Michael Saag, MD, the prominent HIV physician and researcher, is on a crusade. Ever since the HIV antiretroviral combination emtricitabine/tenofovir disoproxil fumarate (F/TDF, Truvada) became the first (and still the only) product approved for pre-exposure prophylaxis (PrEP) in 2012, Saag and many other clinicians have been trying to get it into the hands of the 1.1 million Americans who would benefit from an HIV prevention pill.
Despite the product's unique status and the data behind it, they haven't been particularly successful. The CDC noted in 2018 that only a fraction of eligible patients had received a prescription for F/TDF as PrEP. There are many reasons PrEP uptake has been poor, including lack of awareness, stigma associated with HIV risk, and limited access to healthcare.
But the main barrier is the "outrageous" price point of F/TDF, said Saag, who heads the Center for AIDS Research at the University of Alabama at Birmingham (UAB) and serves on the Presidential Advisory Council on HIV/AIDS. F/TDF's manufacturer, Gilead Sciences, has set a list price of $1,780 per month for the product in the U.S., whereas it's sold for less than 5% of that in Europe and Australia.
It's true that F/TDF is often covered by insurance, but many of those most in need of PrEP are those with poor or no insurance. Uptake of PrEP has been particularly poor among African Americans and people living in the South -- precisely the populations that face the greatest burden of HIV.
African Americans account for 13% of the U.S. population but 43% of new HIV diagnoses. In 2015, 500,000 African Americans were eligible for PrEP, yet only 7,000 got a prescription. White Americans did better but still fell far short of the ideal, with 42,000 prescriptions filled out of an estimated 300,000 eligible.
The high price of F/TDF has drawn the attention of Congress, where House members held a hearing earlier this month, and is now the subject of an antitrust lawsuit filed by six HIV activists.
Gilead was contacted for this article but did not respond. In a testimony prepared for the House hearing, however, CEO Daniel O'Day insisted that F/TDF's price was justified by the $1.1 billion the company spent on developing F/TDF, including paying for the trials underpinning the PrEP approval. O'Day also said its pricing takes into account a number of factors, including the competitive landscape and the "clinical and economic value" a medication provides.
As criticism of its pricing policies has mounted, the company recently said it would introduce a generic version early next year, and also promised to donate enough F/TDF to the CDC to cover 200,000 uninsured people.
But Saag isn't waiting for the political and legal showdown to work itself out. Instead, he's advocating for a creative -- if slightly unorthodox -- workaround to the pricing conundrum.
Would Other Antiretrovirals Work as Well?
Rather than prescribe F/TDF as PrEP, he said, prescribers should sidestep the brand-name product and instead give their PrEP-eligible patients a generic HIV drug combination that uses lamivudine (3TC) with TDF.
In fact, when Saag was invited to speak at the CDC's National HIV Prevention Conference earlier this year, he used his platform to urge the conference's 3,000+ attendees to consider prescribing 3TC/TDF as an off-label PrEP regimen -- a suggestion that has since ignited a debate among HIV providers and activists about the medical and ethical implications of off-label PrEP prescribing.
"If Mike Saag is talking about it this way, I think that all of us are going to start thinking about it," said Rupa Patel, MD, MPH, an HIV specialist at Washington University in St. Louis.
"My job in Missouri is to spread PrEP around," said Patel, and "cost is fundamentally and absolutely a barrier." Although Gilead has assistance programs for PrEP, Patel said that in her experience, insurance companies nowadays are less willing to apply those vouchers against her patients' deductibles, increasingly leaving patients with high out-of-pocket costs. Patients without insurance are forgoing PrEP entirely.
"Theoretically," she said, "3TC should be just as good. I would definitely be willing to start looking at this."
The FDA's 2012 approval of F/TDF as PrEP was based on two large clinical trials, one in HIV negative men and transgender women and the other in serodiscordant heterosexual couples. Even though in-human studies on 3TC/TDF as PrEP are limited, there's a strong scientific rationale that this regimen should also work to protect people from HIV, according to pharmacologist Andrew Hill, MD, of the University of Liverpool in England.
