• Nicholas I Paton, Cissy Kityo, Anne Hoppe, Andrew Reid, Andrew Kambugu, Abbas Lugemwa, Joep J van Oosterhout, Mary Kiconco, Abraham Siika, Raymond Mwebaze, Mary Abwola, George Abongomera, Aggrey Mweemba, Hillary Alima, Dickens Atwongyeire, Rose Nyirenda, Justine Boles, Jennifer Thompson, Dinah Tumukunde, Ennie Chidziva, Ivan Mambule, Jose R Arribas, Philippa J Easterbrook, James Hakim, A Sarah Walker, Peter Mugyenyi, and EARNEST Trial Team.
• From the Medical Research Council Clinical Trials Unit at University College London, London (N.I.P., A.H., J.B., J.T., A.S.W.); Yong Loo Lin School of Medicine, National University of Singapore, Singapore (N.I.P.); Joint Clinical Research Centre (JCRC) (C.K., D.T., P.M.), Infectious Diseases Institute (A.K., I.M., P.J.E.), and St. Francis of Nsambya Hospital (R.M.), Kampala, JCRC, Mbarara (A.L.), JCRC, Fort Portal (M.K.), JCRC, Mbale (M.A.), JCRC, Gulu (G.A.), JCRC, Kabale (H.A.), and JCRC, Kakira (D.A.) - all in Uganda; University of Zimbabwe Clinical Research Centre, Harare (A.R., E.C., J.H.); Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre (J.J.O.), Dignitas International, Zomba (J.J.O.), and Mzuzu Central Hospital, Mzuzu (R.N.) - all in Malawi; Moi University School of Medicine, Eldoret, Kenya (A.S.); University Teaching Hospital, Lusaka, Zambia (A.M.); and Hospital La Paz, Madrid (J.R.A.).
• N. Engl. J. Med. 2014 Jul 17; 371 (3): 234-47.

BackgroundThe efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit.MethodsIn this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%).ResultsGood HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001).ConclusionsWhen given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.).

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