To Treat or Not to Treat: The Conundrum of Immune-Tolerant Chronic HBV

Traditionally, patients who are infected with hepatitis B virus (HBV) early in life, particularly during the neonatal period, enter a prolonged phase that may last for years or decades, known as the immune-tolerant phase. The foundation for understanding this phase is the prevailing concept that liver damage in chronic hepatitis B is not directly related to the virus but rather to the immunologic response to the virus. The immune-tolerant phase is characterized by hepatitis B e antigen (HBeAg) positivity and very high HBV DNA levels resulting from a relatively permissive state for viral replication attributed to the relative absence of an immune response. During this phase, the liver cells remain undamaged and alanine aminotransferase (ALT) levels remain within the normal range. Correspondingly, liver biopsies performed during this window show no active necroinflammation and almost always no fibrosis because the patient has not been through an immune-active phase that is necessary to generate scarring or fibrosis.

Current Guidelines
Despite the very high HBV DNA levels in these patients, the American Association for the Study of Liver Disease (AASLD) continues to recommend against routine treatment. Historically, there have been several reasons for this recommendation. The first is the general absence of necroinflammation or fibrosis throughout this phase. Multiple publications have reported a low risk of liver damage in patients with immune-tolerant disease. Most notably, a 2007 Hepatology study from Hui and colleagues followed 48 immune-tolerant patients with chronic HBV infection and found that only 6.3% had fibrosis progression after 5 years whereas 12.0% actually had regression of mild fibrosis to no fibrosis (F1 to F0). None of the patients progressed to more advanced stages of fibrosis (≥F3), indicating that the immune-tolerant phase, although reflecting a highly permissive state for viral replication, is not associated with progressive liver damage.

Do Immune-Tolerant Patients Respond to Treatment?
A second argument was that immune-tolerant patients simply do not respond to therapy; they rarely have an HBeAg conversion from positive to negative, whether with interferon treatment or treatment with nucleos(t)ides. Starting in the 1990s and continuing for many years, such a seroconversion was considered the benchmark for patients to eventually be able to stop therapy with a good chance of viral quiescence persisting for a long time or indefinitely in the years that followed. Because that main endpoint was essentially nonattainable with interferon, treatment was considered inappropriate for these patients. 

This dogma persisted as the first antivirals became available, including lamivudine in 1998. Again, unfortunately, given the absence of HBeAg seroconversion in most immune-tolerant patients, treatment would have continued indefinitely to maintain viral suppression, and patients usually developed resistance, arguably leaving them worse than they were before treatment. Indeed, lamivudine has a very poor resistance barrier, with up to 70% of patients becoming resistant after 4 years of treatment and potential adverse implications for the subsequent ability to treat them.

Since that time, HBV treatment goals have changed. There has been widespread acceptance that long-term viral suppression, whether attained with finite therapy or long-term therapy, is strongly associated with improved clinical outcomes. However, the arguments against treatment for patients with immune-tolerant disease persisted, as the initial antivirals did not suppress HBV DNA levels as potently in this stage vs the immune active stage; fewer immune-tolerant patients became HBV DNA undetectable. Although technically correct, profound viral suppression with >6 log reduction in the long-term is routinely attainable with agents that confer high resistance barriers.

Pushing Back on Treatment Candidacy
In my opinion, patients with immune-tolerant HBV should always be considered for treatment. To expand on this position, let us address each of the arguments against treatment.

Risk of Hepatocellular Carcinoma and Liver Transplant
First is the observation that these patients do not seem to progress over the follow-up periods that have been studied. It is important to recognize that over these time spans, biological events might be occurring within the patient’s liver that are not measurable by liver biopsy. One example is viral integration into human chromosomes, which is thought to be one of the oncogenic pathways to liver cancer in the context of chronic HBV infection. Recall that immune-tolerant patients maintain extremely high levels of HBV DNA, affording the virus many opportunities for integration. This could initiate a slow progression to liver cancer that might play out over many years or decades, a time span that was not evaluated in the study by Hui et al previously described.

Indeed, in 2018, Kim and colleagues published a study in Gut comparing 413 immune-tolerant patients who did not receive treatment to 1497 immune-active patients who did receive treatment. They found that the 10-year cumulative incidence of hepatocellular carcinoma was higher in the immune-tolerant group vs the immune-active group (12.7% vs 6.1%, respectively; P = .001). Similarly, death or liver transplantation occurred in 9.7% of immune-tolerant patients vs 3.4% of immune-active patients (P <.001).

A criticism of this study has been that the mean age of the immune-tolerant patients was 38 years. The classical immune-tolerant patient profile includes patients younger than 30 years, and it is among these younger patients where the real controversy about whether to treat resides. However, I would argue that it is reasonable to compare the outcomes in these 2 groups, as the mean age of the immune-active group was similar to, although statistically higher than, that of the immune-tolerant group, at 40 years vs 38 years, respectively. At the least, this study makes a strong argument for treating patients who meet the criteria for immune tolerance who are also older (ie, older than 30 years).

HBV DNA Integration Into Host Chromosomes
Let us further explore the biological foundations of this ongoing debate. Renewed debate on the question of treating immune tolerant patients was fueled by Mason and colleagues in 2016 with a publication of a study that assessed HBV DNA integration, clonal hepatocyte expansion, and immune responses in 26 patients with chronic hepatitis B. The cohort included 9 patients with HBeAg-positive immune-tolerant disease, 10 patients with HBeAg-positive immune-active disease, and 7 patients with HBeAg-negative immune-active disease. Of importance, they found a high level of HBV DNA integration randomly distributed among the chromosomes in all 3 groups. Moreover, the degree of clonal hepatocyte expansion in immune-tolerant patients was greater than expected. Finally, HBV-specific T-cells were detectable in the blood of patients in all 3 phases, including the immune-tolerant phase.

