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J Infect Dis. 2014 Oct 15;210(8):1217-27. doi: 10.1093/infdis/jiu233. Epub 2014 Apr 16.

HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial.

Author information

1
Department of Medicine, University of California AIDS Research Institute, University of California.
2
Department of Medicine, University of California.
3
J. David Gladstone Institutes.
4
AIDS Research Institute, University of California.
5
Department of Epidemiology, University of California, San Francisco.
6
Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
7
Veterans Affairs Medical Center, San Francisco.
8
Bridge HIV, San Francisco Department of Public Health, California.
9
Asociación Civil Impacta Salud y Educación, Lima, Peru.
10
Department of Medicine, University of California J. David Gladstone Institutes.

Abstract

BACKGROUND:

The iPrEx study demonstrated that combination oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) as preexposure prophylaxis (PrEP) protects against HIV acquisition in men who have sex with men and transgender women. Selection for drug resistance could offset PrEP benefits.

METHODS:

Phenotypic and genotypic clinical resistance assays characterized major drug resistant mutations. Minor variants with FTC/TDF mutations K65R, K70E, M184V/I were measured using 454 deep sequencing and a novel allele-specific polymerase chain reaction (AS-PCR) diagnostic tolerant to sequence heterogeneity.

RESULTS:

Control of primer-binding site heterogeneity resulted in improved accuracy of minor variant measurements by AS-PCR. Of the 48 on-study infections randomized to FTC/TDF, none showed FTC/TDF mutations by clinical assays despite detectable drug levels in 8 participants. Two randomized to FTC/TDF had minor variant M184I detected at 0.53% by AS-PCR or 0.75% by deep sequencing, only 1 of which had low but detectable drug levels. Among those with acute infection at randomization to FTC/TDF, M184V or I mutations that were predominant at seroconversion waned to background levels within 24 weeks after discontinuing drug.

CONCLUSIONS:

Drug resistance was rare in iPrEx on-study FTC/TDF-randomized seroconverters, and only as low-frequency minor variants. FTC resistance among those initiating PrEP with acute infection waned rapidly after drug discontinuation. Clinical Trials Registration.NCT00458393.

KEYWORDS:

454 deep sequencing; AS-PCR; FTC/TDF; HIV-1; PrEP; drug resistance; minor variant; preexposure prophylaxis

PMID:
24740633
PMCID:
PMC4176446
DOI:
10.1093/infdis/jiu233
[Indexed for MEDLINE]
Free PMC Article
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