title: Phenotypic Coreceptor Tropism in Perinatally HIV-infected Youth Failing Antiretroviral Therapy.
abstract: Perinatally HIV-infected (PHIV) children and youth are often heavily treatment-experienced, with resultant antiretroviral resistance and limited treatment options. For those with virologic failure (VF), new agents such as CCR5 (R5) antagonists may be useful; however, reports of R5 antagonist susceptibility in children have mostly relied on genotypic testing, which may not accurately reflect the phenotypic tropism of the viral populations. We characterized phenotypic coreceptor usage among PHIV children and youth with VF on antiretroviral treatment to identify predictors of CXCR4 (X4) tropism which preclude R5 antagonist use.
  
  
  
  Plasma samples with >1000 HIV RNA copies/mL were obtained from 73 PHIV antiretroviral treatment-treated children and youth (age 9-21 years) enrolled in the multicenter Pediatric HIV/AIDS Cohort Study. Samples were analyzed using the Trofile phenotypic assay. Multiple logistic regression was performed to identify factors associated with detectable X4 tropism.
  
  
  
  Tropism results were obtained for 59 (81%) of the 73 children and youth; 32 (54%) had X4-tropism. Persistent viremia (≥80% of HIV RNA measurements >400 copies/mL) was associated with detectable X4 tropism (adjusted odds ratio: 6.6, 95% confidence interval: 1.4, 31.4), while longer cumulative nucleoside reverse transcriptase inhibitor use was associated with lower risk of X4 tropism (adjusted odds ratio: 0.6, 95% confidence interval: 0.5, 0.9).
  
  
  
  Using a phenotypic assay, >50% of PHIV children and youth with VF had X4 tropism, similar to that in experienced adults, and higher than the 30% reported for children using genotypic assays. Persistent viremia and shorter nucleoside reverse transcriptase inhibitor exposure are associated with X4-tropism in children and youth and may help target phenotypic testing to those most likely to benefit from R5 antagonist.
authors.affiliation: From the *Division of Pediatric Infectious Diseases, Department of Pediatrics, †Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‡Center for Biostatistics in AIDS Research (CBAR), Harvard School of Public Health, Boston, Massachusetts; §Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ¶Monogram Biosciences, South San Francisco, California; ‖Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; **Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland; and ††Section of Infectious Diseases, Department of Pediatrics, Tulane University School of Medicine, New Orleans, Los Angeles.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Agwu
authors.forename: Tzy-Jyun
authors.initials: TJ
authors.lastname: Yao
authors.forename: Susan H
authors.initials: SH
authors.lastname: Eshleman
authors.forename: Kunjal
authors.initials: K
authors.lastname: Patel
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Burchett
authors.forename: George K
authors.initials: GK
authors.lastname: Siberry
authors.forename: Russell B
authors.initials: RB
authors.lastname: Van Dyke
mesh_terms: D000293:Adolescent; D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use*; D002648:Child; D015331:Cohort Studies; D005260:Female; D057809:HEK293 Cells; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D010641:Phenotype; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000097:blood*; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D015728:Receptors, HIV / Q000037:antagonists & inhibitors; D017211:Treatment Failure; D056189:Viral Tropism
chemical_list: D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV