GlaxoSmithKline, Brentford, Middlesex, United Kingdom.
HEOR Ltd, Cardiff, United Kingdom.
Clin Ther. 2022 Jun;44(6):886-900. doi: 10.1016/j.clinthera.2022.04.007. Epub 2022 May 21.
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/mm from baseline through week 24 (mean difference = 7.05 cells/mm; 95% CI, -60.88 to 74.98 cells/mm; 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/mm; 95% CI, 91.93-179.63 cells/mm; 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/mm; 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.
多重耐药 HIV-1 的大量治疗经验（HTE）患者的治疗选择有限。在 BRIGHTE 试验中，在优化背景治疗（OBT）的基础上添加首个附着抑制剂福替司韦，可使 HTE 参与者在 96 周内持续实现病毒学和免疫应答。在缺乏福替司韦与其他抗逆转录病毒方案之间长期直接比较证据的情况下，本分析通过调整人口统计学和基线特征，间接比较了各个相关试验中的疗效和安全性。
进行了系统文献检索，以确定与 BRIGHTE 设计和人群具有可比性的试验。使用匹配调整的间接比较分析，将 BRIGHTE 中的个体参与者数据重新加权，以在试验之间创建平衡人群，并比较疗效和安全性结局。
确定了三项比较试验，其中两项反映了没有福替司韦的优化治疗（仅 OBT）：TMB-301（ibalizumab 和 OBT）、BENCHMRK-1/-2（仅 OBT）和 VIKING-3（仅 OBT）。与 ibalizumab 和 OBT（N=40）相比，福替司韦和 OBT（未调整，N=347；调整，N=236）的病毒学抑制优势比（OR）数值更高，但无显著意义（OR=1.44；95%CI，0.74-2.80；P=0.284），并且在第 24 周时从基线开始 CD4 细胞计数增加约 65 个细胞/mm（平均差值=7.05 个细胞/mm；95%CI，-60.88 至 74.98 个细胞/mm；P=0.834）。与 BENCHMRK-1/-2 的 OBT 相比（N=237），福替司韦和 OBT（调整，N=126）的病毒学抑制优势比（OR）更高，差异有统计学意义（OR=3.26；95%CI，2.08-5.11；P<0.001），并且在第 96 周时 CD4 细胞计数增加（135.78 个细胞/mm；95%CI，91.93-179.63 个细胞/mm；P<0.001）。与 VIKING-3 的 OBT 相比（N=183），福替司韦和 OBT（调整，N=78）的病毒学抑制优势比（OR）更高，但无统计学意义（OR=1.34；95%CI，0.78-2.30；P=0.297），且在第 48 周时 CD4 细胞计数略有增加（26.86 个细胞/mm；95%CI，-10.79 至 64.52；P=0.162）。所有原因停药和安全性比较因研究而异。
尽管匹配调整的间接比较分析存在局限性，但这些结果支持在多重耐药 HIV-1 的大量治疗经验患者中使用福替司韦和 OBT 作为重要的治疗选择。
