title: Frequent emergence of N348I in HIV-1 subtype C reverse transcriptase with failure of initial therapy reduces susceptibility to reverse-transcriptase inhibitors.
abstract: BACKGROUND
  It is not known how often mutations in the connection and ribonuclease H domains of reverse transcriptase (RT) emerge with failure of first-line antiretroviral therapy (ART) in subtype C human immunodeficiency virus type 1 (HIV-1) infection and how these mutations affect susceptibility to other antiretrovirals.
  
  
  METHODS
  We compared full-length RT sequences in plasma obtained before therapy and at virologic failure of initial ART among 63 participants with subtype C HIV-1 infection enrolled in the Comprehensive International Program of Research on AIDS in South Africa (CIPRA-SA) study. Recombinant viruses containing full-length plasma-derived RT sequences from participants with N348I at virologic failure were assayed for drug susceptibility.
  
  
  RESULTS
  Y181C and M184V mutations in the RT polymerase domain were associated with failure of stavudine-lamivudine-nevirapine (d4T/3TC/NVP; P < .01), and K103N, V106M, and M184V with failure of d4T/3TC/efavirenz (EFV; P < .01). N348I in the RT connection domain emerged in 45% (P = .002) and 12% (P = .06) of participants receiving failing regimens containing NVP or EFV, respectively. Longitudinal analyses revealed that nonnucleoside RT inhibitor resistance mutations in the polymerase domain generally appeared first. N348I emerged at the same time, or after, M184V. N348I in the context of polymerase domain mutations reduced susceptibility to NVP (8.9-13-fold), EFV (4-56-fold), etravirine (ETV; 1.9-4.7-fold) and decreased hypersusceptibility to zidovudine (AZT; 1.4-2.2-fold).
  
  
  CONCLUSIONS
  N348I emerges frequently with virologic failure of first-line ART in subtype C HIV-1 infection and reduces susceptibility to NVP, EFV, ETV, and AZT. Additional studies are warranted to characterize the effects of N348I on virologic response to second- and third-line regimens in resource-limited settings where subtype C predominates.
authors.affiliation: University of Pittsburgh School of Medicine, S818 Scaife Hall, 3550 Terrace St, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Brehm
authors.forename: Dianna L
authors.initials: DL
authors.lastname: Koontz
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wallis
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Shutt
authors.forename: Ian
authors.initials: I
authors.lastname: Sanne
authors.forename: Robin
authors.initials: R
authors.lastname: Wood
authors.forename: James A
authors.initials: JA
authors.lastname: McIntyre
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Stevens
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sluis-Cremer
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
mesh_terms: D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase