Targeting angiogenesis in chronic liver diseases with portal hypertension: anti–placenta growth factor inhibitor or multikinase inhibitor sorafenib?

We read with interest the article titled ‘‘Emergence of hepatitis B virus S gene mutants in patients experiencing HBsAg seroconversion after peginterferon therapy’’ by Hsu and Yeh. In this study, the authors found different substitutions within and outside the ‘‘a’’ determinant. They further tested the reactivity of those mutations. However, variations in the hepatitis B virus (HBV) surface protein (HBs) have also been reported in chronic carriers who did not receive vaccine/drug, with a frequency of 11% in spite of the presence of antibody to HBs (anti-HBs). Due to the quasispecies nature of HBV, the finding of different variants in a viral pool by molecular cloning is not surprising. Further, the authors did not test the patient’s samples before the treatment (or sequential samples during the study), and therefore, they cannot be sure those mutations arose after interferon therapy. We believe that the variants found in the study by Hsu et al. could have emerged during the natural chronic course of HBV infection, regardless of pegylated interferon (PEG-IFN) therapy. Although the immune modulatory effect of drugs on anti-HBs seroconversion cannot be ignored, the anti-HBs in these patients may be possibly directed against the epitopes outside the ‘‘a’’ determinant, such as d/y or w/r subtype determinants. It seems that the consequence of selection pressure posed by natural antibodies would be the emergence of immune escape mutations which no longer could be recognized by the host immune system. Interestingly, patients with both HBs antigen (HBsAg) and anti-HBs–positive have been reported in 10%-25% of chronic active, hepatitis B e antigen (HBeAg)-positive patients. In our study of HBsAg mutants in 310 chronic HBsAg treatment-naive patients, we found numerous point mutations in 11% within the surface protein. Overall, 32 amino acid substitutions were found in the ‘‘a’’ determinant. A portion of those patients experienced anti-HBs seroconversion, but yet were still positive for HBV DNA (unpublished data). Therefore, the data suggest that escape mutations could be induced by an immunological pressure exerted on the major hydrophilic region (within or upstream and downstream of the ‘‘a’’ determinant), even in patients who are found to be negative for serum HBsAg by use of the routine assay.