title: Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naïve populations and associate with reduced treatment efficacy.
abstract: BACKGROUND
  Transmitted HIV-1 drug resistance can compromise initial antiretroviral therapy (ART); therefore, its detection is important for patient management. The absence of drug-associated selection pressure in treatment-naïve persons can cause drug-resistant viruses to decline to levels undetectable by conventional bulk sequencing (minority drug-resistant variants). We used sensitive and simple tests to investigate evidence of transmitted drug resistance in antiretroviral drug-naïve persons and assess the clinical implications of minority drug-resistant variants.
  
  
  RESULTS
  We performed a cross-sectional analysis of transmitted HIV-1 drug resistance and a case-control study of the impact of minority drug resistance on treatment response. For the cross-sectional analysis, we examined viral RNA from newly diagnosed ART-naïve persons in the US and Canada who had no detectable (wild type, n = 205) or one or more resistance-related mutations (n = 303) by conventional sequencing. Eight validated real-time PCR-based assays were used to test for minority drug resistance mutations (protease L90M and reverse transcriptase M41L, K70R, K103N, Y181C, M184V, and T215F/Y) above naturally occurring frequencies. The sensitive real-time PCR testing identified one to three minority drug resistance mutation(s) in 34/205 (17%) newly diagnosed persons who had wild-type virus by conventional genotyping; four (2%) individuals had mutations associated with resistance to two drug classes. Among 30/303 (10%) samples with bulk genotype resistance mutations we found at least one minority variant with a different drug resistance mutation. For the case-control study, we assessed the impact of three treatment-relevant drug resistance mutations at baseline from a separate group of 316 previously ART-naïve persons with no evidence of drug resistance on bulk genotype testing who were placed on efavirenz-based regimens. We found that 7/95 (7%) persons who experienced virologic failure had minority drug resistance mutations at baseline; however, minority resistance was found in only 2/221 (0.9%) treatment successes (Fisher exact test, p = 0.0038).
  
  
  CONCLUSIONS
  These data suggest that a considerable proportion of transmitted HIV-1 drug resistance is undetected by conventional genotyping and that minority mutations can have clinical consequences. With no treatment history to help guide therapies for drug-naïve persons, the findings suggest an important role for sensitive baseline drug resistance testing.
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America. JJohnson1@cdc.gov
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Jin-Fen
authors.initials: JF
authors.lastname: Li
authors.forename: Xierong
authors.initials: X
authors.lastname: Wei
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lipscomb
authors.forename: David
authors.initials: D
authors.lastname: Irlbeck
authors.forename: Charles
authors.initials: C
authors.lastname: Craig
authors.forename: Amanda
authors.initials: A
authors.lastname: Smith
authors.forename: Diane E
authors.initials: DE
authors.lastname: Bennett
authors.forename: Michael
authors.initials: M
authors.lastname: Monsour
authors.forename: Paul
authors.initials: P
authors.lastname: Sandstrom
authors.forename: E Randall
authors.initials: ER
authors.lastname: Lanier
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D008040:Genetic Linkage; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents