Hepatitis C direct-acting antivirals

Hepatitis C direct-acting antivirals

Hepatitis C direct-acting antivirals

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Mechanism of Action - The Viral Achilles' Heels

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

HCV Replication Cycle with DAA Targets

  • 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.

Class (Target)SuffixExample Drugs
NS3/4A Protease Inhibitor-previrGrazoprevir, Glecaprevir
NS5A Inhibitor-asvirLedipasvir, Pibrentasvir
NS5B Polymerase Inhibitor-buvirSofosbuvir, Dasabuvir

⭐ 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.

Practice Questions: Hepatitis C direct-acting antivirals

Test your understanding with these related questions

You are seeing a patient in clinic who recently started treatment for active tuberculosis. The patient is currently being treated with rifampin, isoniazid, pyrazinamide, and ethambutol. The patient is not used to taking medicines and is very concerned about side effects. Specifically regarding the carbohydrate polymerization inhibiting medication, which of the following is a known side effect?

1 of 5

Flashcards: Hepatitis C direct-acting antivirals

1/10

_____, tenofovir, and IFN-alpha can be used to treat HBV

TAP TO REVEAL ANSWER

_____, tenofovir, and IFN-alpha can be used to treat HBV

Lamivudine

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