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Updated: Sep 12, 2025
A Protocol for Analyzing Hepatitis C Virus Replication
Published on: June 26, 2014
HCV serology: an unfinished agenda
Claudio Galli1, Mario Plebani2,3
1Independent Researcher, Rome, Italy.
Insights
Hepatitis C virus (HCV) serological diagnosis has seen few advances, relying on outdated methods. Current anti-HCV testing limitations lead to indeterminate results, impacting patient care and requiring improved diagnostic strategies.
Area of Science:
- Virology
- Immunology
- Clinical Diagnostics
Background:
- Hepatitis C virus (HCV) was identified 36 years ago, yet serological diagnostic methods remain largely unchanged.
- Current anti-HCV antibody testing primarily targets the HCV Core region and non-structural antigens, with limited detection of envelope region antibodies.
Purpose of the Study:
- To review the historical development of HCV serology.
- To highlight the limitations of current HCV diagnostic assays.
- To explore potential future developments in HCV serodiagnosis.
Main Methods:
- Review of historical data and current literature on HCV serological assays.
- Analysis of limitations in detecting anti-HCV antibodies, including discrepant and indeterminate results.
- Examination of alternative diagnostic markers like HCV core antigen.
Main Results:
- Anti-HCV testing remains dependent on core and non-structural antigens, with envelope antibodies often undetectable in initial screening.
- Discrepant results are common, leading to 'indeterminate' findings that lack clear clinical significance.
- HCV core antigen assays offer a surrogate for HCV RNA but with lower sensitivity; combined antigen/antibody assays are a recent development.
Conclusions:
- Significant advancements in HCV serological diagnostics are lacking despite decades of research.
- Current diagnostic limitations hinder accurate patient management and counseling.
- Future developments should focus on more sensitive and specific assays to overcome existing challenges in HCV diagnosis.
Abstract:
Over 50 years have elapsed since the clinical definition of non-A, non-B hepatitis and 36 years since the unveiling of hepatitis C virus (HCV) and the availability of specific serological assays, but few advances in the serological diagnosis of HCV infection have occurred. Testing for anti-HCV is still based on the detection of reactivity towards the structural Core region of HCV, which appears to be dominant throughout the different phases of infection, plus antibodies towards antigens expressed by several non-structural regions. Unlike testing for other viral diseases, antibodies towards the envelope region are not detectable by the first line assays employed for screening or diagnosis and are scarcely represented in the supplementary assays employed to confirm the reactivity by screening assays. Clinical laboratories are often confronting issues on samples that give discrepant results among assays and are not confirmed by supplemental testing. Results obtained on those samples are usually labelled as 'indeterminate' and are often considered as false positive - though a true reference to define anti-HCV positivity is still lacking. The diagnostic answer is then deprived of clinical significance and affects patient management and counselling. The only advance, though not recent, has been the availability of assays detecting the HCV core antigen, which is considered as a surrogate of HCV RNA, with lesser sensitivity but bearing some operational and economic advantages in diagnosis and population screening, and lately of assays combining HCV antigen and anti-HCV detection. This paper summarizes the history of HCV serology and provides some insights on its limitations and potential developments.
