HBV immune tolerant phase may not be disease free
medwireNews: Researchers have found evidence of hepatitis B virus (HBV) disease progression markers and HBV-specific T cells in patients considered to be in the initial immune-tolerant phase of infection.
“These results raise questions about the perception that the [immune-tolerant] phase is disease-free, as well as the premise on which treatment decisions are made”, they write in Gastroenterology.
William Mason (Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA) and team believe that “the term high-replicative low-inflammatory (HRLI) [chronic hepatitis B] more accurately reflects this early disease phase, and thus should be adopted into clinical practice.”
The study included nine hepatitis B e antigen (HBeAg)–positive patients in the immune-tolerant phase and 17 age-matched patients with active disease, 10 of whom were HBeAg-positive while the remaining were negative for HBeAg.
Inverse polymerase chain reaction analysis of DNA from liver biopsy samples showed high levels of HBV DNA integration in not only the HBeAg-positive and -negative immune-active participants, but also for those considered immune tolerant.
Immune-tolerant patients also had increased hepatocyte turnover as shown by the greater than expected sizes of hepatocyte clone sizes. Specifically, the maximum observed clone sizes were larger than would be expected for random liver turnover in six patients each in the immune-tolerant and HBeAg-positive immune active groups, as well as in all HBeAg-negative immune-active patients.
The study authors suggest that the clonal hepatocyte expansion could be “in response to hepatocyte turnover mediated by HBV-specific T cells”, which they observed in peripheral blood cells isolated from all patients irrespective of the infection phase.
“The comparable levels of peripheral HBV-specific T-cell responses in [immune-tolerant] patients with those in the other 2 groups suggested that infected hepatocytes might be targeted for T-cell–mediated destruction in all patients including those diagnosed as [immune-tolerant]”, observe Mason et al.
Furthermore, the level of HBV DNA integration and clonal hepatocyte expansion, both of which are risk factors for progression to hepatocellular carcinoma, was comparable for immune-tolerant and HBeAg-positive immune-active patients, say the investigators, reiterating that taken together the results “are thus at odds with the concept of a disease-free state”.
In a related editorial, David Milich (VLP Biotech, Inc, San Diego, California, USA) argues that there is insufficient evidence “to change the nomenclature from the [immune-tolerant] phase to the HRLI phase of chronic HBV infection”.
Noting the similarities in age, and in virological, serological and histological parameters between immune-tolerant and -active patients, he writes that “it is not surprising that no differences in HBV-specific T-cell responses, HBV integration events, or hepatocyte clonal expansion were observed”.
“One cannot exclude that selecting younger (ie, 0-14 years) [immune-tolerant] patients would have yielded differences.”
The authors of a second accompanying piece think, however, that the study “stimulates an important discussion about whether the stage definition of chronic HBV infection can be based on immune parameters.”
Ulrike Protzer and Percy Knolle, both from Technische Universität München in Germany, write: “The clinical evidence that hepatocellular carcinoma development also occurs in ‘[immune-tolerant]’ patients with high replicative, low inflammatory liver disease further underscores that staging as well as the nomenclature of chronic hepatitis B stages should be revisited.”
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