Background: Advanced Kaposi sarcoma (KS) is a potentially life-threatening complication of HIV infection where access to chemotherapy is limited and HIV and KS herpesvirus coinfection rates are high. No evidence-based standard of care (SOC) guideline for advanced KS exists in settings where resources for safe preparation and administration of intravenous (IV) chemotherapy are scarce.
Methods: Participants at 11 ACTG sites in 5 sub-Saharan African countries and Brazil with measurable, previously-untreated, biopsy-proven, advanced (T1 stage) AIDS-related KS, adequate organ function and performance status, and limited (≤42 days) or no ART exposure were prospectively randomized 1:1:1 to receive oral etoposide plus ART (ET+ART), IV bleomycin and vincristine+ART (BV+ART), or IV paclitaxel+ART (PTX+ART). Randomization was stratified by CD4 count (< 100 or ≥100 cells/mm³) and country. PTX+ART, a standard regimen in resource-rich settings, was considered the active control. The trial was designed to evaluate whether ET+ART (an oral regimen affording significant logistical advantages in resource-limited settings [RLS]) and/or BV+ART (a commonly-used regimen in RLS) were noninferior to PTX+ART. Noninferiority was defined as a week-48 progression-free survival (PFS) rate within 15% of the PFS rate of the PTX+ART arm, projected at 65% and based on Kaplan-Meier methods.
Results: Entry and on-study characteristics are shown in Table 1. An interim Data and Safety Monitoring Board (DSMB) review in 3/2016 found the ET+ART arm inferior to the PTX+ART arm. The ET arm was closed; accrual continued for the two remaining arms. A subsequent interim DSMB review in 3/2018 found the BV+ART arm inferior to the PTX+ART arm; further accrual was halted. PTX was offered to all remaining eligible study participants. Week-48 PFS rates (95% CI) at the time each study arm was closed were 19% (8,35), 43% (34,53) and 63% (54,72), respectively for the ET+ART, BV+ART and PTX+ART arms (Fig.1). There were no safety concerns about any of the treatment regimens; ~90% had HIV VL < 400c/mL by week 12.
Conclusions: These findings establish PTX+ART as a SOC for initial treatment of advanced AIDS-KS, and underscore both the urgent need to improve the cancer therapeutic infrastructure and the accessibility of essential chemotherapeutic agents in RLS.