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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.
Oliver Bacon is an associate professor of clinical medicine at UCSF in the HIV Division at San Francisco General Hospital.
References
[1] Grant RM, Lama JR, Anderson PL et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587–2599.
[2] Baeten JM, Donnell D, Ndase P et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367:399–410.
[3] Thigpen MC, Kebaabetswe PM, Paxton LA et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012;367:423–434.
[4] Solomon MM, Lama JR, Glidden DV et al. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS 2014;28:851–859.
[5] Mugwanya KK, Wyatt C, Celum C et al. Changes in glomerular kidney function among HIV-1-uninfected men and women receiving emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial. JAMA Intern Med 2015;175:246–254.
[6] Liu AY, Vittinghoff E, Sellmeyer DE et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One 2011;6:e23688.
[7] Smith DK, Herbst JH, Zhang X et al. Condom effectiveness for HIV prevention by consistency of use among men who have sex with men in the United States. J Acquir Immune Defic Syndr 2015;68:337–344.
[8] Myron S, Cohen MD, Ying Q et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493–505.
[9] United States Centers for Disease Control and Prevention. Statistics Center.
[10] San Francisco Department of Public Health. HIV Epidemiology Annual Report 2013.
[11] McCormack S & Dunn D. Pragmatic open-label randomised trial of preexposure prophylaxis: the PROUD study. Conference on Retroviruses and Opportunistic Infections: 23–26 February 2015, Seattle, Washington. Abstract 22LB.
[12] Molina JM, Capitant C, Spire B et al. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS IPERGAY trial. Conference on Retroviruses and Opportunistic Infections: 23–26 February 2015, Seattle, Washington. Abstract 23 LB.
[13] Buchbinder SP, Glidden DV, Liu AY et al. HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect Dis 2014;14:468–475.
[14] Kessler J, Myers JE, Nucifora KA et al. Averting HIV infections in New York City: a modeling approach estimating the future impact of additional behavioral and biomedical HIV prevention strategies. PLoS One 2013;8:e73269.
[15] Gomez GB, Borquez A, Case KK et al. The cost and impact of scaling up pre-exposure prophylaxis for HIV prevention: a systematic review of cost-effectiveness modelling studies. PLoS Med 2013;10:e1001401.
