How Effective Is PrEP in Preventing HIV?

Infection in two men on prevention pill in raises concern

107091581.jpg SAN ANSELMO, CA - NOVEMBER 23: Bottles of antiretroviral drug Truvada are displayed at Jack's Pharmacy on November 23, 2010 in San Anselmo, California. A study published by the New England Journal of Medicine showed that men who took the daily antiretroviral pill Truvada significantly reduced their risk of contracting HIV. (Photo Illustration by Justin Sullivan/Getty Images)
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It was widely reported on February 25, 2016 that a man taking the HIV prevention drug, Truvada, contracted the virus despite being fully adherent to the once-daily drug regimen. The news raised serious concerns among some as to how effective the strategy—known as HIV pre-exposure prophylaxis (PrEP)—actually is ensuring that HIV-negative persons remain uninfected.

In their report, investigators with the Maple Leaf Medical Clinic (MLMC) in Canada confirmed that a 43-year-old gay man had tested positive for HIV while on PrEP, and that a review of both pharmacy records and the patient’s therapeutic drug tests (used to measure drug concentration in blood) paid evidence to the individual's high level of compliance.

Further genetic testing eventually revealed that the man had acquired a "rare" mutated strain of HIV, which was resistant to the two individual drug agents that comprise Truvada.

So the question remains: is this case as "rare" as some in the media have reported? Or does the incident, in fact, expose a possible chink in the armor of this much-touted HIV prevention strategy?

Real-World Efficacy of PrEP

Most HIV organizations today will advise you that PrEP, if taken correctly in the form of a daily Truvada tablet, can reduce a person's risk of getting HIV by 90 percent or more. They will also caution users, particularly those at high risk, that the drug is not to be used in isolation but rather as part of an overall HIV prevention program (including condoms, limiting the number of sex partners, etc.)

But the message is often filtering down to the public is far different ways, with social media and news outlets frequently over-hyping or skewing the actual evidence.

Today it is not uncommon to hear that PrEP is "99 percent effective" in preventing HIV, or to see research sensationalized in order to declare that PrEP "100 percent effective" among high-risk gay men don't use condoms.

And while it is true that some studies among high-risk gay men have reported no infections among those fully adhered to therapy, these kinds of results don't necessarily translate to real-world situations, where numerous confounders can significantly reduce the efficacy of PrEP an individual level.

It is many of these confounders that place the Canadian incident in a more telling light.

Factors Affecting PrEP Effectiveness

In their research, the MLMC investigators suggested that the Canadian man was infected by an HIV-positive partner whose own antiretroviral therapy was failing. After genetic resistance testing, the partner's virus was shown to be resistant to both tenofovir and emtricitabine (the component drugs of Truvada), effectively canceling out the protective benefit of PrEP.

While some pundits have asserted that this type of multi-drug resistance is rare—with a prevalence of less than one percent—other research paints slightly a different picture. We know, for example, that tenofovir resistance currently runs anywhere from 20 percent (in Europe) to 57 percent (in Africa) among patients failing therapy, according to a 2016 report from the TenoRes Study Group.

In cases like this, even if the emtricitabine component were to remain viable, its ability to prevent infection remains, at the very best, low to negligible. This alone questions whether the conditions for infection in the Canadian case were necessarily "rare,” while highlighting the challenges faced by communities where tenofovir resistance rates run high.

Meanwhile, other confounders can potentially undermine the efficacy of PrEP. Chief among them:

  • The failure to achieve and maintain the adequate levels of Truvada in the bloodstream. While inconsistent dosing is most often the cause of these failures, it is also known that patients starting PrEP need to be on treatment for around 20-30 days before the drug can be considered effective. Once therapeutic drug levels are achieved, occasional missed doses become less of an issue—at least in gay male populations.
  • A disparity in the effectiveness of PrEP in gay men versus heterosexual women. There is now also evidence to suggest that PrEP may not be as effective in women and that even with complete, uninterrupted adherence, the protective benefit may fall well below the 90 percent threshold seen in gay men.

    In their totality, these facts suggest two things: that the effectiveness of PrEP in some populations will be far lower than in others, and that the need for condoms and other preventive interventions remain as relevant as ever.

    PrEP and Multiple Sex Partners

    With that being said, the efficacy of PrEP does not appear to be inherently diminished by many of the traditional risk factors associated with infection. While inconsistent condom use and multiple sex partners, for instance, are known to increase the potential for HIV, they don't necessarily mitigate the effectiveness of PrEP in high-risk individuals.

    In fact, among gay men seen to be among the highest level of risk, the use of PrEP is still associated with an estimated 86 percent protective benefit over counterparts who don't use PrEP. The benefit is only seen to increase in those who dose consistently, who use condoms regularly, and who limit their number of sex partners (particularly those of unknown status or treatment status).

    With that being said, PrEP still cannot be considered a "magic bullet" that somehow negates the benefits of other forms of protection, such as condoms. In February 2017, a third man tested positive while on PrEP. In this case, however, researchers believe that transmission occurred in large part because of the "remarkably high" number of sex partners he had.

    The 50-year-old Dutch man was a participant in a European PrEP study and reported over 90 sex partners and over 100 acts of condomless anal sex during the 12-week trial. While he was on PrEP, the man was twice diagnosed with rectal gonorrhea and once with rectal chlamydia.

    While the extreme nature of the case had led come to believe that this is a one-off incident, others are not so sure. In testing the man's virus, they found there were no HIV resistant mutations of any sort and this his virus is considered a so-called "wild type."

    What this means is that, given his record of adherence, the drugs should still have provided protection unless the other factors facilitated the infection. If so, these still-unidentified factors may place others at risk. Until researchers know more, safer sex practices should be adhered to if only to provide an additional layer of protection.

    Sources:

    Hoornenborg, E. and de Bree, J. "Acute Infection With a Wild-Type HIV-1 Virus in PrEP User With High TDF Levels." Conference on Retroviruses and Opportunistic Infections; Seattle, Washington; February 13-16, 2017; abstract 953.

    Molina, J.; Capitant, C.; Spire, B.; et al. "On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection." New England Journal of Medicine. December 1, 2015; published online in advance of print; DOI: 10.1056/NEJMoa1506373.

    POZ Magazine. "PrEP Fails in Gay Man Adhering to Daily Truvada, He Contracts Drug-Resistant HIV." February 25, 2016.

    TenoRes Study Group. "Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study." Lancet Infectious Diseases. January 28, 2016; published online; DOI: 10.1016/S1473-3099(15)00536-8.

    UK PROUD Trial Steering Committee. "PROUD study interim analysis finds ​pre-exposure prophylaxis (PrEP) is highly protective against HIV for gay men and other men who have sex with men in the UK." London, England; press release issued October 16, 2014.

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