title: Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial.
abstract: BACKGROUND
  Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites.
  
  
  METHODS
  Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance-failure association.
  
  
  RESULTS
  In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex-treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04-2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22-.98).
  
  
  CONCLUSIONS
  In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible.
  
  
  BACKGROUND
  NCT00084136.
authors: Division of Infectious Diseases, Department of Medicine, Brown University, Providence, Rhode Island.
authors: Rami
authors: R
authors: Kantor
authors: Center for Biostatistics in AIDS Research, Harvard School of Public Health, Harvard University, Boston, Massachusetts.
authors: Laura
authors: L
authors: Smeaton
authors: Center for Biostatistics in AIDS Research, Harvard School of Public Health, Harvard University, Boston, Massachusetts.
authors: Saran
authors: S
authors: Vardhanabhuti
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Sarah E
authors: SE
authors: Hudelson
authors: Lancet Laboratories, Johannesburg, South Africa.
authors: Carol L
authors: CL
authors: Wallis
authors: National AIDS Research Institute, Pune, India.
authors: Srikanth
authors: S
authors: Tripathy
authors: Laboratory of AIDS and Molecular Immunology, Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
authors: Mariza G
authors: MG
authors: Morgado
authors: YRG-CARE, Chennai, India.
authors: Shanmugham
authors: S
authors: Saravanan
authors: YRG-CARE, Chennai, India.
authors: Pachamuthu
authors: P
authors: Balakrishnan
authors: Division of Infectious Diseases, Department of Medicine, Brown University, Providence, Rhode Island.
authors: Marissa
authors: M
authors: Reitsma
authors: Frontier Science and Technology Research Foundation, Amherst, New York.
authors: Stephen
authors: S
authors: Hart
authors: Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pennsylvania.
authors: John W
authors: JW
authors: Mellors
authors: Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pennsylvania.
authors: Elias
authors: E
authors: Halvas
authors: Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil.
authors: Beatriz
authors: B
authors: Grinsztejn
authors: University of North Carolina Project-Malawi, Lilongwe.
authors: Mina C
authors: MC
authors: Hosseinipour
authors: Department of Internal Medicine, University of Malawi, College of Medicine, Blantyre.
authors: Johnstone
authors: J
authors: Kumwenda
authors: Asociacion Civil Impacta Salud y Educacion, Barranco, Lima, Peru.
authors: Alberto
authors: A
authors: La Rosa
authors: Enhancing Care Foundation, Durban, South Africa.
authors: Umesh G
authors: UG
authors: Lalloo
authors: Asociacion Civil Impacta Salud y Educacion, Barranco, Lima, Peru.
authors: Javier R
authors: JR
authors: Lama
authors: Department of Medicine, University of Witwatersrand; Helen Joseph Hospital, Themba Lethu Clinic, Johannesburg, South Africa.
authors: Mohammed
authors: M
authors: Rassool
authors: Serviço de Infectologia, Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil.
authors: Breno R
authors: BR
authors: Santos
authors: Research Institute for Health Sciences and Faculty of Medicine, Chiang Mai University, Thailand.
authors: Khuanchai
authors: K
authors: Supparatpinyo
authors: Department of Medicine, University of Zimbabwe, Harare.
authors: James
authors: J
authors: Hakim
authors: Division of Infectious Diseases, Department of Medicine, Brown University, Providence, Rhode Island.
authors: Timothy
authors: T
authors: Flanigan
authors: Laboratory of AIDS and Molecular Immunology, Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
authors: Nagalingeswaran
authors: N
authors: Kumarasamy
authors: Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora.
authors: Thomas B
authors: TB
authors: Campbell
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Susan H
authors: SH
authors: Eshleman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology* / Q000821:virology; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D017211:Treatment Failure; D019562:Viral Load; D055815:Young Adult; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D054302:pol Gene Products, Human Immunodeficiency Virus
keywords: HIV; clinical trial; drug resistance; subtype