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 D. 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 journalArticlepeer-review

318 Scopus citations

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

Bibliographical note

Funding Information:
Potential conflicts of interest: M.J.K. has received grant support from Merck, Tibotec, and Boehringer-Ingleheim. M.J.K. receives patent royalties from Stanford University for some HIV diagnostic tests. Yale and the US Department of Veterans Affairs have submitted a patent for viral assays developed by M.J.K. M.J.K. is a consultant for Stanford University, Merck, and Schering-Plough Research Institute. M.J.K. has received honoraria, speaker fees, and reimbursement for travel expenses from Abbott and Roche. R.D.M. has received speaking honoraria and consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Abbott, Pfizer, Gilead Sciences, Boehringer-Ingelheim, and Roche and has received speaking honoraria from Merck. R.D.M. has received grant support from GlaxoSmithKline, Pfizer and Abbott. R.M.N. has consulting agreements with Pfizer, Abbott, Gilead Sciences, Tibotec, and Boehringer-Ingleheim and also has research contracts with Bristol-Myers Squibb, Abbott, GlaxoSmithKline, and Merck. J.D.B. has served as a consultant for Bayer Diagnostics and

Funding Information:
Financial support: US Department of Veterans Affairs (Merit and Career Development Award to M.J.K.); National Institute of Allergy and Infectious Diseases (NIAID) (grant support for the Terry Beirn Community Programs for Clinical Research on AIDS [CPCRA] and the FIRST Study, 5U01AI042170–10 and 5U01AI046362–03); NIAID sponsored the FIRST study, and had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Ultra-deep sequencing was performed by 454 Life Sciences free of charge. a B.B.S. and J.F.S. contributed equally to the project.

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