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Hepatitis C: Pathophysiology & Treatment Masterclass

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Participants 396

  • Allison Clemens
  • April
  • ababaabhay
  • achoi2392
  • adhoward1
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Treatment Goals 

  • Eradicate virus
  • Prevent progression of liver disease and death
  • Prevent hepatocellular carcinoma
  • Achieve sustained virologic response (SVR) at week 12 post-treatment
    • Surrogate marker – aim to have absence of detectable virus in blood

Class Mechanism of Action Medications
NS3/4A protease inhibitor Prevents cleavage of HCV-encoded polyprotein (into mature forms of NS3, NS4A, NS5A, NS5B proteins), essential for viral replication Glecaprevir

Grazoprevir

Voxilaprevir

Paritaprevir

Simeprevir

First generation NS5A inhibitor Potent antiviral activity against HCV NS5A (essential for viral replication and virion assembly) Daclatasvir

Ledipasvir

Ombitasvir

Second generation NS5A inhibitor Pibrentasvir

Elbasvir

Velpatasvir

NS5B polymerase inhibitor Metabolized to active uridine analog triphosphate and acts as chain terminator for NS5B polymerase Sofosbuvir

Hepatitis B Reactivation – Black Box Warning

  • Test for current or prior HBV infection
  • If HBV not treated, may result in reactivation and lead to fulminant hepatitis, hepatic failure, and death
  • Measure hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment
  • Risk in HBsAg positive and in those HBsAg negative + anti-HBc positive
  • In those with serologic evidence, monitor for clinical and lab signs of hepatitis flare or HBV reactivation (increase in aminotransferase levels, bilirubin levels)

Ledipasvir/sofosbuvir [Harvoni]

  • Patients > 3 years old
  • Once-daily tablet (adults)
  • Tablets or pellets depending on weight-based dosing (children)
    • Pellets must be swallowed whole
    • Can be sprinkled into non-acidic soft food at or below room temperature and consumed within 30 minutes of mixing
  • No dose adjustments for renal impairment including end stage renal disease (ESRD)
    • No safety data in pediatric population
  • Indications:
    • Genotype 1, 4, 5, 6 w/out cirrhosis or w/ compensated cirrhosis
    • Genotype 1 with decompensated cirrhosis + ribavirin
    • Genotype 1 or 4 s/p liver transplant without cirrhosis or w/ compensated cirrhosis + ribavirin
  • ADR: headache, fatigue, asthenia

Interactions

  • Amiodarone = fatal cardiac arrest; bradycardia (may occur up to 2 weeks after initiating HCV treatment)
  • P-gp inducers may decrease plasma concentrations
  • Antacids = decrease ledipasvir concentration
    • Separate administration by 4 hours
  • H2-receptor antagonist = administer with or 12 hours apart
    • Famotidine 40 mg PO twice daily is max dose
  • Proton pump inhibitors = administer with under fasting conditions
    • Omeprazole 20 mg PO daily is max dose
  • Anticonvulsants, antimycobacterials, HIV antiretrovirals, HMG-CoA reductase inhibitors (statins)

Sofosbuvir/Velpatasvir [Epclusa]

  • Patients >6 years old or weighing at least 17 kg
  • Tablets

  • No dose adjustments for renal impairment including end stage renal disease (ESRD)
    • No safety data in decompensated cirrhosis or pediatric patients
  • Pangenotypic (covers all genotype)
  • ADR: headache and fatigue

Interactions

  • Amiodarone = fatal cardiac arrest; bradycardia (may occur up to 2 weeks after initiating HCV treatment)
  • P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 may decrease plasma concentrations of sofosbuvir and/or velpatasvir
  • Antacids = decrease velpatasvir concentration
    • Separate administration by 4 hours
  • H2-receptor antagonist = administer with or 12 hours apart
    • Famotidine 40 mg PO twice daily is max dose
  • Proton pump inhibitors = AVOID. If medically necessary, take sofosbuvir/velpatasvir with meal and 4 hours before omeprazole 20 mg PO daily
    • No other proton pump inhibitor has been studied

Glecaprevir/pibrentasvir [Mavyret]

  • Patients > 3 years old
  • Three tablets daily (adults)
  • Tablets or pellets depending on weight-based dosing (children)

  • Must be taken with food
  • Pellets should be sprinkled on small amount of soft food with low water content that can be swallowed whole (e.g., peanut butter, cream cheese, Greek yogurt)
  • Contraindicated in:
    • Moderate to severe hepatic impairment (Child Pugh B or C) or those with history of prior hepatic decompensation
    • Coadministration with atazanavir or rifampin
  • Pangenotypic (covers all genotype)
  • ADR: headache, fatigue

Interactions

  • P-gp/CYP3A4 inducer can decrease glecaprevir/pibrentasvir plasma concentrations
  • Coadministration with ethinyl estradiol-containing products may increase risk of ALT elevations
  • Coadministration with HMG-CoA reductase inhibitors can increase statin concentrations
    • Dose reduction
    • Consider use of lower dose
    • Avoid atorvastatin, lovastatin, and simvastatin

Sofosbuvir + velpatasvir + voxilaprevir [Vosevi]

  • Adult patients
  • 1 tablet by mouth daily with food x 12 weeks
  • Not indicated in moderate to severe hepatic renal impairment (Child Pugh B or C)
  • Indications:
    • Without cirrhosis or compensated cirrhosis
    • Genotype 1, 2, 3, 4, 5, 6 with prior treatment containing NS5A inhibitor
    • Genotype 1a or 3 with prior treatment containing sofosbuvir without NS5A inhibitor
  • ADR: Headache, fatigue, diarrhea, nausea

Interactions

  • Amiodarone = fatal cardiac arrest; bradycardia (may occur up to 2 weeks after initiating HCV treatment)
  • P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 may decrease plasma concentrations of sofosbuvir + velpatasvir + voxilaprevir
  • Antacids = decrease velpatasvir concentration
    • Separate administration by 4 hours
  • H2-receptor antagonist = administer with or 12 hours apart
    • Famotidine 40 mg PO twice daily is max dose
  • Proton pump inhibitors = administer with using omeprazole 20 mg PO daily max
    • No other proton pump inhibitor has been studied
  • Anticoagulants, anticonvulsants, antimycobacterials, antiretrovirals, HMG-CoA reductase inhibitors

Ribavirin

  • Used in combination with decompensated cirrhosis and in certain clinical scenarios (e.g., genotype 3 with prior sofosbuvir-based treatment failure)
  • Weight-based, split-dosing and administered with food
  • ADR: anemia, cough, insomnia, dyspnea, pruritus, rash, nausea