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Top 10 Clinical Review

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Tenofovir Alafenamide Fumarate (TAF) Is FDA Approved: A Top HIV Clinical Development of 2015

December 2, 2015

Just as Google, Facebook, and Apple have become a ubiquitous part of daily life, tenofovir disoproxil fumarate (TDF) is practically unavoidable in the treatment of HIV infection. And, like these tech behemoths, TDF emerged on a scene that was desolate and desperate (remember Netscape Search, MySpace and "mobile" phones the size of a platypus?) and then proceeded to set a new standard. Nucleoside reverse transcriptase inhibitor (NRTI) therapy no longer had to have life-threatening toxicities such as anemia and lactic acidosis or to be dosed twice a day -- and as a bonus it could be coformulated with other antiretrovirals into a single daily tablet. But as anyone who has been burned badly by an operating system update knows all too well, even cherished things can be imperfect.

TDF's problems can be summed up in two words: renal and bone. Although nephrotoxicity at the hands of TDF is not common, serum creatinine elevations in people living with HIV are. Simply the potential for TDF to cause kidney problems triggers worry and a requisite workup for tubulopathy. Less obvious and perhaps more concerning is the effect of TDF on bone mineralization. Initiation of any antiretroviral therapy is associated with declines in bone mineral density (BMD) -- in part a consequence of immune reconstitution that leads to increased bone turnover. However, TDF-containing regimens lead to deeper drops in BMD comparatively, raising concerns about long-term administration in those who are older and at risk for osteopenia/porosis, as well as in the very young whose bones are still developing.

Enter tenofovir alafenamide fumarate (TAF). TAF has made my list of top 10 HIV stories in prior years, but in 2015 a truck load of TAF clinical trial data were delivered, culminating in U.S. Food and Drug Administration (FDA) approval of the drug in November as part of a coformulated single tablet with elvitegravir, cobicistat, and emtricitabine -- what's being marketed as Genvoya.

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The data from two large phase-3 treatment-naive trials of TAF versus TDF not only show non-inferior efficacy and better kidney and bone safety for TAF, they wag a finger at its predecessor for its mostly (but not always) subclinical protein-spilling and bone-wasting ways. A series of switch studies also demonstrated TAF's different and minimal impact on bone and renal parameters. In one study, even those with renal insufficiency didn't see their kidneys flinch when given TAF.


The Bottom Line

Frustration with agents in the NRTI class has led to a rising interest in nucleoside-free or -lite regimens. TAF may be coming on the scene just in time -- or perhaps just a tad too late. But, that there is a nucleotide that appears to be the "fairest of them all" in terms of toxicity potential can only be a boon for patients for whom a nuke is desired or required.

To support such use, TAF has been explored from practically every angle, including initial therapy and simplification switch. Other data are supportive of its use in specific populations such as those with renal insufficiency. Studies have answered clearly the question of TAF's efficacy and safety. Less clear is to what extent providers will adopt TAF. First only available in a coformulation with elvitegravir/cobicistat/emtricitabine (FTC), and priced the same as the same combination that included TDF (Stribild), it is expected that a stand-alone TAF/FTC tablet will be available in 2016. Other coformulations with rilpivirine (Edurant) and later darunavir/cobicistat (Prezcobix) will follow. This ubiquity will make using this agent practically inescapable -- whether you like it, or "friend" it, or not.

What are some other top clinical developments of 2015? Read more of Dr. Wohl's picks.

David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.


Copyright © 2015 Remedy Health Media, LLC. All rights reserved.




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