Description

Sofosbuvir (trade name Sovaldi) is a direct-acting antiviral (DAA) medication used for the treatment of chronic hepatitis C virus (HCV) infection. It is a nucleotide analog and a prodrug, meaning it is inactive until it is metabolized in the body. Sofosbuvir has been a game-changer in the treatment of hepatitis C, offering a highly effective, well-tolerated, and short-duration cure for many patients. It is not used as a monotherapy but is always part of a combination regimen with other antivirals to prevent resistance and maximize efficacy.

Indication

Sofosbuvir is indicated for the treatment of chronic hepatitis C virus infection in adults and children (typically 3 years of age and older). Its specific use depends on the HCV genotype and the patient’s condition. It is used as a component of a combination antiviral treatment regimen for:

• HCV Genotypes 1, 2, 3, 4, 5, and 6: Sofosbuvir is effective against all major HCV genotypes.

• Various Patient Populations: It is used in both treatment-naïve patients and those who have failed previous therapies (e.g., interferon-based regimens).

• Patients with Liver Disease: It is used in patients with compensated liver disease, including cirrhosis, and in some cases, with decompensated cirrhosis in combination with other drugs like ribavirin.

• Co-infected Patients: It is also used to treat patients co-infected with HIV-1 and HCV.

Sofosbuvir is most commonly seen in fixed-dose combination tablets with other DAAs, such as ledipasvir (in Harvoni) or velpatasvir (in Epclusa), which simplifies the treatment and boosts cure rates to over 90% in most cases.

Mechanism of Action

Sofosbuvir’s mechanism of action is highly specific and targets a crucial enzyme in the hepatitis C virus’s life cycle.

1. Prodrug Activation: After oral administration, sofosbuvir is absorbed and undergoes a series of metabolic steps inside the liver cells (hepatocytes). It is converted into its active form, uridine analog triphosphate (GS-461203).

2. Targeting the HCV Polymerase: The active form, GS-461203, is a defective substrate for the HCV RNA-dependent RNA polymerase, known as NS5B. This enzyme is the catalytic subunit of the viral replication complex and is essential for transcribing the viral RNA and replicating the viral genome.

3. DNA Chain Termination: As a uridine analog, GS-461203 is incorporated into the new viral RNA strand during replication. Because of its specific chemical structure, once it is incorporated, it prevents the addition of any further nucleotides. This causes premature termination of the viral RNA chain.
4. Inhibition of Viral Replication: By halting the synthesis of the viral RNA, sofosbuvir effectively stops the virus from replicating, leading to a rapid and dramatic decrease in the viral load and, in most cases, the complete eradication of the virus from the body. This targeted mechanism is a key reason for its high efficacy, favorable safety profile, and high barrier to resistance.