I. Basic understanding of the role of interferon
Patients with chronic hepatitis B who have indications for antiviral therapy should first consider pursuing higher therapeutic goals
Priority is given to interferon therapy with a high rate of sustained response, and pegylated interferon can be recommended for patients who are eligible for it.
Second, interferon application of individualized treatment issues
In the use of interferon treatment should be implemented individualized treatment plan
nAccording to the patient’s tolerance of the drug, the onset of effect or not or the onset of effect time, etc., on the basis of the basic treatment plan of the Guidelines to adjust the monitoring and follow-up time, the dose, the course of treatment, if necessary, according to the patient’s early response to consider whether to change the treatment plan
Treatment target selection
Among the patients with antiviral indications
Relatively young patients (including adolescent patients)
C Patients who wish to have children within the next few years
C Patients who expect to complete treatment in the short term
C Patients who are receiving antiviral therapy for the first time
C Patients with a strong immune response (e.g., low viral load, high ALT level, high degree of liver inflammation)
Interferon therapy should be recommended first, and priority can be given to those patients who are eligible for it.
Recommended pegylated interferon therapy
IV. Timing of treatment
(1) For patients with recurrent mildly elevated ALT levels (1-2×ULN) or normal ALT, liver biopsy is recommended if the patient is older (over 40 years old), has a family history of chronic hepatitis B or liver cancer, is HBeAg negative, and B-mode ultrasound or CT examination indicates chronic liver lesions. For patients with G2 or above, implementation of antiviral therapy (including interferon) is recommended
IV. Timing of treatment
(2) Antiviral therapy should be administered for significantly elevated ALT levels (>10×ULN). If the use of interferon is considered, the change in condition should be closely observed first, while symptomatic and supportive treatment such as liver protection should be given appropriately. Once the ALT level starts to decrease, or has decreased below the upper limit of 1/10th of normal, without significant bilirubin elevation, interferon therapy can be initiated. It can be started at regular dose or small dose according to patient’s specific situation
(3) When considering interferon therapy for patients with significantly elevated ALT levels (>10×ULN), it should be administered by or under the guidance of a specialist with extensive experience in the clinical application of interferon. During the course of treatment, changes in the condition should be closely observed and adjustments to the treatment plan can be considered when necessary.
V. Basic dose and course of treatment and individualized adjustment
n After treatment, patients with total peripheral blood leukocyte count ≤ 1.5×109/L, or neutrophil count ≤ 0.75×109/L, or platelet count ≤ 50×109/L should continue treatment by adjusting the dose downward to 135μg and strengthening monitoring.
If the total peripheral blood leukocyte count ≤ 1.0×109/L, or neutrophil count ≤ 0.5×109/L, or platelet count ≤ 2.5×109/L, it should be suspended for 1 time and rechecked after 1 week.
If the indexes rebound, regular dose treatment can be resumed or started from a small dose. For patients with significant decrease in neutrophil or platelet count, recombinant granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF), or recombinant platelet production factor can be used as symptomatic treatment.
V. Basic dose and course of treatment and individualized adjustment
(2) For patients who have met the criteria of complete response in our Guidelines, maintain consolidation therapy for at least 6 months, and if necessary, extend the course of therapy appropriately.
For patients with partial response, even if they have completed 1 year of basic treatment, they should continue treatment until they achieve complete response and maintain consolidation for at least 6 months.
V. Basic dose and duration of treatment and individualized adjustment
(3) Patients who have not yet responded to treatment after 3 months of treatment may be followed up with continued treatment.
If treatment response does not appear after 6 months of treatment, communication with the patient should be strengthened and the next step of treatment should be decided according to the patient’s will and cooperation.
For patients with a certain degree of decrease in HBV DNA or HBeAg quantification and good cooperation, the treatment can be continued for 1-3 months and then decide whether to continue treatment or change the treatment plan according to the patient’s response
VI. Monitoring, follow-up and treatment during the course of treatment
n Baseline measurement of important indicators before treatment, including HBV DNA quantification, HBeAg/HBsAg quantification or semi-quantification, ALT/AST, TBiL/DBiL, blood routine, etc. Ultrasound or CT examination of liver should be performed, and fasting glucose, thyroid function or thyroid autoantibodies (TSH, FT3, FT4, TgAb, TPOAb) should be detected.
n Monitor blood count once a week after starting treatment and treat appropriately according to changes (see Recommendation 10 for recognition and management of adverse reactions). The interval between tests can be gradually extended after stabilization or improvement of the indicators until monitoring once a month
(3) ALT and HBV DNA should be monitored once a month for the first 3 months after the start of treatment, and the monitoring interval can be extended until once every 3 months after a significant decrease or reversion. HBeAg-positive patients should be monitored for quantitative or semi-quantitative changes in HBeAg/anti-HBe at the same time, and quantitative changes in HBsAg/anti-HBs can also be detected if necessary
(4) For patients who end treatment after reaching the treatment endpoint, they should be closely followed up, initially once a month, and gradually extending the follow-up interval after 3 months. Patients with maintenance response and stable disease can be followed up once every 3-6 months
VII. Efficacy predictors and time points
When making efficacy predictions for patients treated with pegylated interferon, it is recommended that.
(1) the efficacy prediction of chronic hepatitis B should not be based on the prediction pattern of efficacy of pegylated interferon for chronic hepatitis C, nor should the efficacy prediction of pegylated interferon for chronic hepatitis B be based on the prediction pattern of efficacy of nucleoside analogs for chronic hepatitis B
(2) When predicting or determining whether a sustained response occurs in patients with chronic hepatitis B treated with pegylated interferon, the observation period should not be too short and should be after 6 months or even longer treatment time
(3) A comprehensive judgment can be made based on the dynamic changes in the patient’s HBeAg or HBsAg quantitative or semi-quantitative tests during the course of treatment, combined with changes in HBV DNA
Eight, HBeAg and HBsAg quantitative or semi-quantitative testing and efficacy prediction and treatment course adjustment issues
(1) In pegylated interferon therapy, HBeAg-positive patients at 24 weeks
n If HBeAg potency decreases to ≤10 PEIU/mL, continue treatment until 48 weeks. For those patients in whom HBeAg seroconversion has not occurred after 48 weeks of treatment, but HBeAg potency is still steadily decreasing, treatment may be extended to 72 weeks.
n If the HBeAg potency of the patient decreases to 10-100 PEIU/mL at 24 weeks, the treatment can be continued for an additional 72 weeks.
n If the patient’s HBeAg potency is ≥100 PEIU/mL and HBV DNA is ≥5.0 log10 copies/mL at week 24, combination or switch to nucleoside (acid) analogue therapy is recommended.
HBeAg quantification at 24 weeks of treatment predicts HBeAg serological conversion at 72 weeks
VIII. HBeAg and HBsAg quantitative testing and efficacy prediction and
Treatment adjustment problems
(2) At 24 weeks of treatment in HBeAg-positive patients, the
n If HBsAg quantification decreases to ≤1500 IU/mL, continue treatment until 48 weeks. Continue to extend treatment to 72 weeks for those patients in whom HBeAg seroconversion has not occurred at 48 weeks of treatment.
n If the patient’s HBsAg quantification decreases to 1500-20 000 IU/mL at 24 weeks of treatment, continue to extend treatment until 72 weeks.
n If the patient’s HBsAg quantification is ≥20 000 IU/mL and HBV DNA is ≥5.0 log10 copies/mL at 24 weeks of treatment, combination or switch to nucleoside (acid) analogue therapy is recommended.
HBsAg levels at 24 weeks of treatment
Correlation with response to PEG-IFN at 6 months post-treatment
HBsAg levels at week 48
Significantly correlated with HBsAg clearance 3 years after treatment
VIII. Quantitative HBeAg and HBsAg testing and efficacy prediction and
regimen adjustment issues
(3) At 24 weeks of treatment in HBeAg-negative patients, the
n If HBsAg quantification decreases >1 log10 IU/mL, continue treatment until 48 weeks. For those patients in whom HBsAg quantification is still >10 IU/mL at 48 weeks of treatment, but HBsAg quantification still continues to decrease steadily may continue to extend treatment until 72 weeks.
n If patients with HBsAg potency decrease <1 log10 IU/mL at 24 weeks of treatment, combination or switch to nucleoside (acid) analogue therapy is recommended.
