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FDA Approves Descovy TAF Combination Pill for HIV Treatment, Not Yet for PrEP

The U.S. Food and Drug Administration (FDA) this week approved Gilead Sciences' Descovy, a new combination pill containing tenofovir alafenamide (TAF), which is easier on the kidneys and bones than the older tenfovir disiproxil fumarate (TDF) version. The new coformulation is similar to Truvada, but it has been approved only for use as a component of HIV treatment, not for pre-exposure prophylaxis or PrEP.

Tenofovir is one of the most widely used antiretrovirals, taken by more than 80% of people with HIV in the U.S. The older TDF formulation (Viread, also in the Atripla, Complera, and Stribild single-tablet regimens) is generally safe and well-tolerated, but it can cause bone loss soon after starting therapy and kidney problems in susceptible individuals.

TAF is a pro-drug that delivers the active agent (tenofovir diphosphate) to HIV-infected cells more efficiently than TDF. TAF produces high drug levels in T-cells with smaller doses, which means lower concentrations in the blood and less drug exposure for the bones, kidneys, and other organs and tissues.

Descovy is a once-daily pill containing TAF and emtricitabine -- similar to Truvada, but with 25 mg of TAF replacing 300 mg of TDF. It should be used with at least 1 other antiretroviral drug, such as an HIV integrase inhibitor, protease inhibitor, or NNRTI. It is approved for HIV-positive adults age 12 and over.

Descovy is the third FDA-approved combination pill containing TAF and emtricitabine, after Genvoya (with the integrase inhibitor elvitegravir and cobicistat) and Odefsey (with the NNRTI rilpivirine). Stand-alone TAF is currently under development as a treatment for hepatitis B.

Approval of Descovy was based on Phase 3 clinical trials showing that a TAF-containing regimen worked as well as TDF-containing regimens in people starting treatment for the first time and in treatment-experienced people switching from TDF to TAF regimens. At least 90% of people taking either type of regimen achieved or maintained undetectable viral load at 48 weeks, but those on TAF had less hip and spine bone loss and more favorable kidney function biomarkers than those on TDF.

At the recent Conference on Retroviruses and Opportunistic Infections (CROI), Joel Gallant from the Southwest Care Center in Santa Fe reported that Descovy suppressed HIV replication as well as Truvada when used in combination regimens with various third drugs, but people who switched from Truvada to Descovy saw improvements in their kidney function and bone density.

It is not clear whether these relatively small improvements will lead to clinical benefits such as reduced risk of bone fractures. David Evans, director of research advocacy at Project Inform, suggested that TAF-containing regimens may be most beneficial for older people and others at increased risk for kidney disease.

Gilead said that the wholesale price for Descovy will be the same as for Truvada. The company offers patient assistance and copay coupon programs to help uninsured and underinsured individuals pay for their medications.

U.S. prescribing information for Descovy includes a boxed warning regarding lactic acidosis and severe hepatomegaly with steatosis -- side effects that must be highlighted on all nucleoside/nucleotide reverse transcriptase labels, though they rarely occur with tenofovir. In addition, stopping tenofovir-containing regimens can lead to sudden exacerbations of hepatitis B known as "flares."

Not Yet for PrEP

Given the kidney and bone benefits of TAF, some have suggested that Descovy might be a good alternative to Truvada for PrEP. But it has not been approved for this indication, and there is not yet enough research to show whether TAF will prevent HIV as well as Truvada, which can reduce the risk of infection by more than 90% when taken consistently.

"Emtricitabine and TAF is not known to work for PrEP, and may work poorly because of low penetration of the drug into rectal and vaginal tissues," said PrEP researcher Robert Grant from the UCSF Gladstone Institutes. "Emtricitabine and TDF is quite safe for PrEP and is known to work when used." 

Other studies presented at CROI offered conflicting evidenceabout how well TAF might work for HIV prevention.

Gerardo Garcia-Lerma from the Centers for Disease Control and Prevention reported thatnone of 6 macaque monkeys pre-treated with TAF and emtricitabine were infected when rectally exposed multiple times to an HIV-like virus, while all monkeys given a placebo became infected after 1 to 10 exposures.

However, an early human study presented by Katy Garrett from the University of North Carolina at Chapel Hillfound that tenofovir levels were lower in vaginal and rectal tissue and fluid samples from healthy HIV-negative women who took TAF compared to those who took TDF. Levels in female genital tissue were about 2-fold lower, while levels in rectal tissue were about 10-fold lower.

The effectiveness of Truvada for HIV prevention is strongly associated with having high enough tenofovir levels as measured in the blood (or hair samples, in some studies). But it is still not clear whether the protective effect is due to adequate drug levels in the blood, in exposed genital or rectal tissue, or in vulnerable cells themselves.

Although doctors are allowed to prescribe Descovy "off-label" for non-approved uses, investigators with both studies emphasized that TAF should not be used for PrEP, and advocates sounded a similar note of caution about substituting Descovy for Truvada for HIV prevention.

"While Descovy has been approved for the treatment of HIV infection, we know absolutely nothing about whether this drug works for PrEP," said Jim Pickett, director of prevention advocacy and gay men's health at the AIDS Foundation of Chicago. "Descovy as PrEP is a data-free zone and we should not make any assumptions. Individuals and providers should not use Descovy for PrEP until -- if and when -- we get positive results from human trials, which are in the early planning stages right now."

4/7/16

Source

Gilead Sciences. U.S. Food and Drug Administration Approves Descovy (Emtricitabine, Tenofovir Alafenamide), Gilead’s Third TAF-Based HIV Therapy. Press release. April 4, 2016.