PrEP is reported to have nearly 100% prevention efficacy in men who have sex with men (MSM) when adherence is high. We report a 43 year old MSM who seroconverted to multi-class resistant HIV-1 (day 0; 4th generation Ag/Ab combo screen positive, p24 positive, Western Blot negative) after 24 months of successful PrEP, despite clinical and pharmacokinetic data suggesting long-term adherence to FTC/TDF.

Pharmacy dispensing records were obtained for FTC/TDF. Liquid chromatography–mass spectrometry (LC-MS) was performed on the untimed plasma sample from day 0 to determine TDF and FTC concentrations. Dried blood spots (DBS) were collected on day 16, while on FTC/TDF-based combination antiretroviral therapy, for determination of intracellular TVF-DP concentration. Standard population sequencing and deep sequencing to 2% of the viral population was completed on day 7 plasma (HIV RNA 28,326 copies/mL), as was phenotypic testing for resistance to integrase inhibitors. Phylogenetic analysis of the V3 loop of envelope protein gp120 was completed on day 7 plasma to characterize the founder virus.

Pharmacy dispensing records demonstrated consistent prescription refills. DBS testing revealed TVF-DP of 2,297 fmol/punch indicating consistent dose-taking in the preceding 1-2 months, thus overlapping with the seroconversion time. LC-MS on day 0 plasma was inconclusive for TDF (calibration range 181-2,385 ng/ml) and FTC (range 736-50,200 ng/ml) due to the untimed nature of the sample relative to dosing and the high lower limit of quantification of the assay. Standard and deep sequencing of virus from day 7 revealed CCR5-tropic clade B HIV-1 with mutations conferring resistance to NRTIs (41L, 67G, 69D, 70R, 184V, 215E), NNRTIs (181C) and INSTIs (51Y, 92Q), suggesting transmitted rather than acquired resistance (table 1). Phenotypic drug resistance testing of the integrase class on day 7 plasma revealed reduced response to all integrase inhibitors (table 1). Phylogenetic analysis revealed a very narrow range of sequence diversity, consistent with infection from a single source.

This patient’s clinical history, pharmacy records and DBS results consistent with long-term dosing of FTC/TDF suggest that HIV infection is possible despite adherence to daily oral PrEP when exposed to FTC/TDF-resistant virus. To our knowledge, this is the first reported case of breakthrough HIV infection with evidence of long-term adherence to FTC/TDF.