The treatment endpoint is a state of durable immune control achieved by antiviral therapy.
Antiviral therapy for chronic hepatitis B has gone through a history of more than 10 years, and the evaluation of efficacy has progressed from the achievement of virological response (HBV DNA conversion), to serologic conversion in HBeAg-positive patients, to the disappearance of HBsAg/serologic conversion in HBeAg-positive or HBeAg-negative patients, and the continuous improvement of therapeutic goals. In the ongoing in-depth study of the understanding of different treatment goals and their clinical significance, it was found that it is not enough to obtain suppression of HBV DNA replication during treatment in both HBeAg-positive and negative patients. In HBeAg-positive patients, no matter how long the suppression of HBV DNA replication is achieved during treatment, and no matter whether it is interferon therapy or nucleoside (acid) analogue (NA) therapy, if HBeAg serological conversion is not obtained, the majority of patients will lead to HBV DNA replication and disease relapse after discontinuation of treatment; in HBeAg-negative patients, if only viral response without HBsAg level decrease during treatment, it will also lead to HBV DNA replication and disease relapse after discontinuation of treatment. HBeAg negative patients, if only viral response without HBsAg level decrease during treatment, will also lead to relapse after stopping treatment. HBeAg-positive patients with HBeAg seroconversion based on suppression of HBV DNA replication and HBeAg-negative patients with significant decreases in HBsAg through treatment often have durable virological responses after discontinuation of the drug.
Chronic hepatitis B occurs when viral replication stimulates the body’s immune response, which in turn leads to damage to liver cells and tissues. Therefore, in the treatment of chronic hepatitis B, either the damage to liver tissue is mitigated by effective suppression of viral replication, which is insufficient to stimulate the immune response, as in the case of NA, or by effective immune stimulation, which is sufficient for the body’s immunity to effectively inhibit viral replication and clear virally infected hepatocytes, mitigating liver tissue damage and slowing disease progression. To enable patients to control viral replication and continue to clear virally infected hepatocytes even after stopping treatment, the body’s ability to control immunity against HBV is ultimately required. Therefore, the concept of immune control has evolved: when a patient achieves durable immune control, it means that the patient can continue to suppress viral replication and stop or delay the progression of liver disease after stopping treatment, which means that the patient can stop the drug, or reach the endpoint of treatment. 2012 ESLA states that durable undetectable HBV DNA levels and HBeAg serological conversion after stopping the drug are satisfactory and persistent HBsAg disappearance or serologic conversion after drug discontinuation as desirable treatment endpoints. As can be seen, the treatment endpoint is a state achieved through treatment, a state of immune control of HBV after discontinuation of the drug; not the length of treatment or simply a course of treatment calculated in terms of time. Although there is a duration of treatment in the drug’s specification, it is only the duration of treatment designed to achieve efficacy in patients in clinical trials before the drug is marketed.
Treatment endpoints and clinical prognosis.
The goal of antiviral therapy for chronic hepatitis B is to maximize long-term suppression of viral replication, thereby reducing liver inflammation, delaying and stopping the progression of liver disease, and ultimately reducing the incidence of liver failure, cirrhosis and its complications, and liver cancer, prolonging patient survival and improving quality of life. The key to achieving these therapeutic goals is whether the treatment reaches the therapeutic endpoint, i.e., the sustained suppression of viral replication even after drug discontinuation. Numerous clinical studies have demonstrated that achieving clinical treatment endpoints after treatment can lead to good long-term outcomes for patients. In HBeAg-positive patients with chronic hepatitis B, HBeAg serologic conversion (satisfactory treatment endpoint) occurs through treatment, and 86% of patients can obtain durable suppression of viral replication after discontinuation of treatment, and the number of patients in whom HBsAg disappearance occurs in immune controllers increases year by year as time increases. In contrast, 96% of patients who did not achieve HBeAg serologic conversion during treatment experienced rebound of HBVDNA after discontinuation. Whereas the achievement of the desired endpoint (HBsAg disappearance/serological conversion) may lead to a more favorable clinical outcome for patients, the results of a long-term cohort study of chronically HBV-infected individuals showed that the only indicator of a favorable long-term outcome for chronically HBV-infected individuals was HBsAg disappearance. In contrast, the results of another study showed that patients with chronic HBV infection who obtained HBsAg disappearance before the onset of cirrhosis had zero incidence of cirrhosis, hepatocellular carcinoma, and death from HBV liver disease-related disease during long-term clinical follow-up. Therefore, achieving the treatment endpoint (obtaining durable immune control) is the therapeutic goal pursued by antiviral therapy for chronic hepatitis B.
HBV virologic and serologic indicators and adjudication of treatment endpoints.
Although EASL 2012 states that HBeAg serologic conversion is a satisfactory treatment endpoint and HBsAg disappearance/serologic conversion is a desirable treatment endpoint. However, the relationship between serum HBV DNA level, HBeAg serologic conversion and HBsAg disappearance should be fully understood in clinical practice. First, HBV DNA conversion during treatment is a necessary condition for HBeAg serological conversion and HBsAg disappearance. If HBV DNA does not reach below the detection limit, even if HBeAg serological conversion occurs, it is difficult to suppress viral replication permanently after drug discontinuation; secondly, attention should be paid to whether HBeAg serological conversion can really reflect immune control of the virus. In clinical practice, there are often patients with high HBV DNA levels and low HBeAg levels, and the low HBeAg levels in these patients are often caused by viral mutation rather than immune clearance of the virus. For those with high HBV DNA load but low HBeAg level before treatment, although HBV DNA negative and HBeAg serological conversion are also achieved through treatment, it is also difficult to demonstrate clearance and immune control of virally infected hepatocytes if there is no decrease in HBsAg level. Third, the true significance of HBsAg disappearance for the individual patient. Studies have shown that HBsAg levels correlate with liver cccDNA levels and the degree of clearance of virally infected hepatocytes, therefore, HBsAg disappearance should be based on serum HBV DNA negativity and HBeAg serological conversion after treatment, although in clinical practice there can be a small number of patients with HBsAg disappearance but still positive for HBeAg, which is just a matter of HBeAg and HBsAg There is some difference in the sequential pattern of disappearance, most clinical patients have HBeAg serological conversion before HBsAg disappearance, but it is indeed observed that a few patients have HBsAg disappearance first and HBeAg serological conversion later. The 2009 EASL clinical problem solving for chronic HBV infection (HBsAg disappearance) is defined as the disappearance of HBsAg or serological conversion, below the HBV DNA detection line and normal ALT levels. In clinical practice, a comprehensive analysis should be performed based on the changes in HBV DNA levels, HBeAg levels and HBsAg levels before and after treatment of patients and their correlation, especially considering the errors caused by the accuracy of the detection reagents.
Rationale for extended treatment to improve immune control rate.
A therapeutic endpoint is a state of immune control of HBV achieved by treatment, after cessation of drug therapy, which occurs on the basis of interferon therapy that effectively inhibits HBV replication while clearing virally infected hepatocytes to a certain level. However, the efficacy of the patient’s treatment is influenced by various factors such as the virus, the immune status of the organism, the intensity of the immune response during interferon therapy and the drug dosage form. Studies have shown that the rate of clearance of free HBV particles in serum, the half-life of viral clearance in blood during interferon therapy, the half-life of virally infected hepatocyte clearance, and the rate of cccDNA clearance vary dramatically between individuals. In patients with chronic hepatitis B in a natural state of infection, the half-life of HBV clearance in blood is determined by the immune status of the host, the HBV level in the blood and the HBeAg status. The lower the viral content in the blood, the faster the viral clearance. The half-life of HBV clearance in the blood of HBeAg-positive HBV-infected patients ranged from 4 to 224 minutes (mean 46 minutes), and the median for HBeAg-negative patients was 2.5 minutes. In contrast, in pegylated interferon a-2b combined with lamivudine for HBeAg-negative patients, the half-life of free virus in the blood was 2.4 to 69.2 hours, and the half-life of virally infected cell clearance was 2.5 to 75 days, while in the recovery of acute HBV hepatitis in orangutans, the half-life of HBV cccDNA was 0.6 to 8 days. In interferon antiviral therapy, the efficacy of interferon was also correlated with the expression of interferon receptors on the surface of immune cells, and the level of interferon receptor expression in immune cells varied significantly among patients. In interferon anti-HBV therapy, the achievement of immune control status depends on the rate of virus clearance, but also on the rate and degree of clearance of virus-infected cells. Therefore, the probability of achieving immune control, the time required to obtain immune control, and the degree of immune control status (HBeAg serological conversion and HBsAg disappearance) vary greatly among individuals with chronic hepatitis B treated with interferon. This means that some patients will require extended treatment to achieve immune control and some will require longer treatment in pursuit of higher immune control goals.
Selection of patients for extended treatment and determination of efficacy.
Immunocontrol and its achievement consists of three levels.
1) The need for a durable viral response in both HBeAg-positive and negative patients.
2) the presence of durable HBeAg serologic conversion in HBeAg-positive patients.
3) The ideal treatment endpoint is the disappearance of HBsAg or serologic conversion in both HBeAg-positive and negative patients.
