Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated with Virologic Failure: Results from the Multinational PEARLS (ACTG A5175) Clinical Trial

Rami Kantor, Laura Smeaton, Saran Vardhanabhuti, Sarah E. Hudelson, Carol L. Wallis, Srikanth Tripathy, Mariza G. Morgado, Shanmugham Saravanan, Pachamuthu Balakrishnan, Marissa Reitsma, Stephen Hart, John W. Mellors, Elias Halvas, Beatriz Grinsztejn, Mina C. Hosseinipour, Johnstone Kumwenda, Alberto La Rosa, Umesh G. Lalloo, Javier R. Lama, Mohammed RassoolBreno R. Santos, Khuanchai Supparatpinyo, James Hakim, Timothy Flanigan, Nagalingeswaran Kumarasamy, Thomas B. Campbell, Susan H. Eshleman

Research output: Contribution to journalArticle

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. Clinical Trials Registration. NCT00084136.

Original languageEnglish (US)
Pages (from-to)1541-1549
Number of pages9
JournalClinical Infectious Diseases
Volume60
Issue number10
DOIs
StatePublished - May 15 2015

Keywords

  • HIV
  • clinical trial.
  • drug resistance
  • subtype

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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    Kantor, R., Smeaton, L., Vardhanabhuti, S., Hudelson, S. E., Wallis, C. L., Tripathy, S., Morgado, M. G., Saravanan, S., Balakrishnan, P., Reitsma, M., Hart, S., Mellors, J. W., Halvas, E., Grinsztejn, B., Hosseinipour, M. C., Kumwenda, J., La Rosa, A., Lalloo, U. G., Lama, J. R., ... Eshleman, S. H. (2015). Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated with Virologic Failure: Results from the Multinational PEARLS (ACTG A5175) Clinical Trial. Clinical Infectious Diseases, 60(10), 1541-1549. https://doi.org/10.1093/cid/civ102