Based on these findings and subsequent studies, these authors have championed a more proactive approach to managing patients with immune-tolerant HBV. They have proposed changing the term “immune tolerant” to a “high replication/low inflammation” phase in recognition of the fact that these patients have demonstrable HBV-specific T-cell activity. Of importance, they have concluded that the practice of not recommending antiviral therapy in the immune-tolerant phase requires reconsideration. Another publication in 2020 reiterated and expanded upon this argument.

Setting the Stage for Oncogenesis
From my perspective, a particularly disturbing aspect of letting young people go for years with high levels of unchecked HBV replication is the demonstrated capacity for certain sequences of viral DNA to integrate into human chromosomes at random sites. Such integration can result in transcription and translation of hepatitis B surface antigen, and possibly hepatitis B x antigen, but cannot give rise to whole virus replication. These integration events might involve sites that are proximate to tumor promoter genes or tumor suppressor genes, which could conceivably result in a tendency toward oncogenesis, albeit only after many years.

At the 2020 virtual American Association for the Study of Liver Diseases (AASLD) meeting, 2 studies were presented that have greatly fueled this argument. The first, from Hsu and colleagues, found that (1) the number of expressed viral integrations in patients with chronic HBV infection was significantly correlated with the degree of viremia and the number of dysregulated genes, and (2) treatment with tenofovir disoproxil fumarate (TDF) significantly reduced the number of expressed viral integrations vs placebo. The integrations they described were associated with dysregulation of host genes, including those potentially relevant to oncogenesis, such as p53 and MAP2K. These results lead to plausible speculation that long-term TDF treatment in immune-tolerant patients could reduce the risk of oncogenesis and liver cancer later in life.

In the second study, Chow and colleagues analyzed HBV viral integration in 28 patients with chronic HBV, including 14 HBeAg-positive and 14 HBeAg-negative patients. Using serial liver biopsies obtained before and after initiating treatment with nucleos(t)ide analog therapy, they found a significant 42.5% decline in the median clone size (a measure of the extent of viral integration) from baseline to 1 year (P = .003). Most dramatically, among 5 patients with available liver biopsies 10 years after starting treatment, 3 no longer had detectable viral integrations. This finding raises many questions about what happened to those viral integrations. Was there a selective loss of the cell lines that harbor those integrations? It is not clear. But certainly, in terms of the theoretical possibility that long-term oncogenesis might follow from viral integrations, these studies suggest that long-term treatment with a safe drug that effectively suppresses viral replication could reduce the long-term risk of cancer.

Advantages of Current Antivirals
Circling back to the argument that immune-tolerant patients do not have sufficient viral suppression on antiviral therapy, current antivirals clearly can achieve marked viral suppression. For example, in 2014, Chan and colleagues showed that both TDF monotherapy and TDF plus emtricitabine led to more than one half of immune-tolerant patients achieving HBV DNA <69 IU/mL at Week 192 (remember that polymerase chain reaction cutoffs were higher in those days; now we have more sensitive assays). Of importance, no patients developed resistance to therapy. None experienced HBsAg loss, and there were very few HBeAg conversions, which some might interpret as supportive of the argument to withhold treatment in these patients. However, from my perspective, it is more important that HBV DNA levels decreased from baseline by 6.3 logs with TDF alone and 6.7 logs in the combination group. Even in the TDF monotherapy group, that is a profound reduction in viral load. Moreover, the old argument that immune-tolerant patients should not receive lamivudine because of the inevitable emergence of resistance is nullified by the remarkable track record of no or very limited resistance to tenofovir and entecavir.

Hence, I would argue that we can suppress virus effectively in immune-tolerant patients, even if few of them achieve complete HBV DNA undetectability compared to their “immune active” counterparts. There is increasing evidence that viral integration may have downstream oncogenic effects that can only be measured over very long-term studies. The large scale, long-term trials needed for treatment recommendations to be made on a strong “evidence basis” have not been done and probably will never be done. However, long-term viral suppression without emergent resistance is eminently achievable and, by all indications safe, with currently available therapies. Moreover, we must not overlook the psychosocial and public health implications associated with the burden of high-level viremia in young people. In general, modern thinking about viral diseases has centered around the notion of early and potent viral suppression, particularly if resistance can be avoided. It is time to extend this principle to the highly replicative state that constitutes the immune tolerant phase. 

Summary
To summarize, current AASLD guidelines recommend antiviral therapy for immune-tolerant chronic HBV infection only for adults older than 40 years with normal ALT, elevated HBV DNA (>1,000,000 IU/mL), and liver biopsy showing significant necroinflammation or fibrosis. By implication, the corollary is that we should not treat patients with immune-tolerant disease and a normal liver biopsy who are older than 40 years, nor treat patients under 40 years of age unless there are additional risk factors such as a first degree relative with a history of HBV-associated HCC. Notably, the European Association for the Study of the Liver (EASL) guidelines have evolved to recommend that immune-tolerant patients be treated if they are older than 30 years regardless of the severity of liver histological lesions. I consider this position to be an advance. In my practice, our approach is to consider all for therapy. At the least, our patients deserve a transparent discussion about the status of this debate, with arguments for and against treatment, and a mutually agreed upon decision should be made in concert with the patient.

Your Thoughts?
How do you approach treatment decisions for patients with immune-tolerant chronic HBV infection? Answer the polling question and join the conversation by posting a comment in the discussion section.