A new analysis of the Phase 3 DISCOVER trial finds that emtricitabine/tenofovir alafenamide (F/TAF, Descovy) has more advantages over emtricitabine/tenofovir disoproxil fumarate (F/TDF, Truvada) as a potential pre-exposure prophylaxis (PrEP) regimen than researchers once thought.
Back in March, topline data from the DISCOVER trial revealed that F/TAF was noninferior to F/TDF. Now, researchers are announcing that F/TAF had dramatically faster onset and more potent staying power once inside the body, making it a potentially more effective PrEP regimen than F/TDF. This analysis was presented on July 23 at IAS 2019, the 10th International AIDS Society Conference on HIV Science, by Christoph D. Spinner, M.D., of the University Hospital Klinikum rechts der Isar in Munich, Germany.
Both drugs contain tenofovir diphosphate, which protects against HIV infection, but F/TAF is a newer formulation that already has an established safety profile in terms of kidney and bone outcomes.
F/TDF is currently the only PrEP regimen approved by the Food and Drug Administration (FDA), but the promising new efficacy data from the DISCOVER trial mean that F/TAF may soon take its place as the preferred PrEP regimen. (F/TAF has been submitted for FDA approval, with a decision expected later this year.)
"There are some really special things in the data," said Carl Dieffenbach, Ph.D., director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases. Notably, "F/TAF loads in two hours [and] also has a 16-day tail," he said.
Some Experts and Advocates Urge Caution on F/TAF Results
But the optimism at IAS 2019 was tempered somewhat by questions about drug access, especially in light of revelations that Gilead, the maker of F/TDF and F/TAF, increased the price of F/TDF after it was FDA approved as PrEP in 2012. Also, questions remain as to what the cost of F/TAF for PrEP will be once it is approved, particularly given that F/TDF will be available in generic form in the U.S. in 2021.
Advocates and providers attending the presentation at IAS 2019 also raised questions about whether or not F/TAF's demonstrated superiority over F/TDF was enough to justify health systems entirely moving most people to F/TAF, including those who don't have indications for kidney damage or bone loss issues that are potential -- but somewhat rare -- side effects associated with F/TDF.
"We need to be cautious in interpreting these results and remember that Gilead has a vested interest in proving that Descovy is a better product," said Jeremiah Johnson, HIV Project director with the Treatment Action Group. "Given that on-demand [F/TDF] PrEP [works], the value of more rapid uptake of TAF is unclear. Also, claims that F/TAF is safer for PrEP remain unsubstantiated, and there are indications that F/TAF may lead to weight gain."
IAS 2019 F/TAF Study Findings in Detail
DISCOVER was a Phase 3 trial that included 5,387 HIV-negative men who have sex with men and transgender women who have sex with men. Study participants did not know which version of PrEP they were taking.
After four weeks of treatment, drug levels of F/TAF were 6.3 times higher than F/TDF. Meanwhile, 98% of F/TAF patients had drug levels at or above the "protective threshold" compared to only 68% of F/TDF patients (P < .001).
Authors combined trial data with data from prior studies to estimate the range of protection and found that F/TAF stuck around for 60% longer than F/TDF -- a finding that is significant because it means F/TAF could offer protection even if PrEP patients miss a pill.
According to the researchers, F/TDF requires several loading doses over three to four days (or more) before the drug reaches a protective threshold in the body, and once people stop taking it, it has a "tail" that only lasts for about 10 days.
The two drugs offer the same level of protection once they're fully "on board" within the body.
This detailed analysis of the DISCOVER trial was partly inspired by the differences in HIV infection rates reported in the initial reveal of the data earlier this year. Back in March, it was reported that 22 people became HIV positive while taking PrEP -- but only seven patients in the F/TAF arm seroconverted, while 15 seroconverted in the F/TDF arm. That translates to 53% fewer HIV infections among study participants taking F/TAF compared to F/TDF. Over the ensuing months, study authors sought to examine potential differences in the study participants that could possibly account for the imbalance in HIV infections between the two arms.
They measured adherence by evaluating drug concentrations from dried blood spots every 12 weeks and peripheral blood mononuclear cells at week 4 from a random subset of participants. They also paired each HIV infection case against five controls that had a similar profile in terms of their treatment arm, diagnosis, number of rectal sexually transmitted infections, and the city or region where the person lived. Ultimately, they were able to pair the 22 HIV infections with 109 "controls."
"We found no differences," said Spinner.
If F/TAF is approved for PrEP in the United States this fall as expected, there are still questions about the way provision of the drug is implemented. Advocates and providers told TheBodyPro that they will work with private and public payers to ensure it will indeed fall under the recent U.S. Preventive Services Task Force (USPSTF) ruling that PrEP be free of cost to patients, and that they will also work to help determine how clinical guidelines will recommend F/TDF and F/TAF to specific categories of patients.