Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single-or dual-agent preexposure prophylaxis

Dara A. Lehman, Jared M. Baeten, Connor O. McCoy, Julie F. Weis, Dylan Peterson, Gerald Mbara, Deborah Donnell, Katherine K. Thomas, Craig Hendrix, Mark A Marzinke, Lisa Frenkel, Patrick Ndase, Nelly R. Mugo, Connie Celum, Julie Overbaugh, Frederick A. Matsen

Research output: Contribution to journalArticle

Abstract

Background Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use. Methods. Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing. Results. Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57%]), compared with the TDF arm (1 of 19 [5.3%]; P =.01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment. Conclusions. These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.

Original languageEnglish (US)
Pages (from-to)1211-1218
Number of pages8
JournalJournal of Infectious Diseases
Volume211
Issue number8
DOIs
StatePublished - Apr 15 2015

Fingerprint

Drug Resistance
Randomized Controlled Trials
HIV
Tenofovir
Infection
Mutation
HIV-2
Virus Diseases
Mutation Rate
Random Allocation
Treatment Failure
Pharmaceutical Preparations
Placebos
Viruses

Keywords

  • antiretroviral resistance
  • HIV
  • HIV prevention
  • pre-exposure prophylaxis

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single-or dual-agent preexposure prophylaxis. / Lehman, Dara A.; Baeten, Jared M.; McCoy, Connor O.; Weis, Julie F.; Peterson, Dylan; Mbara, Gerald; Donnell, Deborah; Thomas, Katherine K.; Hendrix, Craig; Marzinke, Mark A; Frenkel, Lisa; Ndase, Patrick; Mugo, Nelly R.; Celum, Connie; Overbaugh, Julie; Matsen, Frederick A.

In: Journal of Infectious Diseases, Vol. 211, No. 8, 15.04.2015, p. 1211-1218.

Research output: Contribution to journalArticle

Lehman, DA, Baeten, JM, McCoy, CO, Weis, JF, Peterson, D, Mbara, G, Donnell, D, Thomas, KK, Hendrix, C, Marzinke, MA, Frenkel, L, Ndase, P, Mugo, NR, Celum, C, Overbaugh, J & Matsen, FA 2015, 'Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single-or dual-agent preexposure prophylaxis', Journal of Infectious Diseases, vol. 211, no. 8, pp. 1211-1218. https://doi.org/10.1093/infdis/jiu677
Lehman, Dara A. ; Baeten, Jared M. ; McCoy, Connor O. ; Weis, Julie F. ; Peterson, Dylan ; Mbara, Gerald ; Donnell, Deborah ; Thomas, Katherine K. ; Hendrix, Craig ; Marzinke, Mark A ; Frenkel, Lisa ; Ndase, Patrick ; Mugo, Nelly R. ; Celum, Connie ; Overbaugh, Julie ; Matsen, Frederick A. / Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single-or dual-agent preexposure prophylaxis. In: Journal of Infectious Diseases. 2015 ; Vol. 211, No. 8. pp. 1211-1218.
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abstract = "Background Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use. Methods. Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing. Results. Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57{\%}]), compared with the TDF arm (1 of 19 [5.3{\%}]; P =.01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment. Conclusions. These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.",
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T1 - Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single-or dual-agent preexposure prophylaxis

AU - Lehman, Dara A.

AU - Baeten, Jared M.

AU - McCoy, Connor O.

AU - Weis, Julie F.

AU - Peterson, Dylan

AU - Mbara, Gerald

AU - Donnell, Deborah

AU - Thomas, Katherine K.

AU - Hendrix, Craig

AU - Marzinke, Mark A

AU - Frenkel, Lisa

AU - Ndase, Patrick

AU - Mugo, Nelly R.

AU - Celum, Connie

AU - Overbaugh, Julie

AU - Matsen, Frederick A.

PY - 2015/4/15

Y1 - 2015/4/15

N2 - Background Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use. Methods. Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing. Results. Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57%]), compared with the TDF arm (1 of 19 [5.3%]; P =.01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment. Conclusions. These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.

AB - Background Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use. Methods. Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing. Results. Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57%]), compared with the TDF arm (1 of 19 [5.3%]; P =.01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment. Conclusions. These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.

KW - antiretroviral resistance

KW - HIV

KW - HIV prevention

KW - pre-exposure prophylaxis

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DO - 10.1093/infdis/jiu677

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