CROI 2020 Abstract eBook
HIV replication in the CNS, which is a deep reservoir, even though BBB is undamaged.
455 A CROSS-SECTIONAL ANALYSIS OF ANTIRETROVIRAL REGIMEN ACTIVITY IN CEREBROSPINAL FLUID Courtney V. Fletcher 1 , Caitlyn McCarthy 2 , Ronald Bosch 2 , Serena S. Spudich 3 , Anthony Podany 1 , Sean N. Avedissian 1 , Lee Winchester 1 , Timothy Mykris 1 , Jon Weinhold 1 , Bernard J. Macatangay 4 , Joshua C. Cyktor 4 , Joseph J. Eron 5 , John W. Mellors 4 , Rajesh T. Gandhi 6 , Deborah McMahon 4 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 3 Yale University, New Haven, CT, USA, 4 University of Pittsburgh, Pittsburgh, PA, USA, 5 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 6 Massachusetts General Hospital, Boston, MA, USA Background: ACTG A5321 is a prospective cohort study of changes in HIV-1 reservoirs among participants with HIV on antiretroviral therapy (ART). We designed a single cross-sectional analysis of antiretroviral (ARV) pharmacokinetics (PK) in cerebrospinal fluid (CSF) and investigated relationships among a novel putative measure of ART regimen CSF activity and concurrent biomarkers of HIV persistence and inflammation. Methods: Participants were on ART for ≥2 years with well-documented sustained plasma viral suppression at time of lumbar puncture (LP). CSF ARV concentrations, cell-associated HIV DNA and inflammatory biomarkers were measured at LP. ARV levels were quantified by LC/MS/MS. CSF inhibitory quotients (IQ) were calculated for each drug in ART regimen as ratio of measured CSF concentration to literature values for in vitro inhibitory concentration. Participants were ranked (low to high) by IQs for TFV, FTC, and third ARV, then drug ranks were averaged to give an overall rank for the ART regimen; a participant with highest IQ for all individual components would have the highest regimen IQ score. Rank-based analyses were used to evaluate associations among regimen IQ ranks and biomarkers. Results: CSF ARV concentrations were available on 55 participants on TDF/ FTC-based regimens: 52 males (95%); 40 (73%) white non-Hispanic, 10 (18%) black non-Hispanic; median age, 48 yrs; median yrs on ART, 8.1 yrs; median CD4 count, 651 cells/µL; 54 (98%) with plasma HIV-RNA <40 copies/mL. Third drugs in ART regimens included: EFV (n=17), ATV/r (8), EVG/c (8), RAL (8), DRV/r (4) and DTG (2). RPV and NVP (n=8) were not analyzed as CSF levels were unavailable. Figure shows CSF IQ values for ARV drugs, which were consistent with CNS Penetration Effectiveness (CPE) scores. Associations among ART CSF IQ and HIV-1 persistence measures were restricted to participants treated during chronic infection (n=44). Average regimen IQ rank was slightly higher in those with undetectable CSF HIV DNA vs detectable (median [Q1, Q3]: 25 [19.7, 34.3] for TND vs. 21.2 [15.7, 28.7] for detected); p=0.25. CSF neopterin was positively associated with average IQ rank (Spearman r = 0.28, p = 0.07 adjusting for age and pre-ART CD4:8 ratio). Conclusion: The ART regimen IQ rank is a new approach to assess regimen vs individual drug activity. This tool provides a basis for continued work to expand regimen IQ data and investigate longitudinal relationships with biomarkers of HIV CSF persistence and inflammation.
456 PRENATAL EFAVIRENZ EXPOSURE INDEPENDENTLY ASSOCIATED WITH FOETAL CYP2B6 GENOTYPE Adeniyi Olagunju 1 , Damien Anweh 2 , Ogechi Okafor 3 , Alieu Amara 4 , Oluseye Bolaji 1 , Ebunoluwa Adejuyigbe 1 , Saye Khoo 4 , Andrew Owen 4 1 Obafemi Awolowo University, Ile-Ife, Nigeria, 2 Federal Medical Centre, Makurdi, Nigeria, 3 Bishop Murray Medical Centre, Makurdi, Nigeria, 4University of Liverpool, Liverpool, UK Background: Understanding the influence of foetal and maternal genetics on prenatal drug exposure could play an important role in assessing observed risk-benefit differentials during pregnancy. In this sub-study of VADICT (NCT03284645), the influence of functional CYP2B6 polymorphisms on prenatal exposure to efavirenz was investigated. Methods: VADICT is a cohort study that started recruiting in June 2017 in four Nigerian hospitals investigating viral and antiretroviral dynamics in fluids important for mother-to-child transmission. Women commencing efavirenz-based regimens before/early/late in pregnancy or postpartum are being recruited with followed-up until breastfeeding ends. For this sub-study, maternal and newborn samples were collected immediately after delivery before breastfeeding started. Genomic DNA was extracted and genotyped by real-time PCR using TaqMan 5’ nuclease assays for CYP2B6 516G>T and 983T>C single nucleotide polymorphisms (SNPs). Efavirenz was quantified using a validated LC-MS/MS method. Linear regression was used to explore association of genetic and non-genetic factors with newborn efavirenz concentrations. Results: A total of 171 samples were available for this analysis (including 81 paired samples) from 86 women and 85 newborns. Mean (SD) maternal age at delivery was 30 (5.2) years, gestational age 40 (3.3) weeks, birth weight 2.9 (0.5) kg and APGAR score 7.6 (1.4). Samples were collected 18.5 (10.1) h after last maternal dose. A strong correlation was observed between maternal and newborn efavirenz concentrations (Figure A). Median (range) newborn efavirenz concentrations were 1180 (69.0-9230) ng/mL in unstratified newborns, 969 (15.9-2910), 1230 (69.2-9230) and 1790 (735-5230) ng/mL in fast (n = 28), intermediate (n = 37) and slow (19) metabolisers, respectively (Figure B). Newborn-to-mother concentration ratio was 0.88 (0.04-2.07). Newborn CYP2B6 516G>T, APGAR score, maternal CYP2B6 516G>T and body weight at delivery were independently associated with newborn efavirenz concentrations. Conclusion: Both maternal and foetal genetics influence prenatal drug exposure. This can help progress assessment of the possible role of drug exposure in adverse foetal outcomes. These data are now being used to further qualify our previously described mechanistic model of prenatal drug exposure.
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