Hepatitis C Virus Persistence After Sustained Virological Response to Antiviral Therapy in Patients With or Without Past Exposure to Hepatitis B Virus

T. N. Q. Pham; C. S. Coffin; N. D. Churchill; S. J. Urbanski; S. S. Lee; T. I. Michalak


J Viral Hepat. 2012;19(2):103-111. 

In This Article

Abstract and Introduction


Hepatitis C virus (HCV) and hepatitis B virus (HBV) frequently coinfect and persist long after clinical resolution. We assessed the incidence of low-level (occult) HCV infection (OCI) after sustained virological response (SVR) to standard anti-HCV therapy in individuals with or without past exposure to HBV to recognize whether HBV could influence the prevalence of OCI, HCV level and hepatic histology. Plasma and peripheral blood mononuclear cells (PBMC) were collected from 24 individuals at 6- to 12-month intervals for up to 72 months after SVR. Liver histology was available for nine patients. HCV and HBV genomes were detected with sensitivity <10 genome copies/mL. In individuals without HBV exposure (n = 15), comprehensive analyses of sequential plasma and PBMC samples revealed HCV RNA in all 15 cases (75% plasma and 61% PBMC). In the group with HBV exposure (n = 9), evidenced by circulating anti-HBc and/or HBV DNA detection by a highly sensitive assay, HCV RNA was identified in all cases (83% plasma and 59% PBMC), at levels similar to those in HBV nonexposed individuals. In both groups of patients, most liver biopsies included those reactive for viral genomes displayed low-grade inflammation (8 of 9) and fibrosis (7 of 9). Sequence polymorphisms at the 5`-UTR between PBMC and liver or plasma, as well as circulating HCV virion-like particles, were observed in patients with or without HBV exposure. In conclusion, the prevalence of OCI after SVR is comparable in individuals with or without past exposure to HBV. HCV loads and liver alterations in OCI appear to be unaffected by low-level HBV DNA carriage.


There are at least 370 million people chronically infected with hepatitis B virus (HBV) and 170 million of those with chronic hepatitis C virus (HCV) infection worldwide. The chronic hepatitis induced by the viruses can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC).[1,2] However, while 90–95% of adults infected with HBV spontaneously resolve acute hepatitis, up to 85% of those infected with HCV develop chronic hepatitis C (CHC).[3,4]

Although hepatocytes are major targets of HBV and HCV, both pathogens can also propagate in the cells of the immune system, as evidenced by the presence of their genomes and respective replicative intermediates and proteins in the lymphatic organs and peripheral blood mononuclear cells (PBMC) of patients with chronic hepatitis B (CHB) and C.[5–10] The existence of small amounts of HBV and HCV genomes in plasma, PBMC or liver after clinical resolution of hepatitis highlighted the natural propensity for these two viruses to induce a persistent infection.[11–15] Occult HBV infection (OBI) is defined as detection of HBV DNA in liver, plasma and/or PBMC in the absence of hepatitis B surface antigen (HBsAg) in serum. Occult HCV infection (OCI) is characterized by low-level HCV RNA persisting in plasma, liver or PBMC in anti-HCV antibody-reactive individuals who resolved hepatitis C either spontaneously or after antiviral treatment or seemingly anti-HCV antibody-negative individuals with infection of unknown aetiology.[14–17] Although the existence of OBI has been generally accepted, that of OCI remains controversial in that HCV persisting in plasma, liver and/or immune cells after resolution of hepatitis C has not been observed by all investigators. This inconsistency is likely related to variations in the sensitivity of HCV RNA detection assays employed, processing of clinical samples, the number of samples tested and the amount of material used for analysis.[18] Because of their shared modes of transmission, coinfection with HCV and HBV is common, particularly in high-risk populations and in areas considered to be endemic for both viruses. Molecular and pathological consequences of interactions between HCV and HBV in coinfected patients are not fully elucidated given the relatively contradicting data that are available. On one hand, acute HCV infection in the context of CHB and vice versa acute HBV infection or OBI in CHC have been associated with a more active liver disease and a greater likelihood of developing cirrhosis and HCC.[19–24] Along this line, HBV superinfection has been correlated with an assumed complete clearance of serum HCV RNA, or even both HCV RNA and HBV DNA, in patients with CHC.[24–26] The reverse was also true for HCV superinfection.[22,24] In cell culture studies, HCV core or nonstructural proteins (e.g. NS5A) were found to repress HBV DNA synthesis.[27–29] On the other hand, in arguing against the negative influence of one virus over the other, other investigations demonstrated not only a coexistence of hepatic HBV and HCV in coinfected patients,[30,31] but also a simultaneous replication of HCV and HBV within the same hepatoma cell.[32,33]

Nevertheless, given the lymphotropic propensity of HCV and HBV, what remained undefined was whether HCV and HBV could affect each other's ability to propagate in immune cells, especially in the context of occult infection. Such recognition would be important in furthering our understanding of the full extent of viral persistence. With this in mind, the current study examined whether HBV exposure would influence the prevalence of HCV occult infection, the level of persisting HCV and liver pathology in patients with clinical resolution of CHC.


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