Intravenous paclitaxel plus antiretroviral therapy (ART) has clear advantages over alternative chemotherapy regimens for the treatment of advanced HIV-related Kaposi sarcoma in low- and middle-income settings, according to the results of a landmark study. Paclitaxel plus ART was compared to cheaper and easier-to-administer therapies and was found to be superior in terms of progression, overall response and response duration.
“Our results provide support for preferring paclitaxel over a commonly used regimen of bleomycin and vincristine or an oral etoposide regimen as first-line chemotherapy for advanced Aids-related Kaposi sarcoma in resource-limited settings,” comment the investigators.
However, they acknowledge that making paclitaxel available will be a significant challenge for many health systems, especially in terms of cost, resources and manpower. “Analysis of the cost-effectiveness of different Kaposi sarcoma treatments would further inform national strategies,” they add.
“The study failed to show non-inferiority of either investigational arm compared to paclitaxel plus ART,” comment the authors. “The clinical interpretation is that paclitaxel plus ART is a superior treatment to both oral etoposide plus ART and bleomycin and vincristine plus ART.”
However, the investigators acknowledge that use of paclitaxel will prove challenging for many low- and middle-income countries. “The overall costs of treatment with paclitaxel plus ART are likely to be higher than for alternative regimens evaluated in this study,” conclude Dr Susan E Krown and her colleagues at the AIDS Malignancy Consortium, New York, Centre for Biostatistics in AIDS Research, Harvard TH Chan School of Public Health, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frontier Science Foundation, UNC Project-Malawi, Lilongwe, department of medicine, University of North Carolina at Chapel Hill School of Medicine, and the University of Colorado School of Medicine.
“Not only is paclitaxel generally more costly than the alternative regimens, but its safe administration requires use of specialised filters and pre-medications to prevent hypersensitivity reactions, further increasing the costs of treatment. Thus, it remains to be seen whether adopting paclitaxel plus ART as the standard of care would be a cost-effective use of resources.”
An accompanying editorial by Dr Esther Freeman and colleagues commended the study. They note the survival rates associated achieved with paclitaxel were comparable to those achieved in richer countries. However, they also note several challenges that need to be overcome for this treatment to become a viable option for many resource-limited countries: cost, scaling up of oncology services and availability of generics.
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.
Susan E Krown, Carlee B Moser, Patrick MacPhail, Roy M Matining, Catherine Godfrey, Stephanie R Caruso, Mina C Hosseinipour, Wadzanai Samaneka, Mulinda Nyirenda, Naftali W Busakhala, Fred M Okuku, Josphat Kosgei, Brenda Hoagland, Noluthando Mwelase, Vincent O Oliver, Henriette Burger, Rosie Mngqibisa, Mostafa Nokta, Thomas B Campbell, Margaret Z Borok