Commentary Argues for Keeping TDF/FTC as First-Line PrEP

In 2020, tenofovir disoproxil fumarate with emtricitabine (TDF/FTC), widely known for usage in pre-exposure prophylaxis (PrEP) by its brand name Truvada, will become available in generic form.

The availability of generic PrEP has the potential to reduce costs at a time when health care systems are seeking to increase PrEP uptake in order to meet ambitious “Ending the HIV Epidemic” initiative goals by 2030.

The manufacturer of Truvada, however, has also recently introduced tenofovir alafenamide with emtricitabine (TAF/FTC) under the market name Descovy. The TAF/FTC formulation received approval from the US Food and Drug Administration for PrEP in men who have sex with men (MSM) and transgender women in October 2019.

Authors of a new commentary in Annals of Internal Medicine argue that given the strong safety and efficacy profile of TDF/FTC, there is no sufficient benefit to warrant changing clinicians emphasis to TAF/FTC.

The commentary was written by Douglas S. Krakower, MD, Demetre C. Daskalakis, MD, Judith Feinberg, MD, and Julia L. Marcus, PhD.

The commentary authors took issue with the claim that TAF/FTC was definitively a safer and more effective drug, noting that support for TAF/FTC is based on a single randomized trial, the DISCOVER study, which demonstrated noninferiority to TDF/FTC.

TDF/FTC, on the other hand, has robust data showing efficacy in a wider range of patient populations, including cisgender women.

“Of note, DISCOVER enrolled only MSM and a very small number of transgender women; thus, Food and Drug Administration approval for TAF/FTC as PrEP excluded those at risk from ‘receptive vaginal sex,’ and its efficacy remains unknown for other priority populations, including persons who inject drugs,” commentary authors wrote.

With respect to efficacy, authors of the commentary addressed the fact that TAF achieves higher and more sustained drug levels than TDF in peripheral blood mononuclear cells. They noted that conversely, TAF achieves lower concentrations in the rectal and genital mucosa, and pointed to a lack of consensus on the exact pharmacokinetic correlates of protection for PrEP.

The commentary also troubled claims that TAF/FTC is safer than TDF/FTC to a clinically significant extent. While authors conceded that TDF can cause renal or bone adverse events as part of multidrug regimens for HIV treatment, they pointed to a decade of research demonstrating excellent safety of TDF/FTC used as PrEP.

“A systematic review of TDF/FTC or TDF alone used as PrEP by thousands of trial participants found no differences in renal or bone harms compared with placebo or no treatment. It is also reassuring that more than 200,000 US patients have been prescribed TDF—/FTC PrEP and no serious toxicities have been reported,” the commentary authors wrote.

During the DISCOVER study, some safety variables favored 1 drug and some the other. Notably, almost no participants in either group found adverse events serious enough to warrant stopping PrEP. This suggests that both PrEP formulations are similar in safety to other commonly prescribed sexual health medications like oral contraceptives.

The commentary emphasized pharmacoeconomic stakes which they believe might bias a potentially premature push away from TDF/FTC.

“This also has major financial implications for Gilead: Generic TDF/FTC will become available in 2020, whereas Gilead has exclusive rights to manufacture TAF/FTC until 2022 and is pursuing a patent extension until 2025. Thus, having TAF/FTC as the preferred PrEP option would extend Gilead's market dominance for years to come,” commentary authors wrote.

On the other hand, the commentary authors cited the case of Australia, where generic TDF/FTC costs $8 per month, compared to an average wholesale price of $2110 per month in the United States. Given social context and similar drug profiles, the authors of the commentary concluded that a shift away from TDF/FTC for PrEP would be premature and costly.

“Given the available clinical evidence and public health context, when people think of PrEP, they should still think of TDF/FTC.”