Concurrent hepatitis B and C virus infection: Is hepatitis C virus stronger?

See article on page 636 Hepatitis B virus (HBV) and hepatitis C virus (HCV) share the same transmission routes, and therefore a dual infection of these viruses may occur and even persist in the same patients. Hepatitis B virus/HCV dual infection may occur as a simultaneous acute infection (co-infection) or as an acute infection by one virus in patients with chronic infection of the other (superinfection). When the infection onset of either or both viruses cannot be clearly defined, the patients seropositive for both hepatitis B surface antigen (HBsAg) and antibodies to HCV (anti-HCV) are classified as HBV/HCV concurrent infection. Seroprevalence studies have shown that concurrent HCV infection was detected in approximately 10–15% of patients with chronic HBV infection, although the prevalence may vary from area to area or country to country.1 The outcome of patients with HBV/HCV dual infection, as well as the interaction between HBV and HCV, have attracted considerable attention and research in the past 10 years. However, controversies remain. In this issue of the Journal, Dai et al. reported a cross-sectional study involving 100 clinicopathologically proven patients with chronic HBV infection, of whom 18 were seropositive for both anti-HCV and HCV-RNA as detected by the use of a second generation enzyme immunoassay and nested RT-PCR, respectively.2 By comparing patients with chronic HBV infection alone, and patients with HBV/HCV dual infection by using multiple logistic regression analysis, Dai et al. found that HCV concurrent infection was significantly associated with a lower HBeAg positive rate and a lower serum HBV-DNA level, and therefore concluded that concurrent HCV infection resulted in a suppression of HBV replication.2 Their findings have confirmed the results of some earlier cross-sectional studies,3–7 but are contradictory to the observation of other studies showing HCV suppression by HBV.8–10 The reasons of this discrepancy have not been addressed. It is worth noting that studies with different conclusions have included different study populations. Studies comparing patients with chronic HBV infection alone versus those with concurrent HCV infection invariably showed a suppressive effect of HCV over HBV.3–7 In contrast, studies comparing patients with chronic HCV infection alone versus patients with concurrent HBV infection invariably showed the contrary.8–10 It appears that such a difference in study design or population may be one of the reasons responsible for the contradictory conclusions. Nevertheless, these contradictory results derived from the use of a different study design may also suggest that either HBV or HCV may dominant over the other. This notion is supported by longitudinal studies showing alternating dominance in replication of one or the other virus.11–13 The chronologic sequence of hepatitis virus infection may also influence the interaction between HBV and HCV. Given the finding that acute non-A, non-B virus (HCV) superinfection suppresses pre-existing chronic HBV infection in chimpanzees,14,15 it is reasonable to suspect that the newcomer may have an advantage to suppress the pre-existing virus in patients with HBV/HCV dual infection.1 The impact of a newcomer on the pre-existing virus has been best demonstrated by the de novo acute HCV superinfection in a patient with pre-existing chronic HBV infection,16 and de novo acute HBV superinfection in several patients with pre-existing chronic HCV infection.17–19 As chronic HBV infection in endemic areas such as Taiwan and Hong Kong are usually acquired perinatally or at early infancy, it is very likely that patients with concurrent HBV and HCV infection in such areas have had chronic HBV infection before they were superinfected with HCV.1 The reverse may be true in other countries, including Japan. Perhaps this can explain why longitudinal studies from Taiwan invariably show that HCV suppresses HBV or may even terminate a HBsAg carrier state,1,20 while studies from Japan and Italy show alternating dominance of either virus.11–13 However, it has been well documented that HCV usually interferes with HBV replication in patients or chimpanzees with HBV and HCV co-infection.21,22 Shih et al. also provided molecular evidence to support the suppressive effect of HCV on HBV in a cotransfection study.23 These lines of evidence strongly suggest that HCV is stronger than HBV in terms of a suppressive effect if the factor of chronologic sequence of infection is excluded. In contrast, it is conceivable that the clinical findings of an interference does not necessarily indicate direct interaction between two viruses because other factors, such as viral load/genotypes and host factors, may have also been involved and confounded the concurrent infection process. This should be taken into consideration in the interpretation of clinical findings and future studies. It is clear that both HBV-DNA and HCV-RNA assays are required for an accurate assessment of patients with HBV/HCV dual infection, including evaluation for therapy.24