Hepatitis C direct-acting antivirals

Mechanism of Action - The Viral Achilles' Heels

DAAs directly target key Hepatitis C non-structural (NS) proteins, halting viral replication.

• NS3/4A Protease Inhibitors (-previr): Block post-translational processing of the HCV polyprotein. 📌 Previr for Protease.
• NS5A Inhibitors (-asvir): Disrupt the NS5A protein's role in viral RNA replication and virion assembly.
• NS5B Polymerase Inhibitors (-buvir): Inhibit the RNA-dependent RNA polymerase (RdRp), preventing synthesis of new HCV RNA.

⭐ DAAs are curative, achieving a sustained virologic response (SVR)-undetectable HCV RNA 12 weeks post-therapy-in >95% of cases. This is a virologic cure.

The 'Virs' - A Viral Name Game

Direct-acting antivirals (DAAs) for Hepatitis C are classified by their target and corresponding suffix. This naming convention helps identify the drug's mechanism of action.

⭐ Sofosbuvir is a nucleotide analog polymerase inhibitor that requires intracellular phosphorylation, while Dasabuvir is a non-nucleoside inhibitor that does not.

Treatment Regimens - The Combo Punch

• Goal: Eradicate HCV by achieving Sustained Virologic Response (SVR), defined as undetectable HCV RNA 12 weeks post-treatment. This is considered a cure.
• Strategy: Combination therapy is mandatory. Monotherapy is ineffective due to the rapid selection of drug-resistant viral variants.
• Pangenotypic Regimens: First-line standard of care, effective against all major HCV genotypes (1-6), simplifying the treatment approach.
  • Glecaprevir + Pibrentasvir
  • Sofosbuvir + Velpatasvir

⭐ Black Box Warning: All patients must be tested for current or prior Hepatitis B virus (HBV) infection before initiating DAAs. Treatment can cause HBV reactivation, leading to fulminant hepatitis and death.

Adverse Effects - The Payoff & Perils

• Generally Well-Tolerated: Most adverse effects are mild and transient.

  • Common complaints: Headache, fatigue, nausea.
  • Less common: Rash, insomnia, diarrhea.

• ⚠️ Black Box Warning: HBV Reactivation

  • DAAs can reactivate Hepatitis B virus in co-infected patients, potentially leading to fulminant hepatitis and liver failure.
  • Action: All patients must be tested for current or prior HBV infection (HBsAg and anti-HBc) before starting therapy.

⭐ Drug Interactions: Co-administration of sofosbuvir with amiodarone is not recommended due to risk of severe symptomatic bradycardia.

• Direct-acting antivirals (DAAs) target HCV non-structural proteins: NS3/4A protease (-previr), NS5A (-asvir), and NS5B polymerase (-buvir).
• DAA therapy always uses a combination of agents from different classes to prevent resistance and achieve high efficacy.
• These regimens achieve >95% cure rates, defined as a Sustained Virologic Response (SVR).
• Black Box Warning: Risk of Hepatitis B reactivation; screen all patients for HBV before starting.
• Watch for significant drug-drug interactions, especially amiodarone with sofosbuvir (severe bradycardia) and CYP450 inducers/inhibitors.