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Sofosbuvir-velpatasvir-voxilaprevir in
adolescents 12 to 17 years old with HCV infection
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First published: 03 February 2022 - Guiseppe Indolfi1 | Deirdre Kelly2 | Gabriella Nebbia3 | Raffaele Iorio4 | Anna Mania5 | Vania Giacomet6 | Leszek Szenborn7 | Jiang Shao8 | Mun Sang Yue8 | Chia-Hsiang Hsueh8 | Bandita Parhy8 | Kathryn Kersey8 | Alessandra Mangia9 | Malgorzata Pawlowska10 | Sanjay Bansal11
Funding information
Gilead Sciences, Inc.
Among children, adolescents have the highest prevalence of HCV.[1] The European Society for Pediatric Gastroenterology, Hepatology and Nutrition advises early treatment of adolescents with HCV, before the risk of horizontal infection increases through sexual transmission or injecting drug use.[17] Intravenous drug abuse is a significant and increasingly common route of HCV infection in adolescents and young adults in the West. In the Appalachian region of the USA, among persons 12 to 29 years, HCV infection increased more than 3-fold from 2006 to 2012.[18] Given the increased transmission among young persons, in early 2020, the U.S. Preventive Services Task Force expanded HCV screening recommendations, suggesting that screening be considered in persons younger than 18 years who have a risk factor for infection, such as history of injection drug use.[19, 20] Screening and treatment efforts among adolescents are important measures for meeting the World Health Organization's goal of eliminating all forms of viral hepatitis as a public health threat by 2030.[21]
Our study supports sofosbuvir-velpatasvir-voxilaprevir treatment in adolescents. Of the 21 DAA-naïve adolescents-43% of whom had HCV genotype 3 infection-all (100%) reached SVR12 with 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. This rate was consistent with the SVR12 rates of 95%-96% observed with sofosbuvir-velpatasvir-voxilaprevir in Phase 3 trials in DAA-naïve adults.[13] Our results support using the current adult dose of sofosbuvir-velpatasvir-voxilaprevir (400/100/100 mg) for adolescents.
Virologic response
Overall, 100% of patients reached SVR12 (21 of 21; 95% CI, 84%-100%) (Table 2). No patients had virologic failure. Most patients (81%, 17 of 21) had HCV RNA < LLOQ by the week-2 treatment visit. Two additional patients reached viral negativity by week 4, and the remaining 2 became HCV RNA-negative during the second month of treatment.
Resistance
The numbers of patients with pretreatment RASs were as follows: 10 patients (48%) with an NS5A RAS, 3 patients (14%) with an NS5B nucleoside inhibitor RAS, and 1 patient (5%) with an NS3/4A RAS (Table 3). The presence of pretreatment NS3/4A, NS5A, and/or NS5B RASs did not affect treatment outcome, as all patients with a pretreatment RAS achieved SVR12 and SVR24. No on-treatment breakthrough or relapse was observed in patients through posttreatment weeks 12 or 24.
Abstract
Background and Aims
Sofosbuvir-velpatasvir-voxilaprevir is a pangenotypic regimen for chronic HCV infection. In the USA and Europe, sofosbuvir-velpatasvir-voxilaprevir once daily for 12 weeks is indicated for adults who previously received an HCV NS5A inhibitor. In Europe, sofosbuvir-velpatasvir-voxilaprevir is also indicated in the absence of prior HCV direct-acting antiviral (DAA) therapy as an 8-week or 12-week regimen. In an open-label study, we evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years with chronic HCV of any genotype.
Methods
In this Phase 2, multicenter study, sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg daily was administered to adolescents for 8 weeks if DAA-naïve or for 12 weeks for cirrhosis or prior DAA failure. The key efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Intensive pharmacokinetic sampling was done in 14 patients at week 2 or 4, and samples for population pharmacokinetics were collected in all patients.
