Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial

Abstract

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.

Funding: US National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health.

Figure 1:. Trial profile

ART=antiretroviral therapy. *Potential participants could be screened more than once and be excluded for multiple reasons; these numbers reflect discrete screening events. †Participants were randomly assigned equally (1:1:1) to the three study arms until March, 2016, when the etoposide plus ART arm was closed, after which participants were randomly assigned equally (1:1) to the two remaining arms (paclitaxel plus ART and bleomycin and vincristine plus ART). ‡Other includes the participant having withdrawn consent, the participant not being willing to adhere to requirements, the participant not being able to get to the clinic, site closure, the participant being unable to continue because of severe debilitation, or the site being unable to contact the participant.

Figure 2:

Comparison of 48-week progression-free survival rates (A), 48-week death rates (B), and 48-week composite progression or death rates (C) according to initial randomised treatment

Figure 3:. Time to death and time to death or progression according to randomised treatment

Kaplan-Meier plots of the time to death (A and B) and composite of time to death or progression (C and D) summarised by treatment comparison. Hazard ratio with 95% CI and p value are from Cox proportional-hazards regression analysis. NE=not estimable.

Figure 4:. HIV-1 RNA and CD4 cell count changes

Proportion of participants in each HIV-1 RNA category by study week for etoposide vs paclitaxel (A) and bleomycin and vincristine vs paclitaxel (B); and median (IQR as error bars) change in CD4 cell counts summarised by study week for etoposide vs paclitaxel (C) and bleomycin and vincristine vs paclitaxel (D).