Indirect Treatment Comparisons of Lenacapavir Plus Optimized Background Regimen Versus Other Treatments for Multidrug-Resistant Human Immunodeficiency Virus.

Heavily treatment-experienced (HTE) people with human immunodeficiency virus (HIV) (PWH) may not achieve virologic suppression (VS) with combination antiretroviral therapy due to multidrug resistance (MDR), intolerance, and safety concerns. These PWH often receive highly individualized treatment regimens, but these regimens may not enable PWH to achieve VS, thereby halting disease progression. Novel medications are required for treating individuals with MDR HIV. Lenacapavir (LEN), a first-in-class HIV capsid inhibitor, is under investigation for the treatment of HTE individuals with MDR HIV in the phase 2/3 CAPELLA study. This study aimed to compare LEN plus optimized background regimen (OBR) with fostemsavir (FTR) + OBR, ibalizumab (IBA) + OBR, and OBR alone in terms of VS, CD4 cell count change from baseline, immunologic recovery, and discontinuation due to adverse events, using indirect treatment comparisons. A systematic review identified clinical evidence on HIV-1 treatments in HTE PWH. A feasibility assessment evaluated the identified studies for indirect treatment comparison analyses based on population characteristics, interventions, comparators, and outcomes of interest. Unanchored simulated treatment comparisons of LEN + OBR versus comparators were conducted. LEN + OBR had 6.57 times higher odds of VS at weeks 24 to 28 than FTR + OBR (95% confidence interval [CI] 1.34-32.28), 8.93 times higher odds of VS than IBA + OBR (95% CI 2.07-38.46), and 12.74 times higher odds of VS than OBR alone (95% CI 1.70-95.37). Change from baseline in CD4 cell count was similar across LEN + OBR, FTR + OBR, and IBA + OBR. LEN + OBR has statistically significantly greater odds of VS at weeks 24 to 28 than its comparators and represents a novel treatment for people with MDR HIV.

Chatzidaki I ，Curteis T ，Luedke H ，Mezzio DJ ，Rhee MS ，McArthur E ，Eddowes LA ... -  《-》

US cost-utility model of lenacapavir plus optimized background regimen (OBR) vs fostemsavir plus OBR and ibalizumab plus OBR for people with HIV with multidrug resistance.

Vardanega V ，New E ，Mezzio D ，Eddowes LA ... -  《-》

Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir.

Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure. At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.

Margot NA ，Naik V ，VanderVeen L ，Anoshchenko O ，Singh R ，Dvory-Sobol H ，Rhee MS ，Callebaut C ... -  《-》

Cross-resistance to entry inhibitors and lenacapavir resistance through Week 52 in study CAPELLA.

Margot N ，Pennetzdorfer N ，Naik V ，Rhee M ，Callebaut C ... -  《-》

Comparative Efficacy and Safety of Fostemsavir in Heavily Treatment-Experienced People With HIV-1.

Heavily treatment-experienced (HTE) people with multidrug-resistant HIV-1 have limited treatment options. Treatment with the first-in-class attachment inhibitor fostemsavir in addition to optimized background therapy (OBT) resulted in sustained virologic and immunologic responses in HTE participants throughout 96 weeks in the BRIGHTE trial. In the absence of long-term direct comparative evidence between fostemsavir-based and other antiretroviral regimens, this analysis indirectly compares efficacy and safety across relevant available trials, adjusting for demographic and baseline characteristics. A systematic literature review was conducted to identify trials with designs and populations comparable to BRIGHTE. Using matching-adjusted indirect comparison analyses, individual participant data from BRIGHTE were reweighted to create balanced populations across trials, and efficacy and safety outcomes were compared. Three comparator trials were identified, 2 of which reflected an optimized therapy without fostemsavir (OBT alone): TMB-301 (ibalizumab and OBT), BENCHMRK-1/-2 (OBT alone), and VIKING-3 (OBT alone). Compared with ibalizumab and OBT (N = 40), fostemsavir and OBT (unadjusted, N = 347; adjusted, N = 236) were associated with numerically higher nonsignificant odds of virologic suppression (odds ratio [OR] = 1.44; 95% CI, 0.74-2.80; P = 0.284) and a similar increase in CD4+ cell count of approximately 65 cells/mm3 from baseline through week 24 (mean difference = 7.05 cells/mm3; 95% CI, -60.88 to 74.98 cells/mm3; P = 0.834). Compared with OBT from BENCHMRK-1/-2 (N = 237), fostemsavir and OBT (adjusted, N = 126) were associated with significantly higher odds of virologic suppression (OR = 3.26; 95% CI, 2.08-5.11; P < 0.001) and increased CD4+ cell count (135.78 cells/mm3; 95% CI, 91.93-179.63 cells/mm3; P < 0.001) at week 96. Compared with OBT from VIKING-3 (N = 183), fostemsavir and OBT (adjusted, N = 78) were associated with numerically higher odds of virologic suppression (OR = 1.34; 95% CI, 0.78-2.30; P = 0.297) and a modest CD4+ cell count increase (26.86 cells/mm3; 95% CI, -10.79 to 64.52; P = 0.162) through week 48; however, differences were not significant. All-cause discontinuations and safety comparisons varied across studies. Although matching-adjusted indirect comparison analyses have limitations, these results support the use of fostemsavir and OBT as an important treatment option in HTE people with multidrug-resistant HIV-1.

Anderson SJ ，van Doornewaard A ，Turner M ，Jacob I ，Clark A ，Browning D ，Schroeder M ... -  《-》