ObjectivesEarly 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.MethodsA 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.ResultsTen 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.DiscussionAlthough 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.

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The currently approved dose of efavirenz (EFV) is 600 mg once daily, although there is much variability in plasma EFV concentrations. The standard reference range for plasma EFV (1-4 mg/L) is based on observations of increased risk of virological failure when levels fell below 1 mg/L [1], and concern about drug resistance. Raised EFV concentrations, above 4 mg/L, may be linked to central nervous system side effects [1], although many patients with raised concentrations are asymptomatic. The cytochrome P450 (CYP) enzymes are responsible for EFV metabolism and the variant T allele at the CYP2B6-516 position is associated with significantly raised EFV concentrations [2]. These findings are particularly relevant in populations with higher T allele frequency, such as the southern Chinese population, with a T allele frequency of between 0.25 and 0.43 [3,4].To assess the differential impacts of CYP2B6-G516T genotypes on plasma EFV concentrations, we reviewed the patterns in HIV-1-positive Chinese patients stable on EFV, taking no concurrent medications, with undetectable HIV viral load, from a large HIV out-patient clinic in Hong Kong, where genotyping of CYP2B6-G516T and EFV therapeutic drug monitoring (TDM) were performed. Sixty-one patients (median age 46 years) were included in the analysis, of whom 54 (88.5%) were men. There were no significant correlations between body weight (P = 0.17), gender (P = 0.82) or length of time on their current regimen (P = 0.79) and plasma EFV concentrations. Older age correlated with lower EFV concentrations (P = 0.046). Genotype frequency and plasma EFV concentration are shown in Table 1. The allelic frequency of CYP2B6-G516T was 0.24. All three patients with the TT genotype had EFV concentrations above 4 mg/L, as did 39.1% (nine of 23) of those with the GT genotype and 5.7% (two of 35) of those with the GG genotype. One patient with the GG genotype had an EFV concentration below 1 mg/L, but maintained viral suppression.Patients with the TT genotype were excluded from further analysis because of the small sample size. There was a significant difference in mean EFV concentration between those with the GG and GT genotypes (P < 0.001): (range = mean ± SD) 1.69-3.37 mg/L for GG and 2.71-5.05 mg/L for GT. Separating the reference ranges of the GG and GT genotypes would more accurately represent the 'normal' ranges of these patients and prevent repeated TDM to monitor symptom-free patients stable on EFV. As all patients in the cohort had undetectable HIV viral load, this implies that the lower EFV concentration achieved by those with the GG genotype can be as effective as the higher concentration achieved by those with the GT genotype with no compromise of clinical outcome. In optimizing future therapy, an alternative approach would therefore be to consider reducing the dose of EFV from 600 mg daily using genotype as a guide. This would not only reduce adverse effects in symptomatic patients with variant genotypes, but also reduce drug cost for patients using a lower EFV dose. Gatanaga e...

A self-administered questionnaire survey was conducted in a specialist HIV clinical service in Hong Kong. A total of 76 male Chinese patients who had been on highly active antiretroviral therapy for over one year were enrolled. All except one had undetectable viral load at the time of the assessment. Though a majority (76%) scored 100% in self-reporting adherence rating, one-third of these had in fact missed at least one dose in the preceding four-week period. Men having sex with men had a lower tendency of missing dose than heterosexuals (13.6% versus 42%, P=0.019). There was no association between missing doses and clinical staging or the regimens. The study revealed that missing doses may occur despite report of almost complete adherence, which, in the long run, could be a cause for concern.

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