title: Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.
abstract: For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings.
  
  
  
  A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715.
  
  
  
  Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes.
  
  
  
  In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity.
  
  
  
  National Institutes of Health.
authors.affiliation: Asociacion Civil Impacta Salud y Educacion, Lima, Peru.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: La Rosa
authors.affiliation: Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Harrison
authors.affiliation: Northwestern University, Chicago, IL, USA.
authors.forename: Babafemi
authors.initials: B
authors.lastname: Taiwo
authors.affiliation: BARC-SA and Lancet Laboratories, Johannesburg, South Africa.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wallis
authors.affiliation: Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kim
authors.affiliation: YRG CARE, Chennai, India.
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.affiliation: University of North Carolina, Chapel Hill, NC, USA; UNC Project, Lilongwe, Malawi.
authors.forename: Mina C
authors.initials: MC
authors.lastname: Hosseinipour
authors.affiliation: Frontier Science and Technology Research Foundation, Buffalo, NY, USA.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Jarocki
authors.affiliation: University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.affiliation: University of Washington, Seattle, WA, USA. Electronic address: acollier@u.washington.edu.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D001938:Brazil / Q000453:epidemiology; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006295:Health Resources / Q000191:economics* / Q000600:supply & distribution; D006297:Health Services Accessibility / Q000191:economics; D006801:Humans; D007194:India / Q000453:epidemiology; D061466:Lopinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008295:Malawi / Q000453:epidemiology; D008297:Male; D008507:Medically Underserved Area; D010568:Peru / Q000453:epidemiology; D012367:RNA, Viral / Q000097:blood; D000068898:Raltegravir Potassium / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013785:Thailand / Q000453:epidemiology; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D000068898:Raltegravir Potassium