What is really ongoing during occult HBV reactivation?†

Abstract

We read with interest the article by Hass et al. 1 documenting the proposal of a posttranscriptional regulation of hepatitis B surface antigen (HBsAg) production in a case of occult hepatitis B virus (HBV) infection reactivation.Convincing in vitro demonstration of the ability of the G458A mutation to affect HBsAg production through the 5Ј splicing site of HBV is provided. These data are very useful from a mechanistic perspective because, despite the improvement of several new generation tests for HBsAg showing excellent sensitivity, occult infections still escape HBsAg-negative detection despite detectable HBV DNA. In most cases there is no change in the a determinant that could explain the lack of HBsAg detection, 2-4 and very few cases (Ϸ10%) are related to obvious "hypermutated" HBV genomes. 5,6 Posttranscriptional regulation due to minor changes in the HBV sequence seems a relevant option. The authors did not discuss the link between HBV reactivation and HIV status of the patients-including HIV viral loads, CD 4ϩ cell counts, and highly active antiretroviral therapy such as 3TC-but it is intriguing that both patients A and B became HBsAg-positive when CD4 ϩ cells decreased to under 200/mL. An important point is that the careful analysis performed to highlight the possible mechanism involved in HBsAg negativity was conducted at the reactivation peak, when HBsAg was in fact positive. Indeed, no HBV sequences from before reactivation-the time at which patient A was HBsAg-negative-have been analyzed. The fact that all the sequences analyzed to provide a new mechanism to explain HBsAg negativity in HBV DNA ϩ patients are derived from an HBsAg-positive sample is worrisome. Finally, because a mixed HBV genome population was documented in patient A, a phenomenon that we 6,7 and others 8 have also observed, one should not overlook the possibility that dynamic processes, over time, affect the HBV genomes circulating in these patients.We can therefore wonder whether the detection of mutation G458A at a point during follow-up when the patient was HBsAgpositive is sufficient to conclude that the G458A-mutated HBV genomes were responsible for the previous lack of HBsAg detection. An alternative hypothesis, based on the fact that there are frequently mixed populations of HBV during occult infections, would be that transcomplementation of two defective HBV genomes may be occurring, which would lead to a chronic HBsAg-negative HBV infection. Reply:Chemin and colleagues discuss two important aspects of our paper 1 : (1) the trigger for HBV reactivation in the two HIV coinfected patients, and (2) the mechanisms leading to HBsAg negativity before reactivation. Both patients seroconverted from anti-HBs to HBsAg concomitant with an HIV-induced drop in CD4 ϩ cells. Therefore, we assume that the appearance of HBsAg is linked to a reduced T cell reactivity highlighting the relevance of the cellular immune response for control of low level HBV persistence. During the further course, HAART was commenced and CD4 ϩ cells began to rise...