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 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

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Drug Resistance
HIV-1
Clinical Trials
HIV
Viral Load
CD4 Lymphocyte Count
Therapeutics
Genotype
Confidence Intervals
Infection
Treatment Failure
Proportional Hazards Models
Cohort Studies
Randomized Controlled Trials
Odds Ratio

Keywords

  • clinical trial.
  • drug resistance
  • HIV
  • subtype

ASJC Scopus subject areas

  • Infectious Diseases
  • Microbiology (medical)

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Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated with Virologic Failure : Results from the Multinational PEARLS (ACTG A5175) Clinical Trial. / Kantor, Rami; Smeaton, Laura; Vardhanabhuti, Saran; Hudelson, Sarah E.; Wallis, Carol L.; Tripathy, Srikanth; Morgado, Mariza G.; Saravanan, Shanmugham; Balakrishnan, Pachamuthu; Reitsma, Marissa; Hart, Stephen; Mellors, John W.; Halvas, Elias; Grinsztejn, Beatriz; Hosseinipour, Mina C.; Kumwenda, Johnstone; La Rosa, Alberto; Lalloo, Umesh G.; Lama, Javier R.; Rassool, Mohammed; Santos, Breno R.; Supparatpinyo, Khuanchai; Hakim, James; Flanigan, Timothy; Kumarasamy, Nagalingeswaran; Campbell, Thomas B.; Eshleman, Susan.

In: Clinical Infectious Diseases, Vol. 60, No. 10, 15.05.2015, p. 1541-1549.

Research output: Contribution to journalArticle

Kantor, R, Smeaton, L, Vardhanabhuti, S, Hudelson, SE, Wallis, CL, Tripathy, S, Morgado, MG, Saravanan, S, Balakrishnan, P, Reitsma, M, Hart, S, Mellors, JW, Halvas, E, Grinsztejn, B, Hosseinipour, MC, Kumwenda, J, La Rosa, A, Lalloo, UG, Lama, JR, Rassool, M, Santos, BR, Supparatpinyo, K, Hakim, J, Flanigan, T, Kumarasamy, N, Campbell, TB & Eshleman, S 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, vol. 60, no. 10, pp. 1541-1549. https://doi.org/10.1093/cid/civ102
Kantor, Rami ; Smeaton, Laura ; Vardhanabhuti, Saran ; Hudelson, Sarah E. ; Wallis, Carol L. ; Tripathy, Srikanth ; Morgado, Mariza G. ; Saravanan, Shanmugham ; Balakrishnan, Pachamuthu ; Reitsma, Marissa ; Hart, Stephen ; Mellors, John W. ; Halvas, Elias ; Grinsztejn, Beatriz ; Hosseinipour, Mina C. ; Kumwenda, Johnstone ; La Rosa, Alberto ; Lalloo, Umesh G. ; Lama, Javier R. ; Rassool, Mohammed ; Santos, Breno R. ; Supparatpinyo, Khuanchai ; Hakim, James ; Flanigan, Timothy ; Kumarasamy, Nagalingeswaran ; Campbell, Thomas B. ; Eshleman, Susan. / Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated with Virologic Failure : Results from the Multinational PEARLS (ACTG A5175) Clinical Trial. In: Clinical Infectious Diseases. 2015 ; Vol. 60, No. 10. pp. 1541-1549.
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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.",
keywords = "clinical trial., drug resistance, HIV, subtype",
author = "Rami Kantor and Laura Smeaton and Saran Vardhanabhuti and Hudelson, {Sarah E.} and Wallis, {Carol L.} and Srikanth Tripathy and Morgado, {Mariza G.} and Shanmugham Saravanan and Pachamuthu Balakrishnan and Marissa Reitsma and Stephen Hart and Mellors, {John W.} and Elias Halvas and Beatriz Grinsztejn and Hosseinipour, {Mina C.} and Johnstone Kumwenda and {La Rosa}, Alberto and Lalloo, {Umesh G.} and Lama, {Javier R.} and Mohammed Rassool and Santos, {Breno R.} and Khuanchai Supparatpinyo and James Hakim and Timothy Flanigan and Nagalingeswaran Kumarasamy and Campbell, {Thomas B.} and Susan Eshleman",
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TY - JOUR

T1 - Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated with Virologic Failure

T2 - Results from the Multinational PEARLS (ACTG A5175) Clinical Trial

AU - Kantor, Rami

AU - Smeaton, Laura

AU - Vardhanabhuti, Saran

AU - Hudelson, Sarah E.

AU - Wallis, Carol L.

AU - Tripathy, Srikanth

AU - Morgado, Mariza G.

AU - Saravanan, Shanmugham

AU - Balakrishnan, Pachamuthu

AU - Reitsma, Marissa

AU - Hart, Stephen

AU - Mellors, John W.

AU - Halvas, Elias

AU - Grinsztejn, Beatriz

AU - Hosseinipour, Mina C.

AU - Kumwenda, Johnstone

AU - La Rosa, Alberto

AU - Lalloo, Umesh G.

AU - Lama, Javier R.

AU - Rassool, Mohammed

AU - Santos, Breno R.

AU - Supparatpinyo, Khuanchai

AU - Hakim, James

AU - Flanigan, Timothy

AU - Kumarasamy, Nagalingeswaran

AU - Campbell, Thomas B.

AU - Eshleman, Susan

PY - 2015/5/15

Y1 - 2015/5/15

N2 - 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.

AB - 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.

KW - clinical trial.

KW - drug resistance

KW - HIV

KW - subtype

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U2 - 10.1093/cid/civ102

DO - 10.1093/cid/civ102

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