Table 4.

Hepatitis C Virus Direct-Acting Antiviral Structure and Likely Cost Limiting Raw Material in Production

HCV DAA Agent	HCV DAA Structure and Retrosynthesis	Comparator HIV Agent
Ribavirin C8H12N4O5 MW: 244 g/mol		Zidovudine C10H13N5O4  MW: 267 g/mol
Daclatasvir  C40H50N8O6  MW: 739 g/mol		Atazanavir  C38H52N6O7  MW: 705 g/mol
Sofosbuvira  C22H29FN3O9P  MW: 529 g/mol		TDF  C23H34N5O14P  MW: 636 g/mol
Faldaprevir  C40H49BrN6O9S  MW: 870 g/mol		Darunavir  C27H37N3O7S  MW: 548 g/mol
Simeprevir  C38H47N5O7S2  MW: 750 g/mol		Lopinavir/r  C37H48N4O5  MW: 629 g/mol

Abbreviations: API, active pharmaceutical ingredients; DAA, direct-acting antiviral; HCV, hepatitis C virus; HIV, human immunodeficiency virus; MW, molecular weight; TDF, tenofovir.

^a Sofosbuvir is presumably synthesized as a mixture of diastereomers on phosphorous. Only one of these 2 diastereomers is desired in the active pharmaceutical ingredients. Separation of diastereomers can be a substantial contributor to the cost of API production, particularly when an undesired diastereomer cannot be efficiently recycled. See US patent 7 390 791 and US application 20130065856 for the tenofovir alafenamide fumarate (TAF) prodrug version of tenofovir, which contains a “ProTide” moiety identical to that present in sofosbuvir. Efficient recycling of diastereomers has been demonstrated for TAF, but we do not presume this is the case for sofosbuvir.