Description

Tenofovir alafenamide (TAF) is a newer oral prodrug of the nucleotide analogue tenofovir, often prescribed as its fumarate salt, tenofovir alafenamide fumarate (TAF). It is a highly effective antiviral agent used to treat chronic hepatitis B virus (HBV) infection and, in combination with other drugs, HIV-1 infection.

Compared to its predecessor, tenofovir disoproxil fumarate (TDF), TAF is designed to be a more efficient and targeted delivery system for the active drug, tenofovir. TAF is more stable in the bloodstream, which allows it to be administered at a much lower dose (about one-tenth of TDF’s dose). This results in significantly lower concentrations of tenofovir in the plasma and a more favorable safety profile, particularly regarding kidney function and bone mineral density.

Indication

Tenofovir alafenamide is indicated for the treatment of:

• Chronic Hepatitis B Virus (HBV) Infection: It is approved for use in adults and pediatric patients (typically 6 years of age and older) with compensated liver disease.

• HIV-1 Infection: It is a component of several fixed-dose combination tablets (e.g., Biktarvy, Descovy, Genvoya) used in combination with other antiretroviral agents for the treatment of HIV-1 in adults and pediatric patients. It is not used as a single agent for HIV.

Before starting TAF for HBV, patients should be tested for HIV-1 to ensure an appropriate and complete treatment regimen is administered for any co-infection.

Mechanism of Action

The mechanism of action of tenofovir alafenamide is an optimized version of the mechanism of tenofovir. The goal is to efficiently deliver the drug to the target cells (hepatocytes for HBV and lymphocytes for HIV) while minimizing systemic exposure.

1. Prodrug Activation and Targeted Delivery: After oral administration, TAF is absorbed and enters the bloodstream. Unlike TDF, which breaks down into tenofovir in the plasma, TAF is highly stable in plasma. This stability allows it to be more efficiently taken up by target cells. Once inside the cells, TAF is hydrolyzed (broken down) by intracellular enzymes like cathepsin A (in lymphocytes) and carboxylesterase-1 (in hepatocytes) to release its active parent compound, tenofovir.
2. Phosphorylation to Active Form: The newly released tenofovir is then phosphorylated by cellular kinases to its active, diphosphate form, tenofovir diphosphate (tenofovir-DP).

3. Inhibition of Viral Reverse Transcriptase/DNA Polymerase: Tenofovir diphosphate is a potent competitive inhibitor of the viral enzymes responsible for replication:
   • HBV DNA Polymerase: It interferes with the synthesis of the HBV DNA genome.

3. • HIV Reverse Transcriptase: It prevents the conversion of HIV’s RNA genome into DNA.
4. DNA Chain Termination: As an analogue of deoxyadenosine triphosphate (dATP), tenofovir diphosphate is incorporated into the growing viral DNA chain. However, its structure lacks a necessary 3′-hydroxyl group, which is essential for further chain elongation. The incorporation of tenofovir-DP therefore leads to premature termination of the DNA chain, effectively stopping viral replication.