CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

606

Pharmacogenetics of Dolutegravir During Rifapentine/Isoniazid Treatment of Latent TB in ACTG A5372 Nia Covington 1 , Annie Luetkemeyer 2 , Marjorie Imperial 2 , Rodney Dawson 3 , Yoninah Cramer 4 , Sue Rosenkranz 4 , Susan Swindells 5 , Irina Gelmanova 6 , Anchalee Avihingsanon 7 , Roberto C. Arduino 8 , Wadzanai Samaneka 9 , Kelly Dooley 10 , Rada Savic 2 , Anthony Podany 5 , David W. Haas 10 1 College of Charleston, Charleston, SC, USA, 2 University of California San Francisco, San Francisco, CA, USA, 3 University of Cape Town, Cape Town, South Africa, 4 Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA, 5 University of Nebraska Medical Center, Omaha, NE, USA, 6 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 7 Thai Red Cross AIDS Research Center, Bangkok, Thailand, 8 University of Texas at Houston, Houston, TX, USA, 9 University of Zimbabwe, Harare, Zimbabwe, 10 Vanderbilt University, Nashville, TN, USA Background: The one-month 1HP regimen (daily rifapentine (RPT) + isoniazid (INH)) effectively treats latent TB in people with HIV (PWH). RPT induces hepatic enzymes that lower dolutegravir (DTG) exposure. A pharmacokinetic (PK) analysis of 32 PWH who received 1HP in ACTG A5372 showed that DTG 50 mg twice daily achieved day-28 DTG trough concentrations higher than those with 50 mg once daily without RPT/INH. We studied whether genetics that affect DTG (UGT1A1 rs887829) and RPT (AADAC rs1803155) PK impacted the RPT-DTG interaction. Methods: In A5372, adult PWH on DTG-containing ART with HIV-1 RNA <50 c/ mL and an indication to treat latent TB received daily RPT/INH (600mg/300mg) for 28 days. DTG was increased to 50 mg twice daily during 1HP. Intensive PK sampling was performed on day 0 (DTG 50 mg once daily without 1HP), and on day 28 (DTG 50 mg twice daily with 1HP). PK and demographics were summarized as median (Q1, Q3). Linear regression models for log-transformed observed DTG trough concentrations were adjusted for BMI. Models with AADAC also adjusted for UGT1A1. Results: Thirty participants were evaluable for genetic associations, including 11 (37%) cis-gender females, 19 (63%) Black/Africans, 8 (27%) Asians; median BMI was 24 (22, 26) kg/m 2 . Median day-0 DTG trough was 1745 (1099, 2694) ng/ mL, and day-28 was 2146 (1412, 2484) ng/mL. UGT1A1 rs887829 was associated with DTG trough at days 0 and 28. At day 28, DTG trough was higher with TT (geometric mean ratio (GMR)=1.65; 90% CI 0.97, 2.78) and CT (GMR=1.38; 90% CI 1.02, 1.86) than with CC. AADAC rs1803155 was associated with day-28 DTG trough, which was higher with GG (GMR=1.79; 90% CI 1.09, 2.93) and AG (GMR=1.48; 90% CI 1.14, 1.90) than with AA (Figure, panel A). Considering both genes, participants with 4 risk alleles for lower DTG trough (UGT1A1 CC + AADAC AA) had median day-28 DTG trough of 1205 (1063, 1897) ng/mL. Those with 1 risk allele had day-28 DTG troughs of 3882 (TT/AG) and 3717 (CT/GG) ng/mL. Those with 2 or 3 risk alleles had intermediate troughs. (Figure, panel B). Conclusion: In PWH receiving DTG 50 mg twice daily with 1HP, AADAC rs1803155 was associated with lower day-28 DTG trough (still >324 ng/mL, the DTG EC 90 for wild-type HIV-1), likely due to higher RPT concentrations causing greater hepatic enzyme induction. Individuals with concomitant AADAC slow metabolizer + UGT1A1 normal metabolizer genotypes (17% of Africans, 15-30% of people worldwide) may be at risk for low DTG trough concentrations with once daily DTG and RPT.

607

Population Pharmacokinetic Approaches to Standardize Antiviral Exposure in the Cerebrospinal Fluid Sean N Avedissian 1 , Ying Mu 1 , Caitlyn McCarthy 2 , Ronald J. Bosch 3 , Serena Spudich 4 , Rajesh T. Gandhi 5 , Deborah K. McMahon 6 , Joseph J. Eron 7 , John W. Mellors 6 , Courtney V. Fletcher 1 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 Harvard University, Cambridge, MA, USA, 4 Yale University, New Haven, CT, USA, 5 Massachusetts General Hospital, Boston, MA, USA, 6 University of Pittsburgh, Pittsburgh, PA, USA, 7 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background: HIV has been shown to persist in the central nervous system (CNS) in persons on antiretroviral therapy (ART). Consequently, CNS persistence may be linked to inadequate ART exposure. When assessing CNS drug levels in participants on ART, it is difficult to estimate drug exposure given sparse sampling and to standardize exposure given different sampling times among participants. We describe pharmacokinetic (PK) methods to estimate CNS exposure (maximum concentration [C max ] , area under the curve [AUC], and trough [C Trough ]) among individuals that allows a standardized evaluation of relative CNS drug exposure. Methods: A5321 is a prospective study of HIV-1 reservoirs among persons with HIV on long-term virologically-suppressive ART. 59 participants had plasma and cerebrospinal fluid (CSF) concentrations measured ranging from 1 to 23hrs post ART dose. Population PK modeling was performed for FTC, TDF, EFV, 3TC, ATV/r, RAL, DTG, DRV/r, and EVG. The simplest PK model of plasma and CSF was considered for each ARV utilizing Pmetrics (version 1.5.0; Los Angeles, CA) for R version 3.2.1 (R Foundation for Statistical Computing, Vienna, Austria). The final PK model was used to obtain predicted plasma and CSF estimates at 12-minute intervals from each participant's measured ARV plasma and CSF concentrations. Noncompartmental analysis was used to calculate AUC. Relative CNS penetration for each ARV was estimated by comparing CSF C max and AUC to plasma C max and AUC (i.e., relative CNS penetration= C max _CSF/ C max _Plasma and AUCCSF/ [Table 1]). The CSF CTrough for each ARV was compared to in vitro literature values of HIV inhibitory concentration values (IC 50 or 90 ) for each ARV. Results: Models converged for a combined plasma and CSF 3-compartment oral absorption model. FTC exhibited the highest median CSF penetration (C max :46%, AUC:72%). The lowest median penetration was observed for both DRV/r (DRV C max :0.95%, AUC:1%) and DTG (C max :0.57%, AUC:0.57%). All ARVs had median CSF C T rough concentrations > IC 50 or 90 except TFV: C Trough :0.0016mg/L < IC 50 :0.1437mg/L. Conclusion: These methods demonstrate an approach of utilizing PK modeling to standardize drug levels to a given time point (i.e., C max or C Trough ) and assess if desired therapeutic drug goals are obtainable in the CNS. Further studies are warranted to address whether CSF exposure as calculated using this method is associated with measures of HIV persistence in the CNS.

Poster Abstracts

608

Antiretroviral Concentrations in Post-Mortem Tissues: Preliminary Results From the Last Gift Program Micol Ferrara 1 , Amedeo De Nicolò 1 , Alessandra Manca 1 , Elisa De Vivo 1 , Sara Soloperto 1 , Davey M. Smith 2 , Antoine Chaillon 2 , Magali Porrachia 2 , Niamh Higgins 3 , Antonio D'Avolio 1 , Stefano Bonora 1 , Sara Gianella Weibel 2 1 University of Turin, Turin, Italy, 2 University of California San Diego, San Diego, CA, USA, 3 University of California San Diego, La Jolla, CA, USA Background: Antiretroviral therapy (ART) successfully inhibits HIV replication but cannot eradicate the viral reservoir in various anatomic compartments. This is partially due to differential antiretroviral (ARV) drug penetration in different compartments. In humans, ARVs measurement in reservoirs is complicated by technical and ethical obstacles in performing tissue biopsies in vivo. Here

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