Hyalornic Acid Level in β-Thalassemic Children Treated for Hepatitis C Virus
Condition: Beta-Thalassemia; Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis; Thalassemia; beta-Thalassemia
Study type: Interventional
Phase: Phase 4

Summary: 
      Patients with transfusion dependent Beta Thalassemia suffer from a high incidence of
      Hepatitis C infection especially in developed countries as Egypt. In our patients we also
      found a high correlation between hepatitic C infection and Liver fibrosis. in this study we
      offer our patients treatment with Direct antiviral drugs and assessed the degree of fibrosis
      before and after treatment. We tested Hyalornic acid as a predictor of the degree of fibrosis
      before and after treatment.
    

Detailed description: 
      The thalassemias are a heterogeneous group of genetic heritable disorders of hemoglobin (Hb)
      synthesis, considered as the most common monogenic disorder in the world, affecting men and
      women equally and poses a severe health and economic burden to patients and families at risk
      (Mohammad and Al-Doski, 2012). Thalassemia is a major health problem in Egypt since it
      estimated out of 1.5 million live births, 1000 children with thalassemia are born annually
      (Youssef et al., 2012).

      Thalassemics can develop liver fibrosis because of iron liver overload and hepatitis virus C
      (HCV) infection. Multicenter cross-sectional studies have reported that the development and
      the severity of liver fibrosis are strongly related to the extent of liver iron overload and
      to the presence of chronic HCV infection (Di Marco et al., 2008). HCV infection is the main
      risk factor for liver fibrosis in transfusion-dependent thalassemics. Excess liver iron is
      now clearly recognized as a cofactor for the development of advanced fibrosis in patients
      with HCV infection (Elalfy et al., 2013). Although, hepatic fibrogenesis has long been
      thought to be an irreversible process, it is now evident that it is a dynamic process with
      significant potential for reversal; unlike cirrhosis, which is irreversible. Identification
      of liver fibrosis at an early stage would be of great significance (Manning DS and Afdhal NH,
      2008, Xu et al., 2003) Liver biopsy is an essential method for assessing fibrosis and it
      continues to have an important role in the diagnosis, prognosis, and management of patients
      with elevated results of iron studies and abnormal liver function test results. Therefore,
      liver biopsy is currently considered the gold standard for assessing hepatic fibrosis (Di
      Marco et al., 2008). However, it is an invasive and painful procedure, with rare but
      potential life threatening complications, limiting its acceptance and repetition in usually
      asymptomatic patients. In addition, the accuracy of liver biopsy in assessing fibrosis may be
      questioned because of sampling error and interobserver variability, which may lead to under
      or overstaging of fibrosis or cirrhosis (Foucher et al., 2006).

      Thus there is a need to develop and validate non-invasive tests that can accurately reflect
      the full spectrum of hepatic fibrosis, cirrhosis, and its severity in liver diseases (Foucher
      et al., 2006). Serum markers and imaging methods are increasingly in vogue non-invasive
      alternatives to liver biopsy and the development of safe, inexpensive, and reliable
      non-invasive fibrosis measurement tools remains a research priority in clinical hepatology
      (Rockey DC 2006).

      Hyaluronic acid (HA) is a high molecular weight glycosaminoglycan which is an essential
      component of extracellular matrix in almost every tissue in the body (Papastamataki, 2010).
      In the liver, HA is mostly synthesized by the hepatic stellate cells and removed via
      sinusoidal cell adhesion molecules (Halfon, 2005). This mechanism is impeded in fibrosis,
      leading to a rise in serum levels of HA. Therefore, serum HA is considered a marker that
      appears early before pathological changes occur (Zheng, 2003). Serum HA levels have been
      shown to correlate with histological stages of liver fibrosis in hepatitis C virus patients.
      Therefore, HA has a good diagnostic accuracy as a noninvasive assessment of fibrosis and
      cirrhosis (Parise et al, 2006).

      Children with chronic hepatitis C (CHC) in are at risk for major complications, including
      cirrhosis, hepatocellular carcinoma, and death. The combined pegylated interferon-α and
      ribavirin (PEG-IFN/ribavirin) remains the standard therapy for CHC in children until 2016
      (Aziz S, 2014, Suzuki et al. 2016, Yang et al 2017). The approved PEG-IFN/ribavirin therapy
      for children aged 3 and older is often held from use until adulthood because of its extensive
      list of potential side effects and high likelihood of causing adverse symptoms. In children
      and adolescents with HCV, treatment and reduction of the spread of HCV before adulthood is
      important, as there can be transmission to other individuals via sexual activity and infected
      females can later vertically transmit the infection during pregnancy, the latter representing
      a common source of transmission for children (Yang et al 2017).

      In recent years, a number of direct-acting antiviral agents (DAAs) are under development for
      treatment of CHC. DAAs reduce the amount of HCV in the body by blocking viral replication
      inhibiting directly one of the several steps of HCV lifecycle preventing the virus from
      multiplying, and in most cases, they cure HCV. DAAs are classified into several categories
      based on their molecular target (Perales et al., 2015, Manns et al., 2016). The recent
      development of DAAs has shown promising results in clinical trials for use in children and
      adults and has dramatically increased the rates of sustained virological response (SVR) while
      improving side effect profiles as compared to interferon based treatments (Yang et al 2017).
      New DAAs available for adults have still not been approved for treatment in children (Aziz S,
      2014, Serranti et al., 2014, Ohmer et al., 2016, Yang et al 2017). However, the approval of
      ledipasvir/sofosbuvir and sofosbuvir with ribavirin for adolescents is potentially
      anticipated as early as 2017 (Yang et al 2017).

      Recently (on April 7, 2017), the U.S. Food and Drug Administration (FDA) approved the first
      DAAs for children that included sofosbuvir (Sovaldi) and sofosbuvir/ledipasvir (Harvoni) to
      treat HCV in children and adolescents aged 12 years and older or weighing at least 35
      kilograms. These DAAs (Harvoni and Sovaldi) were previously approved to treat HCV in adults.
      These approvals will help change the landscape for HCV treatment by addressing an unmet need
      in children and adolescents (FDA News Release 2017, HCV Guidance 2017). The adult fixed-dose
      of ledipasvir/sofosbuvir resulted in similar plasma exposure of ledipasvir, sofosbuvir, and
      GS-331007 (the inactive metabolite of sofosbuvir) in adolescents as in adults, thus the adult
      dose was used for this age group (Schwarz et al. 2016). Similarly, giving half the adult
      fixed-dose of ledipasvir/ sofosbuvir, 45 mg/200 mg, to children ages 6-11 resulted in
      comparable plasma exposure of ledipasvir, sofobuvir, and GS-331007 as in adults, without any
      severe adverse events or laboratory abnormalities (Garrison et al 2016).
    

Intervention name(s): Ledipasvir 90 MG / Sofosbuvir 400 MG [Harvoni]
Intervention type(s): Drug
Intervention description(s): The fifty (50) thalassemic children infected with HCV received the new direct-acting antiviral therapy in the form of Ledipasvir (90 mg)/Sofosbuvir (400 mg); (Harvoni) as a single oral tablet /day for 12 weeks Follow up of these patients was performed for 24 weeks. Re-evaluation of these children after 24 weeks from initiation of Ledipasvir/Sofosbuvir treatment was performed by repeating clinical assessment, Fibroscan of liver , laboratory investigations including quantitative HCV RNA by PCR and serum hyaluronic acid measurement.
Other intervention name(s): Measuring level of Hyalornic Acid; Fibroscan of liver
Intervention MeSH terms: Sofosbuvir; Ledipasvir, sofosbuvir drug combination; Ledipasvir
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment