CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusions: Despite significant reductions in DTG exposure with RIF, C tau was reduced to a similar extent with higher RIF doses, suggesting maximum induction at standard 10mg/kg. This is supported by preliminary probe data. Additionally, most individuals remained above the DTG EC 90 . Further DTG dose adjustment may not be necessary with high dose RIF.

10 weeks resulted in 14% and 16% deviation in estimates of CL/F and AUC 0-inf relative to estimates from the full profile. Subsequent truncation resulted in significant deviation of estimates from those achieved with the full profile for all parameters (>26% deviation) with poorer precision of estimates reflected in higher relative standard errors. Conclusions: Analysis was undertaken using a single dataset for CAB LAI, which represents a best-case scenario for a generic product by mimicking an identical product given to the same recipients. Despite this low bar, truncation of the profiles to below 10 weeks for 800mg fittings was unable to accurately predict parameters determined from the full profile. The analysis sheds light on the complexity of the challenge and may be useful to inform further development of strategies for accelerated “equivalence” evaluation for generic LAI.

Poster Abstracts

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TAF Achieves Adequate Intracellular Tenofovir-DP Concentrations With Rifampicin-Based TB Therapy Rephaim Mpofu 1 , Nomathemba Chandiwana 2 , Simiso M. Sokhela 2 , Michelle Moorhouse 2 , Francois Venter 2 , Peter Anderson 3 , Lubbe Wiesner 1 , Marta Boffito 4 , Gary Maartens 1 , Phumla Sinxadi 1 1 University of Cape Town, Cape Town, South Africa, 2 Ezintsha, Johannesburg, South Africa, 3 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 4 Chelsea and Westminster NHS Foundation Trust, London, UK Background: Co-administration of rifampicin with tenofovir alafenamide fumarate (TAF) significantly reduces plasma tenofovir and intracellular tenofovir diphosphate (TFV-DP) concentrations. Standard dose TAF with rifampicin (RIF) was associated with TFV-DP concentrations that were markedly higher than those observed with tenofovir disoproxil fumarate (TDF) without rifampicin in healthy volunteers, however, data from people with TB/HIV-1 are needed to inform guidelines. Methods: An open-label, three-period sequential PK study was conducted in participants with HIV-1 that were on antiretroviral therapy (ART) and virally suppressed, and who were also in the maintenance phase of therapy for RIF sensitive TB. Steady-state TFV‑DP and plasma tenofovir concentrations were measured during three treatment periods: 1) TDF+RIF during the maintenance phase of TB therapy; 2) TAF+RIF after one month of treatment during the maintenance phase of TB therapy, and 3) TDF one month after completion of TB therapy. TAF and TDF were dosed at the standard daily doses (25 mg and 300 mg respectively) and were combined with efavirenz (600 mg), and either emtricitabine (200 mg) or lamivudine (300 mg). Area under the concentration time curve over 24 hours (AUC 0-24h ) were estimated, and AUC 0‑24h geometric mean ratios (GMR) with 95% confidence intervals (95% CI) were calculated to compare concentrations across periods. Results: Eighteen participants were enrolled: median age of 41 years; 56% male. TAF+RIF was associated with a TFV-DP AUC 0-24h GMR of 5.58 (95% CI 4.34, 7.17) and 5.43 (3.90, 7.55) when compared with TDF+RIF and TDF-only, respectively (Figure). The plasma tenofovir AUC 0-24h GMR was 0.07 (0.06, 0.09) when treatment with TAF+RIF was compared with both TDF+RIF and TDF-only periods. Conclusions: TAF and RIF co-administration was associated with higher TFV-DP concentrations than TDF, both with and without RIF. This study confirms previous findings among healthy volunteers and supports the co-administration of standard-dose TAF with RIF in the management of people with TB/HIV-1 co-infection.

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Drug Interactions Between Dolutegravir (DTG) and Escalating Doses of Rifampicin (RIF): DORIS Study Yashna Singh 1 , Jerome R. Semakula 2 , Peter Chodacki 1 , Sheetal Kassim 1 , Lucy Read 3 , Laura Dickinson 4 , Laura J. Else 4 , Helen E. Reynolds 4 , Jim Read 3 , Duolao Wang 3 , Catriona Waitt 4 , Catherine Orrell 5 , Saye Khoo 4 , for the DoRIS Study Group 1 Desmond Tutu HIV Foundation, Cape Town, South Africa, 2 Infectious Diseases Institute, Kampala, Uganda, 3 Liverpool School of Tropical Medicine, Liverpool, UK, 4 University of Liverpool, Liverpool, UK, 5 University of Cape Town, Cape Town, South Africa Background: Evidence suggests higher RIF doses may be more effective for tuberculosis (TB) treatment. It is unclear if incremental RIF doses will increase risk of drug interactions through more potent induction of CYP3A4 enzymes and drug transporters. Some data suggest induction may be at maximum with standard dose (10mg/kg). Using standard, medium and high RIF doses, we characterised the impact of UGT1A1 induction on the pharmacokinetics (PK) of DTG, and induction of CYP3A4 on midazolam (MDZ) and the transporter P-gp on digoxin (DIG). Methods: DoRIS was an open-label, fixed-sequence, 4-phase study in TB-infected HIV-negative adults nearing the end of the continuation phase of standard anti-TB therapy (ATT). DTG (50mg BID for 1 week) exposure from intensive sampling was compared when dosed with RIF at 10mg/kg (Day 14), 20mg/kg (Day 28) and 35mg/kg (Day 42), and ≥4wks post-ATT (at 50mg OD). Single dose MDZ (0.025mg/kg) and DIG (0.25mg) were given on PK sampling days. Changes in PK parameters were evaluated by geometric mean ratio (GMR) and considered statistically significant if the 90% CI did not cross 1.0. Results: Of 36 participants from South Africa and Uganda [11% female at birth, median (range) age 35years (18-62), weight 61kg (50-93), DTG and RIF PK were available from 33 individuals (Figure 1). Geometric mean (GM) DTG C tau were 665, 660, 657ng/mL on Day 14, Day 28, Day 42 vs. 687 ng/mL post-ATT (GMR, 90%CI: 1.01 [0.75-1.36]; 0.97 [0.75-1.27]; 0.87 [0.71-1.07], respectively). DTG C max and AUC 0-12 were significantly lower with RIF on Day 14: 0.59 [0.52-0.67] and 0.72 [0.64-0.81], Day 28: 0.60 [0.51-0.69] and 0.71 [0.62-0.81], Day 42: 0.59 [0.53-0.65] and 0.72 [0.65-0.80]. Proportion of C tau above DTG EC 90 (342 ng/mL) was 79, 88, 90 and 83% on Day 14, Day 28, Day 42 and post-ATT, respectively. RIF increased supraproportionally with dose, AUC 0-12 GMR, 90%CI: 2.93 [2.35-3.66] (20mg/kg) and 4.60 [3.65-5.79] (35mg/kg). Preliminary MDZ and DIG data showed little change with higher RIF doses (D28, D42) compared to standard dose (MDZ C max 0.99 [0.58-1.69]; 0.99 [0.73-1.34] and DIG C max 1.11 [0.84-1.47]; 0.97 [0.74-1.26]; n=5).

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