CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

649

Reduced Metformin Concentrations in Obese Women With HIV Treated With Dolutegravir Roland van Rensburg 1 , Tracy Kellermann 1 , Veshni Pillay-Fuentes Lorente 1 , Christiena du Plessis 1 , Catherine Orrell 2 , Innocent Maposa 1 , Gert van Zyl 1 , Giovanni Schifitto 3 , Eric Decloedt 1 1 Stellenbosch University, Cape Town, South Africa, 2 University of Cape Town, Cape Town, South Africa, 3 University of Rochester Medical Center, Rochester, NY, USA Background: The prevalence of obesity among women with HIV (WWH) is nearly 2-fold higher than in men with HIV, especially in sub-Saharan Africa. Obesity is closely associated with dysglycemia, and in the context of HIV frequently necessitates the co-administration of the first-line antiretroviral dolutegravir (DTG) and the insulin sensitizer metformin. However, a drug interaction exists whereby DTG inhibits the exclusive renal clearance of metformin. A pharmacokinetic study determined that DTG increased the overall metformin plasma exposure by 79%, prompting regulatory and guideline recommendations to limit the maximum metformin dose to 1000 mg/day when co-administered with DTG. The study was conducted in 15 white, male, non obese healthy volunteers, in contrast to the largest target population of black African, obese WWH. Importantly, obesity has been linked to lower metformin exposures, and our study aimed to verify the metformin pharmacokinetic exposure in the specific target population of obese WWH. Methods: We conducted intensive plasma sampling over 8 timepoints in virally-suppressed WWH receiving metformin 1000 mg and DTG 50 mg daily at steady-state. Both drugs were administered with a moderate-fat meal under observation. Dual-energy X-ray absorptiometry (DEXA) was performed to quantify body fat composition. Non-compartmental analysis of metformin and DTG concentrations was performed, and our findings compared to the reference study. Linear regression was used to identify covariates associated with metformin exposure. Results: We enrolled 15 participants with a mean body mass index of 45.6 kg/m 2 (range 35.6–56.7). Metformin and DTG exposures in obese WWH were approximately half of that in the non-obese healthy volunteers (Table 1). Metformin and DTG clearance were 1.7- and 2.2-fold higher, respectively. We did not detect an association between body fat composition and metformin or DTG exposures. Conclusions: Limiting metformin to 1000 mg daily is likely to lead to subtherapeutic exposures in obese WWH on DTG. Lower metformin exposures appear to be due to the reduced inhibitory effect of the lower DTG exposure on metformin clearance. Increased volume of distribution due to obesity may also contribute to lower exposures. Our study included obese patients only, and we could therefore not establish an association of body composition with pharmacokinetic exposures. Future studies should include the full range of body mass indices, and determine optimal metformin dosing when co-administered with DTG.

