Pharmacokinetic evaluation of sofosbuvir/velpatasvir for the treatment of Chronic Hepatitis C in pediatrics aged 3 and older

ABSTRACT

Introduction

The World Health Organization proposed targets to eliminate hepatitis C virus (HCV) by 2030, aiming to treat ≥80% of people with HCV, decreasing new chronic infections by 90% and liver-related mortality by 65%. While children/adolescents represent a minority of cases, the true burden is underestimated. Advances in drug development have resulted in simplified treatments that are well-tolerated, effective, and pangenotypic in activity. Sofosbuvir/velpatasvir, a combined nucleotide analog NS5B polymerase inhibitor and NS5A inhibitor, respectively, is approved for HCV treatment for individuals ≥3 years, supported by safety data using lower-dose, novel formulations.

Areas covered

This review discusses chemistry, pharmacokinetics/pharmacodynamics, dosing, efficacy, and safety of sofosbuvir/velpatasvir highlighting pediatric data. Literature review included publications/conference abstracts from PubMed, Google, and Google Scholar. Information from key clinical trials/regulatory approvals is reviewed.

Expert opinion

Sofosbuvir/velpatasvir is a safe and effective therapy for the treatment of pangenotypic chronic HCV infection with limited cases of virologic relapse and adverse events among pediatric populations aged 3 years and older. However, the tolerability among children less than 6 years could be improved by alternative formulations, if not, shorter treatment durations. An aspirational role of direct-acting antivirals (DAAs) that should be explored is for the prevention of infection in exposed and at-risk pediatric populations.

KEYWORDS:

• Hepatitis C
• pharmacokinetics
• sofosbuvir
• velpatasvir
• Drug evaluation

Article highlights

• Sofosbuvir (a nucleotide analog NS5B polymerase inhibitor)/velpatasvir (an NS5A inhibitor) is a co-formulated, safe, and highly effective direct-acting antiviral therapeutic for the treatment of hepatitis C infection, with recent approval extended to pediatric participants aged 3 years and older (in June 2021, the label was expanded to children aged 3 to under 6 years of age).

• Sofosbuvir/velpatasvir has activity against all major HCV genotypes 1, 2, 3, 4, 5, or 6. Individuals with decompensated cirrhosis benefit from the addition of ribavirin to achieve cure.

• In key clinical trials, sofosbuvir/velpatasvir has demonstrated high resistance barrier, low rates of treatment failure, almost no treatment-emergent drug resistance and favorable tolerability and adverse event profile.

• For children with prior exposure to interferon ± ribavirin and/or sofosbuvir but with no prior exposure to NS3/4A protease or NS5A inhibitors, a 12-week course of weight-based sofosbuvir/velpatasvir ± ribavirin may be used to treat those with and without cirrhosis.

• Though NS3/4A resistance associated mutations are not expected to impact the efficacy of Sofosbuvir/velpatasvir, there are limited data in pediatric populations about this option.

• No dose adjustment is needed for adults with severe renal impairment including those on dialysis and also those with severe hepatic impairment; there are limited data on children.

• Sofosbuvir/velpatasvir levels may be impacted by gastric acid reducers (velpatasvir levels are lowered) and inducers of p-glycoprotein and moderate to strong inducers CYP2B6, CYP3A4, and CYP2C8 may reduce sofosbuvir ± velpatasvir levels significantly threatening its efficacy.

Declaration of interests

O Ogbuagu has received honoraria as an advisory board member and for participation in speakers’ bureaus for HIV treatment and prevention from Gilead Sciences, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.