Conquest of Invisible Enemies by Jie Jack Li

Author:Jie Jack Li
Language: eng
Format: epub, pdf
Publisher: Oxford University Press
Published: 2022-06-15T00:00:00+00:00

Fig. 3.5 Antonín Holý © Czech Post

In 2016, Gilead gained approval of tenofovir alafenamide (Vemlidy), the only approved HBV drug during the last decade. Considering none of the five previous nucleoside HBV drugs represented a cure, a new drug must show clear differentiation in terms of improved efficacy, high genetic barrier to mutation, and a better safety profile. Tenofovir alafenamide surpasses those really high hurdles. The trick is switching the prodrug portion of tenofovir disoproxil to a superior phosphoramidate prodrug known as ProTide, which stands for Prodrugs of nucleoTides. Having taken a page from their success of the HCV drug sovaldi (vide infra), Gilead installed the same ProTide prodrug onto tenofovir to make tenofovir alafenamide, which demonstrated similar efficacy to tenofovir disoproxil at a mere twenty-five mg daily dosage, one-tenth of the latter. It has improved kidney and bone safety due to increase exposure of active form of tenofovir in liver and reduced systemic circulation of tenofovir.22

All six previously discussed nucleoside analogs have been shown to suppress viral replication, as measured by serum HBV DNA levels. These drugs resulted in enhanced treatment outcomes, including the normalization of serum alanine aminotransferase (ALT) levels and improvements in liver histology. Although virologic resistance remains a concern with nucleoside analog therapy, newer agents approved subsequent to lamivudine, particularly entecavir, adefovir dipivoxil, tenofovir disoproxil, and tenofovir alafenamide have shown much improved resistance profiles.

In summary, the six nucleoside HBV drugs on the market are:

• lamivudine (3TC, Epivir, GSK) in 1998,

• adefovir dipivoxil (Hepsera, Gilead) in 2002,

• entecavir (Baraclude, BMS) in 2005,

• telbivudine (LdT, Tyzeka, Novartis) in 2006,

• tenofovir disoproxil (Viread, Gilead) in 2008, and

• tenofovir alafenamide (Vemlidy, Gilead) in 2016.

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