The immune tolerant (IT) phase, the first phase of chronic hepatitis B virus (HBV) infection, has historically been perceived as a benign period in the natural history of this disease. Perinatal infection leads to a prolonged IT phase, with transition to immune clearance with seroconversion to anti-HBe in the second to third decade, whereas immediate progression to immune clearance usually occurs in newly infected children and adults (1). Since HBV is a non-cytopathic virus and hepatic damage stems from host immune activity, the IT moniker was derived from early studies demonstrating an inverse correlation between circulating HBV DNA and histologic damage (2). The IT phase is characterized by positive hepatitis B e-antigen (HBeAg), high viremia (typically >107–108 IU/mL), and normal alanine aminotransferase (ALT) activity, but the hallmark is no/minimal necroinflammatory activity and no fibrosis on liver histology (3). Recent studies have challenged the traditional view that the host immune system “tolerates” the virus, as both innate and B-cells responses have been found to be quite active during IT phase, with trained immunity seen in HBV-infected newborns (4,5). Reflecting this new understanding of the hepatitis B immunopathogenesis, alternative terms have been proposed for the IT phase, including “high replicative, low inflammatory” (6) and “non-inflammatory HBeAg positive” (7) phase.
In the absence of curative therapies, the primary objective of HBV therapy remains the prevention of cirrhosis and hepatocellular carcinoma (HCC). The strong positive correlation between HCC risk and HBV DNA levels, independent of ALT and fibrosis stage, identified in the REVEAL-HBV cohort study has fostered consideration of antiviral suppressive therapy across a broader spectrum of HBV-infected. However, since the REVEAL-HBV cohort was 85% HBeAg-negative with median age of 45 years, the number of IT adults included in the cohort was low (8,9). Thus, there remains an important knowledge gap—what is the risk of HCC in adults in the IT phase and can we identify a subgroup of adult IT patients who warrant consideration of HBV suppression for HCC prevention? Kim et al. attempt to address this question in their recent Gut article (10). Using a large retrospective cohort of Korean genotype C patients, they compared incidence of HCC, liver transplantation and mortality over 10 years between 413 IT patients and 1,497 IA patients treated with oral HBV therapy. IT phase was defined as HBeAg-positive, HBV DNA level ≥20,000 IU/mL, and normal ALT (<19 U/L in females and <30 U/L in males) for one year. Patients who transitioned to IA phase [ALT ≥2× upper limit of normal (ULN)] or started on therapy within one year were excluded. The principal finding of their study was a substantially increased risk of HCC (HR 2.5; 95% CI: 1.5–4.2) and death or transplantation (HR 3.4; 95% CI: 1.9–6.2) in IT patients as compared to treated IA patients in adjusted models.
On the surface, these findings are quite concerning. However, the question is whether this was an IT cohort at baseline and for the duration of the study. There are several considerations that suggest this may not be the case. Firstly, 26% had HBV DNA levels <107 IU/mL, (lower than expected for IT patients), 25% with platelet count <167×109/L (suggesting more advanced fibrosis) and the median age of the IT patients (38 years) was older than typically seen in IT phase, although studies have shown genotype C patients tend to seroconvert much later (11). Restricting analysis to patients that better fit the IT phenotype, i.e., age <40 with HBV DNA >107 or 108 and absence of significant fibrosis would have been informative. Second, the baseline characteristics of IT patients who developed HCC warrant a comment. Of those with available liver samples and HCC, 70% had F3-4 fibrosis. A prior high-quality prospective study with paired biopsies showed minimal fibrosis progression in IT patients with persistently normal ALT over 5 years (12). We would argue that if advanced fibrosis is found in an IT patient, high viremia alone is not the only factor; rather, either misclassification occurred, or accumulation of risk with age or additional co-factors such as alcohol, fatty liver or aflatoxin exposure contributed to HCC risk. Since fibrosis assessments were not performed in this study, a subset of patients in the IT group could have had significant fibrosis at baseline, although results were consistent on additional matched analyses that should adjust for fibrosis severity. Most importantly, the transition to MA or IA disease should lead to initiation of antiviral therapy and whether this was systematically undertaken in all IA patients is unclear. Per the reimbursement criteria in Korea, treatment was only started if ALT ≥80 IU/mL. Thus, while patients were censored when treatment was initiated, an unknown number of patients with MA or IA disease remained in the IT cohort. Considering these points, it is difficult to conclude that adults in the IT phase are a high-risk group for HCC.
What this study does highlight is the need for careful evaluation of adults with an IT profile, particularly those over the age of 40 years and those with lower HBV DNA levels (<107 IU/mL) or mildly elevated ALT levels. Serial monitoring and staging of inflammation/fibrosis in HBV patients with an IT serologic profile is crucial to assess for transition and need for antiviral therapy. Guidelines recommend routine assessment for significant fibrosis in HBeAg-positive patients with ALT > ULN but <2× ULN on follow-up (7,13). Growing availability of non-invasive testing such as transient elastography allows for more efficient, accessible and repeated measurements. A potential shortcoming of non-invasive testing is the inability to distinguish fibrosis from moderate-to-severe necroinflammation as both would warrant consideration of therapy in an IT population. A lower necroinflammatory threshold to treat, in addition, may be considered in older patients with reduced capacity for hepatic regeneration (14). As a fully infected liver yields 109–1010 IU/mL of virus in serum, a declining level of HBV DNA (<108 IU/mL) may reflect hepatocyte injury or clonal expansion of virus-resistant hepatocytes. This interesting hypothesis leads to the suggestion that HBV DNA levels, especially if <107–108 IU/mL, may be a marker of transition to a more inflammatory phase, even if ALT levels are not elevated (15). While more natural history studies are needed, the study by Kim et al. serves to remind us of the dynamic nature of chronic hepatitis B and the importance of comprehensive follow-up.
Given the safety of currently approved therapies, one might argue that treatment should be given to all adults with the IT profile, citing the strong correlation between HBV DNA levels and risk of HCC. Concerns for viral integration and clonal hepatocyte repopulation among persons with higher quantities of circulating virus also have been raised (16). Further research in the IT population is needed to clarify this issue. On the other hand, reasons to hold off on antiviral therapy in children and adults with the IT profile include low rates of response (as defined by HBeAg and HBsAg loss) (17,18), cost of long-term therapy, and a lack of established benefit in preventing HCC.
Looking to the future, additional biomarkers to ascertain adults in the IT phase who are at risk for HCC would be highly desirable. In the meantime, a rigorous definition of IT phase in HBV patients is needed in clinical research and in guiding clinical practice. Failure to recognize when an adult in the IT phase is transitioning to a more inflammatory phase is a missed opportunity to prevent future liver complications. In essence, we must no longer simply “tolerate” the adult in the IT phase, but rather actively manage risk factors that promote fibrosis and HCC, such as alcohol use or fatty liver, and serially track changes in the IT profile that signal phase transition to more active disease and the need to initiate antiviral therapy.
Funding: Dr. Zhou is supported by T32 5T32DK060414-14 from the NIDDK.
Conflicts of Interest: K Zhou has no conflicts of interest to declare. N Terrault reports grant support from Gilead Sciences and BMS.
- McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49:S45-55. [Crossref] [PubMed]
- Chu CM, Karayiannis P, Fowler MJ, et al. Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum. Hepatology 1985;5:431-4. [Crossref] [PubMed]
- Andreani T, Serfaty L, Mohand D, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol 2007;5:636-41. [Crossref] [PubMed]
- Vanwolleghem T, Hou J, van Oord G, et al. Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells. Hepatology 2015;62:87-100. [Crossref] [PubMed]
- Hong M, Sandalova E, Low D, et al. Trained immunity in newborn infants of HBV-infected mothers. Nat Commun 2015;6:6588. [Crossref] [PubMed]
- Gish RG, Given BD, Lai CL, et al. Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities. Antiviral Res 2015;121:47-58. [Crossref] [PubMed]
- European Association for the Study of the Liver. Electronic address: email@example.com; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-98. [Crossref] [PubMed]
- Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65-73. [Crossref] [PubMed]
- Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-86. [Crossref] [PubMed]
- Kim GA, Lim YS, Han S, et al. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut 2017. [Epub ahead of print]. [Crossref] [PubMed]
- Livingston SE, Simonetti JP, Bulkow LR, et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 2007;133:1452-7. [Crossref] [PubMed]
- Hui CK, Leung N, Yuen ST, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology 2007;46:395-401. [Crossref] [PubMed]
- Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016;63:261-83. [Crossref] [PubMed]
- Schmucker DL, Sanchez H. Liver regeneration and aging: a current perspective. Curr Gerontol Geriatr Res 2011;2011:526379.
- Chen CF, Lee WC, Yang HI, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology 2011;141:1240-8, 1248.e1-2.
- Mason WS, Gill US, Litwin S, et al. HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant. Gastroenterology 2016;151:986-998.e4. [Crossref] [PubMed]
- Chan HL, Chan CK, Hui AJ, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology 2014;146:1240-8. [Crossref] [PubMed]
- Jonas MM, Block JM, Haber BA, et al. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology 2010;52:2192-205. [Crossref] [PubMed]
Cite this article as: Zhou K, Terrault N. Immune tolerant HBV and HCC: time to revise our tolerance levels for therapy? AME Med J 2018;3:27.