Introduction
Sovaldi (sofosbuvir) is a revolutionary direct-acting antiviral agent developed by Gilead Sciences for the treatment of chronic hepatitis C virus (HCV) infection. Approved by the FDA in December 2013, Sovaldi represents a breakthrough in HCV therapy as the first oral nucleotide analog NS5B polymerase inhibitor. It has transformed hepatitis C treatment by offering significantly higher cure rates, shorter treatment durations, and improved tolerability compared to previous interferon-based regimens.
Mechanism of Action
Sovaldi (sofosbuvir) is a prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203). This active metabolite incorporates into HCV RNA by the NS5B polymerase, acting as a chain terminator. By inhibiting the HCV NS5B RNA-dependent RNA polymerase, sofosbuvir effectively suppresses viral replication. The drug demonstrates potent activity against multiple HCV genotypes with a high barrier to resistance.
Indications
Sovaldi is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults and pediatric patients 3 years of age and older. It is used in combination with other antiviral medications:
- Genotype 1, 2, 3, or 4: In combination with ribavirin
- Genotype 1 or 4: In combination with peginterferon alfa and ribavirin
- Genotype 5 or 6: Limited data support use with ribavirin
Sovaldi is also a component of several fixed-dose combination products (Epclusa, Harvoni, Vosevi) for HCV treatment.
Dosage and Administration
Standard Adult Dose: 400 mg orally once daily with or without food Treatment Duration:- Genotype 1 and 4: 12 weeks with peginterferon alfa and ribavirin
- Genotype 2: 12 weeks with ribavirin
- Genotype 3: 24 weeks with ribavirin
- Renal impairment: No dose adjustment needed in mild to moderate impairment; not recommended in severe renal impairment (eGFR <30 mL/min/1.73m²)
- Hepatic impairment: No dose adjustment needed
- Pediatric patients (≥3 years): Weight-based dosing (200 mg for 17-35 kg, 400 mg for ≥35 kg)
Pharmacokinetics
Absorption: Peak plasma concentrations achieved in 0.5-2 hours; bioavailability approximately 92% Distribution: Protein binding approximately 61-65%; volume of distribution ~250 L Metabolism: Activated intracellularly by cathepsin A, carboxylesterase 1, and histidine triad nucleotide-binding protein 1 Elimination: Half-life of sofosbuvir is 0.4 hours; half-life of metabolite GS-331007 is 27 hours; primarily renal excretion (80%) with fecal elimination (14%)Contraindications
- Concomitant use with strong P-gp inducers (rifampin, St. John's wort, carbamazepine, phenytoin)
- Known hypersensitivity to sofosbuvir or any component of the formulation
- Use with amiodarone due to risk of serious symptomatic bradycardia
Warnings and Precautions
Hepatitis B Virus Reactivation: Risk of HBV reactivation in patients coinfected with HCV and HBV; test all patients for HBV before initiating therapy Bradycardia with Amiodarone: Serious symptomatic bradycardia reported when coadministered with amiodarone Risk of Reduced Efficacy: Concomitant use with P-gp inducers may significantly decrease sofosbuvir concentrations Pregnancy Considerations: Ribavirin-containing regimens are contraindicated in pregnancy; effective contraception requiredDrug Interactions
Significant Interactions:- P-gp inducers: Rifampin, St. John's wort, carbamazepine, phenytoin (decrease sofosbuvir levels)
- P-gp inhibitors: Cyclosporine, digoxin, dabigatran (may increase levels of these drugs)
- Amiodarone: Risk of serious bradycardia (contraindicated)
Adverse Effects
Common Adverse Reactions (≥10%):- Fatigue
- Headache
- Nausea
- Insomnia
- Anemia (with ribavirin-containing regimens)
- Hepatitis B reactivation
- Symptomatic bradycardia (with amiodarone coadministration)
- Severe dermatological reactions (rare)
Monitoring Parameters
Baseline:- HCV genotype and viral load
- HBV serology
- Liver function tests (ALT, AST, bilirubin)
- Complete blood count
- Renal function
- Pregnancy test (if ribavirin-containing regimen)
- HCV RNA at weeks 4, 12, and 24 (if applicable)
- Liver function tests
- CBC (with ribavirin-containing regimens)
- Cardiac monitoring if amiodarone was recently discontinued
- Sustained virologic response (SVR) at 12 and 24 weeks after treatment completion
- HBV DNA monitoring in coinfected patients
Patient Education
- Take Sovaldi exactly as prescribed, once daily with or without food
- Do not stop taking unless directed by healthcare provider
- Inform all healthcare providers about all medications being taken
- Use effective contraception during and for 6 months after treatment if taking ribavirin-containing regimen
- Report any symptoms of slow heart rate (dizziness, lightheadedness, fatigue) immediately
- Keep all follow-up appointments for monitoring
- Sovaldi is not effective for preventing HCV transmission to others
References
1. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887. 2. Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2021. 3. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2018;67(4):1477-1492. 4. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69(2):461-511. 5. Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug therapy for hepatitis C: a proof-of-concept study. Lancet. 2015;385(9973):1107-1113.