Antiretroviral chemoprophylaxis: PROUD and pragmatism

About 20 years ago, very shortly after antiretroviral drugs were fi rst shown to inhibit HIV replication and improve clinical outcomes, studies of animals showed that preexposure and post-exposure antiretroviral treatment could protect against retroviral challenges. The fi rst use of antiviral drugs for chemoprophylaxis in human beings was that of zidovudine in HIV-infected pregnant women to prevent transmission to their children. Subsequently, seven effi cacy trials of antiretroviral primary prevention have shown that tenofovir-based regimens can prevent HIV acquisition in African male and female heterose xuals, men and transgender women who have sex with men in Asia, Africa, Europe, and the Americas, and men and women in Thailand who inject drugs. Protection was directly correlated with adherence to treatment. Individuals who were highly adherent achieved levels of protection that exceeded those associated with consistent condom use. Despite early studies showing the effi cacy of antiretroviral pre-exposure prophylaxis (PrEP), widespread uptake has not been immediate. Because the safety threshold for the use of drug treatments by otherwise healthy people must be high, concerns were raised about the potential for tenofovir–emtricitabine to cause symptoms, to be nephrotoxic, or to deplete bone mineral density, although initial studies of thousands of participants showed that, with routine monitoring, adverse events were few, and were readily manageable. Some commentators suggested that irregular use of antiretroviral drugs could lead to selection for drugresistant strains, but few PrEP-related resistant infections have been recorded, primarily because most individuals who became infected were non-adherent, limiting selection pressure. Because tenofovir–emtricitabine is expensive in many countries (up to US$15 000 per year), some questioned whether PrEP could be cost eff ective. However, in high-incidence settings, access to PrEP by people at greatest risk for infection could save money, since PrEP use can be limited to a period of risk, whereas, if HIV infection occurs, treatment with more expensive triple antiretroviral combination treatment is lifelong. The most contentious concerns about PrEP involve risk compensation: the fear that increased access to PrEP would lead people to abandon condom use. This hypothesis refl ects an odd mix of naivety and moralism. If condoms were being consistently used, the rates of new HIV infections would not remain at 2 million new infections per year. Rates of new HIV infections remain alarmingly high in several key populations (ie, young women in Africa, men who have sex with men and transgender women in most countries, sex workers, and people who inject drugs in countries that were part of the former Soviet Union, where access to eff ective prevention methods, such as clean syringes and opiate substitution treatment, have been supplanted by punitive laws and mass incarceration). The existence of coercive policies aff ecting vulnerable populations has led some advocates to question whether PrEP implementation could increase stigma and coercion by medicalising HIV risk, enabling authorities to avoid dealing with social drivers of HIV spread. Others have questioned whether PrEP could be readily implemented outside the controlled environment of a clinical trial and remain suffi ciently eff ective to warrant wider use. According to Sheena McCormack and colleagues’ PROUD study published in The Lancet, the answer is a resounding yes. The investigators enrolled 544 men who have sex with men who were seeking services at English sexual health clinics, and randomly assigned them to immediate PrEP (n=275) or deferred PrEP (n=269), to begin after 1 year. The deferred group had to be ended early, because of the 86% effi cacy (90% CI 64–96) in the immediate group. There was a worrying 9% yearly HIV incidence rate in the deferred PrEP group, who received counselling, condoms, and Published Online September 10, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)00153-1