HCV treatment experience in children over 12 years old with a combined direct acting antiviral containing glecaprevir and pibrentasvir

Abstract

Hepatitis C virus (HCV) is one of the main causes of cirrhosis. In childhood, the disease is usually lowsymptomatic and progresses slowly, however, in some cases, a severe fibrosis, cirrhosis, and hepatocellular carcinoma might occur. Direct antiviral drugs (DAAs) have radically changed pediatric practice and the tactics of HCV treatment among kids.

The aim of the study was to analyze safety and efficacy of a combined DAA (glecaprevir/pibrentasvir) in HCV treatment in children 12 y.o. and above.

Material and methods. The drug (glecaprevir/pibrentasvir) was prescribed to 47 patients aged 12–17 with a confirmed HCV for either 8 or 12 weeks, depending on the genotype of the virus and the experience of previous therapy.

Results. 8 (17%) patients were previously cured by interferon-containing regimens, but a sustained virological response was not achieved. 44.7% of children had comorbidities. For most children biochemical activity of HCV was low and did not correlate with the level of viral load, in most cases the level of transaminases (alanine aminotransferase) was within the reference values, in 34.7% cases there was a minimal increase (up to 2 norms), 1 (2.17%) patient had low biochemical activity (2–5 norms), 1 (2.17%) patient had moderate activity (5–10 norms). The majority of children in the study group had the initial stages of fibrosis. 1 child also had stage II steatosis, 2 children had stage III steatosis.

For all patients, the level of transaminases normalized 2 weeks after the start of treatment, viremia persisted in 2 cases only. 4 weeks after the start of therapy 100% of patients showed early virological response. There were no registered serious adverse events during the treatment with glecaprevir/pibrentasvir. The most common adverse event was hyperbilirubinemia, 2 children noted severe pruritus.

Conclusion. The results of the study confirmed the validity of early start of HCV treatment in adolescents, as well as the safety and high efficacy of combination glecaprevir/pibrentasvir in children 12–17 y.o. The availability of DAAs for children in regional programs helps us to achieve the goals of chronic hepatitis C elimination in Russia.

Keywords:chronic hepatitis C, HCV, fibrosis, cirrhosis, antiviral therapy, direct acting antiviral, DAA, HCV treatment in children

Funding. Authors declare no funding.

Conflict of interest. The authors declare that they have no conflicts of interest.

For citation: Ventslovayte N.D., Goriacheva L.G., Goriacheva V.A., Efremova N.A., Shilova I.V. HCV treatment experience in children over 12 years old with a combined direct acting antiviral containing glecaprevir and pibrentasvir. Infektsionnye bolezni: novosti, mneniya, obuchenie [Infectious Diseases: News, Opinions, Training]. 2021; 10 (3): 57–66. DOI: https://doi.org/10.33029/2305-3496-2021-10-3-57-66 (in Russian)

1. Indolfi G., Easterbrook P., Dusheiko G., El-Sayed M.H., Jonas M.M., Thorne C., et al. Hepatitis C virus infection in children and adolescents. Lancet Gastroenterol Hepatol. 2019; 4 (6): 477–87. DOI: https://doi. org/10.1016/S2468-1253(19)30046-9

2. WHO. Global hepatitis report, 2017. Geneva: World Health Organization, 2017.

3. Pawlowska M., Sobolewska-Pilarczyk M., Domagalski K. Hepatitis C virus infection in children in the era of direct-acting antiviral. World J Gastroenterol. 2018; 24 (24): 2555–66. DOI: https://doi.org/10.3748/wjg.v24.i24.2555

4. Dhiman R.K., Grover G.S., Premkumar M., Taneja S., Duseja A., Rathi S., Satsangi S. Direct-acting antiviral therapy is safe and effective in pediatric chronic hepatitis C: the public health Perspective. J Pediatr Gastroenterol Nutr. 2019; 68 (1): 74–80. DOI: https://doi.org/10.1097/ MPG.0000000000002139

5. El-Shabrawi M., Hassanin F. Paediatric hepatitis C virus infection and its treatment: Present, past, and future. Arab J Gastroenterol. 2019; 20 (3): 163–74. DOI: https://doi.org/10.1016/j.ajg.2019.09.003

6. Razavi H., El-Sayed M. Updated global estimate of HCV infection in the pediatric population. 2016. http://cdafound.org/content/ Downloads/ Pediatric%20Prevalence%20161201.pdf (date of access: July 18, 2021)

7. Mizuochi T., Takano T., Yanagi T., Ushijima K., Suzuki M., Miyoshi Y., et al. Epidemiologic features of 348 children with hepatitis C virus infection over a 30-year period: a nationwide survey in Japan. J Gastroenterol. 2018; 53 (3): 419–26.

8. Bortolotti F., Muratori L., Jara P., et al. Hepatitis C virus infection associated with liver-kidney microsomal antibody type 1 (LKM1) autoantibodies in children. J Pediatr. 2003; 142 (2): 185–90.

