After much optimism surrounding the introduction of oral pre-exposure prophylaxis (PrEP) there have been many disappointments around its unrealised promise, particularly for high-risk women in sub-Saharan Africa. Even when uptake has been high, adherence and retention often prove low, markedly so when confirmed by biomarkers. The main reasons for suboptimal use are anxiety about being mistaken for someone living with HIV, dislike of and difficulty maintaining daily pill-taking, and low risk perception. Among female sex workers (FSW) additional barriers include supply disruptions due to mobility, fear of violence from clients, and discrimination within health settings. Our AMETHIST trial was among studies yielding contradictory results; despite high PrEP uptake among FSW, out of 569 women tested in the endline survey just 2 (0.04%) had protective levels in dried blood samples.