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Antiretroviral therapy (ART) has dramatically changed both mortality and morbidity associated with HIV infection, but treatment is lifelong and costly. The greatest disease burden, affecting 23 million people, is in Sub Saharan Africa where ART coverage for those in need is estimated at below 60%.1 The continued high rate of new infections demands urgent intervention, and, in the absence of an effective prophylactic vaccine, studies using ART to prevent HIV acquisition among uninfected individuals have been undertaken.
Baeten and colleagues report the results of a randomised trial among 4747 HIV-1–serodiscordant heterosexual couples from Kenya and Uganda comparing prophylactic single agent tenofovir (TDF), with tenofovir–emtricitabine (TDF-FTC) against placebo for pre-exposure prophylaxis (PrEP). Monthly follow-ups were conducted for up to 36 months.
The trial showed a protective efficacy of 67% and 75% for Tenofovir and TDF-FTC, respectively; irrespective of gender of the uninfected participant. These findings are in agreement with the TDF2 trial, which also reported a positive protective effect of PrEP.2 However, in contrast, the similarly designed FEM-PrEP study was terminated early for futility,3 and in contrast to the TDF-only arm of the study by Baeten and colleagues, the oral tenofovir arm of the VOICE trial was closed due to lack of protection.4
These conflicting findings are striking and require more detailed investigation; probably reflecting multiple factors which include: different sexual exposure routes (anal vs vaginal mucosae), different populations enrolled into the studies, and, importantly adherence to PrEP.3 PrEP adherence may be the key discriminatory factor explaining different trial outcomes. When adhered to the high level of efficacy reported by the positive trials has led to approval for use as PrEP by the Food and Drug Administration (FDA).
However, despite this, the complexity of messaging for the ‘rollout’ of PrEP, uncertainty of the safety of its widespread prescription and the current global fiscal crisis challenges the capability and commitment of many countries to offer widespread use of oral PrEP at a population level. In many countries the ability to provide ART for all those in ‘need’ as defined by CD4 (<350 cells/cc3) is challenged by constraints in funding and overstretched capacity making the potential additional burden of delivering PrEP currently unfeasible.
At a population level, there are complexities of safely prescribing TDF-FTC PrEP. In the setting of a clinical trial regular HIV testing (monthly) was undertaken, however, it will be difficult to deliver such frequent testing at a population level. In the absence of frequent HIV testing, with continued HIV exposure, the use of TDF-FTC among individuals who may be unknowingly HIV infected will increase the risk of drug resistant virus, negating the efficacy of TDF-FTC for HIV treatment—currently part of standard first-line therapy in most countries.5 Trials testing other antiretroviral agents with longer half-lives and not currently part of first-line treatment regimens are underway to explore this further. As illustrated in the FEMPREP clinical trial, good adherence is a critical factor for effectiveness and it is likely this could be more of a problem in a non-trial environment.5 For how long an individual may safely continue taking PrEP is unknown, with no data on the long-term toxicities of these drugs in HIV uninfected individuals. The concern that the use of PrEP may be accompanied by sexual disinhibition, potentially reversing its benefits, must be explored if it is to be delivered at a population level.
Following the dramatic protective effect (96% reduction) of suppressive ART in an HIV+ individual to reduce risk of HIV transmission to their partner, from HPTN 052 in addition to individual level health benefit,5 the WHO recommendation to offer ART earlier for the HIV+ partner in serodiscordant couples6 to reduce the risk of viral transmission has led to a pragmatic decision in many countries to preserve the use of valuable ART agents for the smaller population of people living with HIV rather than use the same drugs for the prevention of uninfected individuals.
The prevention of HIV transmission must remain a critical global health priority. Further data is needed to evaluate the comparative cost effectiveness between PrEP and ‘ART for prevention’. The protective effect of PrEP contributes significantly to the armoury of prevention tools and, in particular, provides an option for vulnerable high risk groups where condom negotiation is difficult.
Competing interests None.