HBsAg at 12 weeks of treatment vs. 24 weeks
Predicting sustained viral response in HBeAg-negative patients
Retrospective analysis of HBeAg-negative patients
n On-treatment HBsAg reduction from baseline was significantly associated with sustained response* at 1 year post-treatment
n HBsAg reduction at 12 and 24 weeks of treatment is highly predictive of sustained virologic response:
? 0.5 log10 IU/mL reduction at week 12: NPV 90%, PPV 89%
? 1 log10 IU/mL at week 24: NPV 97%, PPV 92%
Prolonged course of Peroxin for HBeAg-positive hepatitis B
Prolonged regimen improves HBeAg and HBsAg clearance
IX. Guided therapy according to response to treatment (RGT) and
Combination therapy issues
Regarding combination therapy according to RGT principles during interferon therapy.
(1) HBeAg-positive patients treated with pegylated interferon for 24 weeks, if HBeAg potency ≥ 100 PEIU/mL or HBsAg quantification ≥ 20 000 IU/mL and HBV DNA ≥ 5.0 log10 copies/mL, combination nucleoside (acid) analogue therapy is recommended
HBeAg quantification at 24 weeks of treatment predicts HBeAg serological conversion at 72 weeks
IX. Guidance of treatment according to response to treatment (RGT) and
Combination therapy issues
Regarding combination therapy according to RGT principles during interferon therapy.
(2) HBeAg-negative patients treated with pegylated interferon for 24 weeks, if HBsAg quantification decreases ≤1 log10 IU/mLl, combination nucleoside (acid) analogue therapy is recommended
IX. Guided therapy according to response to treatment (RGT) and
Combination therapy issues
Regarding combination therapy according to RGT principles during interferon therapy.
(3) After 24 weeks of combination therapy, according to the dynamic changes of the patient’s HBeAg or HBsAg level, decide whether to continue combination therapy or to switch to one of the single drugs to continue therapy
n If HBV DNA drops below detectable levels and there is seroconversion of HBeAg or near disappearance of HBsAg quantification, discontinuation of nucleoside (acid) analogs to continue pegylated interferon therapy up to 72 weeks may be considered.
n If HBV DNA decreases below the detection level, but HBeAg or HBsAg levels do not decrease significantly, consider discontinuing pegylated interferon and continuing long-term treatment with pegylated interferon analogs
High rate of HBsAg disappearance with Pyroxin combined with ADV therapy
Piroxin combined with ADV for HBeAg positive patients
X. Major adverse reactions and recognition, prevention and management
Regarding the recognition and management of major adverse reactions to interferon.
(1) Peripheral blood changes should be closely monitored and patients with obvious abnormalities should be treated as in recommendation 5.(1)
(2) Great attention should be paid to possible psychiatric abnormalities in patients during interferon therapy. For patients with mild depression, symptomatic treatment may be appropriate; for patients with obvious symptoms, joint consultation with a psychiatrist should be conducted; for patients with severe psychiatric abnormalities, interferon therapy should be interrupted in a timely manner
X. Major adverse reactions and recognition, prevention and treatment
(3) Thyroid function or thyroid autoantibodies and other related indicators (TSH, FT3, FT4, TgAb, TPOAb) and symptoms associated with thyroid disease should be monitored regularly.
C For patients with normal TSH and negative thyroid autoantibodies should be monitored once every 3 months until the end of interferon therapy
C For patients with normal TSH and positive thyroid autoantibodies should be monitored every 2 months until the end of interferon therapy
C For patients with abnormal TSH the cause should be identified and treated promptly.
In general, interferon therapy can be continued concurrently with thyroxine therapy for hypothyroid patients and with anti-thyroxine therapy for patients with mild Grave’s disease, but both should be closely monitored.
Patients with severe thyroid disease that develops during treatment should be seen in consultation with the relevant specialist and interferon therapy may be discontinued if necessary.