , Mitchell Geffner 6 , Irwin J. Kurland 7 , Helene C. Cote 8 1 Icahn Sch of Med at Mt Sinai, New York, NY, USA, 2 Massachusetts General Hosp, Boston, MA, USA, 3 Univ of Mississippi, Jackson, MS, USA, 4 Cameroon Baptist Convention Hlth Services, Bamenda, Cameroon, 5 Columbia Univ, New York, NY, USA, 6 Univ of Southern California, Los Angeles, CA, USA, 7 Albert Einstein Coll of Med, Bronx, NY, USA, 8 Univ of British Columbia, Vancouver, Canada Background: In utero HIV/antiretroviral (ARV) exposure has been associated with mitochondrial dysfunction. Few studies have evaluated mitochondrial DNA (mtDNA) content in HIV-exposed uninfected (HEU) infants in Africa or the relationship between mtDNA levels and pathways of intermediary metabolism. Methods: We quantified dried blood spot mtDNA content (ratio of mtDNA:nuclear DNA) by quantitative PCR at 6 weeks of life in HEU and HIV-unexposed uninfected (HUU) infants in Cameroon from 2011-2014. Infants were in utero HIV/ARV and postnatally exposed to either zidovudine (HEU-A) or nevirapine (HEU-N) or HUU. Acylcarnitines (ACs) and branch- chain amino acids (BCAAs), biomarkers of intermediary metabolism occurring in mitochondriae, were measured via tandemmass spectrometry. We used principal component analysis (PCA) to consolidate the ACs and BCAAs into 7 uncorrelated principal components (PC). Linear regression models were fit to assess the association of in utero/postnatal HIV/ARV exposure and infant mtDNA while adjusting for confounders and PCA-derived AC/BCAA component scores. Results: Of 366 singletons, 38 were HEU-A, 118 HEU-N, and 210 HUU infants. Mothers of HEU-A and HEU-N were older than those of HUU infants (median age 30 vs. 30 vs. 28 years respectively, p=<0.01). Amongst HEU infants, 15 (10%) were exposed to no ARVs, 33 (21%) to AZT monotherapy, and 108 (69%) to combination ARV therapy in utero. Of the latter, all but two were exposed to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. The in utero ARV exposures did not differ significantly between HEU-A and HEU-N infants. Mean mtDNA content was lowest in HEU-A infants (140 vs. 160 in HEU-N vs. 174 in HUU, p<0.01). After adjusting for confounders, HEU-A infants remained at increased risk for lower mtDNA content (ß:-4.92, p=0.03 for HEU-A vs. HUU; ß:-1.60, p=0.29 for HEU-N vs. HUU). Furthermore, PC1 (composed of long chain ACs C14, C16, C16:1, C18, C18:1, C18:2, C0) was associated with lower (ß:-2.29, p<0.01) and PC3 (composed of short chain and BCAA-related ACs C2, C3, C4, C4-OH, C5-OH, C3-DC, C4-DC, C5-DC, C8:1) with higher (ß:2.37, p=0.02) mtDNA content. Conclusion: Compared to HUU infants, HEU infants receiving postnatal AZT appear to be at increased risk for lower mtDNA content at 6 weeks of life. Moreover, mtDNA content in HEU infants may be associated with altered mitochondrial fuel utilization. Further studies are needed to assess the longterm significance of these findings. 781 LOPINAVIR/RITONAVIR INITIATED AT 7 DAYS OF LIFE IMPAIRS INFANT GROWTH Nicolas Nagot 1 , Thorkild Tylleskär 2 , Chipepo Kankasa 3 , Nicolas MEDA 4 , James Tumwine 5 , Mandisa Singata 6 , Marianne Periès 1 , Philippe Van de Perre 1 , Stephane Blanche 7 , for the ANRS 12174Trial Group 1 INSERM, Montpellier, France, 2 Univ of Bergen, Bergen, Norway, 3 Univ Teaching Hosp, Lusaka, Zambia, 4 Cntr MURAZ, Bobo-Doulasso, Burkina Faso, 5 Univ of Makerere, Kampala, Uganda, 6 Univ of Fort Hare, East London, South Africa, 7 Necker Hosp, Paris, France Background: Lopinavir/ritonavir (LPV/r) remains a key drug for therapy of pediatric HIV and proved efficacious as an infant prophylaxis in the ANRS 12274 trial. However, reports of growth retardation in LPV/r vs. Nevirapine based combinations in HIV-infected children prompt the need to assess whether this drug could impact infant growth during the first year of life. Methods: In the ANRS 12174 trial, implemented in 4 African countries, 1273 HIV-uninfected breastfed children born from HIV-infected mothers were randomized at 7 days for either lamivudine or LPV/r until the end of breastfeeding (max 50 weeks) as pre-exposure prophylaxis. Each month, weight and height were measured using standardized high- quality assessments. For these analyses, children were censored when they stopped the study drugs or when they became infected with HIV (N=19). Z-scores were calculated and compared between arms using the least mean squares method at 26 and 50 weeks, linear mixed models and spline regression models. Results: Overall, 1266 children were included in the analyses, who accumulated 12443 visits. While the length for age score was not different between arms, the weight for age (WHA) score was consistently lower in the LPV/r arm than in the 3TC arm: difference of -0.18 (95%CI: -0.30;-0.5, p=0.006) at 26 weeks, and of -0.24 (95%CI : -0.44 ;-0.05, p=0.02) at 50 weeks. The weight for height (WHZ) score was similarly lower in the LPV/r arm, with differences of -0.22 (95%CI: -0.34;-0.09, p<0.001) at 26 weeks, and of -0.25 (95%CI: -0.46 ;-0.03, p=0.02) at 50 weeks. For both WHA and WHZ, the reduction over time was confirmed by linear mixed model (p=0.02 and p<0.001, respectively), while spline regression models suggest that this reduction occurs early and remain constant thereafter (p=0.02 with knot at 118 days for WHA, and p<0.001 with knot at 44 days for WHZ). Interestingly, the impact of LPV/r was much higher in girls than in boys, and in Burkina Faso and Uganda than in Zambia and South Africa. Conclusion: This large randomized trial comparing LPV/r vs. 3TC administration in exposed-uninfected children provided a unique opportunity to evaluate the impact of LPV/r on growth. LPV/r initiated at 7 days of life induced a lower weight gain among HIV-uninfected children. These findings have implications for the early treatment of HIV-infected children and for further choice of prophylactic regimen.

Poster and Themed Discussion Abstracts

CROI 2017 338