A Review of Reported Cases of HIV Pre-Exposure Prophylaxis Failure With Resultant Breakthrough HIV Infections

KW To; SS Lee


HIV Medicine. 2021;22(2):75-82. 

In This Article

Abstract and Introduction


Objectives: Early randomized controlled trials (RCTs) have confirmed high efficacy of pre-exposure prophylaxis (PrEP) for preventing HIV infection in men who have sex with men (MSM) with high HIV exposure risk. Nevertheless, some PrEP failure cases have been reported despite adequate drug adherence. This review aims to summarize the common features of PrEP failure cases and discuss the implications of upscaling PrEP programmes.

Methods: A search based on articles and clinical trials was conducted through Medline and OVID, with keywords for accessing publications reporting 'true' PrEP failure in the presence of documented adherence to daily regimen of co-formulated tenofovir disoproxil fumarate/emtricitabone.

Results: Ten cases of 'true' PrEP failure were identified, all of which were preceded by continued practice of condomless anal sex, despite documented adherence. Dried blood spot and/or hair analyses provided supporting evidence of adherence in eight cases. There was strong association of PrEP failure with recurrent or multiple sexually transmitted diseases and infection with resistant HIV viruses. Seroconversion was usually atypical or delayed because of significantly suppressed viral load, making diagnosis a clinical challenge.

Discussion: Although it is uncommon, 'true' PrEP failure can occur in a real-world situation, contrary to the outcome of early RCTs. Failure to identify HIV infection while on PrEP can potentially lead to the emergence of drug-resistant virus. To achieve effective HIV prevention, PrEP programmes should emphasize safer sexual practice in addition to drug adherence. Early identification of PrEP failure is crucial, which requires the development of highly sensitive assays and their clinical application.


Pre-exposure prophylaxis (PrEP) has revolutionized the strategies for the prevention of HIV infection. Currently, the regimen approved by the World Health Organization (WHO) and other national/international organizations for PrEP is a single tablet comprising two antiretrovirals: emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF). Early studies showed that with regular daily dosing, high efficacy of TDF/FTC in preventing HIV infection can be achieved.[1] Subsequent studies showed that high efficacy was possible with an on-demand dosing regimen,[2] although it carries the risk of breakthrough infection if the drug level becomes suboptimal. In an open-label randomized control trial (RCT) cohort involving an immediate and a deferred group of MSM for PrEP initiation, there were significantly fewer HIV infections in the immediate group.[3]

As an HIV prevention strategy, failure of PrEP is the most feared outcome. In the 72-week study, 28 out of 1225 MSM/transgender women became HIV-infected after PrEP.[4] In the open-label PROUD study, only three HIV infections occurred in 275 MSM receiving immediate PrEP for at least 2 years.[3] In these two studies, the HIV incidence was < 2/100 person-years in people on daily PrEP.[3,4] The IPERGAY study reported an HIV incidence of 0.19 per 100 person-years in MSM receiving on-demand PrEP.[5] Another open-label observational study in Australia reported no breakthrough seroconversion in over 300 persons (mostly MSM) during PrEP, but 30 individuals were lost to follow-up so the specific outcome was unknown.[6] The Bangkok Tenofovir Study enrolled 2413 people who inject drugs, and, of these, there were 17 breakthrough infections in those on daily TDF.[7] In the large Partners PrEP Study enrolling over 10 000 heterosexual males and females, and seroconversion occurred in 17 and 13 participants who were taking TDF and TDF/FTC, respectively.[8] Their association with non-adherence could be inferred from the observation that only 31% had detectable TFV at the seroconversion visit. In the service setting, there was no reported HIV infection during over 5000 person-years of PrEP in a cohort in the United States.[9]

Currently there is no consensus definition of 'PrEP failure'. The broadest definition of PrEP failure is the inclusion of all HIV seroconversions occurring at any time along the care continuum for PrEP.[10] In practice, failure may occur as a result of non-adherence leading to sub-therapeutic drug levels in the body or acquisition of resistant viruses. Some cases might have been infected before PrEP took effect. With the increasing use of a TDF-based regimen for PrEP from clinical trials to HIV prevention service programmes, failure was considered to be relatively uncommon.[9] Seroconversions in the course of PrEP have been reported, some of them with suboptimal drug levels, while others seroconverted despite the maintenance of an adequate drug levels. It is important to differentiate between different forms of PrEP failures, and the strategy for their prevention and management vary considerably. We define 'true PrEP failure' as the occurrence of HIV seroconversion despite reported documentation of adherence to the standard daily TDF-based regimen, supported by results of available pharmacological monitoring. In this review, we summarized the features and associations of true PrEP failure cases, and discussed their implications in the implementation of PrEP in real-world situation.