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TAF Re-Introduction: A Top HIV Clinical Development of 2013

December 8, 2013

Tenofovir

Just picture the ad copy: "New and improved! It's tenofovir, but less bone depleting and renal threatening." Tenofovir alafenamide fumarate (TAF) is a pro-drug of tenofovir disoproxil fumarate (what we call tenofovir or TDF, itself a pro-drug of actual tenofovir or TFV). The drug enters the circulation through the gut, remains stable in the plasma, and then within target cells is converted to TDF. The result is less exposure of the blood plasma to TDF, which is associated with renal and bone toxicity, and more concentration of the active drug in the cell.

We first learned about TAF a couple of years ago, but in 2013 we saw the drug in action in a phase 2 trial that enrolled 150 antiretroviral-naive patients randomized 2:1 to TAF co-formulated with emtricitabine (FTC, Emtriva) and elvitegravir/cobicistat or to plain old tenofovir/emtricitabine co-formulated with elvitegravir/cobicistat (i.e., QUAD). At 48 weeks, about 90% of the patients in each arm of the study had a plasma HIV-RNA level below 50 copies/mL. Nausea, diarrhea and fatigue were more common in the TAF arm.

Interestingly, there was a statistically significant smaller decline in eGFR in the TAF arm compared to the QUAD arm -- the meaning of which remains unclear as such a decline should have been a consequence of the cobicistat effect on creatinine transport and, therefore, no different between the regimens. Bone changes were impressively minimal over the course of the study for those on TAF, whereas a typical 2% - 4% decline in spine and hip density was observed with QUAD.


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The Bottom Line

Tenofovir was a quantum leap forward from its predecessors, zidovudine (AZT, Retrovir) and stavudine (d4T, Zerit) (ugh!). Yet, over the years, there has been some fatigue among providers who must apprehensively monitor serum creatinine, dose reduce when glomerular filtration rates fall, avoid concomitant nephrotoxic agents, and adjudicate whether any change in renal function is due to tenofovir, a separate cause, or both. A learned helplessness has set in as alternatives to tenofovir, like NRTI-sparing approaches, have fizzled. This may partially explain the hope-against-hope, maybe-it-does-but-maybe-it-doesn't faith that more than some providers have in abacavir (Ziagen). As HIV-infected patients and their kidneys age, there will be little tolerance for tenofovir's renal and bone baggage.

Therefore, provided no toxicity of concentrated intracellular tenofovir emerges, TAF promises to be a proverbial game changer. Its low dose invites co-formulation (a tantalizing TAF/emtricitabine/darunavir/cobicistat single tablet is in the works), and its renal- and bone-sparing properties can make this the holy grail of NRTIs. It's great and it's about time.

What are some other top clinical developments of 2013? 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 © 2013 Remedy Health Media, LLC. All rights reserved.



This article was provided by TheBodyPRO.com. It is a part of the publication HIV JournalView.
 

 

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