Occult hepatitis C infections: time to change the defined groups.

Abstract

Hepatitis C virus (HCV) naturally infects both humans and chimpanzees. The high burden of the disease is related to the induction of chronic liver disease in 80% of infected humans, with 20% of the infected people developing liver cirrhosis and end-stage liver diseases as well as hepatocellular carcinoma.1 About half of the infected people do not show any noticeable symptoms until starting the cirrhotic stage of the disease. Elevated liver enzymes and serological screening of HCV antibodies are used to initially evaluate the level of exposure to HCV. Individuals with positive results are then subjected to screening for the presence of viral RNA to confirm active infection.2 Occult (OCI) HCV infection, first detected in 2004,3 is a mysterious form of the disease in which HCV infection is masked. OCI is characterized by the absence of HCV RNA in serum and the presence of actively replicating HCV RNA in hepatocytes or peripheral blood mononuclear cells (PBMCs), as evidenced by the presence of antigenomic negative-sense single-stranded RNA. The prevalence of OCI differs greatly based on the cluster of patients: 1.3–3.3% in patients without apparent liver disease, 8.9–10.0% in patients with cryptogenic liver diseases, and 57% in patients with abnormal liver enzymes, as reviewed by Austria and Wu.3 Although there is an evidence of active replication of HCV in OCI patients, insufficient data exist about the potential infectivity and also the response after treatment using direct-acting antiviral agents.3 OCI could be presented in three clinical forms, with all three showing no HCV RNA in the serum but positive viral RNA in the liver cells or PBMCs: (i) seronegative with elevated liver enzymes, (ii) seropositive with normal liver enzymes, (iii) seropositive patients whose HCV infection resolved after antiviral treatment. However, the absence of HCV RNA in the serum is not absolute, as evidenced by the successful detection of HCV RNA in the serum of OCI patients after ultracentrifugation of serum, or by adopting assays with improved sensitivity, as reviewed by Welker and Zeuzem.4 By contrast, seronegative HCV infection is a condition in which there is no detection of HCV antibodies, but there is a viral RNA extracellularly in serum and intracellularly in the liver or in PBMCs in immunocompromised individuals. It is assumed to result from (i) delayed prolonged seroconversion, (ii) insufficient viral antigen with very low or absent plasma cell response, (iii) antigenic variants not recognized in standard serologic tests, or (iv) immune tolerance. Although it is also a mysterious masked form of HCV infection, the presence of detectable serum level of HCV RNA does not match with the definition proposed for OCI. Accordingly, I here suggest setting up a new classification system by including seronegative HCV infection in the definition of OCI as that this is also a mysterious form of hepatitis. This new classification, given as follows, is based on the presence of serum HCV RNA detected using the current assays and seroconversion as main cornerstones: (i) OCI Ab(−)/serum RNA(−) (sRNA), HCV seronegative with the absence of detectable serum HCV RNA; (ii) OCI Ab(+)/sRNA (−), HCV seropositive with the absence of detectable serum; and (iii) OCI Ab(−)/sRNA(+), HCV seronegative with the presence of detectable serum HCV RNA. In the first two clusters, HCV RNA is present in the liver and PBMCs, whereas the last cluster represents seronegative HCV infection in which HCV RNA is present in serum, liver, and PBMC. The author has no financial or personal conflict of interest.