Natural history of HCV infection in children

Post by Master, Doctor Mai Vien Phuong - Department of Examination & Internal Medicine - Vinmec Central Park International General Hospital

HCV infection differs in children and adults in terms of mode of transmission, rate of clearance, progression of fibrosis, and duration of chronic infection at birth. Longitudinal mother-to-child transmission of HCV is reported to be the leading cause of infection in children worldwide.

A recent review found that the longitudinal risk of HCV infection to the offspring of HCV antibody-positive and HCV-RNA-positive women was 5.8% [95% confidence interval (CI), 4, 2-7.8] for children of HIV-negative women and 10.8% (95% CI, 7.6-15.2) for children of HIV-positive women with symptomatic acute HCV Rare in childhood, but may present with coma, fever, and myalgia. About 20%-25% of acute HCV infections resolve on their own. About 20% of patients are infected, usually in children 4 years old. Children who fail to clear HCV spontaneously will develop chronic infections, often asymptomatic infections in pediatric patients. During the chronic process, transaminase levels may be normal or intermittently elevated. Serum HCVRNA levels can also fluctuate significantly, but are not associated with immediate prognosis. Histological findings are usually insignificant, but the presence of cirrhosis has been reported in 1%-4% of patients. Overall, the risk of severe liver complications in pediatric patients is low Information on liver progression from childhood to adulthood is lacking and the proportion of HCV-infected children who develop serious long-term liver disease is unclear
Liver fibrosis is reported in less than 2% of pediatric cases, but the incidence is much higher in patients with long-term follow-up, suggesting that the development of fibrosis correlates with age and duration of infection. coincide. In a recent study from the United Kingdom that included 1049 patients with chronic hepatitis C acquired in childhood, one-third developed liver disease, with a median duration of 33 years after infection. Patients with longitudinal infection developed cirrhosis at an earlier age (36 years) than patients with childhood HCV due to drug abuse (48 years), blood transfusion (46 years), or with a Unknown route of infection (52 years, P < 0.0001). In that cohort, the incidence of hepatocellular carcinoma (HCC) was 5%; 4% needed a liver transplant and 3% died.

Long-term liver complications include cirrhosis, hepatocellular carcinoma or the requirement for a transplant. In adults, the natural history of chronic HCV infection is influenced by associated medical and social factors including hepatic steatosis, alcohol consumption, malignancy, and viral HIV and HBV co-infection. Extrahepatic manifestations of chronic HCV (eg, positive nonorgan-specific autoantibodies, autoimmune thyroiditis, glomerulonephritis) are rare in children. In conclusion, early acquired hepatitis C infection is a clinically and histologically silent condition. However, it can become insidious. Although the rate of children developing cirrhosis in adulthood is low, it is likely to progress after the second decade of life. Thus, the primary aim of therapeutic interventions in pediatric patients is not to treat ongoing liver disease, but to prevent progression by early eradication of the infection.

In 2011 boceprevir and telaprevir, two first-generation NS3/4A protease inhibitors, were approved for use in combination with pegylated interferon (peg-IFN) and ribavirin for the treatment of adults with chronic HCV infection. Response rates to triple therapy with boceprevir or telaprevir were improved when compared with dual therapy with peg-IFN and ribavirin, but were associated with significant adverse events. Since then, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have approved 13 different DAAs and six fixed-dose combinations for the treatment of adults with HIV infection. Chronic HCV (sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir). DAAs are classified into several categories according to their molecular targets. These agents are designed to inhibit specific viral proteins that are important in HCV replication. These include NS3/4A protease inhibitors (eg, simeprevir, paritaprevir, grazoprevir, voxilaprevir, and glecaprevir), nucleotide (eg, sofosbuvir) and non-nucleotide (eg, dasabuvir) NS5B polymerase inhibitors and inhibitors NS5A (eg, daclatasvir, ledipasvir, ombitasvir, velpatasvir, elbasvir, and pibrentasvir). The development of combinations of DAAs was based on the notion that at least two drugs are needed to achieve the therapeutic goal of virological response >95%) without selecting for resistance mutations. When the core of treatment is an NS5B nucleoside inhibitor such as sofosbuvir, usually only another drug, an NS3/4A protease inhibitor or an NS5A inhibitor, is usually required. In contrast, a non-nucleoside NS5B inhibitor such as dasabuvir should be used in conjunction with both the NS3/4A protease and the NS5A inhibitor.

These regimens are oral, patient-friendly, have a shortest course of 8 weeks, are highly effective, and have few side effects. Given these clear advantages over IFN-based therapies, DAAs have become the preferred treatment for adults with HCV. Notably, the latest generation of DAAs (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir) have total genotypic activity, thus simplifying treatment decisions.
Purpose of HCV treatment with DAAs The goals of HCV treatment with DAAs are many. The first is to prevent complications of HCV-related liver disease, namely cirrhosis, liver failure, and HCC. Second, treatment can improve the quality of life of patients with chronic infections and remove the social stigma of being HCV positive. Finally, effective treatment for HCV eradication also prevents further transmission of the infection, which is aimed at global HCV eradication. The excellent efficacy and safety profile of DAAs, have also made antiretroviral therapy possible for patients with advanced liver disease and those on the liver transplant (LT) waiting list. leads to significant clinical improvement, avoids graft infection, and allows for unlisting up to one-third of patients. Unfortunately, the lack of specific initial clinical data on the treatment of DAA in adolescents and children with chronic HCV infection has delayed the introduction of these agents into pediatric use. Several recent studies have demonstrated the safety and efficacy of various DAA-based regimens in pediatric patients, supporting their use in that setting.