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Hepatitis C: An Update <p style='font-size:16px;line-height:26px;'>A Recent paper has recommended that swallowability assessment should be done before starting the direct acting antivirals.</p>
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12 Jun, 2024
Hepatitis C: An Update

A Recent paper has recommended that swallowability assessment should be done before starting the direct acting antivirals.

About 3.2 million children and adolescents live with hepatitis C virus (HCV) (1). There is not much data available regarding the prevalence of HCV in children in India. However, Chowdhury, et al. did a community-based study and has shown prevalence of HCV 0.31% in children less than 10 years of age and 0.83% in adolescents (10-19 years) (2). Mother to child transmission is the primary route of transmission in young children with transmission rate of 5%. Other route of transmission include parenteral route, sexual contact, tattooing reuse or unsterilized medical instruments and blood not screened before transfusion. Children with history of multiple transfusion are at higher risk of contracting HCV infection (13-65%) (3).

HCV is hepatotropic RNA virus single stranded and belongs to Flaviviridae family. It is classified into 7 genotypes based on sequence variations. In India genotype 3 is predominant comprising of 80% cases (1). Genotype 1 is prevalent in Europe, American and Australia and genotype 4 is seen in middle east and Africa. HCV such genetic diversity and ability to mutate rapidly has hindered the development of pan genotype HCV vaccines.

Screening of HCV is done by antibody testing, and a positive HCV antibody test will not differentiate between remote or recent infection. Hence quantitative or qualitative nucleic acid amplification test (NAAT) for detection of HCV RNA should be done after all positive HCV antibody test (4). Post exposure if the HCV antibody test is negative a repeat antibody testing or NAAT should be done within 6 months of the exposure (5). Recommendation for perinatally exposed young infants is that only NAAT should be done till 18 months age, with serological testing after 18 months of age as maternal antibodies persist till 18 months of life (6). There has been latest WHO recommendations for HCV screening to improve diagnosis which includes viral load NAAT assays, HCV core antigen detection where NAAT is not easily available, mandatory RNA HCV testing in all HCV antibody positive patients, use of dried blood spot specimens for testing and HCV self-testing kits(7).

Treatment

The natural progression of HCV in children is usually benign but it can progress in 10 years to chronic hepatitis and eventually can lead to cirrhosis or hepatocellular carcinoma (8). The objective of anti-HCV treatment is to eliminate the infection and avoid progression of the liver disease. Oral direct acting antivirals (DAAs) are highly effective and their evolution has changed the game in management and outcome of HCV infection. Sustained virological response (SVR12) is defined as non-appearance of HCV RNA 12 weeks after the end of treatment, and this the endpoint of therapy with DAA.

In consensus WHO, IDSA, ESPGHAN and EASL have recently recommended antiviral treatment for children and adolescents above 3 years of age irrespective of the disease severity. Both pangenotypic and genotype specific DAA regimen are recommended. The accessibility of pangenotypic regimens is easy and does not require assessment of genotype hence are preferred. Regimens with shorter duration are preferred to increase compliance. Patients who have failed the regimen they were started on are then shifted to second line treatment which consists of Sofosbuvir/ Velpatasvir / Voxilaprevir. The combination of sofosbuvir plus daclatasvir is recommended by WHO as pediatric pangenotypic DAA regimen and is less expensive and easily available increasing the accessibility to treatment in lower- and middle-income countries. However, it is not approved by the United States Food and Drug Administration and the European Medicines Agency (7).

Although the efficacy and tolerability of oral DAA is good there is difficulty in taking oral medication leading to poor compliance and treatment failure. ESPGHAN has recently recommended in a paper that before starting the oral DAAs swallowability evaluation should be done and tailor the formulation and regimen in accordance to the result (9).

To conclude WHO is aiming for elimination of HCV through various initiatives like increasing diagnosis through screening and making shorter and more compliant regimen available. The recommendation of treating all children above 3 years of age and adolescents irrespective of the disease severity is playing pivotal role in HCV elimination.



