CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

878 LOPINAVIR/RITONAVIR INDUCES MITOCHONDRIAL TOXICITY IN HIV- EXPOSED UNINFECTED CHILDREN Audrey Monnin 1 , Nicolas Nagot 2 , Marianne Periès 3 , Roselyne Vallo 3 , Nicolas Meda 4 , Mandisa Singata 5 , James Tumwine 6 , Pascal Reynier 7 , Thorkild Tylleskär 8 , Philippe Van de Perre 2 , Jean-Pierre Molès 1 1 INSERM, Montpellier, France, 2 CHU de Montpellier, Montpellier, France, 3 L’Université de Montpellier, Montpellier, France, 4 Centre MURAZ, Bobo-Doulasso, Burkina Faso, 5 University of Fort Hare, East London, South Africa, 6 Makerere University, Kampala, Uganda, 7 CHU de Angers, Angers, France, 8 University of Bergen, Bergen, Norway Background: Long-term ART, such as lopinavir-ritonavir (LPV/r) and lamivudine (3TC) can be given to newborns either for HIV treatment or prophylaxis (PrEP) to prevent maternal transmission through breastfeeding. The potential mitochondrial toxicity of these drugs has never been evaluated without the concurrent confounding effect of HIV. This study aimed to quantify the mitochondrial toxicity of 3TC or LPV/r regimens after 1 year of PrEP among HIV-exposed uninfected infants. Methods: We have randomly selected 151 participants having completed the ANRS 12174 randomized controlled trial which enrolled HIV-uninfected children from untreated HIV-infected mothers. We showed that infant 3TC and LPV/r PrEP given from day 7 until 1 year could reduce postnatal HIV transmission to 1.3%. The number of mitochondrial DNA copies per cell (MCN) and the percentage of mitochondrial DNA carrying deletions (MDD) were assessed by real time PCR on stored dried blood spots collected at 7 days after birth and at 1 year. PCR protocols were performed according to the criteria for the diagnostic of mitochondriopathies from the French reference center. A clinically-relevant mtDNA depletion was defined as a reduction of 70% of MCN at 1 year. Results: Before PrEP initiation (D7), the median MCN was within normal range (823, IQR:555-1076), while any MDD was unexpectedly detected in 147/149 children, with a median 11.2% (IQR:8.5-15.1) of mtDNA deleted, without difference between arms. After 1 year of PrEP, overall median MCN dropped by 41.2% (IQR:6.9-64.2) without difference between arms (p=0.59). Twenty-nine (19.2%) children showed a mtDNA depletion, without difference between arms (p=0.19). After adjustment for gender, duration of breastfeeding, duration of pre-partummaternal prophylaxis and gestational age, LPV/r tented to be associated with mtDNA depletion (reference = 3TC; OR=1.98, IC95%:0.81-4.87; p=0.14). Similarly, the rate of MDD remained high in both arms (13.7%, IQR:3.2- 16.5 for 3TC and 14.6%, IQR:9.6-19.1 for LPV/r) but without difference between them (p=0,42). Conclusion: At D7, the mtDNA deletion rate among HIV-exposed infants was close to rates observed in some inherited mitochondrial diseases. After 1 year of PrEP, an unexpected and important mitochondrial toxicity was observed (mtDNA depletion) for LPV/r, which compares to the expected effect of 3TC. The severity of these defects contrasts with the paucity of clinical sign and symptoms related to mitochondriopathies. 879 HEU BLOOD MTDNA CONTENT REMAINS ELEVATED FROM BIRTH INTO EARLY LIFE (0-3 YEARS) Abhinav Ajaykumar 1 , Mayanne Zhu 1 , Hugo Soudeyns 2 , Fatima Kakkar 2 , Jason Brophy 3 , Ari Bitnun 4 , Ariane Alimenti 1 , Deborah M. Money 1 , Helene C. Cote 1 1 University of British Columbia, Vancouver, BC, Canada, 2 CHU Sainte-Justine, Montreal, QC, Canada, 3 Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada, 4 University of Toronto, Toronto, ON, Canada Background: Maternal combination antiretroviral (ARV) therapy (cART) during pregnancy has been successful in preventing vertical HIV transmission. However, in utero exposure to ARVs, many of which can cross the placenta, could have long term effects on HIV-exposed uninfected (HEU) infants. Some ARVs can cause mitochondrial toxicity and affect mitochondrial DNA (mtDNA) quantity and quality. Previous studies among HEU infants exposed to cART in utero have been inconsistent, with some reporting increased blood mtDNA levels at birth compared to HIV-unexposed uninfected (HUU) infants, while others report a decrease. Our objective was to compare HEU and HUU infant blood mtDNA content at birth and over the first 3 years of life, and investigate any relationship to cART exposure. Methods: Peripheral blood mtDNA content was measured by monochrome multiplex qPCR in 324 HEU (0-3y, of whom 214 had ≥2 blood samples) and 308 HUU children (0-3y, each with a single blood sample) enrolled in the CARMA cohort study. A subset of these children was randomly age- and sex-matched 1:1 for a cross-sectional comparison of mtDNA content over the first 3y of

was no evidence suggesting that in utero exposure to ARVs, whether its duration, drug class or combinations, increased the likelihood of NDs. Conclusion: The results suggest no direct association between ARVs and NDs within HEU children in our cohort. Prevalence of NDs is higher in HEUs; however, sociodemographic factors may play a role, including some we were not able to consider. These findings highlight a need for holistic support for pregnant women as well as careful developmental monitoring of HEU children, and access to early interventions, particularly among those born preterm and those exposed to substances of addiction. 877 MENTAL HEALTH DIAGNOSES, SYMPTOMS, AND SERVICE UPTAKE IN US YOUTH WITH PHIV EXPOSURE Renee Smith 1 , Yanling Huo 2 , Katherine Tassiopoulos 2 , Richard Rutstein 3 , Suad Kapetanovic 4 , Claude A. Mellins 5 , Deborah Kacanek 2 , Kathleen Malee 6 1 University of Illinois at Chicago, Chicago, IL, USA, 2 Harvard University, Cambridge, MA, USA, 3 Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 4 University of Southern California, Los Angeles, CA, USA, 5 Columbia University, New York, NY, USA, 6 Northwestern University, Chicago, IL, USA Background: Adolescents and young adults perinatally exposed to HIV in the U.S. are at increased risk for mental health (MH) problems and lower uptake of MH services, raising concerns about increased risk of antiretroviral therapy non- adherence, poor virologic outcome, and secondary transmission for youth with perinatal HIV infection (PHIV). Identifying prevalence and factors associated with these problems in this aging population of youth with a chronic and stigmatizing health condition is critical for their mental and physical wellness, and informing prevention and intervention efforts. Methods: Data from standardized interviews, behavioral assessments, and chart reviews were used to estimate prevalence of any MH diagnoses, clinically significant (CS) symptoms, and MH treatment uptake among 355 PHIV youth and 196 exposed but uninfected (PHEU) youth, aged 10-22yrs, who were enrolled at 15 U.S. sites of the Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study (PHACS). We used univariable and multivariable logistic regression models to evaluate associations of youth, family, and environmental characteristics with the most prevalent MH diagnoses (mood/anxiety and ADHD) and MH treatment utilization. Results: Overall, 36% of all youth had a previous or current MH diagnosis, with no significant HIV status group differences. Among youth with a current MH diagnosis, 61%were receiving MH treatment; PHIV youth had greater uptake of services than PHEU youth (67% vs 51%; p=0.04). In each group 15% reported CS symptoms, of whom a third had no diagnosis, and half were not receiving treatment. In multivariable models, viral load and immunologic status were not associated with risk of a MH diagnosis or MH treatment uptake for PHIV youth. Among all youth, caregiver characteristics (previous MH diagnosis, IQ >85, and non-biologic relationship to child) were associated with more treatment uptake. Age and sex of child, stressful life events, HIV status, and caregiver factors (IQ, MH diagnosis, and relationship to child) were associated with anxiety/mood disorders and/or ADHD (see table). Conclusion: Prevalence of MH diagnoses in this sample was higher than in the general U.S. population, but lower than in similar HIV-affected cohorts. There were unmet service needs, particularly among PHEU youth, yet uptake rates were higher than among those from some national population surveys. Family characteristics are key factors in the early diagnosis and treatment of MH problems of HIV-exposed youth.

Poster Abstracts

CROI 2018 333