Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Drug resistance and plasma viral RNA level after ineffective use of oral pre-exposure prophylaxis in women Robert M. Grant a,b , Teri Liegler b , Patricia Defechereux a , Angela D.M. Kashuba c , Douglas Taylor d , Mohamed Abdel-Mohsen b , Jennifer Deese d , Katrien Fransen e , Irith De Baetselier e , Tania Crucitti e , Gordon Bentley a , Walter Agingu f , Khatija Ahmed g and Lut Van Damme h Background: Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine (FTC)/ tenofovir disoproxil fumarate may select for drug resistance if there is low adherence. Methods: Plasma viral HIV-1 RNA level, CD4 þ T-cell counts, and drug resistance were evaluated among seroconverting women in the FEM-PrEP trial (clinicaltrials.gov NCT00625404) using standard clinical tests, allele-specific PCR (ASPCR), and by deep sequencing. Tenofovir, FTC, and their intracellular metabolites were measured in plasma and cells. Results: There was no difference in plasma HIV-1 RNA level or CD4 þ cell count among seroconverters in the active arm versus those receiving placebo. Tenofovir resistance was not observed. FTC resistance was detected using clinical assays in five serocon- verters (four in the active arm and one in the placebo arm); two in the active arm occurred among women having moderate concentrations of PrEP drugs in the blood. The first evidence of infection occurred at the first postenrollment visit in three of the four with FTC resistance, although none had detectable viral nucleic acids at enroll- ment. FTC-resistant minor variants were detected in an additional four seroconverters (one in the active arm and three in the placebo arm). Conclusions: Drug resistance detected during ineffective PrEP use had characteristics suggesting transmitted infection or incubating infection prior to starting PrEP. Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. AIDS 2015, 29:331–337 Keywords: antiretroviral resistance, HIV, pre-exposure prophylaxis Introduction Emtricitabine (FTC) or tenofovir (TFV) resistance was not observed among pre-exposure prophylaxis (PrEP) users with incident HIV infections in PrEP trials that demonstrated efficacy [1–4]. Resistance may occur more frequently when adherence to daily PrEP is ineffective, as occurred in the FEM-PrEP trial [5]. Such resistance could undermine the activity of first-line therapies, which frequently include these agents. Concerns that a Gladstone Institutes, b University of California, San Francisco, San Francisco, California, c Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, d FHI360, Durham, North Carolina, USA, e Institute of Tropical Medicine, Antwerp, Belgium, f Impact Research and Development Organization, Kisumu, Kenya, g Setshaba Research Centre, Soshanguve, Pretoria, South Africa, and h Bill and Melinda Gates Foundation, Seattle, Washington, USA. Correspondence to Robert M. Grant, MD, MPH, 1650 Owens Street, San Francisco, CA 94158, USA (formerly of FHI360). Tel: +1 415 734 4810; e-mail: rgrant@gladstone.ucsf.edu Received: 20 August 2014; revised: 30 October 2014; accepted: 25 November 2014. DOI:10.1097/QAD.0000000000000556 ISSN 0269-9370 Copyright Q 2015 Wolters Kluwer Health, Inc. All rights reserved. 331