Pre-exposure prophylaxis failure with tenofovir disoproxil

Pre-exposure prophylaxis (PrEP) is emerging as an alternative HIV prevention method in individuals at a high risk of acquiring HIV [1]. The use of daily oral tenofovir-disoproxil (TDF) or in combination with emtricitabine (FTC) is a well tolerated intervention and has been shown to prevent HIV infection under recommended dosing and strict adherence of up to 100%. The WHO and International AIDS Society recently released guidelines recommending oral tenofovir-based PrEP to be offered as part of comprehensive HIV prevention package. Failure of PrEP has generally been related to a lack of adherence in all larger clinical studies [1,2]. Here, we report on a 25-year old, sexually active, promiscuous man, who has sex with men, presenting with asymptomatic syphilis and hepatitis B virus (HBV) infection with viral load of 17 860 000 HBV-DNA copies/ml, but nonreactive HIV-AK/Ag (Fig. 1). HIV-status was confirmed to be nonreactive 6 and 12 months after first presentation. Syphilis was successfully treated with benzathine-penicillin-G intramuscularly in a single dose. The patient received a 300 mg TDF once-daily regimen. Although TDF treatment was not initially intended as PrEP, monitoring of HBV-DNA viral loads served as an efficient surrogate measure for drug adherence. Indeed, HBV-DNA viral loads declined below the limit of detection within 8 months after treatment initiation, which was then monitored bimonthly and remained below the detection cut-off. A year after initial presentation, the patient presented with chlamydia as well as gonorrhoea infections. Despite ongoing TDF treatment, the patient was also tested positive for HIV-1. Retrospective analysis of stored samples indicated the presence of low levels of HIV RNA. The first confirmed reactive HIV-test coincided with symptomatic gonorrhoea 536 days after initial presentation and 3 months after the last negative HIV test (103 days). Thus, given the high frequency of HIV testing, it is likely that he contracted HIV during the period of 3 months during ongoing TDF therapy. To understand potential reasons for HIV infection in the presence of TDF, we performed targeted sequencing from plasma virus and identified a highly TDF-resistant K65R mutation suggesting that the patient had been exposed to a TDF-resistant virus. The emergence of viral resistance in the context of PrEP use is one of the most contentious issues [3,4]. Most PrEPs are performed in combination therapy with FTC raising the barrier to infection. Although the frequency of exposure to TDF-resistant viruses has been estimated in large clinical trials to be nearly 0.06% [5], this case of HIV infection in the presence of efficacious TDF therapy of chronic HBV-infection highlights that PrEP is an important tool in the HIV prevention toolbox, but should not replace other prevention methods, whenever possible.Fig. 1: Summary of laboratory findings.Initial HBV infection was treated with 300 mg tenofovir disoproxil (TDF) once daily. HBV DNA viral load performed by Siemens bDNA/Abbott real-time assays (blue, left axis) dropped below limit of detection by day 328. HIV results were negative day 108, 209, 385 and 433, respectively. First HIV-positive test was confirmed on day 536; first detectable HIV viral load of 59 RNA copies/ml (red, right axis; Abbott real time assays) was at day 536. Chlamydia trachomatis infection was diagnosed on day 381 and gonorrhoea on day 486. Antiretroviral therapy was switched after HIV diagnosis to TDF, emtricitabine (FTC) and ritonavir-boosted darunavir (DRV/r).Acknowledgements Conflicts of interest The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense.