EACS2023: 497 Efficacy and safety of doravirine/islatravir (100 mg/0.75 mg) once daily in heavily treatment-experienced persons with HIV-1: week 49 results from a phase 3 trial R. Mngqibisa , I. Khaertynova , P. Kumar , A. Carr , S. Haider , Y. Zhang , T. Correll , E. Asante-Appiah , W. Greaves Enhancing Care Foundation, King Edward Hospital, Durban, South Africa, Kazan State Medical Academy, Kazan, Russian Federation, Georgetown University, Washington, DC, United States, St Vincent's Hospital, Sydney, Australia, McMaster University, Hamilton, Canada, Merck & Co., Inc., Rahway, United States General data Abstract category: Antiretroviral therapy – randomised clinical trials Abstract body Purpose: Doravirine/islatravir (DOR/ISL) is being investigated for the treatment of HIV-1. This phase 3 trial evaluated the efficacy and safety of DOR/ISL in heavily treatment-experienced (HTE) participants with HIV‑1. Method: This 2-part trial (MK8591A-019; NCT04233216) evaluated participants on failing antiretroviral therapy (ART) for ≥3 months with confirmed HIV‑1 RNA ≥500 copies/mL and triple-class resistant HIV-1 (resistance to NRTI, NNRTI, and either PI or InSTI classes), leaving ≤2 available antiretrovirals for a viable regimen. In part 1, eligible participants were randomized 1:2:1:1 to add blinded ISL 0.75 mg, DOR 100 mg, DOR/ISL (100 mg/0.75 mg), or placebo once-daily to their ART from day (D) 1 to D7. On D8 (part 2), all participants were given open-label DOR/ISL plus optimized background therapy through week (W) 97. Primary endpoints were percentage of participants achieving ≥0.5 log decrease in HIV-1 RNA at D8 and safety assessments through W49. Enrollment stopped early due to findings of decreased lymphocyte and CD4+ T-cell counts in other ISL studies. Results: Thirty-five participants completed part 1; 5 participants discontinued by W49. All participants were hepatitis C negative and had HIV-1 with NRTI, NNRTI, and PI substitutions; 71% had InSTI resistance. Participants had baseline median HIV-1 RNA ≥4.0 log copies/mL; most had baseline CD4+ T-cell counts ≤200 cells/mm (Table 1). By D8, 6 participants (85.7%) in DOR/ISL+ART and none in placebo+ART achieved ≥0.5 log decrease in HIV-1 RNA (Figure 1). The D8 mean changes in HIV-1 RNA and CD4+ T-cells were highest in DOR/ISL+ART (Figure 2). Differences in CD4+ T-cells between groups at W49 were modest. Few serious AEs were reported (Table 2). Three participants discontinued due to drug-related AEs with no attributable clinical infections. Table 1. Participant demographics and baseline characteristics ISL+ART n = 7 DOR+ART n = 14 DOR/ISL+ART n = 7 PBO+ART n = 7 Total N = 35 Male, n (%) 5 (71.4) 10 (71.4) 6 (85.7) 6 (85.7) 27 (77.1) Age, median (range), years 44 (32-63) 54 (28-61) 55 (35-65) 43 (34-60) 52 (28-65) Race, White, n (%) 2 (28.6) 7 (50.0) 6 (85.7) 5 (71.4) 20 (57.1) CD4+ T-cell count, >200 cells/mm , n (%) 3 (42.9) 3 (21.4) 3 (42.9) 2 (28.6) 11 (31.4) Plasma HIV-1 RNA, median (range), log copies/mL 4.0 (2.7-5.3) 4.3 (2.5-5.7) 4.6 (2.9-5.1) 4.0 (3.6-5.3) 4.3 (2.5-5.7) HIV-1 with M184V/I substitution, n (%) 6 (85.7) 14 (100.0) 6 (85.7) 7 (100.0) 33 (94.3) ART, antiretroviral therapy; DOR, doravirine; InSTI, integrase strand transfer inhibitor; ISL, islatravir; PBO, placebo; PI, protease inhibitor. Table 2. Adverse event summary by treatment group from D1 to W49 n (%) ISL+ART n = 7 DOR+ART n = 14 DOR/ISL+ART n = 7 PBO+ART n = 7 Total N = 35 ≥1 AEs 5 (71.4) 12 (85.7) 6 (85.7) 6 (85.7) 29 (82.9) DRAEs 2 (28.6) 8 (57.1) 5 (71.4) 2 (28.6) 17 (48.6) Grade ≥3 AEs 1 (14.3) 5 (35.7) 0 2 (28.6) 8 (22.9) Grade ≥3 DRAEs 0 2 (14.3) 0 0 2 (5.7) Serious AEs 1 (14.3) 1 (7.1) 0 0 2 (5.7) Serious DRAEs 0 0 0 0 0 Discontinuations Due to AE 0 2 (14.3) 1 (14.3) 0 3 (8.6) Due to DRAE 0 2 (14.3) 1 (14.3) 0 3 (8.6) Due to serious AE 0 0 0 0 0 AE, adverse event; ART, antiretroviral therapy; D, day; DOR, doravirine; DRAE, drug-related adverse event; ISL, islatravir; PBO, placebo; W, week. 1 2 3 4 5 6 6 6 6 1 2 3 4 5 6 10 10 3 10 3 10
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