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It has been nearly three years since the US Food and Drug Administration (FDA) approved daily emtricitabine/tenofovir (FTC/TDF, marketed as Truvada) as pre-exposure prophylaxis (PrEP) to prevent HIV infection in adults at increased risk of infection.

In 2014, the World Health Organization (WHO) recommended that men who have sex with men (MSM) should consider taking antiretroviral (ARV) medicines as an additional precaution against contracting HIV. Emerging evidence now adds further weight to the concept that PrEP, when used appropriately, could help halt the spread of infection among individuals at increased risk of HIV infection.

The time has come for governments and health bodies to adopt policies that incorporate the use of PrEP to protect people at risk of infection and help fight the spread of HIV, as they have done in countries such as the United States.

The ARVs tenofovir and emtricitabine have long been used in combination with other ARVs to treat HIV. When someone is exposed to HIV, emtricitabine/tenofovir can keep the virus from establishing a permanent infection — treatment can be combined with condoms and other prevention methods to provide even greater protection than when used alone.

When properly adhered to, PrEP has been shown to reduce the risk of HIV infection by up to 92% in men who have sex with men (MSM), and in heterosexuals at increased risk of HIV infection, including those in serodiscordant relationships[1],[2],[3].

Safety and tolerability

Critics of PrEP have expressed concerns that a healthy person should not be taking powerful drugs normally used to treat those infected with HIV because of the adverse effects associated with their use. However, an analysis of the safety profile of PrEP disproves this concern.

Tenofovir, when used in combination antiretroviral therapy (ART), especially with a protease inhibitor, is well known to cause a small drop in creatinine clearance and bone density in some HIV-infected persons (emtricitabine, the other drug in FTC/TDF, seems to have few side effects). A small but clinically unremarkable decrease in creatinine clearance versus placebo has been demonstrated in randomised trials of FTC/TDF for PrEP, which usually appears by week four, remains steady, and resolves after drug is stopped[4],[5].

Similarly, although FTC/TDF used for PrEP is associated with a small but significant decrease in bone mineral density, there is no increase in fractures[6]. A “start-up syndrome”, most commonly consisting of mild nausea, bloating, and loose stools, has been observed in approximately 10% of PrEP trial participants, usually resolving in several days to a week[1],[2],[3]. Unlike ARVs from the protease inhibitor and non-nucleoside reverse transcriptase inhibitor classes, the nucleotide reverse transcriptase inhibitors (NRTIs) FTC/TDF have almost no known drug interactions.

Halting new infections

Beyond efficacy and safety data, another justification for implementing PrEP is that it may fill gaps in the current methods in use to shrink the epidemic, such as HIV testing, condom promotion and treatment of HIV-infected persons with ART.

An analysis by the US Centers for Disease Control and Prevention estimates that condoms, when used 100% of the time, reduce HIV risk from an HIV-infected partner by 70% for anal sex to 87% for vaginal sex. When used inconsistently, they are no more protective, statistically, than sex without condoms — only 16% of MSM reported 100% use with partners regardless of HIV status[7].

PrEP is not going to encourage people to stop using condoms consistently. Many people have already stopped, even if they know they should use them or would like to use them. PrEP will also protect people when condoms break, or slip off, or when they are not an option, as in some cases of non-consensual sex.

The remarkable degree of protection afforded by testing and treatment (also known as treatment as prevention, or TasP) — a 96% risk reduction shown in the HPTN052 randomised trial of ART in serodiscordant heterosexual couples[8] — depends on people knowing their HIV status and starting ART as soon as possible after receiving a positive test. Until testing and immediate treatment are universal (and a look at the current treatment cascade suggests this will take a while), people will continue to get infected with HIV by partners unaware of their own infection, or aware of their positive status and unable or unwilling to access ART.

Around 50,000 new infections occur in the United States each year, an incidence that has not changed in the past 12 years[9], even though condoms have been in use for HIV prevention since the early 1980s when the AIDS epidemic began, and effective ART has been available since 1996.

Even in San Francisco, where I work as an HIV doctor and where ART initiation has been recommended regardless of CD4 count since 2010, there were 467 new infections in 2012, a year when 68% of newly diagnosed persons achieved viral suppression through ART[10]. As a prevention method controlled entirely by the individual, independent of his or her ability to use condoms at the time of intercourse and his or her partner’s testing status or viral load, PrEP complements the prevention methods we have.

Latest evidence and cost-effectiveness

Preliminary results of new PrEP trials, released at the Conference on Retroviruses and Opportunistic Infections (CROI) in February 2015, provide hope that approval will soon follow in other countries. It is about time.

On 23 February 2015, CROI attendees heard the preliminary results from the PROUD and IPERGAY studies of PrEP in MSM. Some attendees likened the feeling in the room to that experienced at the 1996 International AIDS Conference in Vancouver, Canada, when it was first shown that three-drug ART led to virologic suppression, immune reconstitution and reduced mortality.

The UK PROUD study[11] randomised 545 MSM at sexual health clinics to start daily FTC/TDF PrEP immediately versus waiting for 12 months, with quarterly follow-up for infections. Intended as a pilot study of PrEP offered in a “real world” setting, the randomised phase of PROUD was halted when interim analysis showed a risk reduction of 86% in the immediate versus deferred arm.

The IPERGAY study[12] randomised 400 MSM in France and Quebec, Canada, to placebo versus “on-demand” FTC/TDF PrEP, consisting of two tablets 2–24 hours before sex, one tablet 24 hours after sex, and another tablet 48 hours after the first dose. As in PROUD, the randomised phase was halted after interim analysis showed a significant reduction in HIV infections (again, 86%) in the active versus placebo arm. In both studies, the only persons who became infected after randomisation to active drug had stopped taking their tablets two months before their estimated date of infection.

Taken together, these two studies show high rates of acceptability and efficacy of FTC/TDF PrEP by MSM at high risk of HIV infection (as demonstrated by infection rates in the placebo arms) and at high risk of inconsistent condom use (as demonstrated by the considerable prevalence of sexually transmitted infections at baseline) in real world settings.

These two studies are also likely to trigger a recalculation of cost-effectiveness estimates of PrEP. Until now, assuming an efficacy of 44% and moderate uptake, these have shown PrEP to be cost-effective, although still expensive, when offered to MSM at increased risk of infection[13],[14],[15]. Improved estimates of cost-effectiveness or, possibly, cost savings should increase pressure on national governments, international funders and pharmaceutical companies to consider including PrEP in national prevention programmes regardless of a county’s level of resources.

The road towards zero new infections

As is the case with so many diseases, until there is an effective vaccine or a safe, accessible curative regimen for HIV, both of which are being sought, the realistic strategy for shrinking the epidemic is going to rely on combining the best methods available. Increased testing, improved use of condoms and immediate treatment of newly diagnosed HIV positive cases have gone a great distance towards containing the epidemic in many countries, rich and poor. Now PrEP offers an effective, safe and acceptable way to extend this progress further still.