Efficacy and Safety of Treatment With Sofosbuvir/Velpatasvir in Patients Aged 6–18 Years With Chronic Hepatitis C

Results of the PANDAA-PED Study

Maria Pokorska-Śpiewak; Ewa Talarek; Małgorzata Aniszewska; Magdalena Pluta; Anna Dobrzeniecka; Magdalena Marczyńska; Giuseppe Indolfi

Disclosures

Liver International. 2023;43(9):1871-1878.

Abstract and Introduction

Abstract

Background and Aims: The aim of this non-commercial, open-label, real-life, non-randomized clinical trial was to analyse the efficacy and safety of a pangenotypic regimen sofosbuvir/velpatasvir (SOF/VEL) in patients aged 6–18 years with chronic hepatitis C virus (HCV) infection.

Methods: Fifty patients qualified for the 12-week treatment were divided into two weight groups: 15 children weighting between 17 and <30 kg received a fixed dose of 200/50 mg of SOF/VEL (tablet) once daily, and 35 patients weighting ≥30 kg were treated with 400/100 mg SOF/VEL. The primary endpoint of the study was efficacy defined as sustained viral response (undetectable HCV RNA using an real-time polymerase chain reaction method) at 12 weeks posttreatment (SVR12).

Results: Median age of the participants was 10 (IQR 8–12) years, 47 were infected vertically, and 3 patients were previously ineffectively treated with pegylated interferon and ribavirin. Thirty-seven participants were infected with HCV genotype 1, 10 with HCV genotype 3 and the remaining 3 with genotype 4. There was no case of cirrhosis. SVR12 was 100%. Thirty-three reported adverse events (AEs) were considered related to the administration of SOF/VEL, all of them were mild or moderate. Children presenting with AEs were older compared to these without AEs: 12 (9.5–13) versus 9 (IQR 8–11) years (p = 0.008).

Conclusions: Results of the PANDAA-PED study indicated a 100% effectiveness of a 12-week therapy with SOF/VEL in children aged 6–18 years with chronic HCV infection and its good safety profile, in particular in younger patients.

Introduction

Hepatitis C has been recognized by the World Health Organization (WHO) as one of the major public health problems worldwide. In 2016, the WHO initiated an ambitious plan to eliminate viral hepatitis as a public health threat by 2030. However, the global WHO strategy updated in 2022 stated that although significant progress had been made, most global health targets for 2020 had been missed.^[1] Nearly 80% of people with hepatitis C virus remain undiagnosed, and affordable treatments are not being implemented.^[1] The latest WHO global strategy established following coverage targets by 2030: diagnosis of 90% of people living with HCV, and treatment of 80% of patients eligible for therapy.^[1] In addition, according to recent WHO guidelines, anti-HCV treatment is recommended for all adults, adolescents and children down to 3 years with chronic hepatitis C.^[2]

It has been estimated that there are over 3.2 million children living with HCV worldwide, most of them remaining undiagnosed.^[3] However, most national hepatitis C policies lack specific recommendations for HCV testing in children and adolescents.^[4] Chronic HCV infection in children is usually considered a mild disease with only slow progression of liver disease.^[5] However, to prevent the consequences of chronic HCV infection,^[6] early anti-HCV treatment should be implemented irrespective of the HCV genotype, previous ineffective antiviral treatment or the extent of liver fibrosis. New, highly effective and safe interferon-free therapies based on direct-acting antivirals (DAAs) have significantly changed the natural history of the disease, providing a chance for HCV eradication. However, due to the high prices of DAAs, only a few countries have included recommendations for the treatment of paediatric patients infected with HCV in their national policies and strategies.^[7,8] Thus, only a small proportion of children and adolescents have been treated, mainly during clinical trials.

Sofosbuvir/velpatasvir (SOF/VEL) is a fixed-dose combination of DAAs. SOF is a pangenotypic inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, which is essential for viral replication. VEL is an HCV inhibitor directed against the HCV NS5A protein, which is essential for both RNA replication and HCV virion formation. The efficacy and safety of SOF/VEL has been documented in studies conducted in adults. For this purpose, five phase III studies (ASTRAL 1–5) were conducted, confirming its high efficacy and a good safety profile in patients infected with HCV genotypes 1–6, with or without cirrhosis.^[9–12] Thus, in 2017 SOF/VEL has been approved by European Medicines Agency (EMA) for use in adult patients with chronic hepatitis C. Since 2022 basing on the preliminary results of a small industry-driven registration study, SOF/VEL has been approved for children as young as 3 years of age.^[13] However, the evidence on the outcomes of treatment with SOF/VEL in children and adolescents is limited and no real-life data are available.^[14] Thus, the aim of this study was to analyse the efficacy and safety of SOF/VEL in children and adolescents aged 6 to 18 years in the real-life setting.

