title: Impact of low abundance HIV variants on response to ritonavir-boosted atazanavir or fosamprenavir given once daily with tenofovir/emtricitabine in antiretroviral-naive HIV-infected patients.
abstract: Population genotyping (PG) can underestimate resistance if resistance-containing low abundance variants go undetected. PG and clonal analysis (CA) results were compared in virologic failures (VFs) from a 48-week clinical trial that evaluated once-daily fosamprenavir/ritonavir (FPV/r) 1400 mg/100 mg or atazanavir/ritonavir (ATV/r) 300 mg/100 mg, each combined with tenofovir/emtricitabine, in antiretroviral-naive patients. VF was defined as confirmed HIV-1 RNA > or =400 copies/ml at > or =24 weeks or viral rebound >400 copies/ml any time following viral suppression. All patients had baseline PG. One hundred and six patients enrolled (53/arm). Baseline resistance mutations were more prevalent in patients receiving FPV/r (10/53) than ATV/r (3/53). Seven patients (7%) were VFs-four on FPV/r and three on ATV/r. In the four FPV/r-treated VFs, baseline HIV TAMs combinations and/or PI mutations were detected in one by PG at VF (RT: L210W + T215C; PR: M46I + L76V) and three others by CA alone (RT: L210W + T215Y; RT: M41L; RT: K65R + K70R; PR: I47V); all four had study drug-associated mutations (CA detecting more HIV-1 resistance mutations than PG). In the three ATV/r VFs, no baseline drug-associated mutations were detected by PG; for one patient CA detected RT: K65R; PR: I84V. Phylogenetic analysis revealed tight clustering for FPV/r-treated VFs with highly related clones, whereas HIV-1 from ATV/r-treated VFs had no outgrowth from baseline of low abundance resistance-containing variants. In conclusion, low-abundance HIV resistance-containing variants were detected in baseline samples from patients with VF. The archived viruses that reemerged under selection pressure and acquired additional mutations were found primarily in patients in the FPV/r arm. Despite this and a baseline resistance imbalance between the two arms, FPV/r and ATV/r provided similar virologic suppression through 48 weeks; however, these findings highlight the necessity for the development of quick and inexpensive methods for detection of minority species to better guide therapy selection.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. lisa.l.ross@gsk.com
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Ross
authors.forename: Winkler G
authors.initials: WG
authors.lastname: Weinberg
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Fischl
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Horton
authors.forename: Keith A
authors.initials: KA
authors.lastname: Pappa
authors.forename: C Tracey
authors.initials: CT
authors.lastname: Lancaster
authors.forename: Gary E
authors.initials: GE
authors.lastname: Pakes
authors.forename: Kimberly Y
authors.initials: KY
authors.lastname: Smith
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D000069446:Atazanavir Sulfate; D002219:Carbamates / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005663:Furans; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage*; D010755:Organophosphates / Q000008:administration & dosage*; D063065:Organophosphonates / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D019438:Ritonavir / Q000008:administration & dosage*; D017423:Sequence Analysis, RNA / Q000379:methods; D013449:Sulfonamides / Q000008:administration & dosage*; D000068698:Tenofovir; D017211:Treatment Failure
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D005663:Furans; D009842:Oligopeptides; D010755:Organophosphates; D063065:Organophosphonates; D011725:Pyridines; D012367:RNA, Viral; D013449:Sulfonamides; D003841:Deoxycytidine; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; D019438:Ritonavir; C426859:fosamprenavir