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

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 t...

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Published in:	The Lancet (British edition) Vol. 395; no. 10231; pp. 1195 - 1207
Main Authors:	Krown, Susan E, Moser, Carlee B, MacPhail, Patrick, Matining, Roy M, Godfrey, Catherine, Caruso, Stephanie R, Hosseinipour, Mina C, Samaneka, Wadzanai, Nyirenda, Mulinda, Busakhala, Naftali W, Okuku, Fred M, Kosgei, Josphat, Hoagland, Brenda, Mwelase, Noluthando, Oliver, Vincent O, Burger, Henriette, Mngqibisa, Rosie, Nokta, Mostafa, Campbell, Thomas B, Borok, Margaret Z, Moses, Agnes, Kanyama, Cecilia, Mukwekwerere, Pamela, Gudza, Ivy, Chauwa, Felluna, Ulaya, Godwin, Kutto, Irene, Cheruiyot, Priscilla, Okello, Clement, Nakaganda, Annet, Koskei, Geoffrey, Keter, Winnie, Netto, Juliana, Baião, Tamiris, Govender, Iveshni, O'Connell-Maritz, Jessica, Cain, Kevin, Okanda, John, Cornelissen, Lynne, Van Schalkwyk, Marije, Sikhosana, Rejoice, Ngcobo, Minenhle, Lee, Jeannette Y., Harrison, Taylor, Wachsman, William, Shin, Katherine, Evans, Scott, Rothenberg, Jennifer, Hosey, Lara, McCarthy, Sean, Martinez-Maza, Otoniel, Rinaldo, Charles, Dittmer, Dirk, Fletcher, Courtney, Rudek, Michelle, Asmelash, Aida, Hughes, Valery, Schouten, Jeffrey, Shugarts, David, Kujinga, Tapiwanashe, Zadzilka, Amanda, Kerui, Fredrick, Robertson, Debora, Rooney, James, Sewal, Krishna, Gottshall, Brian
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 11-04-2020 Elsevier Limited
Subjects:	Acquired immune deficiency syndrome Active control Adult Africa AIDS AIDS-Related Opportunistic Infections - drug therapy AIDS-Related Opportunistic Infections - mortality Allergies Anemia Anti-HIV Agents - administration & dosage Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - adverse effects Antineoplastic Agents, Phytogenic - administration & dosage Antineoplastic Agents, Phytogenic - adverse effects Antineoplastic Combined Chemotherapy Protocols Antiretroviral agents Antiretroviral drugs Antiretroviral therapy Antiretroviral Therapy, Highly Active - methods Bleomycin Bleomycin - administration & dosage Bleomycin - adverse effects Cancer therapies Chemotherapy Clinical trials Developing Countries Drug therapy Drug Therapy, Combination Efavirenz Emtricitabine Etoposide Etoposide - administration & dosage Etoposide - adverse effects Female Health services HIV Human immunodeficiency virus Humans Income Infections Infectious diseases Infrastructure Intravenous administration Kaposis sarcoma Low income groups Male Medical diagnosis Morbidity Neutropenia Paclitaxel Paclitaxel - administration & dosage Paclitaxel - adverse effects Progression-Free Survival Safety Sarcoma Sarcoma, Kaposi - drug therapy Sarcoma, Kaposi - mortality Serum albumin Tenofovir Vincristine Vincristine - administration & dosage Vincristine - adverse effects Weight loss Africa Brazil Zimbabwe Uganda Malawi
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Summary:	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. 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. 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. 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. US National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health.
Bibliography:	SEK, MZB, CBM, TBC, PM, and CG developed the concept and designed the study. MCH, WS, MNy, NWB, FMO, JK, BH, NM, VOO, HB, and RM provided study material or participants, and CBM and RMM did the data analyses. SEK, CBM, and MZB wrote the initial draft of the manuscript, and TBC, PM, RMM, CG, MCH, NWB, HB, RM, and MNo provided critical comments and editing. SRC coordinated the data collection and the independent endpoint review committee process. All authors contributed to the data interpretation, reviewed the analyses of this manuscript, and approved its final version. Contributors
ISSN:	0140-6736 1474-547X
DOI:	10.1016/S0140-6736(19)33222-2