Sofosbuvir/Velpatasvir

Sofosbuvir/velpatasvir attacks two distinct, essential, and non-overlapping steps of HCV replication: sofosbuvir’s active metabolite arrests RNA chain elongation at NS5B, while velpatasvir blocks the assembly and function of the HCV replication complex via NS5A. The two molecules have additive antiviral effect, non-overlapping resistance profiles, and a combined high barrier to resistance that supports a uniform 12-week pan-genotypic regimen.

Mechanism of Action

Sofosbuvir (NS5B nucleotide polymerase inhibitor)

• Sofosbuvir is a uridine nucleotide prodrug intracellularly activated to GS-461203, a defective substrate for HCV NS5B RNA-dependent RNA polymerase.
• Incorporation of GS-461203 into the nascent viral RNA strand causes chain termination, halting replication.
• The NS5B active site is the most conserved region of the HCV genome, conferring pan-genotypic activity. The principal resistance mutation (S282T) drastically reduces viral fitness and is rarely selected in vivo.

Velpatasvir (NS5A inhibitor)

• Velpatasvir binds domain I of NS5A, a multifunctional non-structural protein essential for HCV replication, virion assembly, and modulation of host immune signalling.
• NS5A inhibition prevents formation of the membrane-associated replication complex, redistributes NS5A to lipid droplets, and disrupts RNA replication and virion morphogenesis.
• Compared with first-generation NS5A inhibitors (ledipasvir, daclatasvir), velpatasvir has substantially higher potency against genotypes 2 and 3 and a higher barrier to resistance.

Combined effect

• Additive viral suppression with non-overlapping resistance pathways.
• Pan-genotypic activity: EC50 values in the low picomolar to low nanomolar range across all six HCV genotypes.
• SVR12 of 93–99% in clinical trials (ASTRAL-1, -2, -3, -4) across genotypes and across patients with or without compensated cirrhosis.
• No clinically relevant QTc prolongation at 5× the recommended velpatasvir dose.

Pharmacokinetics

Sofosbuvir — see the dedicated Sofosbuvir product page for full pharmacokinetics. Briefly: rapidly absorbed, Tmax 0.5–2 h, parent half-life ~0.4 h, predominant inactive metabolite GS-331007 half-life ~27 h, intracellular triphosphate half-life >18 h supporting once-daily dosing; predominantly renal excretion of GS-331007.

Velpatasvir

• Absorption: oral bioavailability 25–30%; Tmax ~3 hours.
• Volume of distribution: 1.4–1.6 L/kg.
• Protein binding: >99.5%.
• Metabolism: predominantly excreted unchanged (~77% as parent in faeces); modest CYP2B6, CYP2C8, and CYP3A4 metabolism.
• Half-life: ~15 hours.
• Excretion: ~94% faecal; ~0.4% urinary.
• Transporters: substrate and inhibitor of P-gp and BCRP/ABCG2; inhibitor of OATP1B1, OATP1B3, and OATP2B1.

• Chronic hepatitis C virus (HCV) infection in adults and paediatric patients (≥3 years or ≥17 kg in current labelling) with HCV genotypes 1, 2, 3, 4, 5, or 6:
  • Without cirrhosis or with compensated cirrhosis (Child-Pugh A): Epclusa 1 tablet once daily for 12 weeks.
  • With decompensated cirrhosis (Child-Pugh B or C): Epclusa 1 tablet once daily for 12 weeks in combination with ribavirin.

Epclusa is recommended as a first-line pan-genotypic regimen by AASLD/IDSA, EASL, WHO, and most national HCV guidelines.

• Hypersensitivity to sofosbuvir, velpatasvir, or any of the excipients.
• Concomitant strong inducers of P-glycoprotein and/or CYP enzymes (rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital, St John’s Wort): substantially decrease sofosbuvir and velpatasvir exposure — co-administration is contraindicated.
• Concomitant amiodarone: severe symptomatic bradycardia has been reported with sofosbuvir-containing DAA regimens — combination should be avoided.

Epclusa is exceptionally well tolerated. Most adverse effects reflect baseline disease, ribavirin co-medication, or are mild and self-limited.

Common (≥1/100 to <1/10) — Epclusa alone: headache, fatigue, nausea, insomnia, asthenia, irritability.

With ribavirin (decompensated cirrhosis): anaemia (commonly), rash, pruritus, increased bilirubin.

Uncommon to rare: depression, suicidal ideation (rare), severe symptomatic bradycardia with amiodarone (boxed warning in some regions), HBV reactivation (class effect for DAAs in HCV-HBV co-infected patients), severe hypersensitivity reactions including angioedema (rare).

HBV reactivation: occasionally fatal HBV reactivation has occurred during or after DAA therapy in patients with current or prior HBV infection — see Special Instructions.

Most clinically relevant interactions involve P-glycoprotein induction (sofosbuvir and velpatasvir), CYP induction (velpatasvir is a substrate of CYP2B6, CYP2C8, CYP3A4), and velpatasvir’s inhibitor activity at OATPs and BCRP.

Contraindicated or strongly discouraged

• Strong CYP3A4/P-gp inducers: rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, St John’s Wort.
• Amiodarone: severe bradycardia.
• Tipranavir/ritonavir: substantially reduces velpatasvir exposure.

