title: Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection.
abstract: BACKGROUND
  Virologic failure in subtype C is characterized by high resistance to first-line antiretroviral (ARV) drugs, including efavirenz, nevirapine, and lamivudine, with nucleoside resistance including type 2 thymidine analog mutations, K65R, a T69del, and M184V. However, genotypic algorithms predicting resistance are mainly based on subtype B viruses and may under- or overestimate drug resistance in non-B subtypes. To explore potential treatment strategies after first-line failure, we compared genotypic and phenotypic susceptibility of subtype C human immunodeficiency virus 1 (HIV-1) following first-line ARV failure.
  
  
  METHODS
  AIDS Clinical Trials Group 5230 evaluated patients failing an initial nonnucleoside reverse-transcriptase inhibitor (NNRTI) regimen in Africa and Asia, comparing the genotypic drug resistance and phenotypic profile from the PhenoSense (Monogram). Site-directed mutagenesis studies of K65R and T69del assessed the phenotypic impact of these mutations.
  
  
  RESULTS
  Genotypic algorithms overestimated resistance to etravirine and rilpivirine, misclassifying 28% and 32%, respectively. Despite K65R with the T69del in 9 samples, tenofovir retained activity in >60%. Reversion of the K65R increased susceptibility to tenofovir and other nucleosides, while reversion of the T69del showed increased resistance to zidovudine, with little impact on other NRTI.
  
  
  CONCLUSIONS
  Although genotype and phenotype were largely concordant for first-line drugs, estimates of genotypic resistance to etravirine and rilpivirine may misclassify subtype C isolates compared to phenotype.
authors.affiliation: Division of Infectious Diseases, Stanford University, California.
authors.forename: Anne
authors.initials: A
authors.lastname: Derache
authors.affiliation: Department of Molecular Pathology, Lancet Laboratories and BARC-SA, Johannesburg, South Africa.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wallis
authors.affiliation: Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Saran
authors.initials: S
authors.lastname: Vardhanabhuti
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: John
authors.initials: J
authors.lastname: Bartlett
authors.affiliation: Y. R. Gaitonde Centre for AIDS Research and Education, Chennai, India.
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.affiliation: Division of Infectious Diseases, Stanford University, California.
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000453:epidemiology / Q000821:virology*; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D013785:Thailand / Q000453:epidemiology
chemical_list: D019380:Anti-HIV Agents
keywords: 2nd NNRTI generation; HIV; first-line failure; genotype/phenotype comparison; subtype C