Several reports have revealed that HBV and HCV are capable of suppressing replication of each other in coinfection conditions. Dominant roles for both HCV and HBV have been suggested by some investigators [10
]. However, our meta-analysis indicates that HBV DNA was not always detectable in patients with HBV/HCV coinfection, and that the rate of HBV DNA resurgence in HBV/HCV coinfection patients with HCV SVR was significantly higher than in those without HCV SVR (31.11% vs. 11.29%, P
0.009). These findings are consistent with the idea that patients with HBV/HCV coinfection show a large spectrum of virological profiles. It is possible that dominance of HBV or HCV may alternate at different periods during the infection. Thus, we speculate that one of the viruses in patients with HBV/HCV coinfection is capable of exerting its particular pathogenic role and masking or silencing that of the other virus. Moreover, once the dominant virus becomes suppressed by treatment, the other may have a tendency towards reactivation. This type of robust activity elicited by one virus can explain the increased severity of disease observed in patients with HBV/HCV coinfection, as opposed to that in patients with mono-infection of either of the two viruses.
The most commonly used clinical therapy to treat either HBV or HCV is interferon, usually administered as a subcutaneous injection. This drug was developed based upon the normal host antiviral and immunomodulatory actions that target invading viral pathogens for destruction and clearance. Previous studies have shown that patients with HCV mono-infection respond remarkably better to combination therapy (interferon supplemented with the nucleoside analogue ribavirin) than to interferon monotherapy (SVR of 43% vs. 10%) [27
]. Moreover, patients with CHB treated with conventional interferon achieved an SVR of 35% [28
], and use of PEG-IFN achieves an even higher SVR in patients with CHB and CHC [39
]. To date, interferon has been the most studied pharmacologic agent for treatment of HBV/HCV coinfected patients, because of its proven activity against both viruses. The efficacy of combination treatment with interferon plus ribavirin in HBV/HCV coinfection patients has been assessed in various studies [41
], but very few studies to date have comparatively analyzed HBV/HCV coinfection and HCV mono-infection, and the conclusions have been largely discordant [30
]. Liu et al. [35
] reported that the efficacy of combination therapy with PEG-IFN and ribavirin was similar between HBV/HCV coinfected and HCV monoinfected patients. However, another study [34
] showed that the HBV/HCV coinfected patients had higher ETVR and relapse rates than monoinfected patients.
Our meta-analysis confirmed that the combination treatment approach, with either conventional interferon or PEG-IFN plus ribavirin, achieved comparable ETVR and SVR in patients with HBV/HCV coinfection and those with HCV mono-infection. Our analysis also showed that patients with HBV/HCV coinfection were at similar risk of HCV relapse to those with HCV mono-infection, regardless of the presence of HCV genotype 1 or HCV non-genotype 1. However, combination treatment achieved higher ALT normalization in HCV mono-infection patients than in those with HBV/HCV coinfection by the ends of both treatment and follow-up. According to the finding that eradication of one hepatitis virus in patients with HBV/HCV coinfection may lead to increased titer of the other, we speculate that the resurgence of HBV might account for the persistent hepatitis activity after the clearance of HCV. Therefore, examination of HBV antigens and HCV replication in the liver compartment is required to confirm this hypothesis.
These findings may provide insights into why the ALT normalization rate in patients with HBV/HCV coinfection was lower than that in patients with HCV mono-infection. Yet undefined viral interactions and their impacts on treatment efficacy (for example, producing similar ETVR and SVR but lower ALT normalization) may explain the suppressive effect of HBV on HCV that has been observed in HBV/HCV coinfected patients. Once the dominant HBV becomes suppressed by IFN-based therapy, coinfected patients may experience HCV reactivation and manifest HCV-specific symptoms [21
]. Therefore, clinicians should exercise caution when treating coinfected patients with combination therapy (the combination of PEG-IFN and ribavirin being the preferred strategy), and perform careful follow-up with systematic supervision. Larger scale studies should be carried out to determine whether prolonging the course of antiviral treatment in patients with HBV/HCV coinfection will increase the risk of ALT normalization.
There are several limitations to our meta-analysis that should be considered prior to generalization of our findings. First, these five studies were composed exclusively of individuals of Asian descent. Second, conclusions were made based upon sub-analyses using calculated p-heterogeneity values. Third, the studies were not identical in the administered doses of interferon and ribavirin, types of interferon administered, or course of treatment; these differences in study design may explain the statistical heterogeneity. Fourth, the data of HCV relapse and ALT normalization in genotype 1 and non-genotype 1 infected patients were unavailable in some studies, which may have affected the accuracy of this meta-analysis.
In conclusion, the results of our meta-analysis demonstrate that combination treatment with interferon plus ribavirin achieves similar ETVR and SVR in HBV/HCV coinfection patients and HCV mono-infection patients. However, HBV/HCV coinfection patients achieve significantly lower ALT normalization and are at significantly higher risk of relapse. The combination of PEG-IFN and ribavirin is more effective than that of conventional interferon and ribavirin for both coinfection and mono-infection.