Tenofovir (Viread) belongs to a family of drugs commonly called nukes. Tenofovir is used as part of potent combination anti-HIV therapy (ART) and is sold in the following fixed-dose combinations:
- Truvada -- tenofovir + FTC
- Atripla -- tenofovir + FTC + efavirenz
- Complera -- tenofovir + FTC + rilpivirine
- Stribild -- tenofovir + FTC + cobicistat + elvitegravir
These drugs are made by Gilead Sciences.
Old Tenofovir (TDF)
The formulation of tenofovir that is currently sold is called TDF (tenofovir disoproxil fumarate). Once it is swallowed and absorbed from the intestines, it moves to the blood and eventually inside cells of the immune system. In the intestines, blood and cells, enzymes process TDF into tenofovir. This final form (tenofovir) is the form of the drug that has antiviral activity.
TDF is not well absorbed from the intestine and does not quickly enter the blood or cells. As a result, a relatively large dose of TDF (300 mg) must be taken by adults who use it as part of ART.
A new oral formulation of tenofovir has been developed by Gilead Sciences. The new formulation is called TAF (tenofovir alafenamide). In lab experiments with cells of the immune system and TAF, researchers have found that TAF is quickly converted into the antiviral form of the drug, tenofovir. Furthermore, levels of tenofovir concentrate inside cells of the immune system, much more so than when the original formulation, TDF, was used. Also, when TAF is used, levels of tenofovir in the blood are considerably lower than when TDF is used. Likely this is because tenofovir that arises from TAF concentrates inside cells of the immune system.
Experiments with dogs have also found that TAF concentrates inside cells of the immune system and lymph nodes and lymphatic tissues.
The greater accumulation of tenofovir arising from TAF in cells of the immune system means that a much smaller dose of TAF can be used (10 to 25 mg per day) compared to TDF.
The relative concentration of tenofovir derived from TAF within the immune system means that less of this drug is in the blood. This likely has safety implications. For instance, the original formulation of the drug could cause kidney injury in some patients because TDF accumulated in the blood and some kidney cells. Clinical trials with TAF suggest that, so far, TAF is safer than TDF when used as part of ART.
The first TAF-containing medicine, Genvoya, was licensed by the U.S. Food and Drug Administration (FDA) in November 2015 and will likely be licensed by Health Canada late in 2015. This medicine will be a fixed-dose combination (all in one pill) of the following drugs:
- TAF + FTC + cobicistat + elvitegravir
There is currently a similar pill called Stribild that contains TDF and the other medicines listed above.
After Genvoya is licensed in Canada, Gilead then has to negotiate with Canada's provinces and territories about the price of this pill on their lists of subsidized medicines. These negotiations can take months; therefore, Genvoya is not likely to be on the list of medicines subsidized by the provinces and territories until late in 2016.
At the beginning of this report we listed several drugs that contain TDF. All of these drugs will have TAF-containing formulations developed over the next several years, and the new versions will follow the same negotiating process as Genvoya to gain access to provincial and territorial formularies.
TAF is being tested as a replacement for TDF in several clinical trials. Next we report on two such studies. Other studies featuring TAF will appear in a future issue of TreatmentUpdate.
- Callebaut C, Stepan G, Tian Y, et al. In vitro virology profile of tenofovir alafenamide, a novel oral prodrug of tenofovir with improved antiviral activity compared to that of tenofovir disoproxil fumarate. Antimicrobial Agents and Chemotherapy. 2015 Oct;59(10):5909-16.
- Margot NA, Johnson A, Miller MD, Callebaut C, et al. Characterization of HIV-1 resistance to tenofovir alafenamide in vitro. Antimicrobial Agents and Chemotherapy. 2015 Oct;59(10):5917-24.
- Sax PE, Wohl D, Yin MT, 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. Lancet. 2015 Jun 27;385(9987):2606-15.