Impact of minority nonnucleoside reverse transcriptase inhibitor resistance mutations on resistance genotype after virologic failure

Jonathan Z. Li, Roger Paredes, Heather J. Ribaudo, Michael J. Kozal, Evguenia S. Svarovskaia, Jeffrey A. Johnson, Anna Maria Geretti, Karin J. Metzner, Martin R. Jakobsen, Katherine Huppler Hullsiek, Lars Ostergaard, Michael D. Miller, Daniel R. Kuritzkes

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Drug-resistant human immunodeficiency virus type 1 (HIV-1) minority variants increase the risk of virologic failure for first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We performed a pooled analysis to evaluate the relationship between NNRTI-resistant minority variants and the likelihood and types of resistance mutations detected at virologic failure. In multivariable logistic regression analysis, higher NNRTI minority variant copy numbers, non-white race, and nevirapine use were associated with a higher risk of NNRTI resistance at virologic failure. Among participants on efavirenz, K103N was the most frequently observed resistance mutation at virologic failure regardless of the baseline minority variant. However, the presence of baseline Y181C minority variant was associated with a higher probability of Y181C detection after virologic failure. NNRTI regimen choice and preexisting NNRTI-resistant minority variants were both associated with the probability and type of resistance mutations detected after virologic failure.

Original languageEnglish (US)
Pages (from-to)893-897
Number of pages5
JournalJournal of Infectious Diseases
Volume207
Issue number6
DOIs
StatePublished - 2013

Bibliographical note

Funding Information:
Financial Support. J. Z. L. has received research support from Bristol-Myers Squibb and Tobira. R. P. has received consulting fees from Pfizer, Merck, Roche Diagnostics; the IrsiCaixa AIDS Research Institute and the Lluita contra la SIDA Foundation have received grant support from Pfizer, ViiV Healthcare, Siemens, Merck, and Boehringer Ingelheim for studies that R. P. serves as principal investigator. E. S. S. and M. D. M. are employees and stock-holders of Gilead Sciences, Inc. Yale University receives grant support from Merck, Pfizer, Gilead, Abbott, ViiV, Vertex, and Bristol-Myers Squibb for studies that M. D. K. serves as the principal investigator. M. D. K. receives royalties from patents owned by Stanford University for some HIV diagnostic tests. A. M. G. has served as a consultant to and/or has received research and travel grants from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Jenssen/Tibotec, and ViiV Healthcare. K. J. M. has received travel grants and honoraria from Gilead, Roche Diagnostics, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, and Abbott; and the University of Zurich received research grants from Gilead, Roche, and Merck Sharp & Dohme for studies that K. J. M. serves as principal investigator. D. R. K. has served as a consultant to and/or has received research grant support from Abbott, Avexa, Bristol-Myers Squibb, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Roche, Tobira, Vertex, ViroStatistics, and ViiV Healthcare; he has also received speaking honoraria from Gilead and Roche. J. Z. L. is the recipient of a Clinical Investigator Training Program Fellowship: Harvard/ MIT Health Sciences and Technology—Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc. and Merck & Co. R. P. was supported in part by the CHAIN (Collaborative HIV and Anti-HIV Drug Resistance Network), Integrated Project no. 223131, funded by the European Commission Framework 7 Program. H. J. R. is supported in part by grants from the National Institutes of Health (NIH; Statistical and Data Management Center of the AIDS Clinical Trials Group U01 AI068634 and Harvard University CFAR P30 AI060354). D. K. is supported by a VA Merit Award. K. H. H. was supported in part by a grant from the NIH (U01 AI042170). K. J. M. is supported by the Swiss National Science Foundation (SNF), grants 324700-120793 and CR32I2_127017, and the European Community’s Seventh Framework Programme (FP7/2007-2013) under the project "Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)," grant agreement no. 223131. R. K. is supported in part by grants from the NIH (U01 AI 068636, K24 RR016482) and a Virology Specialty Laboratory subcontract from the ACTG. Potential conflicts of interest. All authors: No reported conflicts.

Keywords

  • HIV-1 drug resistance
  • minority variants
  • resistance genotyping
  • virologic failure

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