Results
All patients (n = 21) were naïve to HCV DAAs, and none had cirrhosis. HCV genotype 3a infection was most common, occurring in 43% of patients. Overall, 100% of patients (21 of 21) reached SVR12. The most common adverse events were abdominal pain and headache (24% each) and nausea (19%); no adverse events led to discontinuation. The only serious adverse event, hypotension, was considered related to study drug and resolved the same day without interruption of treatment. Sofosbuvir-velpatasvir-voxilaprevir exposures were similar to those observed in adults.
Conclusions
The pangenotypic regimen of sofosbuvir-velpatasvir-voxilaprevir is highly efficacious and well-tolerated in treating chronic HCV infection in adolescents.
INTRODUCTION
Approximately 3.25 million children worldwide have chronic infection with HCV.[1] The prevalence of pediatric HCV varies throughout the globe, with estimates of 0.05%-0.36% in the USA and Europe and 5.8% in regions of Africa.[2] A minority of children spontaneously clear infection, usually by age 7 years.[3-5] Most children with chronic HCV are asymptomatic or have mild nonspecific symptoms.[6, 7]However, approximately 20% of infected children have clinical signs or symptoms of HCV, with hepatomegaly being the most common.[6] Even when signs or symptoms are present, infection can remain unsuspected, given the subtle clinical presentation. Twenty-five percent of HCV-infected children have persistent alanine aminotransferase (ALT) elevations,[6] and HCV infection in childhood can lead to serious liver damage in adulthood. Fortunately, successful treatment before development of advanced liver disease improves outcomes.[8]
Indeed, successful treatment for chronic HCV has the benefits of decreasing liver inflammation, halting or reversing fibrosis progression, and lowering risk of HCC.[9-11] In 2017, the first all-oral, interferon-free antiviral regimens were approved for treating children with chronic HCV, with an indication for adolescents aged 12 to 17.[12] Currently, four interferon-free direct-acting antiviral (DAA) regimens have been approved for adolescents.[13]
The pangenotypic regimen sofosbuvir-velpatasvir-voxilaprevir includes targeted inhibitors of HCV’s NS5B polymerase, NS5A phosphoprotein, and NS3/4A protease. In clinical studies, sofosbuvir-velpatasvir-voxilaprevir has sustained virologic response (SVR) rates of ≥95% in adults treated with 8 or 12 weeks depending on HCV treatment history.[14-16] We evaluated the safety, efficacy, and pharmacokinetics of 8 or 12 weeks of sofosbuvir-velpatasvir-voxilaprevir in adolescents aged 12-17 years old.
RESULTS
Patient population
From January to December of 2019, 21 patients were treated at 10 study sites in Italy, Poland, and the UK. The median age for the study population was 14 years (range 12-16 years), and 76% (16 of 21) were infected through perinatal transmission (Table 1). No patients had previously received treatment with an HCV DAA; 24% (5 of 21) had failed prior treatment with pegylated-interferon or interferon plus ribavirin, including 1 patient who had failed two prior courses of pegylated-interferon plus ribavirin. Sixty-two percent (13 of 21) of patients were female, and 76% (16 of 21) were White. Nine patients (43%) were infected with HCV genotype 3a. No patients had cirrhosis based on prior biopsy or investigator assessment; noninvasive liver fibrosis test results are summarized in Table 1. All 21 patients who initiated treatment completed it (Figure 1).
Virologic response
Overall, 100% of patients reached SVR12 (21 of 21; 95% CI, 84%-100%) (Table 2). No patients had virologic failure. Most patients (81%, 17 of 21) had HCV RNA < LLOQ by the week-2 treatment visit. Two additional patients reached viral negativity by week 4, and the remaining 2 became HCV RNA-negative during the second month of treatment.
Resistance
The numbers of patients with pretreatment RASs were as follows: 10 patients (48%) with an NS5A RAS, 3 patients (14%) with an NS5B nucleoside inhibitor RAS, and 1 patient (5%) with an NS3/4A RAS (Table 3). The presence of pretreatment NS3/4A, NS5A, and/or NS5B RASs did not affect treatment outcome, as all patients with a pretreatment RAS achieved SVR12 and SVR24. No on-treatment breakthrough or relapse was observed in patients through posttreatment weeks 12 or 24.
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