Effects of Sofosbuvir/Ledipasvir Therapy on Chronic Hepatitis C Virus Genotype 4, Infected Children of 3–6 Years of Age

Enas M. Kamal; Mortada El-Shabrawi; Hisham El-Khayat; Mostafa Yakoot; Yehia Sameh; Yasser Fouad; Dina Attia


Liver International. 2020;40(2):319-323. 

In This Article


To our knowledge, this is the first prospective study that included a considerable number of children in the age group of 3–6 years infected with chronic HCV genotype 4. Recently, the FDA approved the sofosbuvir/ledipasvir combination for the 3-year-old children genotypes 1 and 4. This combination in this age group genotype 4 was studied by Schwarz and colleagues[20] in only one patient, which is considered a limited number. In our study, children (n = 22), aged 3–6 years, received a single daily dose of the sofosbuvir/ledipasvir combination regimen. Patients were classified into two groups according to their duration of treatment, as follows: 8 weeks and 12 weeks. The overall response was 100% in all patients and both groups showed no serious adverse effects. The treatment in this age group with the approved interferon/ribavirin based therapy is controversial because, on the one hand, the incidence of progression to chronic liver disease is minimal yet still exists, especially when associated with a comorbidity as obesity, the lifelong expectancy of children, and the children being a reservoir of infection, which is in favour of treatment.[21] On the other hand, the serious side effects associated with the availability of a pegylated interferon/ribavirin regimen and the non-favourable response to the treatment in genotypes 1 and 4 as well as the associated side effects and this limits the treatment indication.[15] The approval of the sofosbuvir/ledipasvir combination in children aged 12–18 years with HCV genotype 4 with no significant side effects has prompted our group to consider examining younger age groups. With the goal of HCV eradication launched by the World Health Organization and the push for screening for HCV in every house in Egypt as part of several campaigns, the identification of the infection in young children whose parents requested treatment could help to avoid any risk of progression to chronic liver disease, as well as limits disease transmission.

We initiated the treatment combination in children in this study very cautiously, with the children having ready access to a doctor during the treatment period. Parents were worried at the beginning of the treatment; however, a few days after the treatment start, their concern was reduced, and all side effects were taken care of. All children were compliant to the treatment as advised by their doctors. At baseline, 13 patients had RNA levels of more than 600,000 IU/L, while, at Week 4, both groups showed HCV RNA loss in 81.8% of the 8-week group vs 90.9% of the 12-week group. At Week 8, the 8-week group showed a complete loss of HCV RNA (EOT), while the 12-week group showed a 90.9% response. At Week 12, the 12-week group showed a loss of HCV RNA (EOT) and 8-week group showed no relapse. No real difference was observed between the 8-week and the 12-week groups until SVR12. No relapse was observed during the follow-up period. Prior to treatment, liver function tests showed around a twofold rise in ALT and AST, but, during the follow-up, levels normalized at Week 4 and remained so thereafter. All children with baseline anaemia prior to treatment received iron supplementation.

No laboratory worsening during treatment was observed. Genotype 4 accounts for more than 90% of Egyptian patients.[7] In this study and the previous performed studies, genotyping was 100% in all children.[11,22]

As described in adult patients,[23,24] adolescents in the age range of 12–18 years, and children in the age range of 6–12 years, no serious side effects were described.[11,22] All the nonspecific side effects that were described during the first few days after treatment were seen in only five children and resolved spontaneously with no specific additional treatment. The case of abdominal pain persisted longer than the other side effects; however, it was nonspecific and improved, similarly, with no specific management. One child aged 3-year old faced difficulty with swallowing the tablet and developed vomiting after the first dose, so the mother was advised to grind the tablet in juice to facilitate drug intake. Difficulty with swallowing the tablets was also mentioned by several other mothers, who similarly ground the tablet in juice. Similar side effects were also reported by Schwartz and colleagues with no serious side effects in treated patients.[20]

Finally, shortening the duration of treatment is not recommended; however, due to any circumstances, treatment discontinuation in this age group may occur, and our study revealed that, the 8-week treatment regimen can be as effective as the 12-week regimen.

This study has several limitations, as follows. First, no liver biopsy was performed prior to treatment; however, no indication for liver biopsy existed and advanced fibrosis and liver cirrhosis were excluded using the transient elastography, which is now the diagnostic tool replacing liver biopsy. Additionally, the number of patients was small; moreover, the true number of children infected in this age group is still unknown, as the screening programme is still running in Egypt and our study patients were collected from multiple large institutes in Egypt. Long-term follow-up of the treatment response is also required to a point that is years after treatment; however, this was only a pilot study to explore the primary effects of this regimen in this age group. Pharmacokinetic and pharmacodynamics analyses are recommended to evaluate further the drug action in this age group; however, this was performed by a recent clinical trial.[20] Finally, the tablet form may not be suitable for use in this age group: we overcame this problem by having mothers grind the tablet in juice, but a suspension form or syrup form could be easier to swallow.

To conclude, sofosbuvir/ledipasvir is safe and effective in children aged 3- to 6-year olds who are infected with chronic HCV genotype 4. Nonspecific early development of side effects may occur, but no serious side effects were observed. The preferred duration of treatment is 12 weeks; however, if treatment is discontinued at 8 weeks, an excellent response can still be expected. An easier form of the drug to promote swallowing is recommended for this age group. Treatment of this age group is recommended specially to avoid infection transmission, disease progression and development of HCC.