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ICAAC 2012: New Tenofovir Pro-drug Matches Potency of Original Version but with Less Toxicity


Tenofovir alafenamide fumarate (TAF), the tenofovir pro-drug formerly known as GS-7340, has antiviral potency similar to that of tenofovir disoproxil fumarate (TDF), and a new "quad" formulation containing TAF works as well as the Stribild single-tablet regimen (elvitegravir/cobicistat/TDF/emtricitabine) but appears to be easier on the bones and kidneys, according to recently released data.

Gilead Sciences' original TDF (marketed alone as Viread and a component of the Truvada, Atripla, Complera, and Stribild combination pills) is among the most potent and widely used nucleoside/nucleotide reverse transcriptase inhibitors. However, it is known to cause bone loss and can cause kidney problems in susceptible individuals.

TDF and TAF are both converted into the active form of tenofovir diphosphate in the body. TAF is more stable in human serum and was designed to reach higher concentrations in cells and lymphoid tissues, and hopefully lower levels in bone and other tissues. A previous 14-day monotherapy study showed that a 50 mg dose of TAF produced an 88% lower plasma tenofovir concentration, but a 4-fold higher intracellular concentration than 300 mg TDF. Prior clinical studies showed that TAF has more potent antiviral activity than TDF.

At the recent 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) in San Francisco, Christian Callebaut and colleagues from Gilead presented data on TAF's virological profile. They evaluated antiviral activity against numerous HIV clinical isolates in peripheral blood cells in the laboratory. They also looked at activity against a variety of other human viruses. Finally, they tested TAF in combination with several other commonly used antiretroviral drugs.


  • TAF demonstrated potent activity against all primary HIV-1 and HIV-2 isolates tested.
  • TAF showed greater antiviral potency than TDF in human serum, with better plasma stability.
  • TAF exhibitedno antagonism (reduction of activity) with any other antiretroviral drugs tested.
  • TAF showed synergy (promotion of activity) with all tested antiretroviral classes, most strongly with integrase inhibitors.
  • TAF showed moderate activity against herpes simplex virus 2 (HSV-2), but not other tested viruses including influenza, rhinovirus, hepatitis C virus, cytomegalovirus, and varicella zoster virus; however, no data was presented on hepatitis B virus, for which TDF is an approved treatment.

The researchers concluded that these findings support development of a novel single tablet regimen with TAF replacing TDF, and trials of this novel combination pill are underway.

TAF Single Tablet Regimen

Gilead announced last week that a randomized, doble-blind Phase 2 trial comparing the new TAF quad pill versus Stribild in 170 treatment-naive adults met its primary objective at 24 weeks; the blinded comparison will continue through 48 weeks.

A once-daily single tablet regimen containing 10 mg TAF, 150 mg elvitegravir, 150 mg cobicistat, and 200 mg emtricitabine had virological efficacy similar to that of Stribild, which contains 300 mg TDF plus the same doses of the other 3 drugs. 87% of study participants randomly assigned to receive the TAF combo achieved HIV RNA < 50 copies/mL at 24 weeks, compared with 90% of Stribild recipients (not a statistically significant difference).

Furthermore, both regimens were generally well tolerated, with no significant differences in frequency or type of adverse events or laboratory abnormalities. According to a Gilead press release, the TAF combo "demonstrated statistically significantly smaller reductions from baseline to week 24 in bone mineral density at the lumbar spine and hip. In addition, small, statistically significant differences were seen in serum creatinine and in calculated creatinine clearance between the 2 arms in favor of the TAF-containing regimen." Creatinine is used as a biomarker for impaired kidney function.

"These interim findings are encouraging and warrant advancing this TAF-containing single tablet regimen into Phase 3 development," said Norbert Bischofberger, Gilead's executive vice president for research and development.

TAF is also being studied in another ongoing Phase 2 trial comparing a single tablet regimen containing TAF, Janssen’s protease inhibitor darunavir (Prezista), cobicistat, and emtricitabine, versus darunavir, cobicistat, and Truvada(the TDF/emtricitabine combination pill). Gilead indicated that the study is fully enrolled and 24-week results will be released in the first half of 2013.



C Callebaut, NMargot, G Stepan, et al. Virological Profiling of GS 7340, a Next-generation Tenofovir Prodrug with Superior Potency over Tenofovir DF. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco, September 9-12, 2012. Abstract H-552.


Gilead Sciences. Gilead ’s Once-Daily Novel Prodrug for the Treatment of HIV Meets 24-Week Primary Objective in Phase 2 Study. Press release. October 31, 2012.