9. Modin L., Arshad A., Wilkes B., et al. Epidemiology and natural history of hepatitis C virus infection among children and young people. J Hepatol. 2019; 70 (3): 371–8.

10. Guido M., Bortolotti F., Leandro G., Jara P., Hierro L., Larrauri J., et al. Fibrosis in chronic hepatitis C acquired in infancy: is it only a matter of time? Am J Gastroenterol. 2003; 98 (3): 660–3. DOI: https://doi. org/10.1111/j.1572-0241.2003.07293.x

11. Indolfi G., Guido M., Azzari C., Resti M. Histopathology of hepatitis C in children, a systematic review: implications for treatment. Expert Rev Anti Infect Ther. 2015; 13 (10): 1225–35. DOI: https://doi.org/10.1586/14787210.2015.1070668

12 Goodman Z.D., Makhlouf H.R., Liu L., et al. Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial. Hepatology. 2008; 47 (3): 836–43. DOI: https://doi.org/10.1002/hep.22094

13. Cesaro S., Petris M.G., Rossetti F., et al. Chronic hepatitis C virus infection after treatment for pediatric malignancy. Blood. 1997; 90 (3): 1315–20. DOI: https://doi.org/10.1182/blood.V90.3.1315

14. Turkova A. The European Paediatric HIV/ HCV Co-infection Study Group in European Pregnancy and Paediatric HIV Cohort Collaboration. Uptake and outcomes of HCV treatment in children and young adults with HIV/ HCV co-infection in Europe. 20th International AIDS Conference; 20–25 July 2014, Melbourne, Australia.

15. Malik S., Dekio F., Wen J.W. Liver transplantation in a child with multifocal hepatocellular carcinoma hepatitis C and management of posttransplant viral recurrence using boceprevir. Pediatr Transplant. 2014; 18 (2): E64–8. DOI: https://doi.org/10.1111/petr.122232

16. González-Peralta R.P., Langham M.R.Jr., Andres J.M., Mohan P., Colombani P.M., Alford M.K., Schwarz K.B. Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr. 2009; 48 (5): 630–5. DOI: https://doi.org/10.1097/MPG.0b013e318170af04

17. Rodrigue J.R., Balistreri W., Haber B., Jonas M.M., Mohan P., Molleston J.P., et al. Impact of hepatitis C virus infection on children and their caregivers: quality of life, cognitive, and emotional outcomes. J Pediatr Gastroenterol Nutr. 2009; 48 (3): 341–7. DOI: https://doi.org/10.1097/ MPG.0b013e318185998f

18. Nydegger A., Srivastava A., Wake M., Smith A.L., Hardikar W. Health-related quality of life in children with hepatitis C acquired in the first year of life. J Gastroenterol Hepatol. 2008; 23 (2): 226–30. DOI: https:// doi.org/10.1111/j.1440-1746.2007.04859.x

19. Morales A., Vallejo-Medina P., Abello-Luque D., et al. Sexual risk among Colombian adolescents: knowledge, attitudes, normative beliefs, perceived control, intention, and sexual behavior. BMC Public Health. 2018; 18 (1): 1377. DOI: https://doi.org/10.1186/s12889-018-6311-y

20. Forsyth S., Rogstad K. Sexual health issues in adolescents and young adults [published correction appears in Clin Med (Lond). 2015. Vol. 15, N 6. P. 565]. Clin Med (Lond). 2015; 15 (5): 447–51. DOI: https://doi.org/10.7861/clinmedicine.15-5-447

21. Goryacheva L.G., Rogozina N.V., Shilova I.V., Karev V.E., Greshnyakova V.A .Diagnostics and treatment of chronic hepatitis in children. Medical benefit. St. Petersburg, 2016. (in Russian)

22. González-Peralta R.P., Kelly D.A., Haber B., et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology. 2005; 42 (5): 1010–8. DOI: https://doi.org/10.1002/hep.20884

23. Goriacheva L.G., Greshniakova V.A. Cascade plazmofiltration in complex therapy of chronic hepatitides at children. In the collection: Current issues of hepatology: experimental hepatology, therapeutic hepatology, surgical hepatology: Materials of the XI International Symposium of Belarusian Hepatologists, Grodno, October 2, 2015, Grodno: Grodno State Medical University, 2015: 33–6. (in Russian)

24. Balistreri W.F., Murray K.F., Rosenthal P., et al. The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12–17 years old with hepatitis C virus genotype 1 infection. Hepatology. 2017; 66 (2): 371–8. DOI: https://doi.org/10.1002/hep.28995

25. Wirth S., Rosenthal P., Gonzalez-Peralta R.P., et al. Sofosbuvir and ribavirin in adolescents 12–17 years old with hepatitis C virus genotype 2 or 3 infection. Hepatology. 2017; 66 (4): 1102–10. DOI: https://doi. org/10.1002/hep.29278

26. Murray K.F., Balistreri W.F., Bansal S., Whitworth S., Evans H.M., Gonzalez-Peralta R.P., et al. Safety and efficacy of ledipasvir-sofosbuvir with or without ribavirin for chronic hepatitis C in children ages 6–11. Hepatology. 2018; 68 (6): 2158–66. DOI: https://doi.org/10.1002/hep.30123

27. Jonas M.M., Squires R.H., Rhee S.M., Lin C.W., Bessho K., FeiternaSperling C., et al. Pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir in pediatric patients with genotypes 1–6 chronic HCV infection: Part 1 of the Dora Study. Hepatology. 2018; 68 (suppl): 1347A–8A.

