Occult Infection with Hepatitis C Virus: Looking for Clear-Cut Boundaries and Methodological Consensus

Abstract

The sustained virologic response and elimination of HCV is widely viewed as a true cure of chronic hepatitis C as it associates with amelioration of histological liver damage and improved clinical outcomes. Therefore, the existence and clinical burden of occult HCV infection (OCI) has been a controversial issue for many years. In this review, we summarize recently published data that adds new information on the molecular and clinical background of OCI and its epidemiological significance. We also identify and discuss the most important methodological pitfalls, which can be a source of inconsistency between studies. Data that have accumulated so far, strongly support the existence of extrahepatic HCV replication in individuals negative for serum HCV-RNA by conventional clinical tests. OCI emerges as a condition where the immune system is unable to fully resolve infection but it is continuously stimulated by low levels of HCV antigens, leading to progression of liver pathology and extrahepatic HCV-related complications. Moreover, the development of monitoring strategies or management guidelines for OCI is still hampered by the lack of clear definition and the confusion regarding its clinical significance. Careful study design and the introduction of uniform protocols for the detection of low-level HCV-RNA are crucial for obtaining reliable data on OCI.

Keywords: HCV-RNA detection; extrahepatic complications; lymphotropism; occult hepatitis C infection; viral persistence.

Figure 1

Schematic overview of OCI as one of the stages in the natural history of HCV infection. This chart summarizes data on the detection of basic parameters at different stages of HCV infection, including seropositive (A) and seronegative (B) OCI. Solid boxes represent a range of relative values of a particular parameter, that can be detected with current methods, and are not organized as a timeline. HCV-specific CD8+/CD4+ responses are marked with black color, the presence of HCV-RNA in different compartments with grey, and red triangles represent the level of anti-HCV immunoglobulins. In a patient with certain diagnosis different parameters can assume various values within the range, e.g., in a patient with seropositive OCI HCV-RNA can be detected in PBMC and not in the serum. LoD, lower limit of detection; CHC, chronic hepatitis C; SVR, sustained virological response; PBMC, peripheral blood mononuclear cells.