title: Antiretroviral regimens for patients with HIV who fail first-line antiretroviral therapy.
abstract: BACKGROUND
  Highly active antiretroviral therapy has reduced the morbidity and mortality of patients with HIV/AIDS. A common first-line ART regimen in low-resource settings includes a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs). If treatment failure occurs, a change to second-line therapy is necessary.
  
  
  OBJECTIVE
  This systematic review aimed to assess the optimum antiretroviral regimen for patients with HIV who fail first-line therapy (ART-naive) with a recommended World Health Organization (WHO) first-line regimen.
  
  
  METHODS
  Electronic databases and conference proceedings were searched with relevant search terms without limits to language.
  
  
  METHODS
  Randomised controlled trials of HIV-infected adolescent and adult patients administered second-line ART after virologic failure of a first-line regimen were included. Observational studies were included given the insufficient number of trials identified. The primary outcome measure included mortality. Secondary outcome measures included rate of adverse events, change in mean CD4 cell count, clinical resolution of symptoms, proportion of patients achieving undetectable viral load (VL) and acquisition of genotypic mutations.
  
  
  METHODS
  Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form. Risk of bias was assessed for individual studies and the GRADE approach for assessing the quality of evidence across a body of evidence was also applied.
  
  
  RESULTS
  One randomised trial in 136 patients studied maintaining lamivudine in second-line regimens or not. There was no difference in virological outcomes in the group who maintained lamivudine and those who did not in their subsequent regimens. Two other small observational studies reported in abstract form also did not report a difference in the proportion of those with viral suppression after six months and time to HIV-1 RNA suppression among those on a lamivudine (3TC) or emtricitabine (FTC) regimen compared to those on a 3TC/FTC-sparing second-line regimen. There were no trials identified comparing boosted protease inhibitors (PIs) or nucleoside backbone combinations after first-line failure on non-thymidine analog combinations. Observational studies of populations starting ART in resource-limited settings suggest that short-term response on boosted PI-based regimens is encouraging.
  
  
  CONCLUSIONS
  There is limited evidence to evaluate second-line therapies in patients with HIV who fail first-line treatment with a WHO-recommended regimen. One randomised trial in 136 patients and two observational studies (both of low quality) suggest no difference in virological suppression whether or not lamivudine is maintained in a second-line regimen. While outcomes of second-line regimens with boosted PIs are favourable in general, there are no studies comparing boosted PIs directly in populations starting second-line regimens. Current recommendations are based on available resources and patient- and public-health-level considerations.
authors.affiliation: Global Health Sciences, University of California, San Francisco, 50 Beale Street, Suite 1200, San Francisco, California, USA, 94105.
authors.forename: Eliza H
authors.initials: EH
authors.lastname: Humphreys
authors.forename: Larry W
authors.initials: LW
authors.lastname: Chang
authors.forename: Jamal
authors.initials: J
authors.lastname: Harris
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D003906:Developing Countries; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D019259:Lamivudine; D000068679:Emtricitabine