Editor's Note:
In view of the hot and difficult question of "whether the immune tolerance period of chronic HBV infection should be treated", the Journal of Clinical Hepatobiliary Diseases published the first article "Should the Immune Tolerance Period of Chronic HBV Infection Be Treated?" by Professor Zhuang Hui in the "Academic Controversy" column of the 2nd issue of 2021. For the guidance, extensively organize experts to discuss. Professor Li Lotian of Langfang People's Hospital, Professor Ye Feng of the First Affiliated Hospital of Xi'an Jiaotong University, Professor Chen Xinyue of Beijing You'an Hospital affiliated to Capital Medical University, Professor Xing Huichun and Professor Xie Wen of Beijing Ditan Hospital affiliated to Capital Medical University discussed the topic. The views of other experts on the topic will be published in the future.
Patients with immunotolenesis for HBV infection should be selectively treated with antiviral therapy
Lotte Lee
Department of Infectious Diseases, Langfang People's Hospital
DOI: 10.3969/j.issn.1001-5256.2021.06.008
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Although the current international mainstream guidelines do not recommend antiviral therapy for patients with immune tolerance for chronic HBV infection, the author believes that antiviral therapy should be given to some immunotobele patients, as described below.
<h1 toutiao-origin="h3" >1</h1>
"Because of the immune tolerance period, the patient has no inflammatory activity or only mild inflammation in the liver", this description does not match the clinical practice, and it is also caused by the incomplete understanding of the concept of "immune tolerance"!
The so-called immune tolerance refers to the specific immune low response or no response state shown by the body's immune system after contact with a certain antigen stimulus under certain conditions. Immune tolerance can be divided into complete immune tolerance and incomplete immune tolerance (also known as partial immune tolerance). Complete immune tolerance refers to the body's stimulation of antigens, with neither a cellular nor a humoral immune response. Cellular immune tolerance is caused by T lymphocyte tolerance, while the formation of humoral immune tolerance may be caused by T lymphocyte tolerance or B lymphocyte tolerance. Incomplete immune tolerance presents with varying degrees of cellular or humoral immune responses. The destruction of hepatocytes is not directly caused by HBV, but by the body's specific immune response to HBV. The body of a fully immune tolerant has neither a cellular immune response nor a humoral immune response to HBV, so it does not cause hepatocyte destruction, and of course there is no elevation of ALT. But a low immune response due to incomplete immune tolerance does not equate to "mild inflammation." Due to individual factors, there may be different degrees of cellular immune response or humoral immune response, resulting in different degrees of destruction of hepatocytes, resulting in different degrees of ALT elevation. This manifests itself in different states such as the immune tolerance phase and the immune clearance phase of chronic HBV infection, and there is no strict and fixed boundary between these two states.
ALT is a dynamic indicator, and the population ALT is continuously distributed, and its normal value is difficult to determine. Since ALT is the most sensitive indicator of hepatocyte damage, countries have made ALT < 1× ULN as an important indicator of the "immune tolerance period", or even the only indicator. The 2018 US guidelines state that "immune tolerance status should be defined according to ALT levels". Our guidelines have always determined the normal standard of ALT as <40 U/L. In fact, ALT levels are independent of viral load. The absence of antiviral therapy because of normal ALT deviates from the therapeutic goal of chronic hepatitis B: to maximize long-term suppression or clearance of HBV. Normal ALT does not equal no inflammatory activity in the liver or only mild inflammation, and in large samples of long-term monitoring cohorts, ALT levels are still associated with liver disease mortality rates even if they are in the normal range for a long time. Multinational studies have shown that more than half of patients with persistently normal chronic HBV infection with hepatic fibrosis staging ≥ F2. Obviously, these so-called immune-tolerated patients should be treated.
2. The idea of "poor antiviral efficacy" during the immune tolerance phase is mostly derived from empirical data on the use of interferons in the past, while there is insufficient evidence for the use of nucleoside (acid) analogues (NAs).
Interferons differ from NAs in their antiviral mechanisms and cannot be applied mechanically. In the phase IV clinical trial of lamivudine, there was no difference in the degree to which NAs reduced viral load regardless of whether the patient's liver function was normal or not, so antiviral therapy should be given to immunototropic patients. It should be clear that the effectiveness of antiviral therapy should be judged on HBV DNA, not other indicators, consistent with the guideline objectives. As noted by the European Society of Hepatology in 2017, "inducing long-term inhibition of HBV DNA is the main therapeutic endpoint of all current treatment strategies".
<h1 toutiao-origin="h3" >3</h1>
Research evidence from Taiwan in China shows that regardless of whether serum ALT is normal or not, elevated HBV DNA is a sensitive indicator for predicting hepatocellular carcinoma in patients with chronic HBV infection. In ALT-normally infected people, elevated HBV DNA levels are an independent risk factor for hepatitis B progression. Patients with immune tolerance usually have a higher HBV DNA load. In addition, HBV can rely on its own HBeAg, HBx and other protein components to interfere with the body's immune system, and high viral load will lead to the body's ability to directly eliminate the virus and induce HBV-specific T lymphocytes to decrease, which is not conducive to virus clearance. Professor Ning Qin has also reported that in patients who have obtained virological suppression after long-term NAs treatment, damaged HBV-specific T lymphocytes have partially recovered their function after in vitro culture. Based on the above points, antiviral therapy for immune-tolerant patients and reducing the HBV DNA load are not only conducive to reducing the risk of cirrhosis and HCC, but also partially relieving the inhibition of the body's immune function by high viral load, which is conducive to breaking immune tolerance, which is more conducive to inhibiting and completely eliminating HBV, which is in line with the goals of the guidelines.
<h1 toutiao-origin="h3" >4</h1>
Major guidelines have made age > 30 or 40 years as an add-on to antiviral therapy, which I think is inappropriate. China's chronic HBV infection immune tolerance stage patients, more than 90% are perinatal and infant stage infection, is incomplete immune tolerance stage patients, such people still have different degrees of immune response to HBV (perinatal and infant stage infection with HBV, 90% and 25% to 30% of develop chronic infection, while only 5% to 10% of infected people after the age of 5 develop chronic infection), resulting in different degrees of immune damage to liver cells. Multiple studies have confirmed that even when HBeAg negative transition occurs, the proportion of HBV-infected people who develop HBeAg-negative chronic hepatitis B increases as they age, which is not conducive to the therapeutic purpose of complete clearance of HBV. The 2017 Guidelines of the European Society of Hepatology propose that HBeAg-positive chronic HBV infection is defined as ALT normal, high levels of HBV DNA, and that such patients who are > 30 years of age may be given (antiviral) therapy regardless of the severity of liver tissue damage. Therefore, it is better to treat patients in the immune tolerance phase appropriately and early.
<h1 toutiao-origin="h3" >5. Antiviral therapy is not advocated for all patients with chronic HBV infection in the "immune tolerance phase"</h1>
Interferons are not effective in "immune tolerance" patients and have large side effects; the mechanism of action of NAs, which only competes with HBV in an "adulterated" manner, is theoretically impossible to completely eliminate the virus. Complete removal of the virus depends on the restoration of the body's immune function. The "immune tolerance phase" patients also include those who are infected in the embryonic stage of the "complete immune tolerance phase", and it is not excluded that a very small number of patients who may be due to genetic differences may cause HBV-specific immune function deficiency, and this population also has no immune response to HBV infection. For such patients, the long-term treatment effect of NAs is not good, and it is easy to lead to drug resistance and viral mutation, so such patients do not need antiviral therapy. How to distinguish whether immune tolerance is "complete"? Although there are currently no relevant studies, it can be roughly distinguished from the presence or absence of an immune response. According to relevant data and clinical practice, in 2009, the author wrote "Suggestions on The Revision of China's Guidelines for the Prevention and Treatment of Chronic Hepatitis B" (published in the "China Medical Tribune" on May 21, 2009, special issue 11-12 editions), in which he proposed to "reduce the normal standard of ALT in China to 30 U/L". It is also proposed that "for patients with chronic hepatitis B, as long as their serum HBV DNA > 105 copies /ml (HBeAg-positive) or HBV DNA > 104 copies/ml (HBeAg negative), and ALT > normal or 1.2 times or 1.5 times normal, antiviral therapy should be actively carried out" should be actively carried out. Before the revision of the 2015 edition of the guidelines in China, the author also published the "Suggestions for the Revision of the Guidelines for the Prevention and Treatment of Chronic Hepatitis B in China (2010 Edition)" in the column chaired by Academician Zhuang Hui on the > "Discussion on the Revision of China<'s Chronic Hepatitis B Guidelines" (published in the "China Medical Tribune" on August 13, 2015, D second edition), which further proposed that "in addition to excluding other causes that may cause elevated ALT (such as drug, alcoholic, fatty, etc.), as long as the ALT > 1× ULN (or ≥ 1.2 ×." ULN), and HBV DNA ≥ 105 copies (HBeAg-positive chronic hepatitis B) or HBV DNA ≥104 copies (HBeAg-negative chronic hepatitis B), early antiviral therapy may be considered." Now, based on relevant data and clinical practice in recent years, the author believes that it is appropriate to set the standard of ALT in the immune tolerance phase to 30 U/L. If the standard is exceeded and the viral load is high, antiviral therapy should be considered.
Zhi Xie: This article acknowledges the valuable revision suggestions provided by Academician Zhuang Hui.
Patients with immune tolerance to HBV infection should be individualized
Cui Zixin, Li Jiayun, Wei Peiyao, Chen Yunru, Li Jianzhou, Ye Feng
Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University
DOI: 10.3969/j.issn.1001-5256.2021.06.009
Currently, there are only 2 treatment strategies for chronic hepatitis B, namely immune control and viral control, and none of the existing antiviral drugs can achieve a true cure. Therefore, it is important to personalize treatment for patients with immune tolerance to HBV infection.
The high viral load and high infectivity of patients with immune tolerance for HBV infection, and the controversy over whether antiviral therapy is available or not, mainly focuses on the efficacy of the drug and when to discontinue the drug. Based on the recommendations of the major guidelines, age and family history are key to initiating antiviral therapy in immunototropic patients. Hui et al. [1] assessed liver disease progression in 57 adult HBV-infected patients in the immune-tolerable phase, all of whom underwent a first liver biopsy and a second liver biopsy after 5 years of follow-up. Initial liver biopsy fibrosis stage (Ishak score) F0 33.3%, F1 66.7%; At the end of the follow-up, 84% were still immune-tolerated (the degree of liver fibrosis was comparable to the initial); Patients with abnormal serum ALT levels have more severe progression of liver disease than those in the immune-tolerated phase. The above data confirm part of the view that most adult HBV carriers in the immune-tolerant phase do have mild liver disease, but that liver disease progresses very little in immune-tolerant patients. Therefore, the risk of disease progression in patients with HBV immune tolerance appears negligible, and anti-HBV therapy is not urgent for this subset of the population. However, there are also studies [2] suggesting that antiviral therapy may help reduce the incidence of end-stage liver disease events in immune-tolerated patients, with 12.7% of immune-tolerated patients without nucleoside analogues followed up, compared with only 6.1% of treated patients. In view of this problem, the author recommends follow-up observation of young immune-tolerated patients; Antiviral therapy may be considered in patients aged 30 to 35 years who have a family history of liver fibrosis in patients with a family history > F1.
While most immunototrope patients are young, a small proportion are > 40 years of age. It is unclear whether antiviral therapy is beneficial in older immune-tolerated patients without significant liver disease activity. However, because the elderly population often combines other diseases, it is more susceptible to drug side effects and drug interactions and adverse drug reactions. Therefore, the application of drugs requires a number of trade-offs. In addition, in patients with persistent HBV DNA levels above 2 000 000 IU/ml but normal ALT levels, high viral load is not associated with the expected high risk of liver cancer [3], so if HBeAg-positive elderly patients are immunotobegged and the degree of liver fibrosis is shown to be very mild by liver biopsy or hepatic fibrotic elastography, immediate antiviral therapy is not necessary. Of course, such an idea needs to be supported by more multicentre, large-sample clinical trials.
High viral load is a marker of active viral replication and is associated with hepatitis activity and high risk of progression to cirrhosis or even liver cancer. However, some studies at this stage suggest that the immune tolerance of viral replication in these patients appears to have prevented the progression of the disease. At present, there is still a lot of controversy in the immunological findings of the immune tolerance period of HBV infection, and it is expected that more convincing evidence will be available in the future to clarify this interesting and important issue. In addition, the understanding of the natural course of the disease in immune-tolerated patients needs to be improved. Only by accurately defining the immune tolerance period can patients be individualized.
In general, the study of immune-tolerated patients needs to be further deepened, and more liver tissue biopsy, family history, and age need to be considered comprehensively for the indications of the drug.
Patients with immune tolerance for chronic HBV infection should be given selective antiviral therapy
Chen Xinyue, Song Aixin
Department I, Liver Disease Center, Beijing You'an Hospital, Capital Medical University
DOI: 10.3969/j.issn.1001-5256.2021.06.010
In the Asia-Pacific region, where HBV is highly prevalent, especially in China, the main route of HBV infection is perinatal transmission or vertical transmission, and a fairly high proportion of newborns or young children will develop chronic infection after infection with HBV and enter the so-called "immune tolerance phase" [1-2], which can last for several years or even decades. In view of the difficulty of treatment of the HBV immune tolerance period and the effect of current drug therapy, for a long time in the past, most guidelines and experts at home and abroad did not recommend antiviral therapy for patients with immune tolerance, believing that the liver damage in this period was mild, the disease progression was slow, and the effect after treatment may be poor. So far, the concept of immune tolerance is still recognized by most scholars. However, since 2015, some scholars believe that there is a lack of meaningful immunological data to support the concept of "immune tolerance". Multiple studies [3-5] suggest that the immune tolerance period may only be superficially "calm", and a considerable number of patients actually have obvious liver inflammation and fibrosis, and the disease continues to progress in long-term follow-up, eventually leading to adverse outcomes such as end-stage liver lesions. In immunotoberating patients, the risk factors affecting the development of hepatocellular carcinoma (HCC) are no less than those in the immune clearance phase [6], so "immune tolerance" should not be taken lightly, and timely intervention may help improve prognosis.
In the past 2 years, the relevant guidelines have begun to take a relatively positive attitude towards the treatment of hepatitis B, and have also put forward different views on whether to treat the immune tolerance period. Based on the current research progress in the immune tolerance period of HBV infection, the author believes that such patients should not only be observed and not treated, even in the current case of limited effectiveness of antiviral drugs, some patients can be tried to treat, but the treatment population is not easy to expand, and should be carried out under the guidance of experienced experts. Although there is no evidence of large sample follow-up studies, the cases of clinically relevant adverse outcomes are worth reflecting on. The author's center has received a young female patient who has a family history of hepatitis B but no HCC risk factors, and the long-term follow-up biochemical and imaging indicators do not indicate disease progression, so antiviral therapy is not given. However, HCC was detected at the age of 38 years and 3 months of gestation, and this outcome was untreatable. Although the probability of such cases occurring is small, it is a devastating blow to the families that occur. In addition, the author also observed in the clinic that patients in the immune tolerance stage underwent laparoscopic surgery due to gallstones, cholecystitis, etc., and found that there were more nodules on the surface of the liver during the operation, and such lessons have exceeded 10 cases. It can be seen that imaging and non-invasive examination have a certain lag, which may cause some patients to make diagnostic errors and delay treatment.
Therefore, the author is more inclined to take a positive attitude towards the treatment of immune-tolerated patients. It is recommended that the following types of patients give priority to treatment: (1) those who are willing to undergo liver puncture examination and confirm the condition after investigation; (2) For high-risk groups with cirrhosis and HCC family history, treatment can be actively carried out regardless of age and sex; (3) Through close follow-up of patients in the immune tolerance stage, combined with their biochemistry, ultrasound, FibroScan and other examination results found that there is disease progression, immediately start treatment. Once the treatment is started, the author believes that the following points need to be fully communicated with the patient and reached consensus: (1) The difficulty of treatment limited to the current immune tolerance period may not be able to achieve "gold and silver" (obtaining HBsAg clearance and HBeAg conversion), and the treatment goal is to focus on the improvement of long-term prognosis, which can delay the occurrence of cirrhosis and HCC, and maintain a good liver foundation in the process of waiting for new drugs to be launched, and then obtain the opportunity for possible cure; (2) Strong, high resistance barrier antiviral drugs should be selected as the basis, long-term medication, for some patients with good response effect, combined immunomodulatory drugs (such as pegylated interferon) can also be considered, so that some patients can not only get a virological response, but also a serological response; (3) Inform that good medication adherence is closely related to the treatment effect, and can avoid the occurrence of poor response or even drug resistance; (4) Even if the corresponding treatment is carried out, it does not mean that you have entered the "safe", and you still need regular and long-term follow-up.
In summary, the author believes that antiviral therapy can be carried out for some immune-tolerant patients and corresponding clinical and basic research can be carried out to accumulate clinical experience and provide evidence-based medical evidence for further expanding the relevant treatment population.
Antiviral therapy is not recommended in patients with real chronic hepatitis B immune tolerance without comorbidities
Quan Min, Xing Huichun
Beijing Ditan Hospital, Capital Medical University, Department III of Liver Disease
DOI: 10.3969/j.issn.1001-5256.2021.06.011
HBV infection is a progressive disease, and 25% of chronic HBV-infected people without antiviral therapy develop cirrhosis and/or liver cancer[1], with HBV being the initiating factor, so antiviral therapy has become critical to treatment. However, in the course of chronic HBV infection, the immune tolerance period is a special period - although the viral load is relatively high, the patient's liver function is normal, and there is no obvious inflammatory necrosis and fibrosis of liver tissue, indicating that HBV virus infection has not caused significant liver damage, and HBV and the host are in a state of "peaceful coexistence". Although the patient carries the virus, his daily work and life are not affected; And the antiviral effect of existing anti-HBV drugs on such patients is also limited. Therefore, antiviral therapy is not recommended for patients in the truly immune-tolerant phase until the advent of more effective anti-HBV drugs.
<h1 toutiao-origin="h3" >1. Antiviral therapy in immunototropic patients is ineffective</h1>
The currently available antiviral regimen has poor seroconversion for most immune-tolerant patients[2], such as Chan et al. [3] Treatment of immunofovir or tenofovir/emtricitabine for 192 weeks, and it was found that only 3 (5%) patients had HBeAg serotransformation, and all patients did not develop HBsAg clearance. Wu et al. [4] Antiviral therapy was administered to 121 immunotobetic patients undergoing IVF assisted reproductive technology, namely tenofovir combined with tibivudine (60 cases) and tenofovir monotherapy group (61 cases), and the HBeAg seroconversion rate was 8.3% vs 3.3% after 2 years, respectively. In a recent study[5] immune-tolerant patients from 11 Asian regions treated with peginterferon and entecavir for 40 weeks, HBeAg clearance was only 4%, and all patients rebounded HBV DNA to baseline levels after discontinuation of treatment. Clinically, some patients aged < 20 years old, HBV DNA > 8 lg IU/ml, liver function is not ideal after antiviral therapy decline is not ideal, and some patients still > 4 lg IU/ml after 2 years. Therefore, antiviral therapy should be treated with caution in such patients.
< h1 toutiao-origin="h3" >2. Liver disease progresses slowly in patients in the immune-tolerant phase</h1>
Hui et al. [6] followed up 57 patients with chronic hepatitis B (CHB) immune tolerance [ALT normal (4-42 U/L), HBV DNA >7.12 lg copy/ml, mean age 31 years], and found that there was no statistical difference in liver histology HIA scores and no significant changes in HBV DNA quantification after 5 years of follow-up. There was no significant change in ALT levels. Lee et al. [7] studies have shown that the cumulative incidence of hepatocellular carcinoma (HCC) in chronic HBV infection in the immune tolerance stage (HBeAg-positive, sustained high levels of HBV DNA, and normal ALT) was 0, 1.1%, 1.9%, and 1.9% in 3, 5, 7, and 9 years, respectively; The cumulative incidence of HCC in inactive HBsAg-carrying states (HBeAg-negative, HBV DNA <2000 IU/ml) was 0, 0, 0.4%, and 1.2%, respectively. HCC was not seen in immune-tolerated patients with HBV DNA > 106 IU/ml, and the risk of developing HCC in immune-tolerated patients was considered negligible. Theoretically, the true immune tolerance period is that there is no obvious inflammation and fibrosis, and the progression of liver disease is naturally slow, which can temporarily delay antiviral therapy. Once liver fibrosis and inflammatory progression are found (no longer in the immune tolerance phase), antiviral therapy is given.
<h1 toutiao-origin="h3" >3</h1>
Although a prospective cohort study based on community populations in Taiwan (REVEAL study)[8] showed that high levels of serum HBV DNA (> 104 copies/ml or >2000 IU/ml) were associated with HCC progression; The incidence of HCC was 6.7% in patients with normal ALT, HBeAg-positive, and HBV DNA levels of 2×104 to 10 IU/ml. But 85 percent of the population included in the study was HBeAg-negative, with an average age of 45 years and people under 30 years of age not included in the study, suggesting that a significant number of patients in this population may have been immune-tolerated. In addition, Korean studies [7 9]] showed that the cumulative incidence of HCC in immuno-tolerated patients (ALT<19 U/L in women and< 30 U/L in men) who did not receive antiviral therapy for 10 years was significantly higher than that of patients receiving antiviral therapy during the immuno-reactive period (ALT>80 U/L) (6.1%). However, the average age of the immune-tolerant patients enrolled in the study was 38 years, which was greater than the age of the generally immune-tolerated patients in the natural history of HBV infection, and 26% of the patients had HBV DNA levels of <107 IU/ml, and whether these patients were still immune-tolerant needed further verification. In addition, the immune-tolerant population included in the study was defined at the time of enrollment, and it is well known that most patients in the immune-tolerant phase enter the immune-active phase with age, the study only excluded patients who turned into the immuno-active phase within 1 year, and in the subsequent 9 years of follow-up, how many patients would break the immune tolerance? If these patients who enter the immune activity phase do not give antiviral therapy in time, the progression of liver inflammation and fibrosis will be higher than that of patients with antiviral therapy. In clinical practice, patients who are regularly followed up will be evaluated in each follow-up, and once it is found that the patient has broken the immune tolerance, antiviral therapy should be actively pursued. Therefore, the question of whether antiviral therapy begins in the immune tolerance period or whether antiviral therapy benefits more after breaking immune tolerance requires more research and clinical experience. The author's team found that if the HBV DNA was lower than the detection line within 24 weeks after receiving antiviral therapy in CHB patients, the baseline HBV DNA load no longer affected the occurrence of adverse events such as HCC and liver disease decompensation. The relationship between different levels of HBV DNA and the occurrence of HCC is not linearly correlated, so it is not recommended to prevent the occurrence of HCC through antiviral therapy in immune-tolerated patients.
<h1 toutiao-origin="h3" >4. Accurate differentiation of immune tolerance periods is critical</h1>
One of the important reasons for the debate over whether to treat patients in the immune tolerance phase is the lack of specific indicators to evaluate whether the patient is immune tolerant. At present, ALT combined with HBV DNA levels are often used clinically. In fact, a significant number of patients may not have mild liver inflammation or fibrosis despite normal ALT [10]. Liver biopsy, as the gold standard for evaluating liver histological injury, cannot be routinely used because of its invasive nature. Therefore, the non-invasive evaluation of immune tolerance should be combined with a number of indicators, including not only ALT level, HBV DNA load, hepatic transient elasticity, imaging characteristics (whether splenomegaly, etc.) need to be considered, and the liver function indicators also need to be dynamically evaluated and excluded from the influence of hepatoprotective drugs. The immune tolerance period is only a period in the disease process, and with age, it is possible to break the immune tolerance at any time and cause liver inflammation and fibrosis. Therefore, under the premise of limited antiviral drugs available, patients in the immune tolerance phase can be suspended from antiviral therapy, but follow-up is required. It is worth paying special attention to how to identify patients in the true immune tolerance phase from the normal population of ALT is very important. For patients who are no longer truly immune-tolerant, antiviral therapy should be aggressive, even if ALT is normal.
It should be noted that special populations in the immune tolerance phase (e.g., those with extrahepatic manifestations: glomerulonephritis, vasculitis, polyarteritis nodosa, peripheral neuropathy, or tuberculosis infection, etc.) are not covered by this article. Antiviral therapy is an important measure to protect patients from hepatitis activity due to complications that may require chemotherapy or immunosuppressive therapy due to extrahepatic injury.
In summary, the author suggests that clinically, it should first be clear whether the patient has extrahepatic comorbidities and whether it belongs to the real immune tolerance period, which should be combined with the ALT level and pay attention to the comprehensive assessment of HBV DNA load; When liver biopsy cannot be achieved, the application of other noninvasive liver fibrosis evaluation indicators should be emphasized. Second, we should pay attention to the age node, 30.7 years old is an age node for the average loss of immune tolerance [11-12]. For those > 30 years of age, infection at a young age, especially in the case of mother-to-child transmission and those with a family history, closer follow-up is required. When formulating antiviral strategies, multivariate analysis and dynamic evaluation of multiple indicators should be comprehensive, neither missing the opportunity to fight the virus, nor recommending antiviral therapy for chronic HBV infection with a truly immune tolerance period and no extrahepatic complications.
How can people with normal ALT and HBeAg-positive chronic HBV infection choose the right time for treatment?
Zhao Hong, Xie Wen
Liver Disease Center of Beijing Ditan Hospital, affiliated to Capital Medical University
DOI: 10.3969/j.issn.1001-5256.2021.06.012
Antiviral therapy in patients with normal ALT and HBeAg-positive chronic HBV infection remains controversial. China's guidelines recommend that for patients with chronic HBV infection with normal ALT, one of the following 4 conditions can be treated with antiviral therapy: (1) liver histology shows significant inflammation and/or fibrosis (G≥2 and/or S≥2) ;(2) has a family history of hepatitis B cirrhosis or liver cancer and is > 30 years old; (3) Those with an age > 30 years old, non-invasive diagnostic techniques, and obvious liver inflammation or fibrosis; (4) HBV-associated extrahepatic manifestations (e.g., HBV-associated glomerulonephritis vasculitis, polyarteritis nodosa, etc.). Current guidelines for chronic HBV infection (HBV DNA positive, normal ALT) with normal ALT do not recommend treatment because of the slow progression of the disease and poor antiviral therapy in these patients. However, in clinical work, regular physical examination ALT is normal, and it is not uncommon for the first diagnosis of liver failure, cirrhosis, and hepatocellular carcinoma (HCC).
In 2006, a prospective cohort study[1] enrolled 3653 HBsAg-positive HBV-infected patients aged 30-65 years, with an average follow-up of 11.4 years, and the cumulative incidence of HCC was related to HBV DNA levels at enrollment, with HBV DNA levels < 300, 300-9999, 10 000-9999, 100 000-9999, and ≥ 1 000 000 copies/ml, respectively, 1.30% of HCC accumulation rates in patients with HBV DNA levels of 300, 300-9999, 1000-9999, 100 000-9999 and ≥ 1 000 000 copies/ml, respectively. , 1.37%, 3.57%, 12.17%, and 14.89%. In 2018, a retrospective cohort study [2] of Korean scholars included 413 patients in the immune-tolerant group, 1497 patients in the immunoactive antiviral therapy group, and 1141 cases in the mildly active group (ALT 1-2 times the upper limit of normal value), and the results showed that the cumulative incidence of HCC in the immune-tolerant group (12.7% vs 6.1%, P=0.001) and the case fatality/transplant rate (9.7% vs. 3.4%, P<0.001) were significantly higher than those in the immunoactive treatment group. Inverse probability weighting, propensity scoring, and competitive risk models were used to analyze, and the results showed that the untreated immune tolerance group was at higher risk of HCC and death/transplantation than the treated immunocompetent group. In 2020, a study on the natural history of immune-tolerated patients[3] included 126 untreated immune-tolerated patients and 621 immune clearance patients, and the baseline indicators of the two groups were balanced by inverse probability-weighted and propensity scores, respectively, and the results showed that the cumulative risk of HCC in untreated immune-tolerant patients was extremely small, comparable to that of immune clearance patients. Therefore, there is controversy about the long-term prognosis of immune-tolerated patients.
At present, there are not many studies on the clinical efficacy of immune-tolerated antiviral therapy in chronic HBV infection. In 2017, a national, multicenter, retrospective study[4] in South Korea included 484 patients with HBeAg-positive, HBV DNA levels > 20 000 IU/ml, ALT <40 U/L, and no evidence of cirrhosis, with the primary endpoint of HCC and the secondary endpoint progression to cirrhosis. The results showed that endpoint events occurred in 3 of the 87 patients in the antiviral treatment group and 22 of the 397 patients in the non-antiviral treatment group. After the propensity score, the risk of HCC (HR=0.234, P=0.046) and cirrhosis (HR=0.235, P=0.015) was significantly reduced in the antiviral treatment group. After counterprobastic weighted balancing baseline features, antiviral therapy significantly reduced the risk of HCC (HR=0.189, P=0.004) and cirrhosis (HR=0.347, P=0.036), suggesting that patients with high levels of HBV DNA and HBeAg-positive chronic HBV infection may still be at risk of disease progression, and antiviral therapy may reduce the risk of HCC and cirrhosis.
HBV DNA levels are an independent risk factor for HCC in chronic HBV-infected patients, and effective antiviral therapy can significantly reduce HBV DNA levels and reduce the occurrence of cirrhosis and HCC. Therefore, for patients in the immune tolerance phase, do you still continue to monitor until the disease progresses to significant liver inflammation and necrosis or fibrosis, or even liver failure, cirrhosis, HCC and then treatment? In today's good safety and accessibility of antiviral therapy drugs, can the timing of treatment be moved forward? Can aggressive antiviral therapy delay disease progression and reduce the incidence of liver failure, cirrhosis, and HCC? In response to the above problems, more relevant clinical studies are needed to provide evidence-based medical evidence, and efforts are needed to better achieve the Goal of "Eliminating the Public Threat of Hepatitis B by 2030" proposed by the World Health Organization.
Academic Controversy | Immune Tolerance Period for Chronic HBV Infection – Treatment? Not treated?
Academic Controversy | Immune Tolerance Period for Chronic HBV Infection – Treatment? Not treated? (Issue 2)
Zhuang Hui, | Academic Controversy: Should chronic HBV infection be treated during the immune tolerance period?