title: Drug susceptibility and resistance mutations after first-line failure in resource limited settings.
abstract: BACKGROUND
  The development of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been associated with baseline human immunodeficiency virus (HIV)-1 RNA level (VL), CD4 cell counts (CD4), subtype, and treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in individuals from Thailand, South Africa, India, Malawi, Tanzania.
  
  
  METHODS
  CD4 and VL were captured at AIDs Clinical Trial Group (ACTG) A5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on an NNRTI regimen. HIV drug-resistance mutation associations with subtype, site, study entry VL, and CD4 were evaluated using Fisher exact and Kruskall-Wallis tests.
  
  
  RESULTS
  Of the 207 individuals who were screened for A5230, sequence data were available for 148 individuals. Subtypes observed: subtype C (n = 97, 66%) AE (n = 27, 18%), A1 (n = 12, 8%), and D (n = 10, 7%). Of the 148 individuals, 93% (n = 138) and 96% (n = 142) had at least 1 reverse transcriptase (RT) mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (P < .001). Differences in drug-resistance patterns in both NRTI and NNRTI were observed by site.
  
  
  CONCLUSIONS
  The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry. Thirty-two percent of individuals remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance.
authors.affiliation: Lancet Laboratories, Johannesburg, South Africa.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wallis
authors.affiliation: Statistical Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Aga
authors.affiliation: Statistical Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Heather
authors.initials: H
authors.lastname: Ribaudo
authors.affiliation: YRG Centre for AIDS Research and Education, Chennai, India.
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Saravanan
authors.affiliation: Medical Affairs Therapeutic Area, Virology and Nanotechnology, Global Pharmaceutical Research and Development, AbbVie, Chicago, Illinois.
authors.forename: Michael
authors.initials: M
authors.lastname: Norton
authors.affiliation: University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Wendy
authors.initials: W
authors.lastname: Stevens
authors.affiliation: YRG Centre for AIDS Research and Education, Chennai, India.
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.affiliation: Duke Global Health Institute, Duke University, Durham, North Carolina Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
authors.forename: John
authors.initials: J
authors.lastname: Bartlett
authors.affiliation: Division of Infectious Diseases, Stanford University, Palo Alto, California.
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006295:Health Resources; D006801:Humans; D007194:India; D061466:Lopinavir / Q000627:therapeutic use; D008295:Malawi / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D009570:Nitriles; D010865:Pilot Projects; D011724:Pyridazines / Q000627:therapeutic use; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D013019:South Africa; D013636:Tanzania; D013785:Thailand; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D061466:Lopinavir; D019438:Ritonavir
keywords: HIV-1 drug resistance; first-line failure; nonsubtype B; resource limited setting