1 2 3 4

Next Section

Table 1. Baseline characteristics of the study group (overall and according to the weight group).
Characteristics	Whole group (n = 50)	Weight group 17 to <30 kg (n = 15)	Weight group ≥30 kg (n = 35)	p
Sex (Male/Female)	23 (46)/27 (54)	7 (47)/8 (53)	16 (46)/19 (54)	1.0
Age (years)	10 (8–12)	7 (6–8)	11 (10–12.5)	<0.001
HCV genotype^a
1a	3 (6)	0	3 (9)	0.68
1b	34 (68)	12 (80)	22 (63)
3	10 (20)	2 (13)	8 (23)
4	3 (6)	1 (7)	2 (5)
Mode of infection
Mother-to-child transmission	47 (94)	14 (93)	33 (94)	1.0
Unknown	3 (6)	1 (7)	2 (6)
Duration of infection (years)	9 (8–12)	7 (6–8)	11 (9–12.5)	<0.001
Treatment experienced^b	3 (6)	0	3 (9)	0.54
Weight (kg)	37 (27–49)	25 (22–27)	46 (37–52)	<0.001
Height (cm)	142 (132–158)	127 (124–133)	152 (142–158)	<0.001
BMI (kg/m²)	18.4 (15.8–20.5)	14.8 (14.1–15.8)	19.1 (18.2–21.9)	<0.001
BMI z-score	0.5 (−0.5–1.2)	−0.5 (−1.2–0.0)	0.9 (0.4–1.5)	<0.001
ALT (IU/mL)	48 (34–65)	47 (38–64)	49 (35–66)	1.0
AST (IU/mL)	48 (39–57)	49 (41–65)	48 (37–53)	0.22
Haemoglobin (g/dL)	13.5 (12.9–14.0)	13.4 (12.7–13.6)	13.6 (13.1–14.1)	0.09
Platelets (G/L)	332 (283–363)	354 (312–385)	325 (274–354)	0.07
Total bilirubin (μmol/L)	9.6 (7.2–13.1)	11.6 (7.9–13.5)	9.5 (7.4–11.1)	0.26
Albumin (G/L)	47.5 (45.8–49.2)	48.6 (46.8–49.6)	47.4 (45.6–48.7)	0.18
Creatinine (μmol/L)	45 (39–50)	38 (37–42)	47 (43–52)	<0.001
Prothrombine index (%)	93 (90–97)	93 (92–97)	93 (89–97)	0.73
HCV viral load (log₁₀ IU/mL)	5.8 (5.4–6.2)	5.6 (5.4–5.9)	5.9 (5.5–6.3)	0.19
Positive HBsAg	0	0	0	–
Positive anti-HBc total	0	0	0	–
Positive anti-HIV	0	0	0	–
Liver fibrosis^c
F0/F1	49 (98)	15 (100)	34 (97)	1.0
F2	0	0	0
F3	1 (2)	0	1 (3)
F4 (cirrhosis)	0	0	0
Liver steatosis^d
S0	48 (96)	15 (100)	33 (94)	1.0
S1	1 (2)	0	1 (3)
S2	1 (2)	0	1 (3)
S3	0	0

Note: Data are presented as numbers (%) or Median (IQR), as appropriate.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index.
^aChildren infected with all HCV genotypes were eligible per protocol.
^bPrevious ineffective treatment with pegylated interferon plus ribavirin.
^cLiver stiffness measurement performed by the transient elastography, corresponded to METAVIR scale.
^dControlled attenuation parameter (CAP; dB/m) was obtained simultaneously with LSM during TE; interpretation: S0—no fibrosis (CAP 0–238 dB/m), S1—mild steatosis (CAP 239–260 dB/m), S2—moderate steatosis (CAP 261–290 dB/m), S3—severe steatosis (CAP >290 dB/m).

Table 2. Growth parameters in children treated with SOF/VEL.
Parameter	Start of treatment (1)	End of treatment (2)	12 weeks posttreatment (3)	p value
Parameter	Start of treatment (1)	End of treatment (2)	12 weeks posttreatment (3)	(1) versus (2)	(1) versus (3)	(2) versus (3)
Height z-score	0.52 (0.11)	0.57 (0.11)	0.51 (0.11)	0.04	1.0	0.003
BMI (kg/m²)	18.69 (0.55)	18.56 (0.53)	18.58 (0.54)	0.29	0.11	0.07
BMI z-score	0.44 (0.16)	0.34 (0.16)	0.27 (0.17)	0.01	0.001	0.05

Note: Data are presented as means (standard deviations).
Abbreviation: BMI, body mass index.

Table 3. Adverse events related to the use of SOF/VEL in the study group.
Symptom	Prevalence among study group, n (%)
Headache	9 (18)
Abdominal pain	8 (16)
Asthenia	6 (12)
Fatigue	4 (8)
Dizziness	3 (6)
Diarrhoea	2 (4)
Nausea	2 (4)
Somnolence	2 (4)
Rash	1 (2)
Calf cramps	1 (2)
Acceleration of period for 11 days earlier	1 (2)