title: Low-abundance HIV species and their impact on mutational profiles in patients with virological failure on once-daily abacavir/lamivudine/zidovudine and tenofovir.
abstract: BACKGROUND
  HIV clonal genotypic analysis (CG) was used to investigate whether a more sensitive analysis method would detect additional low-abundance mutations compared with population genotyping (PG) in antiretroviral-naive patients who experienced virological failure (VF) during treatment with abacavir/lamivudine/zidovudine and tenofovir.
  
  
  METHODS
  HIV was analysed by PG and CG (771 baseline and 657 VF clones) from subjects with VF (confirmed HIV RNA > or = 400 copies/mL at 24-48 weeks).
  
  
  RESULTS
  Fourteen of 123 subjects (11%) met VF criteria; their median baseline HIV RNA was 5.4 log(10) copies/mL, and 4.0 log(10) copies/mL at VF. By baseline PG, 2/14 had HIV-1 with nucleoside reverse transcriptase inhibitor (NRTI) or non-NRTI mutations. By baseline CG, 9/14 had HIV-1 with NNRTI and/or NRTI mutations; 7/9 had study drug-associated mutations. By PG at VF, 10/14 had selected for resistance mutations [2, K65R; 1, M184V; and 7, thymidine analogue mutations (TAMs) +/- M184V]. By CG at VF, for subjects with TAMs, T215F was more commonly detected (5/14 samples) than T215Y (2/14). For one subject who selected K65R at VF, both K65R-containing clones and TAM-containing clones (both T215A and T215F) were observed independently but not conjunctively in the same clone in a post-VF sample.
  
  
  CONCLUSIONS
  The majority of subjects with VF had major and minor mutations detected at VF; CG detected additional low-abundance variants at baseline and VF that could have influenced mutation selection pathways. Both PG and CG data suggest TAMs, not K65R selection, are the preferred resistance route, biased towards 215F selection. No HIV clone contained both K65R and T215F/Y mutations, suggesting in vivo antagonism between the two mutations. The once-daily zidovudine usage and high baseline viraemia may also have contributed to rapid selection of HIV with multiple mutations in VFs.
authors.affiliation: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. lisa.l.ross@gsk.com
authors.forename: L L
authors.initials: LL
authors.lastname: Ross
authors.forename: E
authors.initials: E
authors.lastname: Rouse
authors.forename: P
authors.initials: P
authors.lastname: Gerondelis
authors.forename: E
authors.initials: E
authors.lastname: DeJesus
authors.forename: C
authors.initials: C
authors.lastname: Cohen
authors.forename: J
authors.initials: J
authors.lastname: Horton
authors.forename: B
authors.initials: B
authors.lastname: Ha
authors.forename: E R
authors.initials: ER
authors.lastname: Lanier
authors.forename: R
authors.initials: R
authors.lastname: Elion
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D015224:Dideoxynucleosides; D004338:Drug Combinations; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D020125:Mutation, Missense; D063065:Organophosphonates / Q000627:therapeutic use*; D012367:RNA, Viral / Q000235:genetics; D000068698:Tenofovir; D017211:Treatment Failure; D014766:Viremia; D055815:Young Adult; D015215:Zidovudine / Q000627:therapeutic use*; D000099227:Abacavir
chemical_list: D000225:Adenine; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; D019259:Lamivudine; D063065:Organophosphonates; D012367:RNA, Viral; D000068698:Tenofovir; D015215:Zidovudine; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir