Why the "New" Tenofovir Is So Important

Fewer Treatment Side Effects May Be Only Part of What the Drug Can Offer

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When the U.S. Food and Drug Administration (FDA) announced the approval of the combination HIV drug Genvoya in November 2015, many may not have realized that it also announced the arrival of an important, new drug into the treatment armament: tenofovir alafenamide (or, more simply, tenofovir AF).

Tenovovir AF—one of the three components of Genvoya (as well as another combination HIV drug, Odefsey)—is considered a major advancement over the much-prescribed tenofovir disoproxil fumarate (tenofovir DF), offering lower drug toxicity and the potential to overcome tenofovir DF-associated drug resistance.

Moving from Tenofovir DF to Tenofovir AF

Tenofovir DF was first approved by the FDA on October 26, 2001 and was considered something of a game changer, able to treat even patients with deep resistance who had withering HIV treatment options. Moreover, it did so with few of the profound side effects seen in many early generation drugs.

Within the span of a few short years, tenofovir DF became regarded as one of the important drugs in the global fight against HIV and was eventually included in the World Health Organization’s List of Essential Medicines. 

Today, tenofovir DF remains among the most prescribed HIV medications in the world, found in such co-formulated drugs as the three-in-one Atripla and dual-formulated Truvada. In sub-Saharan Africa and many other developed countries, it is considered the cornerstone of national treatment programs, with over 5 million people receiving the drug in South Africa alone.

But the widespread use of tenofovir DF has also come with its downsides, with rates of drug resistance building on the population level, as well as a higher incidence of drug toxicities affecting key, at-risk populations.

Today, research suggests that rates of tenofovir DF-associated resistance runs everywhere from 10% to 20% in Europe and North America, while rates can be as high as 57% in parts of sub-Saharan Africa.

Furthermore, the risk of treatment-associated kidney impairment and/or failure (a potential side effect of tenofovir DF use) is seen to hit African countries particularly hard, where the incidence of underlying kidney disease is already 300% to 400% higher than in the U.S.

How Tenofovir AF Works (and Why That's Important)

While tenofovir AF and DF are both classified as nucleotide reverse transcriptase inhibitors and prevent HIV replication in the exact same manner, they differ in one key way: tenofovir AF does not contain any of the active drug molecule.

Instead, tenofovir AF acts as a pro-drug, meaning that it uses the body's own metabolism to synthesize and deliver the active molecule directly to cells.

By contrast, with tenofovir DF, the active molecule is delivered directly into the bloodstream via an oral tablet. This required dosages of 300mg daily in order to achieve ideal serum concentrations, leaving residual drug to accumulate in the kidneys and cause impairment.

Because of its pro-drug form, tenofovir AF requires only a 25mg daily doses and delivers the active molecule more effectively to cells. This not only reduces the risk of treatment-associated kidney dysfunction but other symptoms related to long-term tenofovir DF use (e.g., bone frailty and other bone-related disorders).

While it is not entirely clear whether tenofovir AF will overcome drug resistance seen in populations where tenofovir DF usage is high, some research suggests that it might. Early studies have shown that tenofovir AF is associated with more effective "drug loading" in so-called peripheral blood mononuclear cells. This increased loading appears to enhance antiviral activity on the cellular level, suggesting that tenofovir AF may retain its utility even in the face of tenofovir DF-resistant viruses.


U.S. Food and Drug Administration. "FDA approves new treatment for HIV." Silver Spring, Maryland; press release issued on November 5, 2015.

The TenoRes Study Group. "Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study." Lancet Infectious Diseases. January 28, 2016; published online.

Brennan, A.; Evans, D.; Maskew, M.; et al. "Relationship Between Renal Dysfunction, Nephrotoxicity and Death among HIV Adults on Tenofovir." AIDS. August 24, 2011; 25(13):1603-1609.

Sax, P.; Wohl, D.; Yin. M.; Post, F.; et al. "Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials." The Lancet. June 27, 2015; 385(9987):2606-2615.

Margot, N.; Johnson, A.; Miller, M.; et al. "Characterization of HIV-1 Resistance of Tenofovir Alafenamide (TAF) In Vitro." Antimicrobial Agents and Chemotherapy. October 2015; 59(10):5917-5924.

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