Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.


DART Trial Team, ; Mugyenyi, P; Walker, AS; Hakim, J; Munderi, P; Gibb, DM; Kityo, C; Reid, A; Grosskurth, H; Darbyshire, JH; Ssali, F; Bray, D; Katabira, E; Babiker, AG; Gilks, CF; Grosskurth, H; Munderi, P; Kabuye, G; Nsibambi, D; Kasirye, R; Zalwango, E; Nakazibwe, M; Kikaire, B; Nassuna, G; Massa, R; Fadhiru, K; Namyalo, M; Zalwango, A; Generous, L; Khauka, P; Rutikarayo, N; Nakahima, W; Mugisha, A; Todd, J; Levin, J; Muyingo, S; Ruberantwari, A; Kaleebu, P; Yirrell, D; Ndembi, N; Lyagoba, F; Hughes, P; Aber, M; Lara, AM; Foster, S; Amurwon, J; Wakholi, BN; Whitworth, J; Wangati, K; Amuron, B; Kajungu, D; Nakiyingi, J; Omony, W; Fadhiru, K; Nsibambi, D; Khauka, P; Mugyenyi, P; Kityo, C; Ssali, F; Tumukunde, D; Otim, T; Kabanda, J; Musana, H; Akao, J; Kyomugisha, H; Byamukama, A; Sabiiti, J; Komugyena, J; Wavamunno, P; Mukiibi, S; Drasiku, A; Byaruhanga, R; Labeja, O; Katundu, P; Tugume, S; Awio, P; Namazzi, A; Bakeinyaga, GT; Katabira, H; Abaine, D; Tukamushaba, J; Anywar, W; Ojiambo, W; Angweng, E; Murungi, S; Haguma, W; Atwiine, S; Kigozi, J; Namale, L; Mukose, A; Mulindwa, G; Atwiine, D; Muhwezi, A; Nimwesiga, E; Barungi, G; Takubwa, J; Murungi, S; Mwebesa, D; Kagina, G; Mulindwa, M; Ahimbisibwe, F; Mwesigwa, P; Akuma, S; Zawedde, C; Nyiraguhirwa, D; Tumusiime, C; Bagaya, L; Namara, W; Kigozi, J; Karungi, J; Kankunda, R; Enzama, R; Latif, A; Hakim, J; Robertson, V; Reid, A; Chidziva, E; Bulaya-Tembo, R; Musoro, G; Taziwa, F; Chimbetete, C; Chakonza, L; Mawora, A; Muvirimi, C; Tinago, G; Svovanapasis, P; Simango, M; Chirema, O; Machingura, J; Mutsai, S; Phiri, M; Bafana, T; Chirara, M; Muchabaiwa, L; Muzambi, M; Mutowo, J; Chivhunga, T; Chigwedere, E; Pascoe, M; Warambwa, C; Zengeza, E; Mapinge, F; Makota, S; Jamu, A; Ngorima, N; Chirairo, H; Chitsungo, S; Chimanzi, J; Maweni, C; Warara, R; Matongo, M; Mudzingwa, S; Jangano, M; Moyo, K; Vere, L; Mdege, N; Machingura, I; Katabira, E; Ronald, A; Kambungu, A; Lutwama, F; Mambule, I; Nanfuka, A; Walusimbi, J; Nabankema, E; Nalumenya, R; Namuli, T; Kulume, R; Namata, I; Nyachwo, L; Florence, A; Kusiima, A; Lubwama, E; Nairuba, R; Oketta, F; Buluma, E; Waita, R; Ojiambo, H; Sadik, F; Wanyama, J; Nabongo, P; Oyugi, J; Sematala, F; Muganzi, A; Twijukye, C; Byakwaga, H; Ochai, R; Muhweezi, D; Coutinho, A; Etukoit, B; Gilks, C; Boocock, K; Puddephatt, C; Grundy, C; Bohannon, J; Winogron, D; Gibb, DM; Burke, A; Bray, D; Babiker, A; Walker, AS; Wilkes, H; Rauchenberger, M; Sheehan, S; Spencer-Drake, C; Taylor, K; Spyer, M; Ferrier, A; Naidoo, B; Dunn, D; Goodall, R; Darbyshire, JH; Peto, L; Nanfuka, R; Mufuka-Kapuya, C; Kaleebu, P; Pillay, D; Robertson, V; Yirrell, D; Tugume, S; Chirara, M; Katundu, P; Ndembi, N; Lyagoba, F; Dunn, D; Goodall, R; McCormick, A; Lara, AM; Foster, S; Amurwon, J; Wakholi, BN; Kigozi, J; Muchabaiwa, L; Muzambi, M; Weller, I; Babiker, A; Bahendeka, S; Bassett, M; Wapakhabulo, AC; Darbyshire, JH; Gazzard, B; Gilks, C; Grosskurth, H; Hakim, J; Latif, A; Mapuchere, C; Mugurungi, O; Mugyenyi, P; Burke, C; Jones, S; Newland, C; Pearce, G; Rahim, S; Rooney, J; Smith, M; Snowden, W; Steens, JM; Breckenridge, A; McLaren, A; Hill, C; Matenga, J; Pozniak, A; Serwadda, D; Peto, T; Palfreeman, A; Borok, M; Katabira, E; (2010) Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. Lancet, 375 (9709). pp. 123-31. ISSN 0140-6736 DOI: https://doi.org/10.1016/S0140-6736(09)62067-5

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Abstract

BACKGROUND: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. METHODS: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. FINDINGS: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). INTERPRETATION: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Epidemiology and Population Health > Dept of Population Health (2012- ) > Dept of Population Studies (1974-2012)
Faculty of Epidemiology and Population Health > Dept of Population Health (2012- )
Research Centre: Centre for Global Non-Communicable Diseases (NCDs)
Tropical Epidemiology Group
Population Studies Group
PubMed ID: 20004464
Web of Science ID: 273664500029
URI: http://researchonline.lshtm.ac.uk/id/eprint/2261

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