This year, pre-exposure prophylaxis (PrEP) advocates noted a stunning disconnect between key organizations that issue guidelines on the use of tenofovir/emtricitabine (TDF/FTC, Truvada) for HIV prevention: The United States Centers for Disease Control and Prevention (CDC) continues to say that people need 20 days of daily TDF/FTC before they can consider themselves protected from vaginal HIV exposure -- but the World Health Organization (WHO) has stated that just seven days of the drug is enough.
Why the disconnect? How come two respected and influential organizations are providing contradictory information? What should physicians and community health workers tell people with vaginas and their partners about how long they need to take PrEP before it becomes effective?
(Note: No specific research has evaluated PrEP levels in vaginal or rectal tissue of transgender women or transgender men, so all recommendations are based on assumptions of relative equivalency of data from other populations.)
These were among the questions that the advocacy organization AVAC attempted to begin to answer in two webinars featuring pharmacologists, PrEP physicians, advocates and guideline developers from the CDC and WHO.
It was, at times, a dive into some pretty complex science. Researchers have to try to draw conclusions that can be used in the real world based on laboratory experiments, small-scale studies, pharmacological principles and mathematical modeling. Scientists who respect each other's work sometimes have different interpretations of the same data.
Mitchell Warren of AVAC warned participants that they would be unlikely to come to a definitive truth by the end of the discussion. But, he hoped that the conversation could make it clear what scientists know and don't know, as well as what they believe and don't believe about time to protection with PrEP.
Most Important? Good Adherence
Dawn Smith M.D., M.P.H., of the CDC said that safety was a key concern: "If we tell one group of people that after X days of drug you're as protected as you're going to be, and we're wrong, then we're exposing people to risk."
But, she said that health care providers could use a model of shared decision making, explaining to patients that there are differences of opinion on the issue. Smith said that, when providing PrEP, she might give her own estimate of time to protection, as well as differing estimates from other experts, with some explanation of why they are different. She would let individuals consider their own priorities and make the decision that feels right for them.
The 2016 WHO guidelines summarize the available evidence as follows: "Pharmacological studies suggest that full protection may require 4 doses for anal sex and 7 doses for vaginal sex." The CDC's guidelines were last updated in 2014 and acknowledge the gaps in the scientific data. The CDC states that maximum concentrations of tenofovir "are reached in blood after approximately 20 days of daily oral dosing, in rectal tissue at approximately 7 days, and in cervicovaginal tissues at approximately 20 days."
But, Smith said that she would emphasize to a patient that by far the most important factor for PrEP effectiveness is taking the drug regularly: good adherence on an ongoing basis.
What We Do and Don't Know
Lab studies show how long it takes for a maximum concentration or "steady state" of drug to be reached in blood, in vaginal tissue and in rectal tissues. Drugs vary in how long they take to achieve this concentration in different parts of the body.
The PrEP pill Truvada contains two active drugs, tenofovir and emtricitabine, both of which have an inhibitory effect on HIV.
Many more studies have been done on how tenofovir behaves in the body than on how emtricitabine behaves. Those studies show that, after five to seven days of taking tenofovir, high levels are reached in rectal tissue, but it may take around 20 days for equivalent levels to be achieved in vaginal tissue. These studies were the basis for the CDC's recommendation.
There are fewer studies on emtricitabine, but they show that the drug is actually better at reaching high levels in vaginal tissue than in rectal tissue. Steady state in vaginal tissue may be achieved after just one or two days of daily dosing.
But Craig W. Hendrix, M.D., of the Johns Hopkins Bloomberg School of Public Health said that we shouldn't assume that reaching this level is the objective. "Time to protection is not necessarily the same as time to steady state," he said. A drug might offer enough protection earlier, at a lower level.
A big challenge for researchers is defining the drug levels that are likely to be protective. While there are well-defined data from the iPrEx study showing what levels of drug concentration in blood correlated with remaining HIV negative when having anal sex, it's less clear from PrEP studies what blood drug concentrations correlate with protection from HIV in people having vaginal receptive sex.