Susan E Krown1, Carlee B Moser2, Patrick MacPhail3, Roy M Matining2, Catherine Godfrey4, Stephanie R Caruso5, Mina C Hosseinipour6, Wadzanai Samaneka7, Mulinda Nyirenda8, Naftali W Busakhala9, Fred M Okuku10, Josphat Kosgei11, Brenda Hoagland12, Noluthando Mwelase3, Vincent O Oliver13, Henriette Burger14, Rosie Mngqibisa15, Mostafa Nokta16, Thomas B Campbell17, Margaret Z Borok18. 1. AIDS Malignancy Consortium, New York, NY, USA. Electronic address: krowns@mskcc.org. 2. Center for Biostatistics in AIDS Research, Harvard T H Chan School of Public Health, Boston, MA, USA. 3. Clinical HIV Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa. 4. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 5. Frontier Science Foundation, Amherst, NY, USA. 6. UNC Project-Malawi, Lilongwe, Malawi; Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Division of Infectious Diseases, Chapel Hill, NC, USA. 7. Parirenyatwa Clinical Research Site, Harare, Zimbabwe. 8. Johns Hopkins Research Project, University of Malawi College of Medicine, Blantyre, Malawi. 9. Moi University School of Medicine, Eldoret, Kenya. 10. Uganda Cancer Institute, Kampala, Uganda. 11. Kenya Medical Research Institute, USA Medical Directorate for Africa/Kenya, Kericho, Kenya. 12. Oswaldo Cruz Foundation, Evandro Chagas National Institute of Infectious Diseases, Rio de Janeiro, Brazil. 13. Kenya Medical Research Institute, Centre for Global Health Research, Centers for Disease Control and Prevention, Kisumu CRS, HIV-Research Branch, Kisumu, Kenya. 14. Family Clinical Research Unit CRS, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa; Division of Radiation Oncology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa. 15. Durban International Clinical Research Site, Enhancing Care Foundation, Durban, South Africa. 16. Office of HIV and AIDS Malignancy, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 17. Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA. 18. Department of Medicine, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.
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 thebleomycin 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.
RCT Entities:
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.
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