28. Volynets G.V. A modern view on the treatment of chronic hepatitis C in children and adolescents. Rossiyskiy Vestnik Perinatologii i Pediatrii [Russian Bulletin of Perinatology and Pediatrics]. 2019; 64 (6): 11–9. DOI: https://doi.org/10.21508/1027-4065-2019-64-6-11-19 (in Russian)

29. Harris H.E., Mieli-Vergani G., Kelly D., Davison S., Gibb D.M., Ramsay M.E.; HCV National Register Steering Group. A national sample of individuals who acquired hepatitis C virus infections in childhood or adolescence: risk factors for advanced disease. J Pediatr Gastroenterol Nutr. 2007; 45 (3): 335–41. DOI: https://doi.org/10.1097/MPG.0b013e3180dc9337 3

30. Iorio R., Giannattasio A., Sepe A., Terracciano L.M., Vecchione R., Vegnente A. Chronic hepatitis C in childhood: an 18-year experience. Clin Infect Dis. 2005; 41 (10): 1431–7. DOI: https://doi.org/10.1086/497141

31. Mohan P., Barton B.A., Narkewicz M.R., Molleston J.P., GonzalezPeralta R.P., Rosenthal P., et al. Evaluating progression of liver disease from repeat liver biopsies in children with chronic hepatitis C – a retrospective study. Hepatology. 2013; 58 (5): 1580–6. DOI: https://doi.org/10.1002/hep.26519

32. Camma C., Di Bonna D., Schepis F., Heathcote E.J., Zeuzem S., Pockros P.J., et al. Effect of peginterferon alfa-2a on liver histology in peginterferon alfa-2a on liver histology in chronic hepatitis C: a meta-analysis of individual patient data. Hepatology. 2004; 39 (2): 333–42. DOI: https:// doi.org/10.1002/hep.20073

33. Rodríguez-Torres M., Rodríguez-Orengo J.F., Ríos-Bedoya C.F., Fernández-Carbia A., Marxuach-Cuétara A.M., López-Torres A., JiménezRivera J. Effect of hepatitis C virus treatment in fibrosis progression rate (FPR) and time to cirrhosis (TTC) in patients co-infected with human immunodeficiency virus: A paired liver biopsy study. J Hepatol. 2007; 46 (4): 613–9. DOI: https://doi.org/10.1016/j.jhep.2006.12.011

34. Chan J., Gogela N., Zheng H., Lammert S., Ajayi T., Fricker Z., et al. Direct-acting antiviral therapy for chronic HCV infection results in liver stiffness regression over 12 months post-treatment. Dig Dis Sci. 2018; 63 (2): 486-92. DOI: https://doi.org/10.1007/s10620-017-4749-x

35. Bachofner J.A., Valli P.V., Kröger A., Bergamin I., Künzler P., Baserga A., et al. Direct antiviral agent treatment of chronic hepatitis C results in rapid regression of transient elastography and fibrosis markers Fibrosis-4 score and aspartate aminotransferase-platelet ratio index. Liver Int. 2017; 37 (3): 369–76.

36. Tada T., Kumada T., Toyoda H., Mizuno K., Sone Y., Kataoka S., et al. Improvement of liver stiffness in patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response. J Gastroenterol Hepatol. 2017; 32 (12): 1982–8. DOI: https://doi.org/10.1111/jgh.13788

37. Fahmy D.M., Shokeir M., El Zeiny S.M., Jonas M.M., Abdallah A. Changes in liver stiffness and noninvasive fibrosis scores in Egyptian adolescents successfully treated with ledipasvir-sofosbuvir for chronic hepatitis C virus infection. J Pediatr. 2021; 231: 110–6. DOI: https://doi. org/10.1016/j.jpeds.2020.12.031

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CHIEF EDITOR
Aleksandr V. Gorelov
Academician of the Russian Academy of Sciences, MD, Head of Infection Diseases and Epidemiology Department of the Scientific and Educational Institute of Clinical Medicine named after N.A. Semashko ofRussian University of Medicine, Ministry of Health of the Russian Federation, Professor of the Department of Childhood Diseases, Clinical Institute of Children's Health named after N.F. Filatov, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Deputy Director for Research, Central Research Institute of Epidemiology, Rospotrebnadzor (Moscow, Russian Federation)

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