Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes

Birgitte B. Simen, Jan Fredrik Simons, Katherine Huppler Hullsiek, Richard M. Novak, Rodger David MacArthur, John D. Baxter, Chunli Huang, Christine Lubeski, Gregory S. Turenchalk, Michael S. Braverman, Brian Desany, Jonathan M. Rothberg, Michael Egholm, Michael J. Kozal

Research output: Contribution to journalArticle

295 Citations (Scopus)

Abstract

Background. Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. Objectives. To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). Methods. The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. Results. Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]). Conclusions. Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.

Original languageEnglish (US)
Pages (from-to)693-701
Number of pages9
JournalJournal of Infectious Diseases
Volume199
Issue number5
DOIs
StatePublished - Mar 1 2009

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High-Throughput Nucleotide Sequencing
HIV
Mutation
Pharmaceutical Preparations
Therapeutics
Confidence Intervals
Reverse Transcriptase Inhibitors
Retroviridae
Nucleosides
Proportional Hazards Models
Drug Resistance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes. / Simen, Birgitte B.; Simons, Jan Fredrik; Hullsiek, Katherine Huppler; Novak, Richard M.; MacArthur, Rodger David; Baxter, John D.; Huang, Chunli; Lubeski, Christine; Turenchalk, Gregory S.; Braverman, Michael S.; Desany, Brian; Rothberg, Jonathan M.; Egholm, Michael; Kozal, Michael J.

In: Journal of Infectious Diseases, Vol. 199, No. 5, 01.03.2009, p. 693-701.

Research output: Contribution to journalArticle

Simen, BB, Simons, JF, Hullsiek, KH, Novak, RM, MacArthur, RD, Baxter, JD, Huang, C, Lubeski, C, Turenchalk, GS, Braverman, MS, Desany, B, Rothberg, JM, Egholm, M & Kozal, MJ 2009, 'Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes', Journal of Infectious Diseases, vol. 199, no. 5, pp. 693-701. https://doi.org/10.1086/596736
Simen, Birgitte B. ; Simons, Jan Fredrik ; Hullsiek, Katherine Huppler ; Novak, Richard M. ; MacArthur, Rodger David ; Baxter, John D. ; Huang, Chunli ; Lubeski, Christine ; Turenchalk, Gregory S. ; Braverman, Michael S. ; Desany, Brian ; Rothberg, Jonathan M. ; Egholm, Michael ; Kozal, Michael J. / Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes. In: Journal of Infectious Diseases. 2009 ; Vol. 199, No. 5. pp. 693-701.
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abstract = "Background. Minor (i.e., <20{\%} prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. Objectives. To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1{\%} prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). Methods. The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. Results. Mutations were detected by standard and ultra-deep sequencing (in 14{\%} and 28{\%} of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, {"}NNRTI strategy{"}), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95{\%} confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95{\%} CI, 1.17-5.36]). Conclusions. Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.",
author = "Simen, {Birgitte B.} and Simons, {Jan Fredrik} and Hullsiek, {Katherine Huppler} and Novak, {Richard M.} and MacArthur, {Rodger David} and Baxter, {John D.} and Chunli Huang and Christine Lubeski and Turenchalk, {Gregory S.} and Braverman, {Michael S.} and Brian Desany and Rothberg, {Jonathan M.} and Michael Egholm and Kozal, {Michael J.}",
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T1 - Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes

AU - Simen, Birgitte B.

AU - Simons, Jan Fredrik

AU - Hullsiek, Katherine Huppler

AU - Novak, Richard M.

AU - MacArthur, Rodger David

AU - Baxter, John D.

AU - Huang, Chunli

AU - Lubeski, Christine

AU - Turenchalk, Gregory S.

AU - Braverman, Michael S.

AU - Desany, Brian

AU - Rothberg, Jonathan M.

AU - Egholm, Michael

AU - Kozal, Michael J.

PY - 2009/3/1

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N2 - Background. Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. Objectives. To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). Methods. The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. Results. Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]). Conclusions. Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.

AB - Background. Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. Objectives. To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). Methods. The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. Results. Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]). Conclusions. Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.

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