HIV-1 Drug Resistance in the iPrEx Preexposure Prophylaxis Trial

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. Me...

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Bibliographic Details
Published in:The Journal of infectious diseases 2014-10, Vol.210 (8), p.1217-1227
Main Authors: Liegler, Teri, Abdel-Mohsen, Mohamed, Bentley, L. Gordon, Atchison, Robert, Schmidt, Timothy, Javier, Jacqueline, Mehrotra, Megha, Eden, Christopher, Glidden, David V., McMahan, Vanessa, Anderson, Peter L., Li, Peilin, Wong, Joseph K., Buchbinder, Susan, Guanira, Juan V., Grant, Robert M.
Format: Article
Language:English
Subjects:
Adenine - administration & dosage
Adenine - analogs & derivatives
Adenine - therapeutic use
Anti-HIV Agents - administration & dosage
Anti-HIV Agents - pharmacology
Antiretrovirals
Antivirals
Clinical trials
Deoxycytidine - administration & dosage
Deoxycytidine - analogs & derivatives
Deoxycytidine - therapeutic use
Drug resistance
Drug Resistance, Viral
Emtricitabine
Female
Genetic mutation
Genotype
HIV
HIV 1
HIV infections
HIV Infections - prevention & control
HIV Infections - virology
HIV-1 - drug effects
HIV-1 - genetics
HIV/AIDS
Homosexuality, Male
Humans
Major and Brief Reports
Male
Mutation
Organophosphonates - administration & dosage
Organophosphonates - therapeutic use
Placebos
Polymerase chain reaction
RNA, Viral - genetics
Tenofovir
Transgender Persons
Viral Load
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Summary: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 lowfrequency minor variants. FTC resistance among those initiating PrEP with acute infection waned rapidly after drug discontinuation.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiu233