Immune‐Tolerant Hepatitis B: Maybe a Misnomer but Still Hard to Treat
Authors: Paul Martin
Journal: Hepatology (2019)

Potential conflict of interest: Dr. Martin consults and received grants from AbbVie, Gilead and BMS. See Articles on Pages 2326 and 2338 An unresolved issue in the management of chronic hepatitis B (HBV) infection has been the role of antiviral therapy in the large number of younger patients infected at an early age with active viral replication and hepatitis B e antigen (HBeAg) positivity without biochemical abnormalities, felt to reflect an immune‐tolerant (IT) state without progressive liver injury. The recent American Association for the Study of Liver Diseases Guidance document defines the IT phase as absence of biochemical dysfunction (alanine aminotransferase [ALT] <35 U/L in men, <25 U/L in women), presence of HBeAg, elevated HBV DNA >1 million IU/L, and minimal inflammation with an absence of fibrosis.1 The authors also suggest, however, that if ALT levels are borderline normal or mildly elevated, evaluation of hepatic fibrosis and inflammation especially in patients >40 years of age with childhood‐acquired HBV infection should be undertaken by liver biopsy or elastography to determine need for antiviral therapy. Monotherapy with interferon and oral agents in IT children had typically not resulted in clearance of HBeAg. D'Antiga and colleagues added interferon to lamivudine after an 8‐week lead‐in in 23 IT children chronically infected with HBV.2 HBeAg seroconversion occurred in 5 (22%) and HBsAg loss in 4 (17%) with virological responses maintained during a median follow‐up of 40 months. Poddar et al. reported similarly encouraging results using the same combination regimen in 24 IT children with chronic HBV.3 In the current issue, Rosenthal et al. report a study of entecavir administered for an initial 8 weeks with the addition of pegylated interferon for the subsequent 40 weeks in 60 children with IT chronic HBV.4 Disappointingly, only 2 (3%) reached the primary endpoint of HBeAg loss and durable HBV DNA suppression ≤1,000 IU/mL, although both also lost HBsAg. Two additional children also cleared HBeAg but did not return for their final study visit, so it is possible that they also met the study endpoints. However, even if they are included, only 7% of treated patients reached the study endpoints. Feld and colleagues also report their experience in the current issue using a similar regimen in adults with IT chronic HBV.5 Only 1 (4%) of the 27 patients achieved HBeAg loss, with none experiencing durable HBV DNA suppression ≤1,000 IU off therapy. In both studies, HBV DNA had rebounded off therapy, suggesting that currently licensed therapies cannot induce durable virological responses in the majority of patients with IT HBV. These two discouraging reports suggest that with our currently available options, antiviral therapy is futile in most IT patients. However, despite the absence of seroconversion on treatment, viral suppression unequivocally occurs. Chan and colleagues had previously studied oral antiviral therapy in IT HBV, comparing tenofovir with tenofovir/emtricitabine administered for 192 weeks. By the end of treatment, in 76% of the combination arm and 55% of the monotherapy arm, serum HBV DNA was nondetectable. Despite HBV DNA suppression, however, only 3 (5%) patients had HBeAg seroconversion, all in the tenofovir monotherapy arm, and no patient cleared HBsAg. Given the lack of durable antiviral response in IT HBV, are there additional considerations? The implication has been that in the absence of histological progression, the sequence of events leading to adverse consequences of chronic HBV infection including hepatocellular carcinoma (HCC) are not already in progress. Although the apparent lack of liver injury in the IT phase had been felt to reflect immune tolerance or lack of immune recognition of the virus, recent data have challenged these assumptions. A recent report from Korea by Kim and colleagues has also raised concern about poor outcomes in untreated IT patients.6 In a series of 417 IT patients seen between 2000 and 2013, the 10‐year cumulative risk of HCC in IT patients was significantly higher (12.7%) than that in 1,497 treated patients in the immune active phase (6.1%). Of note, the IT patients had a mean age of 38 years at entry and were older than is typical, suggesting that some of the patients were no longer IT and had transitioned to the immune active phase. In a study looking at molecular events in chronic HBV, Mason and colleagues collected serum and liver biopsy material including DNA from a series of 26 patients with chronic HBV, of whom 9 were IT, 10 were HBeAg positive in the immune reactive phase, and the other 7 were HBeAg negative with active hepatitis.7 HBV‐specific T cells were detected in all 3 groups in similar quantities with comparable ability to detect HBV‐specific peptides. Furthermore, although cirrhosis was not detected in the IT group, fibrosis and inflammation were not absent. The authors were also able to identify HBV DNA integration into hepatocyte DNA in the IT group, suggesting a capacity to mutate host genes, a possible step in the development of HCC. Mason and colleagues also used HBV DNA integration to detect clonal expansion of hepatocytes, which was present at a rate not consistent with normal hepatocyte turnover and again suggests that events that may culminate in development of HCC are already underway in IT HBV. It has been suggested that the latter might be more accurately referred to as the “noninflammatory, high viremic” phase.8 Although newer antivirals and regimens are currently undergoing clinical evaluation, what should the approach be to the IT patient while we await better treatment? Furthermore, although emergence of viral resistance is an at least theoretical concern in nucleoside‐naïve patients, this is not an issue with the currently available first‐line agents. It is clearly difficult to endorse therapy for every IT patient given the underwhelming results of antiviral therapy reported in the current issue. Liver biopsy has been suggested to identify IT patients who have developed fibrosis and provide a rationale for antiviral therapy if present. Transient elastography has an increasing role in the evaluation of liver disease in patients with chronic hepatitis B9 and can help identify IT patients who may be more appropriate for therapy based on detection of fibrosis.10 Other considerations may include older patient age >35 years and a family history of HCC even in the absence of fibrosis.10 However, what is most needed for these patients are therapies that are universally effective in not only suppressing HBV infection but also clearing HBsAg and covalently closed circular DNA. Until then, IT patients will remain a challenging patient group with treatment decisions made on a case‐by‐case basis.