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PrEP and Drug Resistance: Cause for Concern?

, by Emily Newman

virusWith a continually increasing number of people beginning to take the drug Truvada as pre-exposure prophylaxis (PrEP) to prevent HIV, some have raised concerns that this might lead to more opportunities for drug resistant strains of HIV to develop. Drug resistance that develops while a person is on PrEP would limit treatment options for those who subsequently become—or are unknowingly—infected with a drug-resistant strain. A recent study in the Journal of Infectious Diseases tempers concern over drug-resistance caused by PrEP, with evidence that worrisome mutations—while discovered—appear to be rare.

“We know from using medications to prevent HIV transmission from mother-to-child, that resistance can occur in those that become infected despite the medication’s use,” explains Dara Lehman, PhD, of the Fred Hutchinson Cancer Research Center, and lead author of the study.

That’s why she and her colleagues set out to find evidence of drug resistance in participants enrolled in the Partners PrEP Study, a large-scale, randomized, placebo-controlled study of PrEP efficacy for serodiscordant couples. Of the study’s 4,747 participants, 26 people who took PrEP tested positive for HIV after the study began. Among these participants, the researchers used an assay—“454 sequencing”—to detect four HIV mutations known to cause resistance to emtricitabine (FTC) or tenofovir disoproxil fumarate (TDF), the two drugs in the PrEP combination pill Truvada.

Out of the 26 people who seroconverted during the study and were on PrEP, five ended up developing strains of the virus with mutations associated with resistance to either FTC or TDF, at a frequency high enough to be clinically significant. People who seroconverted during the study were significantly more likely to develop a strain of HIV resistant to PrEP  when treated with PrEP versus treated with placebo. And among people who were assigned to active study drug, people were more likely to develop HIV with a PrEP-related resistance mutation when the levels of TDF in their plasma samples were detectable versus undetectable.

Despite these statistically significant findings, Lehman explains that the amount of drug resistance they detected was “actually quite low.” She adds that, “This is really encouraging in terms of the ability to use PrEP on a broader scale. It’s important to remember that if you take PrEP, and if you’re adherent, it’s actually a very effective prevention method. You don’t have to worry about resistance if you don’t get infected.”

She and her colleagues estimate that 123 new infections were prevented over the course of the Partners PrEP Study, and comment in the paper that the five cases of drug resistance that emerged “should be weighed against the number of HIV infections averted.”

This view is shared by Dr. Robert Grant, MD, MPH of the Gladstone Institutes, the University of California at San Francisco, and San Francisco AIDS Foundation, and Teri Liegler also of University of California. In an editorial commentary published by JIS in response to the original study, they explain that “As such, there were 25 HIV infections prevented for every drug-resistant infection caused…The cumulative risk of drug resistance from PrEP services could be much lower than that associated with treating infections that would otherwise occur.”

Without minimizing the concern and attention now being paid to drug resistance, Grant and Liegler contextualize the study’s results and impart a larger message so as not to invoke fear or hesitation among the many who are considering—or taking—PrEP. They explain that:

  • Although there were more instances of drug resistance among people taking the PrEP combination of FTC/TDF than TDF alone, it does not make sense to use TDF alone for PrEP since it’s less effective at preventing HIV than the combination of FTC/TDF;
  • Most of the drug resistant mutations were specific to FTC, which leaves many treatment options open for successful combination ART; and,
  • Seroconversions on PrEP are more likely to occur during penile/vaginal sex than during anal sex, which helps explain why drug resistance developing during PrEP hasn’t been observed in groups of MSM and trans women who have seroconverted after receiving PrEP.

Grant and Liegler also underscore an important lesson learned from the study about the importance of accurate HIV testing prior to beginning PrEP.

Nine people started on PrEP in the Partners PrEP Study were actually already infected with HIV when they began PrEP. At the time, they were thought to be HIV negative – they had not yet developed antibodies, which standard HIV tests detect as a marker of HIV infection. Lehman and colleagues were able to verify these nine instances of prior infection by retroactively testing plasma samples taken at the beginning of the Partners PrEP Study using a highly sensitive HIV RNA detection test. Three of these nine went on to develop PrEP-associated drug resistance.

“We showed that the highest risk of resistance comes from those who start—or restart—PrEP during unrecognized infection,” says Lehman. “Standard HIV tests detect antibodies and those are not present immediately after infection. So if you use a standard HIV test to screen someone and then put them on PrEP, there’s a chance that they were actually infected at the time of the test. It is important to work to improve that.”

What does this mean in practice?

Grant and Liegler recommend that prior to starting a patient on PrEP, clinicians should use an HIV test that detects HIV RNA if possible. The PrEP clinic at Magnet, San Francisco AIDS Foundation’s sexual health clinic, uses a rapid HIV antibody test followed by an HIV RNA test. This reduces the “window period,” the time when a person may be infected with HIV but still test negative, to about two weeks.

Pierre-Cedrick Crouch, NP, PhD, the nursing director at Magnet, says that the clinic further minimizes the risk that someone newly infected with HIV begins PrEP by asking clients about potential times when they might have been exposed to HIV in the last two weeks, and doing a full physical to look for acute HIV infection symptoms.

Selected sources.

Lehman, D. A. and others. Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single- or dual-agent preexposure prophylaxis. Journal of Infectious Diseases. 2015.

Grant, R. M. & Liegler, T. Weighing the risk of drug resistance with the benefits of HIV preexposure prophylaxis. Journal of Infectious Diseases. Journal of Infectious Diseases. 2015.


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