Of these three levels, for the vast majority of patients, the clinical pursuit of HBeAg serologic conversion, and HBsAg disappearance/serologic conversion is most important. Numerous studies have shown that prolonged therapy can significantly improve HBeAg seroconversion rates in HBeAg-positive chronic hepatitis B, improve durable viral response rates in HBeAg-negative patients, and improve HBsAg disappearance rates. Although controlled clinical studies have demonstrated that prolonged therapy can improve the rate of durable immune control, in clinical practice, it may be more important to individualize patient treatment so that patients have a greater chance of achieving durable immune control or higher levels of immune control, and clinical practice must identify who needs prolonged therapy, when to prolong therapy, and discontinuation criteria for patients. Based on a synthesis of evidence-based medical evidence, “Some Supplements to Expert Recommendations on Interferon Therapy for Chronic Hepatitis B” (“Expert Recommendations”) made the following recommendations for extending treatment or not for patients with chronic hepatitis B: 1) For HBeAg-positive patients, continue treatment until 48 weeks if HBsAg quantification decreases to ≤1500 IU/ml at 24 weeks of treatment. For those with HBeAg serological conversion at 48 weeks and HBsAg quantification continues to drop significantly to less than 250 IU/ml, the course of treatment can be extended to 72 weeks or longer to achieve HBsAg clearance; for patients who have not experienced HBeAg serological conversion at 48 weeks, continue to extend to 72 weeks. If HBsAg quantification decreases to 1500-20000 IU/ml at 24 weeks of treatment, continue to extend to 72 weeks. 2) Interferon treatment for HBeAg negative patients at 24 weeks, if HBsAg quantification decreases >llg IU/mL, continue treatment to 48 weeks. At 48 weeks of treatment, those with HBsAg quantification <10 IU/mL and continued decline can extend treatment for 72 weeks or longer to achieve HBsAg clearance; at 48 weeks of treatment, patients with HBsAg >10 IU/mL but still continued steady decline can continue to extend treatment to 72 weeks or longer to reduce virological relapse after drug discontinuation.
The Expert Recommendations indicate the rubric for deciding whether or not to extend treatment in patients, but for the treatment of individuals with chronic hepatitis B, the following points are more important to note.
1) Although the role of HBV DNA changes in predicting achievement of treatment endpoints is not specifically stated in the Recommendations, the achievement of HBV DNA below the detection line during treatment is fundamental to the achievement of durable immunologic control and the achievement of treatment endpoints; therefore, patients who fail to achieve HBV DNA below the detection line early in treatment should promptly adjust their regimens.
(2) Although the level of HBsAg at 24 weeks can predict the acquisition of HBeAg serologic conversion, the magnitude of the decrease in HBsAg level may be more important as an individual patient on treatment compared to baseline, and the magnitude of HBsAg decrease may better reflect the extent of clearance of virally infected hepatocytes during interferon therapy. The goal of durable immune control is difficult to obtain even if the HBsAg level is below 1500 IU/ml for those who do not have a significant decrease at 24 weeks of treatment.
3) While observing the changes in HBsAg levels, it is also necessary to see whether and to what extent the levels of HBeAg have decreased. For those who have no decrease or only a mild decrease in HBeAg levels at 24 weeks of treatment, it is also necessary to adjust the treatment strategy, not just to extend the course of treatment. Studies have shown that only 4% of patients with chronic hepatitis B treated with pegylated interferon a 2a alone who still had HBeAg levels >100 PEIU/ml at 24 weeks of treatment were able to obtain HBeAg serological conversion at 48 weeks of treatment.
(4) For HBeAg-positive chronic hepatitis B patients, while observing the changes in HBsAg and HBeAg levels during treatment, the degree of matching between HBeAg levels and HBV DNA levels before treatment should also be analyzed, and patients with high HBV DNA levels and low HBeAg levels may have to be treated as HBeAg-negative patients to some extent, with more emphasis on HBsAg levels.
5) Extending treatment to 72 weeks does not mean treating to 72 weeks either, the duration of treatment is not the end point, but should depend on whether HBeAg serological conversion or HBsAg disappearance occurs. For pegylated interferon a 2a treatment if HBeAg serological conversion is not obtained, 96% of patients showed recurrence of HBV DNA after 1 year of discontinuation.
(6) During extended treatment, note that the efficacy enters a plateau, that is, no further decrease in HBeAg levels, especially HBsAg levels, as the course of treatment is extended. When there is no further decrease in HBsAg or HBeAg during extended treatment, it may have a similar meaning as no decrease at the beginning of treatment for 24 weeks, meaning that further extension of treatment will not improve the efficacy.
7) Although HBsAg disappearance is the ideal treatment endpoint, HBsAg serologic conversion should be pursued more because serologic conversion can more truly reflect HBsAg disappearance. In the recovery phase of acute hepatitis B, anti-HBs generally appear 2-3 months after HBsAg disappearance, therefore, even if HBsAg levels reach below the detection line, it is difficult to identify if there is no serologic conversion as “HBsAg below the detection limit” or “HBsAg disappearance”, therefore, it is important to pay attention to and pursue the production of anti-HBs and continue treatment under HBsAg reaching the detection line in order to achieve HBsAg serological conversion.
Summary.
The endpoint of antiviral therapy for chronic hepatitis B is a state of immune control of HBV, and the course of treatment for patients is determined by the time required to reach the endpoint of treatment. The judgment of the efficacy of patients in treatment should be based on a comprehensive analysis of the changes in HBV DNA, HBeAg levels and HBsAg levels, with HBV DNA reaching below the detection line being the basis for whether patients can reach the endpoint of treatment, and for patients in treatment with HBeAg and For patients whose HBeAg and HBsAg levels continue to decrease during treatment, the course of treatment should be extended to gradually pursue HBeAg serological conversion and HBsAg disappearance, and further pursue HBsAg serological conversion to achieve the ultimate goal of individual treatment for patients with chronic hepatitis B.