A5263: A Randomized Comparison of Three Regimens of Chemotherapy with Compatible Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings

Background: Optimal treatment regimens for AIDS-associated Kaposi sarcoma, a frequent contributor to morbidity and mortality among people with HIV, have not been systematically evaluated in low-income and middle-income countries, where the disease is most common. In this study, we aimed to investigate optimal treatment strategies for advanced stage disease in areas of high prevalence and limited resources. Methods: In this open-label, non-inferiority trial, we enrolled people with HIV and advanced stage AIDS-associated Kaposi sarcoma attending 11 AIDS Clinical Trials Group sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) with a centralised computer system to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with antiretroviral therapy (ART; combined efavirenz, tenofovir disoproxil fumarate, and emtricitabine). The primary outcome was progression-free survival (PFS) at week 48, using a 15% non-inferiority margin to compare the investigational groups against the active control group. Safety was assessed in all eligible treated study participants. The study was registered with ClinicalTrials.gov, NCT01435018. Findings: 334 participants were enrolled between Oct 1, 2013, and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm, as per the recommendations of the Data and Safety Monitoring Board (DSMB). The etoposide plus ART arm also closed due to inferiority in March, 2016, following a DSMB recommendation. Week-48 PFS rates were higher in the paclitaxel plus ART arm than in both investigational arms. The absolute differences in PFS were –30% (95% CI –52 to –8) for the comparison of paclitaxel plus ART (week 48 PFS 50%, 32 to 67; n=59) and etoposide plus ART (20%, 6 to 33; n=59), and –20% (–33% to –7%) for the comparison of paclitaxel plus ART (64%, 55 to 73; n=138) and bleomycin and vincristine plus ART (44%, 35 to 53; n=132). Both CIs overlapped the non-inferiority margin. The most common adverse events, in 329 eligible participants who began treatment, were neutropenia (48 [15%]), low serum albumin (33 [10%]), weight loss (29 [9%]), and anaemia (28 [9%]), occurring at similar frequency across treatment arms. Interpretation: Non-inferiority of either investigational intervention was not shown, with paclitaxel plus ART showing superiority to both oral etoposide plus ART and bleomycin and vincristine plus ART, supporting its use in treating advanced AIDS-associated Kaposi sarcoma in resource-limited settings.背景：艾滋病相关卡波西肉瘤（AIDS-associated Kaposi sarcoma）是HIV感染者发病与死亡的常见诱因，但在该病高发的中低收入国家中，尚未对其最优治疗方案开展系统性评估。本研究旨在针对患病率高、资源有限地区的晚期艾滋病相关卡波西肉瘤，探索最优治疗策略。 方法：本项开放标签非劣效性试验，纳入巴西、肯尼亚、马拉维、南非、乌干达及津巴布韦的11家艾滋病临床试验组（AIDS Clinical Trials Group）中心就诊的HIV感染者及晚期艾滋病相关卡波西肉瘤患者。符合入组标准的受试者通过中心化计算机系统以1:1:1的比例随机分组，分别接受静脉注射博来霉素+长春新碱、口服依托泊苷（两个试验组），或静脉注射紫杉醇（对照组），同时联合抗反转录病毒治疗（ART：依非韦伦、富马酸替诺福韦二吡呋酯及恩曲他滨联合方案）。本研究的主要终点为第48周时的无进展生存期（PFS），以15%的非劣效界值比较试验组与阳性对照组的差异。所有符合入组标准且接受治疗的受试者均接受安全性评估。本研究已在ClinicalTrials.gov注册，编号NCT01435018。 结果：2013年10月1日至2018年3月8日期间，本研究共纳入334名受试者，后因数据与安全监察委员会（DSMB）建议，博来霉素+长春新碱联合ART组显示劣效，研究提前终止。依托泊苷联合ART组亦因DSMB建议，于2016年3月因劣效性结果提前关闭入组。紫杉醇联合ART组的第48周PFS率高于两个试验组。紫杉醇联合ART组与依托泊苷联合ART组的PFS绝对差值为-30%（95%置信区间：-52~-8），其中紫杉醇联合ART组第48周PFS率为50%（95% CI：32~67，n=59），依托泊苷联合ART组为20%（95% CI：6~33，n=59）；紫杉醇联合ART组与博来霉素+长春新碱联合ART组的PFS绝对差值为-20%（95%置信区间：-33~-7），前者第48周PFS率为64%（95% CI：55~73，n=138），后者为44%（95% CI：35~53，n=132）。两组置信区间均覆盖非劣效界值。在329名接受治疗的符合入组标准受试者中，最常见的不良事件为中性粒细胞减少症（48例，占15%）、低白蛋白血症（33例，占10%）、体重下降（29例，占9%）及贫血（28例，占9%），各治疗组的不良事件发生频率相似。 解读：本研究未证实任一试验干预措施的非劣效性，紫杉醇联合ART方案较口服依托泊苷联合ART及博来霉素+长春新碱联合ART方案均显示出优效性，支持其在资源有限地区用于治疗晚期艾滋病相关卡波西肉瘤。