title: Assessment of second-line antiretroviral regimens for HIV therapy in Africa.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  In 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%).
  
  
  RESULTS
  Good 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).
  
  
  CONCLUSIONS
  When 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.).
authors.affiliation: 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.).
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Paton
authors.forename: Cissy
authors.initials: C
authors.lastname: Kityo
authors.forename: Anne
authors.initials: A
authors.lastname: Hoppe
authors.forename: Andrew
authors.initials: A
authors.lastname: Reid
authors.forename: Andrew
authors.initials: A
authors.lastname: Kambugu
authors.forename: Abbas
authors.initials: A
authors.lastname: Lugemwa
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
authors.forename: Mary
authors.initials: M
authors.lastname: Kiconco
authors.forename: Abraham
authors.initials: A
authors.lastname: Siika
authors.forename: Raymond
authors.initials: R
authors.lastname: Mwebaze
authors.forename: Mary
authors.initials: M
authors.lastname: Abwola
authors.forename: George
authors.initials: G
authors.lastname: Abongomera
authors.forename: Aggrey
authors.initials: A
authors.lastname: Mweemba
authors.forename: Hillary
authors.initials: H
authors.lastname: Alima
authors.forename: Dickens
authors.initials: D
authors.lastname: Atwongyeire
authors.forename: Rose
authors.initials: R
authors.lastname: Nyirenda
authors.forename: Justine
authors.initials: J
authors.lastname: Boles
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thompson
authors.forename: Dinah
authors.initials: D
authors.lastname: Tumukunde
authors.forename: Ennie
authors.initials: E
authors.lastname: Chidziva
authors.forename: Ivan
authors.initials: I
authors.lastname: Mambule
authors.forename: Jose R
authors.initials: JR
authors.lastname: Arribas
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Easterbrook
authors.forename: James
authors.initials: J
authors.lastname: Hakim
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.forename: Peter
authors.initials: P
authors.lastname: Mugyenyi
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara; D000368:Aged; D018791:CD4 Lymphocyte Count; D002648:Child; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D006678:HIV / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D011760:Pyrrolidinones; D018894:Reverse Transcriptase Inhibitors; D000068898:Raltegravir Potassium