Sofosbuvir + Velpatasvir

Approved Indications:

• Chronic Hepatitis C Virus (HCV) Infection:
• Treatment of adult and pediatric patients (≥6 years or weighing ≥17 kg) with chronic HCV infection of all genotypes (GT 1–6), with or without compensated cirrhosis (Child-Pugh A).
• For adult patients with decompensated cirrhosis (Child-Pugh B or C), the combination is used with ribavirin.

Off-label/Clinically Accepted Uses:

• Post-liver transplant HCV recurrence.
• HCV/HIV co-infection.
• HCV in patients with chronic kidney disease (non-dialysis).
• HCV in patients with hemophilia or thalassemia (in case of coinfection).

Adults (with or without cirrhosis):

• One tablet once daily for 12 weeks, with or without food.
• Each tablet contains Sofosbuvir 400 mg + Velpatasvir 100 mg.

Adults with decompensated cirrhosis:

• Same dose plus Ribavirin for 12 weeks.
• Ribavirin dosing: based on body weight and renal function.

Pediatric Patients (6 years and older or ≥17 kg):

• Body weight 17–29 kg: 1 tablet daily of Sofosbuvir 200 mg + Velpatasvir 50 mg.
• Body weight ≥30 kg: 1 adult-strength tablet daily (400 mg/100 mg).
• Duration: 12 weeks in all genotypes.

Renal Impairment:

• Mild to moderate (eGFR ≥30 mL/min): No dose adjustment.
• Severe renal impairment or dialysis: Use with caution; not recommended due to limited safety data.

Hepatic Impairment:

• Compensated (Child-Pugh A): No adjustment needed.
• Decompensated (Child-Pugh B or C): Use only in combination with ribavirin under specialist supervision.

Sofosbuvir is a nucleotide analog prodrug that is intracellularly converted into the active uridine analog triphosphate, which inhibits HCV NS5B RNA-dependent RNA polymerase, a key enzyme for viral RNA replication. Velpatasvir is an NS5A inhibitor, which targets the HCV NS5A protein, disrupting viral replication, assembly, and secretion. Together, the combination provides potent, pangenotypic antiviral activity and prevents the virus from multiplying inside the liver cells, leading to sustained virological response (SVR) and viral clearance.

Sofosbuvir:

• Absorption: Peak plasma concentration in ~0.5–2 hours.
• Bioavailability: High after oral administration.
• Metabolism: Hepatic via hydrolysis and phosphorylation; active metabolite is GS-461203.
• Half-life: ~0.4 hours (parent), 27 hours (active metabolite).
• Elimination: Mainly renal (80%).

Velpatasvir:

• Absorption: Tmax ~3 hours.
• Bioavailability: Enhanced by food (high-fat meals increase AUC).
• Metabolism: Minimal hepatic via CYP2B6, CYP2C8, and CYP3A4.
• Half-life: ~15 hours.
• Elimination: Primarily fecal (94%), renal ~0.4%.

• Pregnancy: No formal FDA pregnancy category (new labeling rules apply). No teratogenicity in animal studies. If combined with ribavirin, it is contraindicated in pregnancy due to ribavirin’s teratogenicity.
• Lactation: Unknown if either drug is excreted in human milk. Based on mechanism, low risk, but caution advised. For nursing mothers, weigh benefit vs. potential infant exposure.

• Primary Class: Direct-Acting Antiviral (DAA) for Hepatitis C
• Subclass: NS5B polymerase inhibitor (Sofosbuvir) + NS5A inhibitor (Velpatasvir)
• Generation: Pangenotypic, once-daily fixed-dose combination

• Known hypersensitivity to sofosbuvir, velpatasvir, or excipients.
• Co-administration with strong inducers of P-gp and CYP enzymes (e.g., rifampicin, carbamazepine, St. John's Wort).
• Pregnancy or male partners of pregnant women (if ribavirin is used concurrently).
• Severe renal impairment (eGFR <30 mL/min) unless benefit outweighs risk.

• Bradycardia risk when combined with amiodarone; avoid unless no alternatives.
• Monitor ALT levels; discontinue if hepatic decompensation symptoms occur.
• Hepatitis B reactivation reported—screen all patients for HBV before initiation.
• Renal function monitoring recommended in patients with pre-existing renal disease.
• Patients with decompensated cirrhosis require specialist supervision, particularly when using ribavirin.

Common (≥10%):

• Fatigue
• Headache
• Nausea

Less Common:

• Insomnia
• Anemia (especially with ribavirin)
• Diarrhea

Serious (rare):

• Severe bradycardia (with amiodarone)
• Hepatitis B reactivation
• Hypersensitivity reactions

Timing: Side effects usually appear within the first few weeks; most are mild to moderate and resolve post-treatment.

Major Interactions:

• Rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s Wort → Reduce plasma levels → loss of efficacy.
• Amiodarone → Risk of life-threatening bradycardia.
• Antacids, H2 blockers, PPIs → Reduce Velpatasvir absorption → Space doses appropriately (e.g., antacids ≥4 hours apart).
• Digoxin → P-gp inhibition may increase digoxin concentration.

Metabolic Enzymes Involved:

• P-glycoprotein (P-gp) substrates
• CYP2B6, CYP2C8, CYP3A4 (Velpatasvir minor metabolism)
• No significant CYP induction or inhibition by Sofosbuvir

• 2023 AASLD and EASL guidelines continue to recommend Sofosbuvir + Velpatasvir as first-line therapy for all genotypes.
• Updates clarify dosage and treatment duration in patients with cirrhosis and renal impairment.
• WHO Essential Medicines List updated to include this fixed-dose combination for global access in low-to-middle-income countries.

• Store below 30°C (86°F) in a dry place.
• Protect from moisture and light.
• Do not refrigerate.
• Keep in original container until use.
• No special handling or reconstitution required.