Response-guided therapy (RGT) strategy refers to guiding treatment according to patient response during interferon therapy for chronic hepatitis B. Clinically, optimization measures such as combining nucleoside (acid) class (NA) drug therapy or extending the course of interferon (IFN) therapy can be chosen.
RGT strategy to improve efficacy and rationalize medical resource allocation
RGT strategy based on HBsAg quantification
For the RGT strategy in patients with HBeAg(+) CHB, the initial evidence-based medical evidence recommends: 24 weeks of PEG-IFN treatment, if HBsAg is <1500
IU/ml, the patient has a high probability of achieving HBsAg conversion and should be encouraged to complete the treatment course; if HBsAg is 1500-20,000
IU/ml, patients should be encouraged to complete 48 weeks of PEG-IFN treatment, and the treatment regimen should be adjusted appropriately to extend the duration of PEG-IFN treatment; if HBsAg is >20,000
IU/ml, patients are very unlikely to obtain a response with PEG-IFN therapy and should switch to or combine with NAs drugs.
With the goal of obtaining durable immune control, a higher goal for CHB treatment is pursued in clinical practice, and the complementary recommendations of the RGT strategy are more clinically actionable, specifically: at 24 weeks of IFN treatment for HBeAg(+) patients, if HBsAg quantification decreases to ≤1500
IU/ml, continue treatment until 48 weeks; for those who have HBeAg serological conversion at 48 weeks of treatment and HBsAg quantification continues to drop significantly to less than 250 IU/ml, extend treatment to 72 weeks or longer to achieve HBsAg clearance; for those who still have not HBeAg serological conversion at 48 weeks, if their HBsAg quantification drops to 1500~ 20,000
IU/ml at 24 weeks of treatment, the treatment can be extended to 72 weeks.
Individualized adjustment of treatment regimen increases patient benefit
In clinical treatment, the RGT principle is often applied, and the lower the HBsAg and HBeAg quantification, the faster the early response and the higher the chance of achieving successful treatment. However, the specific treatment regimen must still be individually adjusted according to the patient’s specific situation, which can enable more patients to achieve effective and sustained immune control of HBV infection or even functional cure, thus enabling patients with chronic hepatitis B to escape from the pain of long-term medication and the safety issues of medication and improving their quality of life.
For patients with poor response, timely adjustment of treatment regimens following the RGT principle and combination application or switching to NAs drug therapy can increase patients’ chances of achieving sustained response, and also allocate medical resources rationally and effectively to reduce patients’ unnecessary economic burden, so as to achieve long-term effective suppression of HBV
The goal is to achieve long-term effective suppression of HBV DNA, reduce the occurrence of hepatitis B-related complications, and reduce the incidence of relapse and drug resistance.
Reflections on RGT for HBeAg-positive patients with chronic hepatitis B
Rational application of RGT strategies can improve the rate of immune control
Currently, the main drugs used for the treatment of CHB are IFN and NAs. NAs act directly on HBV and can achieve viral suppression in most CHB patients, but the rate of HBsAg disappearance and serological conversion is low. IFN has both antiviral and immunomodulatory effects, but can only achieve durable immune control in about 1/3 of HBeAg(+) CHB patients. For patients with poor response, they still face the dilemma of long-term or even lifelong treatment.
Combination therapy with IFN and NAs drugs or an extended course of therapy can increase the rate of durable immune control in patients by 10-20%. A higher rate of durable immune control was achieved after IFN treatment in HBeAg(+) compared to HBeAg(-) CHB patients. Therefore, in patients with HBeAg(+) CHB, the rational and flexible use of RGT strategy can aim to maximize the durable immune control obtained in such patients, even HBsAg clearance, and reach the ideal endpoint of treatment.
Autoimmune system contributes to durable viral control
HBV is a virus that is highly dependent on host mechanisms for replication (e.g., transcription, translation, and viral secretion processes). The escape of HBV from natural immunity can lead to chronic HBV infection in the body, where T-cell dysfunction may be a key cause of chronic HBV infection, and studies of the natural history of hepatitis B suggest that age at infection is the most important factor influencing chronicity, e.g., 90% of HBV patients infected perinatally will develop For example, 90% of HBV patients infected in the perinatal period will develop chronic infection, while only 5-10% of those infected after the age of 5 years develop chronic infection.
Clinical practice has found that a small percentage of patients with CHB can recover spontaneously, indicating that the host can produce durable viral control through the autoimmune system. Clinical studies have also shown that HBV-specific T-cell responses can be restored in patients with disappearance of HBsAg or serologic conversion, suggesting that T-cell malfunction is reversible in the course of CHB.
cccDNA clearance and HBsAg serologic conversion are therapeutic targets
A recent study reported that the combination of NAs drugs and IFN for the treatment of HBeAg(+) CHB, NAs drugs can suppress HBV while IFN can cause rapid activation of the body’s immune system, while the application of RGT strategy can screen superior patients who may achieve durable immune control. In fact, the treatment process of chronic hepatitis B is a process in which the body gains immune recovery and immune reconstitution.
A deeper understanding of the life cycle of HBV infection reveals that the presence of covalently closed cyclic deoxyribonucleotides (cccDNA) in hepatocytes is a key barrier to clinical cure of CHB. cccDNA newly formed in HBV-infected hepatocytes can be effectively blocked or inhibited during NAs drug therapy, but the pool of cccDNA already present within them is difficult to be cleared by NAs drugs. Because NAs drugs act downstream of cccDNA synthesis in the retroviral process, NAs drugs can block the production of new viral groups, but cannot inhibit the transcription of viral mRNA, translation and secretion of viral antigens.
In other words, patients can have antigenemia that exists independently of viremia, or can still produce antigenemia after viremia is suppressed. Therefore, regimens that can cure chronic hepatitis B must affect the cccDNA pool or achieve durable control of viral replication by enhancing the body’s immune response.
Current therapeutic strategies based on following the principles of RGT, via effective restoration of the antiviral T-cell immune response, are worth exploring. Currently, new therapeutic approaches and strategies are urgently needed from the theoretical and practical needs of patients to achieve the desired limited course of CHB treatment and functional cure goals.
Therefore, in the future, both viral and host interaction novel drugs and therapeutic strategies will be directed towards cccDNA clearance and serological conversion of HBsAg.
Case information
General The patient was male, 37 years old and married. He was found to be positive for hepatitis B virus surface antigen (HBsAg) for more than 20 years and positive for hepatitis B virus e antigen (HBeAg) and hepatitis B virus core antibody (HBcAb). During this period, the patient had irregular checkups and his liver function was basically normal. In the past two years, the patient had repeatedly fluctuating elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), accompanied by malaise, which could be relieved after rest. No family history of hepatitis B, no history of smoking and occasional alcohol consumption.
HBsAg (+), HBeAg (+), HBV DNA
4.65×107 IU/ml, ALT
248.1 U/L, AST
HBsAg (+), HBeAg (+), HBV DNA 4.65×107 IU/ml, ALT 248.1 U/L, AST 171.5 U/L, total bilirubin (TBIL) 7.5 μmol/L. Routine blood tests, blood glucose, lipids, autoantibodies and thyroid function tests were normal, and HBV genotype was C.
Diagnosis and treatment The diagnosis was “HBeAg (+) chronic hepatitis B (CHB)”. A subcutaneous pegylated interferon (PEG-IFN) 180 μg/w was chosen.
The 48-week regimen was adjusted according to the RGT strategy, during which each test index was shown in the table.
At 24 weeks of treatment, HBsAg quantification decreased to 514.6
IU/ml, a decrease of more than 2
logIU/ml, while HBV
DNA also decreased to 214 IU/ml, and treatment was continued until 48 weeks according to the RGT principle. At the end of treatment, the patient obtained HBeAg serological conversion, while HBsAg quantification decreased to 25.96
IU/ml, so PEG-IFN treatment was extended to 72 weeks. At 24 weeks of discontinuation, the patient achieved HBsAg seroconversion and produced hepatitis B virus surface antibody (HBsAb).
▪ Commentary
The treatment in this case followed the principles of RGT and was applied flexibly according to the patient’s actual situation. During the baseline evaluation, the patient was considered for PEG-IFN treatment, taking into account her young age, recurrent ALT elevation in the past two years, no previous family history of hepatitis B, and no history of other diseases such as diabetes mellitus.
After 24 weeks of treatment, the patient responded well and it was judged that the patient might have a good expected outcome at 48 weeks, so the patient was encouraged to continue the treatment and actively manage the side effects of the drug, etc. to increase the patient’s compliance. The patient successfully completed the 48-week course of treatment. At 48 weeks of treatment, it was found that the patient showed HBeAg serological conversion through the previous treatment, and his HBsAg quantification had been continuously decreasing to 25.96
IU/ml, so the patient was again advised to complete 72 weeks of treatment. The patient was encouraged to continue treatment and eventually achieved durable immune control with ideal HBsAg clearance and HBsAb production.
Individualized treatment of patients with HBeAg(+) CHB can be simply divided into pre-treatment baseline directed therapy and on-treatment RGT strategies. Physicians can flexibly apply baseline guideline assessment according to the patient’s specific situation and needs with reference to factors that may affect treatment response such as age, gender, obesity, insulin resistance, duration of infection, ALT level, baseline viral level, genotype, liver tissue lesion, etc., to select patients suitable for IFN treatment, determine prognosis by quantitative changes in HBsAg at 24 weeks of treatment, and promptly according to the assessment results Adjusting the subsequent treatment plan according to the assessment results is the key to successful treatment guidance using RGT strategy.