collected. At week 12, intensive PK samples were collected at hrs 0, 0.5, 1, 2, 4 and 24, and analyzed for plasma BIC, FTC, TAF, and TFV; samples at 0, 4, and 24 hrs were analyzed for TFV-DP and FTC-TP in PBMC and DBS. Plasma AUC, C max , and C trough were determined with non-compartmental methods; Css was calculated for TFV-DP and FTC-TP. Plasma PK values were compared with PWH with similar renal function [package inserts]; TFV-DP and FTC-TP were compared with PWH values from QUANTI-TAF [NCT04065347; controls]. Results: Final results included 19 subjects, 18 with evaluable PK, mean age 56 [range 38 – 69] yrs; 13 male; 17 Black; 8 transplanted in Hope in Action initiative. There were no statistical differences observed in the means of renal safety parameters. Mean CrCl day 1 vs week 72: 54.9 vs 60.9 mL/min, p=0.11. Tacrolimus (TAC) trough concentrations remained stable, without need for dose adjustment. HIV viral suppression was maintained in all (< 50 c/mL). Plasma PK AUC were comparable to historical data in PWH with similar renal function (CrCl 30-59ml/min; Table), which were approximately 2-fold higher than values in PWH with normal renal function, as expected. The CrCl was higher in QUANTI TAF controls (mean >60ml/min) than study. Geometric mean for TFV-DP in DBS was 5775 (study) and 3386 (controls) fmol/punches, and PBMC was 1637 (study) 570 (controls) fmol/10 6 cells and that for FTC-TP in PBMC was 15.4 (study) and 5.6 (controls) pmol/10 6 cells. Conclusions: BIC, TAF, TFV, and FTC AUCs were comparable to historical data for PWH with CrCl between 30-60ml/min for which B/F/TAF is indicated. The higher concentrations for TFV-DP and FTC-TP were commensurate with plasma increases for CrCl of 30-60ml/min. CrCl and TAC doses remained stable throughout and HIV remained suppressed at 72 weeks. B/F/TAF demonstrated a high safety margin and was efficacious in PWH status post-renal transplant. Tenofovir Diphosphate in Dried Blood Spots and HIV-1 RNA Suppression Among PWH on TAF (ACT Study) Ryan P. Coyle 1 , Mary Morrow 1 , Sarah C. Mann 1 , Nicholas Barker 1 , Erin Garst 1 , Vincent A. Mainella 1 , Stefanie Schwab 1 , Corwin Coppinger 1 , Lucas Ellison 1 , Jia-Hua Zheng 1 , Lane Bushman 1 , Kristina Brooks 1 , Samantha Mawhinney 1 , Jose Castillo-Mancilla 2 , Peter Anderson 1 1 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2 ViiV Healthcare, Brentford, UK Background: ACT (NCT05335590) is an ongoing observational study that aims to evaluate tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots (DBS) among persons with HIV (PWH) receiving tenofovir alafenamide (TAF)- based antiretroviral therapy (ART) with suppressed compared with detectable HIV-1 RNA. Previously, QUANTI-TAF (NCT04065347) reported a pharmacokinetic (PK)-based TFV-DP in DBS benchmark of ≥1800 fmol/punches for PWH with ≥85% adherence using digital pills to objectively quantify adherence. We investigated the relationship between this concentration threshold and HIV-1 RNA suppression (<200 c/mL) in the ACT Study. Methods: PWH prescribed TAF-based ART (25mg ± booster or 10mg + booster) for ≥3 months were prospectively enrolled and completed up to three convenience-based visits within 48 weeks during which HIV-1 RNA and DBS were collected. Results through July 18, 2024 were included in analysis. We reported TFV-DP in DBS mixed model estimates as geometric mean (GM [95% CI]) and used generalized linear mixed effects models with a logit link to estimate the odds ratio (OR [95% CI]) for HIV-1 RNA suppression (<200 c/mL) according to dichotomized TFV-DP in DBS (<1800 or ≥1800 fmol/punches). Results: Paired TFV-DP in DBS and HIV-1 RNA results were available in 69 participants (205 person-visits): 61 (88%) males, 6 (9%) females, and 2 (3%) transgender persons; 63 (91%) were receiving unboosted TAF 25mg or boosted TAF 10mg. Median (IQR) age was 55 (42-61) years. HIV-1 RNA was <20, 20-199, and ≥200 c/mL at 141 (69%), 51 (25%), and 13 (6%) visits, respectively. GM (95% CI) TFV-DP in DBS for PWH with HIV-1 RNA <20, 20-199, and ≥200 c/mL was 3583 (3102, 4138), 3314 (2413, 4551), and 898 (565, 1428) fmol/punches, respectively (Figure). For TFV-DP in DBS ≥1800 fmol/punches, the OR for an

Poster Abstracts

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650

Pharmacokinetics of Switching to B/F/TAF in PWH Post-Renal Transplant: BIK Switch Study Corwin Coppinger 1 , Stanley Cooper 2 , Britta Witting 2 , Ryan P. Coyle 1 , Alexandra Dunbar 1 , Lucas Ellison 1 , Lane Bushman 1 , Kristina Brooks 1 , Peter Anderson 1 , Catherine Small 2 1 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2 Weill Cornell Medicine, New York, NY, USA Background: The impact of antiretroviral therapy (ART) on renal preservation is critical for persons with HIV (PWH) post-renal transplant. Clinical trials have demonstrated B/F/TAF is safe and efficacious, with low risk of renal toxicity. Little is known about its pharmacokinetics (PK) in PWH post-renal transplant. Methods: Single arm, open-label, switch study among virally suppressed (HIV VL < 50 c/mL) PWH post renal transplant, switched from baseline ART to B/F/ TAF and followed for 72 weeks. Baseline and monitoring of renal function (CrCl), viral efficacy (HIV VL), and tacrolimus (TAC) trough concentrations were

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