**1. Background**

It is estimated that over 3.25 million (95% confidence interval 2.07–3.90) children are infected with hepatitis C virus (HCV) globally, which corresponds to a prevalence of 0.13% (0.08–0.16) [1]. Among them, 3500 (2600–4200) subjects are considered to be living in Poland, which makes the HCV prevalence 0.05 (0.04–0.06) [1]. However, according to the data published by the National Institute of Public Health, Warsaw, Poland, between 2010 and 2019, only 545 cases of hepatitis C were reported in patients aged 0–19 years, which suggests that most cases of HCV-infected children remain undiagnosed [2]. Chronic hepatitis C (CHC) in children is usually considered a mild disease with only a slow progression of liver disease. However, recent studies reported a significant proportion of pediatric patients who develop significant fibrosis or even cirrhosis as a result of early infection with HCV [3–5]. In addition, Younossi et al. [6] showed that HCV infection in adolescents may be associated

**Citation:** Pokorska-Spiewak, M.; ´ Dobrzeniecka, A.; Aniszewska, M.; Marczy ´nska, M. Real-Life Experience with Ledipasvir/Sofosbuvir for the Treatment of Chronic Hepatitis C Virus Infection with Genotypes 1 and 4 in Children Aged 12 to 17 Years—Results of the POLAC Project. *J. Clin. Med.* **2021**, *10*, 4176. https:// doi.org/10.3390/jcm10184176

Academic Editors: Maria Carla Liberto and Nadia Marascio

Received: 12 August 2021 Accepted: 14 September 2021 Published: 15 September 2021

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with decreased health-related quality of life, poor social functioning, and a reduction in intelligence and memory testing. To prevent these consequences of CHC, early anti-HCV treatment should be implemented. New, extremely effective, and safe interferon-free therapies based on direct-acting antivirals (DAAs) have significantly changed the natural history of CHC, and they have provided a chance for HCV eradication [7]. The first DAA, ledipasvir/sofosbuvir (LDV/SOF), was approved for use in children aged 12–17 years by the European Medical Agency (EMA), Amsterdam, The Netherlands, and U.S. Food and Drug Administration (FDA), Silver Spring, MD, US, in 2017 [8]. Since 2019, LDV/SOF has been used in children aged at least 3 years [9,10]. However, due to the prohibitive prices of DAAs, only a few countries have included recommendations for the treatment of pediatric patients infected with HCV in their national policies and strategies [11,12]. Thus, only a small proportion of children and adolescents with CHC have been treated, mainly during clinical trials. As a result, available real-world data on the efficacy and safety of LDV/SOF in pediatric patients are limited [13,14]. Thus, in this prospective, single-arm, observational, open-label single-center study, we aimed to present our real-life experience with LDV/SOF for the treatment of CHC in children aged 12 to 17 years infected with HCV genotypes 1 and 4.

#### **2. Materials and Methods**

In Poland, patients below 18 years of age are not included in the national therapeutic programs for CHC. However, courtesy of a donation of LDV/SOF by the pharmaceutical company in August 2019, our single tertiary health care pediatric infectious disease department launched the real-life therapeutic program 'Treatment of Polish Adolescents with Chronic Hepatitis C Using Direct Acting Antivirals (POLAC project)'. In this project, we qualified consecutive patients aged 12–17 years (weighing at least 35 kg) infected with genotype 1 and 4 HCV for therapy with LDV/SOF (fixed-dose tablet of 90/400 mg). CHC was diagnosed in subjects with over a 6-month duration of disease confirmed with positive nucleic acid testing, HCV RNA, using quantitative real-time polymerase chain reaction (RT-PCR) (Abbott RealTime HCV, Abbott Laboratories, Abbott Park, Illinois, USA; measurement linearity range 12–1.0 × 10 8 IU/mL). Patients were eligible for the treatment regardless of the extent of liver fibrosis or previous ineffective treatment. The duration of treatment was established according to the recommendations of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), Geneva, Switzerland: patients received 12 weeks of therapy unless they were infected with HCV genotype 1 with a history of previous ineffective interferon-based treatment and presented with cirrhosis. This specific group of patients was treated for 24 weeks [15]. Before starting the treatment, the possibility of drug interactions between LDV/SOF and other medicines received by the patient was excluded using the online HEP Drug Interactions Checker provided by the University of Liverpool (www.hep-druginteractions.org).

#### *2.1. Treatment Monitoring and Outcomes*

All participants in this study were followed every 4 weeks during the treatment, at the end of the therapy, and at week 12 posttreatment. During all visits, physical examination and biochemical evaluation were performed, and adherence to treatment and possible adverse events were analyzed. HCV RNA testing was performed at baseline, at 4 weeks, and at the end of the treatment (EOT). To assess the efficacy of the therapy, a sustained virological response (SVR12) was evaluated based on negative testing for HCV viral load using an RT-PCR method at week 12 posttreatment. Nonresponders were defined as patients with persistent HCV during treatment, and relapsers were considered as cases in which a reappearance of HCV RNA after its previous disappearance during or after the therapy occurred. Biochemical serum testing was performed using commercially available laboratory kits. For both alanine and aspartate aminotransferase (ALT and AST) serum levels, 40 IU/L was considered an upper limit of normal. Liver METAVIR fibrosis was assessed by the FibroScan device (Echosens, Paris, France) [16]. Transient elastography (TE) examination was performed in all patients on the day the patient started treatment, and in patients presenting with significant fibrosis (F ≥ 2), it was also performed at week 12 posttreatment. Body mass index standard deviation (SD) scores (BMI z-scores) were calculated according to the WHO (Geneva, Switzerland) Child Growth Standards and Growth reference data using the WHO anthropometric calculator AnthroPlus v.1.0.4.

#### *2.2. Statistical Analysis*

Data distribution was evaluated with the Kolmogorov–Smirnov test before elaboration. Qualitative variables were reported as absolute and relative (percentage) frequencies. Quantitative variables were described as medians (interquartile ranges, IQRs), according to their non-parametric distribution. To compare continuous variables between more than two groups, repeated measures analysis of variance (ANOVA) testing was performed. A twosided *p*-value of <0.05 was considered to indicate significance. All statistical analyses were performed using MedCalc Statistical Software version 20.009 (MedCalc, Ostend, Belgium).

#### *2.3. Ethical Statement*

The local ethics committee of the Medical University of Warsaw, Poland, approved this study (Number of approval: KB/87/2019; date of approval: 13 May 2019). Written informed consent was collected from all the patients and/or their parents/guardians before their inclusion in the study. The investigation was performed in accordance with the ethical standards in the 1964 Declaration of Helsinki and its later amendments.