Activity Product Approval Formulations Doses by Weight Age Treatment Duration
Genotype Cirrhosis Status Treatment Weeks
Pangenotypic Glecaprevir/pibrentasvir EMA and US FDA >3 Y Film-coated tablets (FDC) 100/40 mg

Coated granules in sachet 50/20 mg
≥45 kg or 12–17 Y: 300/120 mg once a day

30–45 kg: 250/100 mg once a day

20–<30 kg: 200/80 mg once a day

12–< 20 kg: 150/60 mg once a day
All genotypes No cirrhosis and compensated cirrhosis Naïve 8
1, 2, 4–6 No cirrhosis Experienced 8
Compensated cirrhosis Experienced 12
3 No cirrhosis and compensated cirrhosis Experienced 16
Sofosbuvir/velpatasvir EMA and US FDA >3 Y Film-coated tablets (FDC) 400/100 mg and 200/50 mg

Coated granules in sachet 200/50 mg and 150/37.5 mg
≥ 30 kg: 400/100 mg once a day

17-<30 kg: 200/50 mg once a day

<17 kg: 150/37.5 mg once a day
All genotypes No cirrhosis and compensated cirrhosis Naïve and experienced 12
Sofosbuvir/velpatasvir/voxilaprevir EMA >12 Y Tablet (FDC) 400/100/100 mg ≥30 kg (12 Y): 400/100/100 mg once a day All genotypes No cirrhosis Naïve 8
Compensated cirrhosis Naïve and experienced 12
No cirrhosis and compensated cirrhosis Experienced 12
Sofosbuvir + daclatasvir Not approved for use in children by EMA and US FDA Daclatasvir: Film-coated tablets 60 mg >26 kg: 400/60 mg once a day 14–25 kg: 200/30 mg once a day All genotypes No cirrhosis and compensated cirrhosis Naïve and experienced 12
Genotype-specific Sofosbuvir/ledipasvir EMA and US FDA >3 Y Film-coated tablets (FDC) 400/90 mg and 200/45 mg
Coated granules in sachet 200/45 mg and 150/33.75 mg
≥35 kg: 400/90 mg once a day
17–35 kg: 200/45 mg once a day
<17 kg: 150/33.75 mg once a day
1, 4, 5, 6 No cirrhosis Naïve and experienced 12 or 8*
Compensated cirrhosis Experienced 24 or 12 with ribavirin
Elbasvir/grazoprevir EMA and US FDA> 12 Y Film-coated tablets (FDC) 50/100 mg ≥30 kg or 12–17 Y: 50/100 mg once a day 1,4 No cirrhosis and compensated cirrhosis Naïve and experienced 12 or 16
*Sofosbuvir/ledipasvir for 8 weeks may be considered in previously untreated genotype 1-infected patients with HCV viremia levels <6 million IU/mL.
Genotype 1a infection, treatment-naïve or experienced (interferon) with baseline NS5A polymorphisms and genotype 4 infection, treatment-experienced (interferon) should be treated with elbasvir/grazoprevir for 16 weeks with ribavirin.
EMA indicates European Medicines Agency; FDC, fixed-dose combination; US FDA, United States Food and Drug Administration; Y, years.

Figure1: Oral DAAs with formulations, dose and duration.( Table 1 - ESPID Reports and reviews – Management of Hepatitis C in Children and Adolescents :An Update)


References:

  1. Hepatitis C Key facts. WHO. 18 July 2023. Available at: https://www.who.int/news-room/fact-sheets/detail/hepatitis-c. Accessed October 24, 2023
  2. Chowdhury A, Santra A, Chaudhuri S, et al. Hepatitis C virus infection in general population: A community-based study in West Bengal, India. Hepatology. 2003;37:802-09.
  3. Shyamala V. Transfusion transmitted infections in thalaessemics: need for reappraisal of blood screening strategy in India. Transfusion Medicine. 2014;24:79-88.
  4. Hepatitis C. CDC Yellow Book. 2024. Available at: https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/hepatitis-c. Accessed October 24, 2023.
  5. HCV Testing and Linkage to Care. Available at: https://www.hcvguidelines.org/evaluate/testing-and-linkage. Accessed November 19, 2023.
  6. World Health Organization. WHO guidelines on hepatitis B and C testing. Geneva: World Health Organization. 2017.
  7. World Health Organization. Updated Recommendations on Treatment of Adolescents and Children with Chronic HCV Infection, and HCV Simplified Service Delivery and Diagnostics. Licence: CC BY-NC-SA 3.0 IGO. Geneva: World Health Organization, ed.; 2022.
  8. Kiyosawa K, Tanaka E, Sodeyama T, et al. Transition of antibody to hepatitis C virus from chronic hepatitis to hepatocellular carcinoma. Jpn J Cancer Res. 1990;81:1089-91.
  9. Indolfi G, Gonzalez-Peralta RP, Jonas MM, et al. ESPGHAN recommendations on treatment of chronic hepatitis C virus infection in adolescents and children including those living in resource-limited settings. J Pediatr Gastroenterol Nutr. 2024. In press.
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