The chemical structures of emtricitabine (F) and lamivudine (3TC) are nearly identical, differing only by the presence of a fluorine molecule in emtricitabine. When used as an HIV treatment and post-exposure prophylaxis, 3TC/TDF is considered interchangeable with F/TDF. 3TC/TDF has been studied as PrEP in animal studies, and in a phase I study in men who have sex with men (MSM) in Brazil.
At the recent House hearing, Robert Grant, MD, the lead investigator of one of the first F/TDF for PrEP studies, noted that 3TC was considered as a PrEP agent "early in the development of PrEP research," but those studies never moved forward because "we were assured by Gilead employees that Gilead's [emtricitabine] would also be off patent by the time efficacy trials of PrEP were completed, and so the price advantage of 3TC would vanish."
Today, the World Health Organization fully endorses the use of 3TC/TDF for PrEP. Regulators in the U.S., however, have stopped short of this endorsement, with CDC guidance specifically warning against the use of alternative antiretrovirals such as 3TC for PrEP.
But Saag argued that with nearly 40,000 new HIV infections per year, the U.S. is facing a "public health emergency" and for those without other options, "TDF/3TC would do just fine."
TDF by itself is a slightly different story. The WHO said that TDF as a standalone pill is powerful enough to be used as PrEP. Outside the U.S., both 3TC/TDF and TDF monotherapy are used broadly as PrEP, Hill said. Meanwhile, CDC guidance does offer a carve-out for TDF monotherapy, endorsing it for heterosexuals and people who inject drugs, but not for MSM because "no trials have been completed at this time."
With gay and bisexual men facing the greatest HIV burden in the U.S., some scientists and physicians argue that TDF monotherapy could be used in these patients as well, even in the absence of large clinical trials.
"For MSM, it is likely that it would be effective as well given how 'forgiving' [F/TDF] it is when it is used intermittently," said Jeanne Marrazzo, MD, director of the Division of Infectious Diseases at UAB.
"When the WHO did the meta analysis of all those studies," said Hill, "they found that most of the work in PrEP is being done by tenofovir [TDF] itself and it's not clear that [emtricitabine] is adding very much."
17-Fold Cost Differential
In the U.S., the price difference between branded F/TDF and generic 3TC/TDF and TDF monotherapy is stark, at least for uninsured or underinsured patients. To pay out of pocket, F/TDF for PrEP currently costs about $1,750 per month. And although 3TC/TDF would have to be taken as two separate pills, the treatment would still cost less than $100 per month. TDF as monotherapy, meanwhile, would cost less than $50. (Prices are estimated according to the drug pricing comparison website GoodRx).
For some providers, the idea of prescribing cheaper antiretrovirals for PrEP off-label isn't just a scientific question -- it's an ethical and logistical one. Patel said she would personally prescribe 3TC/TDF as PrEP, but points out that in lieu of formal CDC guidance, it's unlikely that non-HIV specialist providers would be comfortable doing so.
For patients with insurance, it would be difficult to get coverage for an off-label prescription, acknowledged Latesha Elopre, MD, another UAB infectious disease specialist, who also said she was uncomfortable with the idea for another reason.
"From a public health standpoint, I understand the impetus of ending the HIV epidemic. We want this to happen," she said. But off-label prescribing may only perpetuate stigma, accentuating the difference between patients who can afford evidence-backed F/TDF and those who will need to take two separate pills as part of a regimen that is not supported by robust clinical studies.
"I think it's an equity issue," Elopre said. "I'm an underrepresented minority myself, and I'm very sensitive to the idea that we're giving something that people who have insurance and people who access care are not being given."
For HIV activist James Krellenstein, co-founder of the PrEP4All Collaboration, the quagmire could be avoided altogether if patients in the U.S. had access to F/TDF at the prices charged in Europe, Africa, and other countries, often at $50 a month or less.
"I think it's a sign of desperation," he said. "I think what we have to ask ourselves is: how are we in a place where we're forced to make this decision?"
In the meantime, Saag's campaign to raise awareness of 3TC/TDF as a PrEP option has more HIV providers considering the off-label combo for patients who don't have access to the brand-name pill.
"The elephant in the room is: are you prepared for people to have nothing because they can't afford [F/TDF]?" said Hill.