In Debate Over PrEP, Researchers Raise Questions About Benefit vs Value

Truvada (tenofovir disoproxil fumarate [TDF]/emtricitabine [FTC]) was approved to treat HIV-1 infection in 2004,¹ and Descovy (tenofovir alafenamide [TAF]/FTC), in 2016,² in combination with other antiretroviral medications in adult and pediatric patients. The 2 medications are also now approved (2012 and 2019, respectively) as pre-exposure prophylaxis (PrEP) in these patient populations. Gilead Sciences is behind both, and that has created controversy.

On July 1, 2019, the FDA removed the risk evaluation and mitigation strategy requirement for Truvada and its generics as PrEP,³ demonstrating the agency’s confidence that: (1) most health care professionals and at-risk individuals are knowledgeable on prevention methods and the drug’s risks and (2) are aware they can find information on PrEP from the CDC. Its initial approval as PrEP came on the heels of positive results from iPrEx (NCT00458393) and Partners PrEP (NCT00557245), 2 large, randomized, double-blind, placebo-controlled clinical trials in HIV-negative men or transgender women who have sex with men and serodiscordant couples, respectively.¹

Now, however, Gilead is claiming that the TAF/FTC combination in Descovy is safer and more effective than Truvada’s TDF/FTC.⁴ With only data from the DISCOVER trial (NCT02842086) to substantiate this claim, several researchers expressed their concerns about Gilead’s claim in a recent article posted online at Annals of Internal Medicine.

“Should we abandon TDF/FTC in favor of TAF/FTC,” they ask?

The implications for making the switch could be far reaching, they claim, because the drugs were not tested in the same patient populations. Whereas TDF/FTC’s effectiveness is proven in gay and bisexual men, transgender women, intravenous drug users, and heterosexual couples where at least 1 partner has HIV, TAF/FTC has only been shown effective in gay and bisexual men and a small number of transgender women.

“In the future, no HIV prevention drug should be allowed to undergo Food and Drug Administration review without data addressing all key populations at risk for HIV,” the authors wrote. “It would be a clinical leap of faith to use TAF/FTC instead of TDF/FTC in other populations.”

Yes, according to the present study, TAF achieves greater concentrations and sustained peripheral blood levels compared with TDF. But it also shows up less so in genital and rectal mucosa. Event-driven PrEP (ie, pericoital PrEP) “could theoretically” favor use of TAF over TDF, but the CDC has not issued recommendations for either drug in this situation. There were also no clinically relevant, statistically significant safety differences shown in DISCOVER.

There are also the hundreds of thousands of patients taking Truvada and the more than 1 million individuals soon to initiate PrEP. If TAF/FTC is indeed safer, they could all need to switch from their current regimen, the authors caution. Gilead is set to dominate the market, and benefit financially, for the near future either way, with generic Truvada a possibility in 2020 and the manufacturer requesting a patent extension on TAF/FTC through 2025 (the current patent is set to expire in 2022), neither or which could be available much cheaper than current prices.⁴

Generic drugs are also sometimes viewed as being less effective than their brand name counterparts. The authors express worry that that, plus Gilead’s claims about using TAF/FTC over TDF/FTC, could worsen generics’ reputation and PrEP uptake in the eyes of patients and clinicians if generic Truvada is looked at in such a way. ⁴ PrEP is already out of reach for many due to its approximately $24,000 yearly cost.⁵

“These drugs are equally effective when used for PrEP in gay and bisexual men and transgender women, and the potential safety benefits of TAF/FTC over TDF/FTC have not yet been shown to be clinically significant,” stated lead study author Douglas Krakower, MD, assistant professor at the Harvard Pilgrim Health Care Institute, Beth Israel Deaconess Medical Center, and Harvard Medical School. “Given the available clinical evidence and public health context, TDF/FTC should remain the first choice for the vast majority of PrEP users.”⁵

References

1. Gilead Sciences, Inc. Drug approval package: Truvada (emtricitabine and tenofovir disoproxil fumarate) tablets. FDA website. www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021752s000_TruvadaTOC.cfm. Published January 31, 2006. Accessed January 12, 2020.
2. FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic [press release]. Silver Spring, MD: FDA; October 3, 2019. www.fda.gov/news-events/press-announcements/fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic. Accessed January 12, 2020.
3. Hunt A. FDA in brief: FDA continues to encourage ongoing education about the benefits and risks associated with PrEP, including additional steps to help reduce the risk of getting HIV [press release]. Silver Spring, MD: FDA; July 1, 2019. www.fda.gov/news-events/fda-brief/fda-brief-fda-continues-encourage-ongoing-education-about-benefits-and-risks-associated-prep. Accessed January 12, 2020.
4. Krakower DS, Daskalakis DC, Feinberg J, Marcus JL. Tenofovir alafenamide for HIV prevention prophylaxis: what can we DISCOVER about its true value [published online January 14, 2020]? Ann Intern Med. doi: 10.7326/M19-3337.
5. Truvada should remain first choice for HIV prevention, experts say [press release]. Boston, MA: Harvard Pilgrim Health Care Institute; January 13, 2020. eurekalert.org/emb_releases/2020-01/hphc-tsr010820.php. Accessed January 13, 2020.