Of note, our study shows a high prevalence of preS/S HBV

mutants in patients with chronic HBV infection and advanced liver disease, in accordance with several previous reports.7, 8, 10-13, 15-17, 31 HBsAg has recently been proposed as a biomarker for response to anti-HBV treatments, as well as a clinical surrogate for intrahepatic HBV cccDNA (reviewed by Sonneveld et al.,25 Liaw,26 and Chan et al.27). However, some evidence indicates that HBsAg levels are closely associated with the HBV replication rate in the HBeAg-positive phase of the infection, whereas HBsAg titers are considerably reduced and dissociated from HBV replication in the HBeAg-negative phase.32-35 Ferroptosis tumor It has been hypothesized that selleck products the strong immunological pressure during the HBeAg-negative phase might favor a redirection of subviral mRNA production resulting in a preferential control of viral replication or, alternatively, that HBsAg might be produced from a source other than the intranuclear cccDNA (i.e., fragments of the HBV genome integrated into the host chromosome).32, 34-35 However, this latter hypothesis—although fascinating—is not supported by any evidence so far. Our study provides new information in this context, demonstrating that the emergence of preS/S HBV variants is associated with

low HBsAg titer independently of viral replication as well as of HBeAg status. Indeed, the prevalence of preS/S mutants was comparable between HBeAg-positive and HBeAg-negative patients, and HBsAg levels were not correlated to HBV DNA amounts either in HBeAg-positive or in HBeAg-negative cases. This last finding is in accordance with the results of our recent

study showing the absence of any correlation MCE between HBsAg concentrations and both serum and intrahepatic HBV DNA amounts in HBeAg-positive and HBeAg-negative patients.36 Taken together, these data indicate that the diagnostic/prognostic use of serum HBsAg titers may be strongly impaired when preS/S mutants are the dominant infecting population. This consideration assumes particular relevance in light of the extensive evidence showing that preS/S mutants are highly prevalent worldwide.7, 10, 12, 13, 31 In this context, we would like to stress that although there is evidence showing a very frequent occurrence of these mutants among HBV genotype C–infected carriers,10, 12, 37 the present study and other previous reports clearly demonstrate the high prevalence of preS/S mutants also in CHB patients infected with genotypes A and D.7, 8, 13, 15 The preS1 and preS2 regions contain both B and T cell epitopes and—as the “a” determinant of HBsAg—are highly immunogenic and potentially under the selective pressure of the immune system.10, 12, 15 Therefore, the preS/S HBV variants may be considered immune escape mutants able to evade the T cell response and/or to escape from anti-HBs antibodies.