1. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naive populations and associate with reduced treatment efficacy
- Author
-
Johnson, Jeffrey A., Li, Jin-Fen, Wei, Xierong, Lipscomb, Jonathan, Irlbeck, David, Craig, Charles, Smith, Amanda, Bennett, Diane E., Monsour, Michael, Sandstrom, Paul, Lanier, E. Randall, and Heneine, Walid
- Subjects
Antiviral agents -- Patient outcomes -- Genetic aspects ,Drug resistance -- Genetic aspects -- Patient outcomes ,Anti-HIV agents -- Patient outcomes -- Genetic aspects ,Drug therapy, Combination -- Patient outcomes -- Genetic aspects ,Biological sciences - Abstract
Background Transmitted HIV-1 drug resistance can compromise initial antiretroviral therapy (ART); therefore, its detection is important for patient management. The absence of drug-associated selection pressure in treatment-naive persons can cause drug-resistant viruses to decline to levels undetectable by conventional bulk sequencing (minority drug-resistant variants). We used sensitive and simple tests to investigate evidence of transmitted drug resistance in antiretroviral drug-naive persons and assess the clinical implications of minority drug-resistant variants. Methods and Findings We performed a cross-sectional analysis of transmitted HIV-1 drug resistance and a case-control study of the impact of minority drug resistance on treatment response. For the cross-sectional analysis, we examined viral RNA from newly diagnosed ART-naive persons in the US and Canada who had no detectable (wild type, n = 205) or one or more resistance-related mutations (n = 303) by conventional sequencing. Eight validated real-time PCR-based assays were used to test for minority drug resistance mutations (protease L90M and reverse transcriptase M41L, K70R, K103N, Y181C, M184V, and T215F/Y) above naturally occurring frequencies. The sensitive real-time PCR testing identified one to three minority drug resistance mutation(s) in 34/205 (17%) newly diagnosed persons who had wild-type virus by conventional genotyping; four (2%) individuals had mutations associated with resistance to two drug classes. Among 30/303 (10%) samples with bulk genotype resistance mutations we found at least one minority variant with a different drug resistance mutation. For the case-control study, we assessed the impact of three treatment-relevant drug resistance mutations at baseline from a separate group of 316 previously ART-naive persons with no evidence of drug resistance on bulk genotype testing who were placed on efavirenz-based regimens. We found that 7/95 (7%) persons who experienced virologic failure had minority drug resistance mutations at baseline; however, minority resistance was found in only 2/221 (0.9%) treatment successes (Fisher exact test, p = 0.0038). Conclusions These data suggest that a considerable proportion of transmitted HIV-1 drug resistance is undetected by conventional genotyping and that minority mutations can have clinical consequences. With no treatment history to help guide therapies for drug-naive persons, the findings suggest an important role for sensitive baseline drug resistance testing., The Editors' Summary of this article follows the references. Introduction Antiretroviral drugs have been remarkably successful in suppressing HIV-1 infection; however, transmitted drug resistance can reduce the efficacy of first-line [...]
- Published
- 2008