Five years after the U.S. Food and Drug Administration (FDA)'s approval of Truvada (tenofovir disoproxil fumarate and emtricitabine) for pre-exposure prophylaxis (PrEP), Gilead has begun marketing the first prevention drug to people at risk of acquiring HIV. Gilead recently relaunched the "Truvada.com" website with images intended to resonate with gay and bisexual men of color, as well as transgender and cisgender women. On the surface, the campaign is sharp, engaging, diverse and respectful. But scrolling down the page, one is exposed to a myriad of alarming safety warnings, notably "lactic acidosis" and "severe liver problems," despite the fact that these side effects were not seen in any efficacy trials, demonstration projects or real world reporting. Why would Gilead list damaging side effects that had not been reported or documented?
I spoke with Jeffrey Murray, M.D., M.P.H., of the FDA, who was able to shed some light on this. Murray said that there is "a case" of someone developing lactic acidosis as a result of using Truvada for PrEP. Previous to July 17, this information had not been reported anywhere. Is one confirmed case of lactic acidosis from PrEP a reason for PrEP users to be concerned?
Knowing the "PrEP Facts"
As someone who began using PrEP in 2011, and teaching and helping and others learn about it the following year, I was thrilled to see Gilead finally marketing this groundbreaking prevention regimen.
I first began speaking openly about taking PrEP after the FDA approval, and I was quickly horrified to learn how much misinformation, myths and mistruths were being circulated about it. I was further dismayed at how credible institutions remained absent from the discourse, allowing complete falsities to be widely promoted by anti-PrEP individuals and organizations. This outrage led to me creating a "PrEP Facts" group on Facebook in 2013, so that people all over the world could learn the actual facts, medical science and empirical research about PrEP, as well as discuss concerns. Central to many of those discussions then, and now, were fears that taking Truvada could destroy the liver. One can easily do a "liver" search on the page to see how often these worries have become deterrents for people to start taking PrEP, and for providers to offer it.
In mid-2014, the Centers for Disease Control and Prevention and the World Health Organization distributed endorsements of PrEP, offering guidelines for any medical provider wanting to responsibly and ethically prescribe to their patients. Notably absent in their directives then, and now, were screening for liver acidosis and liver complications, given these were not adverse events seen in either the iPrEx trial or the Partners PrEP efficacy trial, which studied nearly 4500 men and women who used PrEP over a two-year period.
PrEP Side Effects in Real-World Settings
So, does the FDA's one case of lactic acidosis from PrEP matter in real-world settings and for individuals who may be considering PrEP? In March 2014, Robert Grant, M.D., M.P.H., principal investigator of iPrEx, stated that, with consistent use of Truvada there was "no effect on liver, glucose, amylase, blood counts." I followed up with Grant to make sure that data held up three years later. He shared that he had seen "no published case of lactic acidosis among PrEP users," but fear of side effects remain one of primary reasons why eligible patients choose not to use PrEP.
To further confirm this information, I checked with Raphael Landovitz, M.D.; David Malebranche, M.D.; Anthony Mills, M.D.; Howard Grossman, M.D.; and Pierre Crouch, Ph.D., NP, all of whom have been prescribing and supervising at PrEP sites for most of the past five years, and between them, they have seen about 5000 individuals successfully start PrEP. They all were able to confirm no known cases of PrEP patients developing liver problems or lactic acidosis from using Truvada for PrEP. Malebranche further shared, "I can count the number of times I've seen lactic acidosis on one hand in the 18 years I've been prescribing antiretrovirals, even the old ones! No cases with PrEP."
So, why would Gilead list safety warnings for an adverse event that has not been known to occur in approximately 125,000 PrEP prescriptions in the U.S.? It turns out the FDA regulates the language Gilead is permitted to use to market its approved drugs.
According to Cindy Collins, associate director of regulatory affairs, advertising and promotion at Gilead, "The FDA label doesn't differentiate between treatment or PrEP, just Truvada. Because the warning is in there, we have to carry it forward. If we don't do that, we are out of compliance with FDA."
The Impact of One Case of Lactic Acidosis
As mentioned before, while there haven't been any reported cases anywhere else, Murray from the FDA revealed to me, "We are aware of a case [of lactic acidosis from Truvada as PrEP] and also in HBV [hepatitis B]-treated patients."
"While the risk of lactic acidosis with Truvada is very low, based on our review of the cumulative data, it is not possible to state that either emtricitabine or tenofovir has zero potential for causing lactic acidosis," Murray added.
When asked for further details about this one case, he said: "I am not sure the case is in our postmarketing reports system, yet. If it is, you would need to request it through FOI [freedom of information]," suggesting that the information is quite new.
Will this one case drastically alter how individuals who may want PrEP perceive their risk factors? Several community leaders offered insights.
"With lactic acidosis, it can be very serious and come on suddenly, but it's very, very rare. People should know that, but for most of the other serious side effects from Truvada, we monitor regularly and people should know that too. They aren't flying without a safety net. So, even if something negative happens, we can usually catch it early and do something about it," said David Evans, director of health care policy at Project Inform.
"Context matters. When I'm talking to someone about PrEP, I'm comfortable saying there is one case of lactic acidosis. But I'm also comfortable saying how many infections occurred when PrEP wasn't used. There is a one out of 125,000 chance that one might get this from taking this for PrEP. On the other hand, what is the likelihood of one becoming HIV positive from engaging in complete unprotected sex? That becomes the choice," said Phill Wilson, president and chief executive officer of the Black AIDS Institute.
After monitoring the Facebook "PrEP Facts" group daily for over four years, I am somewhat certain that the revelation of this case will result in a sense of fear, dread and trepidation for some. However, like Wilson above, I intend to help people consider the context of known risk factors with or without PrEP and to remind members that all activities of everyday life entail some sort of thoughtful risk mitigation. My hope is that consumers and providers will continue to review the evidence, learn the facts and make informed health care decisions that result in empowerment, connection and pleasure.