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.

CLINICAL TRIALS REGISTRATION:

NCT00084136.

• Authors: 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 Rassool, Breno R Santos, Khuanchai Supparatpinyo, James Hakim, Timothy Flanigan, Nagalingeswaran Kumarasamy, Thomas B Campbell, Susan H Eshleman, AIDS Clinical Trials Group (ACTG) A5175 Study Team
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 60 Issue 10 Pg. 1541-9 (May 15 2015) ISSN: 1537-6591 [Electronic] United States
• PMID: 25681380 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• pol Gene Products, Human Immunodeficiency Virus

Topics

• Adolescent
• Adult
• Aged
• Case-Control Studies
• Cohort Studies
• Drug Resistance, Viral
• Female
• Genotype
• Genotyping Techniques
• HIV Infections (drug therapy, epidemiology, virology)
• HIV-1 (classification, drug effects, genetics, isolation & purification)
• Humans
• Male
• Middle Aged
• Randomized Controlled Trials as Topic
• Treatment Failure
• Viral Load
• Young Adult
• pol Gene Products, Human Immunodeficiency Virus (genetics)