Development of novel agents for the treatment of chronic hepatitis C infection: Summary of the FDA Antiviral Products Advisory Committee recommendations
Year: 2007
Type: article
Abstract: epatitis C virus (HCV) infection has emerged as a major contributor to morbidity and mortality in the United States and abroad.In the United States, liver disease is the 12th leading cause of death among all age groups, and increases to the fifth leading cause of mortality among those in the 35-to 54-year-old age group. 1 HCV alone or with alcohol abuse accounts for approximately two-thirds of identified liver disease in surveillance cohorts. 2 HCV is a small positive-strand RNA virus in the Flaviviridae family.Its RNA genome is nearly 10,000 nucleotides long and codes for capsid and envelope proteins, as well as functional nonstructural proteins involved with its replication strategy.Potential drug targets include the internal ribosomal entry site, the serine protease, a helicase, and an RNA-dependent RNA polymerase.Other targets include agents that might interfere with cellular binding, entry, uncoating, formation of replication complexes, assembly and maturation, or viral release.3 The HCV virus is thought to replicate primarily in hepatocytes within the liver, though up to 4% of replication may occur in extrahepatic sites including lympho-cytes.4 Extremely high levels of replication on the order of 10 10 -10 12 virions/day lead to frequent mutations and genomic drift.5,6 Codominant genomic forms within an individual patient are referred to as quasispecies.Genotypes represent significant shifts in the master sequence of the virus, which developed in unique geographic areas.Both forms of mutation are highly relevant to new drug development, because binding site targeting may be genotype specific and emergence of site polymorphisms may lead to viral escape.7 Chronic HCV infection leads to development of liver fibrosis in many but not all patients.Variable rates of fibrotic progression are described, and may be influenced by gender, age, and comorbidities including HIV coinfection, alcohol use, and presence of fatty liver (steatosis).8 Advanced fibrosis or cirrhosis leads to physiologic changes associated with development of hepatic decompensation manifested by ascites, encephalopathy, variceal bleeding, and coagulopathy.Predictive modeling suggests that without effective treatment interventions, the U.S. population will experience significant increases in HCV-associated liver morbidity, mortality, and health care costs.9,10 Current treatment of HCV is based upon administration of pegylated interferon (PEG-IFN) with ribavirin.[11][12][13] Genotype-specific durations of therapy lead to treatment cycles of 24 to 48 weeks of continuous drug administration.The primary treatment outcome is sustained viral response (SVR), which is defined as HCV viral undetectability using a sensitive polymerase chain reaction-based assay 24 weeks following completion of therapy.This response is thought to be highly durable, and may result in improvement in liver fibrosis over time.There is also evidence from retrospective data that SVR reduces the risk of developing hepatocellular carcinoma and overall liver-related mortality.14 Response rates in highly selected subjects are 40%-45% for genotype 1 HCV and greater than 70% for genotypes 2 and 3.However, PEG-IFN and ribavirin are associated with a poorly tolerated adverse event profile, which limits treatment in many patients.15
Source: Hepatology
DOI: 10.1002/hep.21985
Language: English
Topic: Hepatitis C virus research
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2115869094