CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

604

Implementation of an Online Drug-Drug Interaction Screener for STRIVE Ensitrelvir Trial for COVID Josh Havens 1 , Nayon Kang 2 , Lucy Chung 2 , Courtney V. Fletcher 1 , Page Crew 2 , Jacquie Nordwall 3 , Birgit Grund 3 , Marcelo Losso 4 , Shikha Vasudeva 5 , Adit Ginde 6 , Jason Baker 3 , for the INSIGHT STRIVE Ensitrelvir Study Group 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 National Institute of Allergy and Infectious Diseases, Baltimore, MD, USA, 3 University of Minnesota, Minneapolis, MN, USA, 4 Hospital JM Ramos Mejía, Buenos Aires, Argentina, 5 Salem VA Medical Center, Salem, VA, USA, 6 University of Colorado Anschutz Medical Campus, Aurora, CO, USA Background: Ensitrelvir (ESV) is an investigational oral protease inhibitor for SARS-CoV-2 infection currently being studied in a randomized placebo controlled trial of patients hospitalized for COVID-19 within STRIVE (Strategies and Treatments for Respiratory Infections and Viral Treatments), a global network. ESV is associated with drug-drug interactions (DDI) due to its inhibition of CYP P450 3A, P-gp, BCRP, and OAT-3. We present the developmental framework and implementation of an online DDI screener for the STRIVE-1 ESV-trial. Methods: A multidisciplinary team assessed DDI potential of commonly used drugs with ESV. Since the trial design is blinded (i.e. ESV or placebo), DDI recommendations considered implications for each participant as if they were assigned to ESV. DDI guidance was compiled into a database accessed by trial sites through an online web-portal (DDI screener). Drugs were categorized as permitted or prohibited. For each prohibited drug, a washout period before ESV administration and start/restart criteria were based on the drugs' characteristics (e.g., half-life, substrate sensitivity, etc). If applicable, alternative permitted drugs were recommended. Current guidance for some drugs supports enrollment with dose modification. Sites can request drugs not in the DDI screener be evaluated and added. Version updates were completed iteratively. Results: The DDI team convened August 2022. Version (v) 1 of the DDI screener went live December 2022, with 615 drugs included. 4 sequential version updates were performed for a current total of 984 total drugs through v5 (Fig, 1A). Guidance for 11 prohibited medications (antihypertensives, antiinfectives, and psychiatric) was revised with permissive dosage adjustments (dose caps, 55%; dose reductions, 45%). To date, 132 participants have enrolled in STRIVE and 38,615 screener searches have been completed through initiation of v5. Top searched drug classes (% of total) include anti-infective, antihypertensive, psychiatric, and analgesic drugs (Fig, 1B). Anticoagulants, certain immunosuppressants, and emergency use drugs posed the greatest guidance challenges due to blinding considerations. Conclusion: To our knowledge, this is the first online DDI management tool developed for a placebo-controlled trial of investigational agents. DDI resources for drugs like ESV with high DDI potential are essential for safe clinical trial conduct. Implementation requires a multidisciplinary and iterative approach that allows for feedback from trial sites.

605

Evidence for Safe Use of Doravirine With Hormonal Contraceptives in African Women Living With HIV Rena Patel 1 , Nkosi Ndlove 2 , La-Donna Kapa 2 , Garoma Basha 1 , Ché K. Moshesh 2 , Nashon Yongo 3 , Krishnaveni Reddy 2 , Nompumelelo Sigcu 2 , Nazneen Cassim 2 , Shukri A. Hassan 1 , David W. Erikson 4 , Kimberly K. Scarsi 5 , Thesla Palanee Phillips 2 , for the EPIC Study Team 1 University of Washington, Seattle, WA, USA, 2 Wits Reproductive Health and HIV Institute, Johannesburg, South Africa, 3 University of Washington in Kenya, Nairobi, Kenya, 4 Oregon Health and Sciences University, Portland, OR, USA, 5 University of Nebraska Medical Center, Omaha, NE, USA Background: Prior to scale-up of new ART, exploring drug-drug interactions between ART and contraceptive methods is crucial. We are conducting EPIC, a parallel group pharmacokinetic study to examine interactions with doravirine (DOR)-containing ART among women of reproductive potential living with HIV in Johannesburg, South Africa. Methods: EPIC began in November 2021 and is ongoing. A ≥6-week oral lead-in period was required after aviraemic participants switched from their existing ART to DOR-containing ART. Participants in the 3 intervention groups self-selected concomitant contraception: intramuscular depo medroxyprogesterone acetate (IM DMPA; Group 1), etonogestrel implant (ETG; Group 2), or copper intrauterine device (IUD; Group 3). Comparator groups included a contemporaneous dolutegravir (DTG) + IM DMPA (Group 4) and a historical DTG + ETG implant (Group 5). Participants were followed up for 12 (Groups 1 & 4) or 24 (Groups 2, 3, & 5) weeks. We analyzed serum MPA and ETG concentrations per visit using validated LC-MS/MS assays. We evaluated DOR-containing ART's effect on MPA or ETG log-transformed C min hormone concentrations with geometric mean ratios (GMR; 90% confidence interval), and a multivariate model adjusted for age and body mass index (BMI). We assessed safety (frequency, severity of adverse events (AE)) and tolerability (patient satisfaction, adherence) of DOR-containing ART. Results: A total of 108 Black African women were enrolled (Table 1): Group 1 (n=21), Group 2 (n=23), Group 3 (n=19), Group 4 (n=21), and Group 5 (n=24). GM Cmin MPA concentrations for Groups 1 and 4 were 561 and 551 pg/mL, respectively (GMR 1.01, 90% CI 0.82, 1.24); adjusted GMR 1.05, 90% CI 0.83, 1.34). GM C min ETG concentrations for Groups 2 and 5 were 312 and 225 pg/mL, respectively (GMR 1.15, 90% CI 1.04, 1.28; adjusted GMR 1.16, 90% CI 1.04, 1.30). Of all AEs reported to date (n=263), AEs attributable to DOR were at grade 1 or 2 and headaches were most frequent (n=31, 16%). Among the DOR groups, only 2 (3%) participants reported any dissatisfaction with this ART and adherence by pill count was 80% for >76% adherence. Conclusion: We did not detect significant effects of DOR-containing ART on MPA or ETG contraceptives. DOR-containing ART appears to be safe and tolerable among women concomitantly using hormonal contraceptives. These data support the viability of this option for those living in resource-limited settings who are intolerant of or unable to take DTG-containing ART.

Poster Abstracts

CROI 2024 168