Sofosbuvir

Sofosbuvir is a prodrug uridine nucleotide analogue that is intracellularly metabolised to the pharmacologically active triphosphate GS-461203 (also written as 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-triphosphate). This active form is incorporated by HCV NS5B RNA-dependent RNA polymerase into the nascent viral RNA strand, where it acts as a chain terminator and arrests viral replication. The 2′-methyl substituent makes it a defective substrate that does not pass selectivity filters of mammalian cellular polymerases, producing a high therapeutic index.

Mechanism of Action

• Nucleotide analogue prodrug activation: sofosbuvir is a uridine monophosphate prodrug with a phenyl-monophosphoramidate group that masks the negative charge of the phosphate, enabling oral absorption. Within hepatocytes, the prodrug is hydrolysed by cathepsin A (CatA) and carboxylesterase 1 (CES1) to release the monophosphate, which is then processed by histidine triad nucleotide-binding protein 1 (HINT1), UMP-CMP kinase (CMPK1), and nucleoside diphosphate kinase (NDPK) to the active triphosphate GS-461203.
• NS5B chain termination: GS-461203 is incorporated by NS5B opposite a template adenosine; the 2′-α-fluoro and 2′-β-C-methyl substituents prevent further nucleotide addition, terminating RNA chain elongation.
• Pan-genotypic activity: the NS5B active site is the most highly conserved region of the HCV genome, conferring activity across genotypes 1–6 with EC50 values in the low nanomolar range.
• High barrier to resistance: the principal resistance mutation (NS5B S282T) markedly reduces viral fitness, so it rarely emerges or persists in clinical practice. Other low-level resistance polymorphisms exist but do not compromise SVR rates in combination regimens.
• No effect on the QTc interval at 3× the recommended dose; well tolerated as a single-agent component of a combination.

Pharmacokinetics

• Absorption: rapidly absorbed; Tmax 0.5–2 hours; Cmax ~567 ng/mL after 400 mg. Bioavailability is not formulation-rate-limited under labelled use.
• Volume of distribution: not formally determined; large apparent volume reflecting hepatocyte accumulation of phosphorylated metabolites.
• Protein binding: 61–65% (parent); the inactive predominant circulating metabolite GS-331007 is essentially unbound.
• Metabolism: extensive intracellular activation as described above; the dominant circulating species in plasma is the inactive deaminated nucleoside metabolite GS-331007 (>90% of sofosbuvir-related material in plasma).
• Half-life: sofosbuvir plasma half-life is short (~0.4 hours); the inactive metabolite GS-331007 has a half-life of ~27 hours; intracellular triphosphate persists with a half-life of >18 hours, supporting once-daily dosing.
• Excretion: primarily renal (~80% of total drug-related material, mostly as GS-331007); ~14% faecal; ~2.5% via exhalation.

Sofosbuvir is used in combination therapy with other direct-acting antivirals (DAAs) to treat chronic hepatitis C virus (HCV) infection in adults and paediatric patients ≥3 years (US weight-band labelling). Specific regimens, by combination product:

Sovaldi (Sofosbuvir, with Ribavirin ± Peginterferon)

Historical use in patients unable to take preferred DAA-only regimens, or in selected genotype 2/3 populations in older guidelines. Now largely supplanted by pan-genotypic DAA combinations.

Harvoni (Sofosbuvir + Ledipasvir)

• HCV genotypes 1, 4, 5, 6 without cirrhosis or with compensated cirrhosis.
• Genotype 1 with decompensated cirrhosis (in combination with ribavirin).
• Genotypes 1 or 4 in liver transplant recipients without cirrhosis or with compensated cirrhosis (with ribavirin).

Epclusa (Sofosbuvir + Velpatasvir)

• HCV genotypes 1–6 without cirrhosis or with compensated cirrhosis (12 weeks).
• HCV with decompensated cirrhosis (12 weeks in combination with ribavirin).
• Pan-genotypic first-line therapy per AASLD and EASL guidelines.

Vosevi (Sofosbuvir + Velpatasvir + Voxilaprevir)

• Salvage therapy after prior DAA failure, including in patients with prior NS5A inhibitor exposure (12 weeks).

Sofosbuvir-containing regimens are also used in HCV-HIV co-infected patients (with attention to antiretroviral drug interactions) and in selected glomerulonephritis/HCV-associated extrahepatic manifestations.

• Hypersensitivity to sofosbuvir or any of the excipients.
• Concomitant amiodarone: severe symptomatic bradycardia (including fatal cardiac arrest and pacemaker-requiring bradycardia) has been reported with sofosbuvir-containing DAA combinations plus amiodarone. Avoid the combination; if unavoidable, monitor cardiac rhythm.
• Strong P-gp inducers (see Drug Interactions): substantially reduce sofosbuvir efficacy.

Side effects with sofosbuvir-containing DAA combinations are mild and far less burdensome than legacy interferon-ribavirin regimens. The most common adverse effects reflect the partner drug and/or ribavirin when used.

Common (≥1/100 to <1/10): headache, fatigue, nausea, insomnia, irritability. When used with ribavirin, anaemia, rash, and pruritus are added.

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

HBV reactivation: all patients should be screened for HBV (HBsAg, anti-HBc) before initiating sofosbuvir-containing DAA therapy; HBV reactivation, occasionally fatal, has been reported during and after DAA therapy in HCV-HBV co-infected patients.

Sofosbuvir is a substrate of P-glycoprotein and BCRP; it does not significantly inhibit or induce CYP enzymes itself. Most clinically meaningful interactions involve P-gp modulation or pharmacodynamic combinations.

• Strong P-gp inducers (rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital, St John’s Wort): substantially reduce sofosbuvir exposure — co-administration is not recommended.
• Amiodarone: severe symptomatic bradycardia — combination should be avoided in any sofosbuvir-containing DAA regimen.
• HMG-CoA reductase inhibitors (statins): with Harvoni, Epclusa, Vosevi, exposure of some statins (rosuvastatin in particular) is increased — dose limits or alternative statin selection required.
• Antiretrovirals: many interactions apply to the partner DAA (especially with tipranavir/ritonavir, efavirenz, and elvitegravir/cobicistat). Tenofovir disoproxil fumarate exposure can increase with Harvoni and Vosevi — monitor renal function.
• Antacids, H2 blockers, proton pump inhibitors: ledipasvir (Harvoni) absorption depends on gastric pH; sofosbuvir itself is not pH-sensitive. Spacing or dose limits apply with PPIs when using Harvoni.
• Anticonvulsants (oxcarbazepine, phenytoin, phenobarbital, carbamazepine): avoid.
• St John’s Wort: avoid.

No clinically significant food interaction for sofosbuvir alone; Epclusa is taken with or without food, Vosevi with food.

Sofosbuvir is administered orally once daily, with or without food (specific combination products may differ — Vosevi must be taken with food). Tablets are swallowed whole.

Adult Dosing (Most Common Regimens)

• Sovaldi (sofosbuvir): 400 mg once daily, in combination with ribavirin ± peginterferon (legacy regimens).
• Harvoni (sofosbuvir 400 mg / ledipasvir 90 mg): 1 tablet once daily for 8, 12, or 24 weeks depending on genotype, prior treatment, and cirrhosis status.
• Epclusa (sofosbuvir 400 mg / velpatasvir 100 mg): 1 tablet once daily for 12 weeks; with ribavirin in decompensated cirrhosis.
• Vosevi (sofosbuvir 400 mg / velpatasvir 100 mg / voxilaprevir 100 mg): 1 tablet once daily for 12 weeks; take with food.

Paediatric Dosing

Available in tablets (200 mg) and pellet packets (150 mg, 200 mg), used per weight-band protocols defined for each combination product. Generally indicated from age 3 years upward.

Renal Impairment

• No dose adjustment required for any sofosbuvir-containing regimen, including in patients with severe renal impairment, end-stage renal disease, or on haemodialysis (label updates from 2019 onward).
• Earlier label restrictions (eGFR <30 mL/min) have been removed in most regions as safety data accrued.

Hepatic Impairment

• No dose adjustment for mild-to-moderate hepatic impairment.
• In decompensated cirrhosis, sofosbuvir-containing regimens are used with ribavirin (Epclusa) or with adjusted duration (Harvoni). Protease-inhibitor-containing regimens (Vosevi) are not recommended in decompensated cirrhosis due to the voxilaprevir component.

Missed Dose

If less than 18 hours have passed, take the missed dose 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 2 hours, take another dose; otherwise, do not redose.

HBV Reactivation

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

Amiodarone Co-administration

Avoid. If unavoidable in patients on combined DAA therapy, hospitalise for 48 hours of cardiac monitoring at initiation and educate on symptoms of bradycardia. Patients who have discontinued amiodarone within the prior several months still require caution due to its long half-life.

Treatment Adherence

Achieving sustained virological response requires high adherence over the 8-, 12-, or 24-week treatment course. Counsel on the importance of completing therapy even after symptomatic improvement.

Genotyping and Resistance Testing

Genotype confirmation is standard before regimen selection. Resistance-associated substitution (RAS) testing is recommended only in specific scenarios (e.g., NS5A inhibitor failure before considering retreatment options).

Pregnancy and Lactation

• Pregnancy: not recommended unless benefits clearly outweigh risks; sofosbuvir-containing regimens with ribavirin are contraindicated in pregnancy and require strict contraception for both partners due to ribavirin teratogenicity.
• Breastfeeding: limited human data; benefit-risk assessment.

Co-infection with HIV

Many sofosbuvir-containing combinations are well tolerated alongside antiretroviral therapy, but careful screening for drug interactions and renal monitoring (especially with tenofovir disoproxil fumarate) is essential.

Effect on Driving

No significant influence. Patients reporting fatigue or insomnia should exercise judgement.

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

6 years for unopened tablets. Do not use after the expiry date.

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