Comparison of tenofovir prodrugs: TAF vs TDF

On September 24, Gilead Sciences (NASDAQ:GILD) said its new investigational combination pill for HIV demonstrated more favorable renal and bone safety compared to Stribild. Here are the two anti-HIV formulations:

New pill: elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TAF 10 mg

Stribild: elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TDF 300 mg

Stribild contains 300 mg TDF while the new formulation contains just 10 mg TAF; doses of the other 3 components are the same.

Both TAF (tenofovir alafenamide fumarate) and TDF (tenofovir disoproxil fumarate) are prodrugs of tenofovir. TDF is highly susceptible to hepatic and blood esterases. However, TAF is metabolised by lysosomal carboxypeptidase cathepsin A which is produced predominately by lymphocytes. In other words, TAF is stable[1] in plasma and then rapidly converted into tenofovir once inside lymphocytes.

The phosphoramidate side chain of TAF is the same as sofosbuvir which is metabolised by cathepsin A, carboxylesterase 1 and histidine traid nucleotide-binding protein 1[2]. The level of cathepsin A expression in subgenomic HCV replicon cells was 5 times higher than in primary human hepatocytes.

Gilead is the world’s biggest maker of HIV drugs and earned more than $9 billion with Atripla, Viread, Truvada and Stribild last year. TAF may help Gilead dominate the HIV-drug market for a long time.

[1] Nucleosides Nucleotides Nucleic Acids. 2001, 20(4-7), 1091-1098.

[2] J Biol Chem. 2010, 285(45), 34337-34347.