The US boxed warning cautions potential onset of lactic acidosis or liver damage due to use of tenofovir disoproxil.

Presentation of nephrotoxicity can appear as Fanconi syndrome, acute kidney injury, or decline of glomerular filtration rate (GFR).

Tenofovir lacks a hydroxyl group in the position corresponding to the 3' carbon of the dAMP, preventing the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation.

Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in people with kidney or liver problems.

[23] During drug development, attention switched to the phosphonate ester derivative, tenofovir disoproxil, which was the subject of extensive process chemistry to provide a viable manufacturing route.

In the second step, the hydroxyl group is reacted with a phosphonic acid derivative, using tert-butyllithium as base to ensure selective O-alkylation, with the formation of an ether bond.

Tenofovir is formed when the diethyl phosphonate group is converted to its acid using trimethylsilyl chloride in the presence of sodium bromide, a further refinement of the original manufacturing route.

[24][25][26] The synthesis of the alternative ester in tenofovir disoproxil is completed by alkylation with the appropriate chloromethyl ether derivative and this may be purified as its fumarate salt.

[24] Tenofovir was initially synthesized by Antonín Holý at the Institute of Organic Chemistry and Biochemistry of the Czechoslovak Academy of Sciences in Prague.

The patent filed in 1986 makes no mention of the potential use of the compound for the treatment of HIV infection but claims activity against herpes simplex virus.

[27] Shortly thereafter, a collaboration with the biotechnology company Gilead Sciences led to the investigation of PMPA's potential as a treatment for HIV infected patients.

In 1997 researchers from Gilead and the University of California, San Francisco demonstrated that tenofovir exhibits anti-HIV effects in humans when dosed by subcutaneous injection.

[28] The initial form of tenofovir used in these studies had limited potential for widespread use because it poorly penetrated cells and was not absorbed when given by mouth.

In this version of the drug, the two negative charges of the tenofovir phosphonic acid group are masked, thus enhancing oral absorption.