Use with caution or with dose adjustment

• Proton pump inhibitors and H2 blockers: velpatasvir solubility is pH-dependent — take Epclusa with food and limit PPI doses (e.g., omeprazole ≤20 mg taken with Epclusa).
• Antacids: separate by ≥4 hours.
• Statins: Epclusa increases exposure of rosuvastatin (limit to 10 mg/day) and atorvastatin (caution); pitavastatin and pravastatin generally safer.
• Tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens: increased TDF exposure — monitor renal function. Tenofovir alafenamide (TAF) interactions are less pronounced.
• Digoxin: increased exposure — monitor digoxin levels.
• Dabigatran: increased exposure — bleeding risk.
• Anticonvulsants (oxcarbazepine): avoid.
• Efavirenz and other strong CYP3A inducers: avoid.

No clinically meaningful interaction

• Methadone, oral contraceptives, tacrolimus, ciclosporin (with caution, may need monitoring).

Food

• Take with or without food. (Distinct from Vosevi, which requires food.)

Tablets are swallowed whole, once daily, at approximately the same time each day, with or without food. Oral pellets are administered as labelled for paediatric weight bands.

Adults

• Genotypes 1–6, without cirrhosis or with compensated cirrhosis: 1 adult tablet (sofosbuvir 400 mg / velpatasvir 100 mg) once daily for 12 weeks.
• Decompensated cirrhosis (Child-Pugh B or C): 1 adult tablet once daily with ribavirin for 12 weeks. Ribavirin is dosed by body weight in patients with normal renal function.

Paediatric (≥3 Years; Weight-Banded)

• ≥30 kg: 1 adult tablet (400/100 mg) daily.
• 17 to <30 kg: 1 paediatric tablet (200/50 mg) daily.
• <17 kg or where granules are preferred: weight-banded oral pellet packets daily.

Treatment duration in paediatrics is generally 12 weeks (mirroring adult use), with ribavirin added in decompensated cirrhosis.

Renal Impairment

• No dose adjustment required for any degree of renal impairment, including end-stage renal disease on haemodialysis (label updated post-2019).

Hepatic Impairment

• Compensated cirrhosis (Child-Pugh A): standard regimen.
• Decompensated cirrhosis (Child-Pugh B or C): add ribavirin for 12 weeks.

Missed Dose

If less than 18 hours from the usual time, take as soon as remembered and take the next dose at the usual time. If more than 18 hours, skip the missed dose and take the next dose at the usual time. Do not double up. If a dose is vomited within 4 hours, take another tablet; otherwise, do not redose.

HBV Reactivation

Screen all patients for HBV (HBsAg, anti-HBc) before initiation. Monitor HBV-coinfected patients (or those with isolated anti-HBc positivity) during and after therapy. Consider HBV antiviral co-therapy in patients with active or high-risk HBV.

Amiodarone Co-administration

Avoid. If unavoidable (rare), perform 48 hours of inpatient cardiac monitoring at DAA initiation and educate the patient on symptoms of bradycardia. Patients who discontinued amiodarone within the prior several months may still be at risk owing to its very long half-life.

Achieving Sustained Virological Response

SVR12 (undetectable HCV RNA 12 weeks after the end of treatment) is the standard cure endpoint. Verify SVR12 with quantitative HCV RNA testing 12 weeks after completion. Adherence is critical — missing more than a few doses risks incomplete suppression and resistance selection.

Drug-Drug Interactions Workflow

Before initiating Epclusa, perform a comprehensive medication review including over-the-counter products, herbal supplements (especially St John’s Wort), antacids, and recreational substances. The University of Liverpool HEP Drug Interactions checker (hep-druginteractions.org) is widely used as a working resource.

Pregnancy and Lactation

• Epclusa alone: limited human data; animal studies do not show teratogenicity. Use only if clearly needed.
• Epclusa with ribavirin: contraindicated in pregnancy and in male partners of pregnant women — ribavirin is teratogenic. Strict contraception during therapy and for 6 months after the last ribavirin dose.
• Breastfeeding: limited human data; benefit-risk assessment.

HIV Co-infection

Compatible with most antiretroviral regimens, with attention to TDF-containing regimens (renal monitoring), tipranavir/ritonavir (avoid), and efavirenz (avoid).

Treatment-Experienced Patients

Patients with prior DAA failure containing an NS5A inhibitor may not respond to Epclusa retreatment — consider Vosevi (sofosbuvir/velpatasvir/voxilaprevir) as salvage therapy with reference to current guidelines.

Effect on Driving

No clinically significant effect; affected patients should exercise judgement if reporting fatigue.

This medicinal product does not require any special storage conditions. Keep in the original packaging.

4 years for unopened tablets and pellet packets. Do not use after the expiry date printed on the packaging.

Prescription required (Rx). Initiated by hepatology, infectious diseases, or appropriately trained primary care providers. In many countries, dispensed via specialty pharmacy under national HCV elimination programmes or payer-specific pre-authorisation. Generic versions are widely available in low- and middle-income countries under Gilead’s voluntary licensing arrangements.