Introduction
Mavyret (glecaprevir/pibrentasvir) is a fixed-dose combination antiviral medication approved by the FDA in August 2017 for the treatment of chronic hepatitis C virus (HCV) infection. It represents a significant advancement in HCV therapy as a pangenotypic regimen with high efficacy across all major HCV genotypes and a shortened treatment duration for most patients.
Mechanism of Action
Mavyret contains two direct-acting antiviral agents:
- Glecaprevir: An NS3/4A protease inhibitor that inhibits viral polyprotein processing
- Pibrentasvir: An NS5A inhibitor that disrupts viral replication complex formation and virion assembly
Together, these components target multiple non-structural proteins essential for HCV replication, providing a potent antiviral effect with a high barrier to resistance.
Indications
Mavyret is indicated for the treatment of chronic HCV infection in adults and pediatric patients 3 years of age and older:
- Genotypes 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
- Treatment-naïve or treatment-experienced patients (including those previously treated with peginterferon, ribavirin, and/or sofosbuvir, but not other NS3/4A protease inhibitors or NS5A inhibitors)
Dosage and Administration
Standard adult dosage: Three tablets taken orally once daily with food (total daily dose: glecaprevir 300 mg/pibrentasvir 120 mg) Treatment duration:- Treatment-naïve patients without cirrhosis: 8 weeks
- Treatment-naïve patients with compensated cirrhosis: 8 weeks (genotypes 1, 2, 4, 5, or 6) or 12 weeks (genotype 3)
- Treatment-experienced patients without cirrhosis: 8 weeks
- Treatment-experienced patients with compensated cirrhosis: 12 weeks
- Patients with prior NS5A inhibitor experience without NS3/4A protease inhibitor experience: 16 weeks
- Renal impairment: No dosage adjustment required
- Hepatic impairment: Not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C)
- Pediatric patients: Weight-based dosing for children ≥3 years old
Pharmacokinetics
Absorption: Peak plasma concentrations reached approximately 5 hours post-dose. Food increases AUC by 1.5 to 2.5-fold. Distribution: >97.5% plasma protein bound. Apparent volume of distribution: 101 L (glecaprevir) and 20.3 L (pibrentasvir). Metabolism: Primarily metabolized by CYP3A and undergoes biliary excretion. Glecaprevir also undergoes oxidative metabolism. Elimination: Half-life: 6 hours (glecaprevir) and 23 hours (pibrentasvir). Primarily excreted in feces (92.1%) with minimal renal excretion (<0.4%).Contraindications
- Patients with moderate or severe hepatic impairment (Child-Pugh B or C)
- Patients with known hypersensitivity to glecaprevir, pibrentasvir, or any component of the formulation
- Coadministration with strong inducers of CYP3A or P-glycoprotein (e.g., rifampin, carbamazepine, St. John's wort)
Warnings and Precautions
Hepatitis B virus reactivation: Screen all patients for current or prior HBV infection before initiation. Monitor HCV/HBV coinfected patients for HBV reactivation during and after treatment. Liver enzyme elevations: Monitor liver function tests before and during therapy. Reduced efficacy in patients with NS5A resistance-associated substitutions: Consider extended duration in certain populations. Pregnancy: Limited data available. Use only if potential benefit justifies potential risk. Breastfeeding: Not recommended during treatment and for 3 days after last dose.Drug Interactions
Significant interactions:- Strong CYP3A inducers: Contraindicated (significantly decrease concentrations)
- OATP1B1/3 inhibitors: May increase glecaprevir concentrations
- P-gp inducers: May decrease concentrations
- Certain statins: May increase risk of myopathy
- Ethinyl estradiol-containing contraceptives: Not recommended due to potential ALT elevations
- Dabigatran, cyclosporine, atorvastatin, rosuvastatin
Adverse Effects
Most common adverse reactions (≥10%):- Headache
- Fatigue
- Nausea
- Hepatitis B reactivation
- Elevated liver enzymes
- Hyperbilirubinemia
- Diarrhea
- Pruritus
- Insomnia
- Asthenia
Monitoring Parameters
Before treatment:- HCV RNA quantification and genotype
- HBV serology (HBsAg, anti-HBc, anti-HBs)
- Liver function tests (ALT, AST, bilirubin)
- Complete blood count
- Assessment of cirrhosis status
- HCV RNA at week 4 (optional) and at end of treatment
- Liver function tests at week 4, week 8 (if 12-week regimen), and end of treatment
- Clinical assessment for adverse effects
- HCV RNA at 12 weeks post-treatment to confirm SVR
- Ongoing monitoring for HBV reactivation in coinfected patients
Patient Education
- Take three tablets once daily with food
- Complete the full course of treatment as prescribed
- Do not miss doses; if a dose is missed within 18 hours of usual time, take as soon as possible. If more than 18 hours late, skip dose and resume normal schedule
- Inform healthcare provider of all medications, including over-the-counter drugs and supplements
- Report any signs of liver problems (fatigue, weakness, loss of appetite, nausea, vomiting, jaundice)
- Use effective contraception during treatment
- Attend all scheduled follow-up appointments
- Do not breastfeed during treatment and for 3 days after last dose
References
1. FDA Prescribing Information: Mavyret (glecaprevir/pibrentasvir). August 2021 2. Asselah T, et al. Gastroenterology. 2018;155(2):349-359 3. Zeuzem S, et al. N Engl J Med. 2018;378(4):354-369 4. AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. 2023 5. Kwo PY, et al. Lancet. 2017;390(10107):1535-1546 6. Forns X, et al. J Hepatol. 2017;67(2):263-271 7. Dore GJ, et al. Gastroenterology. 2018;155(4):1120-1127 8. Brown RS, et al. Hepatology. 2019;69(4):1647-1661