X. Treatment goals
The goal of treatment: to maximize long-term inhibition of HBV replication, reduce inflammatory necrosis of hepatocytes and liver fibrosis, achieve delay and reduce the occurrence of liver failure, cirrhosis loss, HCC and other complications, thus improving the quality of life and prolonging survival time. In the course of treatment, clinical cure of chronic hepatitis B, i.e., sustained virological response after cessation of treatment, disappearance of HBsAg with ALT normalization and improvement of liver histology, should be pursued as much as possible for some suitable patients. Zheng Yushan, Department of Hepatology, Jining Fourth People’s Hospital
Treatment endpoints.
1. desirable endpoint: HBeAg-positive and HBeAg-negative patients who obtain durable HBsAg disappearance with or without HBsAg serologic conversion after drug discontinuation.
2. Satisfactory endpoints: HBeAg-positive patients, obtaining sustained virological response and ALT normalization with HBeAg serological conversion after drug discontinuation; HBeAg-negative patients, obtaining sustained virological response and ALT normalization after drug discontinuation.
3. Essential endpoints: if sustained response after drug discontinuation cannot be obtained, long-term maintenance of virological response during antiviral therapy (undetectable HBVDNA).
XI. Indications for antiviral therapy
The indications for antiviral therapy are determined primarily by serum HBVDNA levels, serum ALT, and severity of liver disease.78,83,84 The need to initiate antiviral therapy is determined by a comprehensive assessment of the patient’s risk of disease progression in conjunction with factors such as age, family history, and concomitant disease. A dynamic assessment is more clinically relevant than a single test. In HBeAg-positive patients, after an elevated ALT level is detected, observation for 3-6 months is recommended, and only if spontaneous HBeAg serologic conversion does not occur is antiviral therapy recommended for consideration.
The following conditions need to be met simultaneously for those recommended to receive antiviral therapy9,80,83,85.
(1) HBVDNA level: HBeAg-positive patients with HBVDNA ≥ 20,000 IU/mL (equivalent to 105 copies/ml); HBeAg-negative patients with HBVDNA ≥ 2,000 IU/mL (equivalent to 104 copies/ml).
(2) ALT level: generally, a sustained elevation of ALT ≥ 2 × ULN (more than 3 months) is required; if treated with interferon, ALT should generally be ≤ 10 × ULN and total serum bilirubin should be < 2 × ULN.
Antiviral therapy may be considered for those who are persistently HBVDNA positive and fail to meet the above treatment criteria, but are at greater risk of disease progression if one of the following circumstances exists.
(1) The presence of significant liver inflammation (grade 2 or higher) or fibrosis, especially liver fibrosis grade 2 or higher (A1).
(2) ALT persistently between 1×ULN and 2×ULN, especially in those older than 40 years, antiviral therapy is recommended after liver aspiration or noninvasive tests to clarify liver fibrosis (B2).
(3) Persistently normal ALT (checked every 3 months for 12 months), aged >30 years, with a family history of cirrhosis or hepatocellular carcinoma, antiviral therapy (B2) is recommended after liver aspiration or noninvasive examination to clarify liver fibrosis.
(4) When an objective basis for cirrhosis exists, aggressive antiviral therapy is recommended regardless of ALT and HBeAg status (A1).
It is especially important to remind that ALT elevation due to co-infection with other pathogens or other factors such as drugs, alcohol, immunity, etc. should be excluded before starting treatment, as well as temporary normalization of ALT after application of enzyme-lowering drugs. In some special diseases such as cirrhosis or taking biphenyl structure derivatives, the AST level may be higher than ALT, and the AST level can be used as the main indicator at this time.
Twelve, interferon alpha therapy
China has approved common interferon (IFN-α) and pegylated interferon (PegIFN-α) for the treatment of chronic hepatitis B.
(I) Regimen and efficacy of interferon alpha therapy
Regular IFN-α has been shown to be effective in treating patients with chronic hepatitis B. PegIFN-α achieved higher HBeAg serological conversion rates, HBVDNA inhibition and biochemical response rates compared to regular IFN-α (86).
In several international multicenter randomized controlled clinical trials, HBeAg-positive chronic hepatitis B patients treated with PegIFN-α-2a180ug/week for 48 weeks had HBeAg seroconversion rates of 32%-36% at 24 weeks of discontinuation, with HBeAg seroconversion rates of 44.8% in patients with baseline ALT>2-5 times ULN at 24 weeks of discontinuation and 44.8% in patients with ALT>5-10 times ULN at 24 weeks of discontinuation. 61.1% for patients with ALT>5-10 ULN; the HBsAg conversion rate at 24 weeks of discontinuation was 2.3-3% (80,87). Foreign studies have shown that similar HBVDNA suppression, HBeAg serologic conversion, and HBsAg clearance can be achieved with PegIFN-α-2b in HBeAg-positive chronic hepatitis B (80), and the HBsAg clearance rate at 3 years of drug discontinuation is 11% (88).
In HBeAg-negative chronic hepatitis B patients (60% Asian) treated with PegIFN-α-2a for 48 weeks, the number of patients with HBVDNA <2000 IU/mL at 24 weeks of discontinuation follow-up was 43% and 42% at 48 weeks of discontinuation follow-up; the HBsAg disappearance rate was 3% at 24 weeks of discontinuation follow-up, increasing to 8.7% at 3 years of discontinuation follow-up80 and Some studies have shown that extending the duration of PegIFN-α therapy to 2 years may improve the response rate.90,91 However, considering the additional side effects and economic burden associated with extended therapy, extended therapy is not recommended at this stage for pharmacoeconomic reasons.
PegIFN-α in combination with NAs or sequential therapy
It is still uncertain whether a treatment regimen combining PegIFN-α with NAs can improve the efficacy. The simultaneous combination regimen has some advantages over PegIFN-α alone in terms of HBeAg conversion, HBsAg clearance, virologic response, and biochemical response at the end of treatment, but did not significantly improve durable response rates after discontinuation.92-94 Another study showed that the addition of ETV to PegIFN-α did not improve HBeAg serologic conversion rates or HBsAg clearance rates 95.
The use of NAs to reduce viral load followed by a combination or sequential PegIFN-α regimen has shown some advantages over NAs alone in terms of HBeAg serologic conversion and HBsAg decline.96-100 A multicenter randomized open study showed that HBeAg-positive patients with chronic hepatitis B treated with ETV monotherapy for 9 to 36 months and achieved HBVDNA <1000copies /ml and HBeAg <100 PEIU/ml, patients treated with sequential Peg-IFN-α-2a for 48 weeks had higher HBeAg serologic conversion rates (14.9% vs. 6.1%) and HBsAg clearance rates (8.5% vs. 0%) compared to patients continuing with ETV monotherapy97; another study showed that HBeAg-positive patients who received NAs (lamivudine, entecavir or adefovir) for 1 to 3 years to achieve HBVDNA <200 IU/mL and HBeAg conversion, and then received PegIFN-α-2a sequential therapy for 48 weeks had HBsAg clearance and conversion rates of 16.2% and 12.5%, respectively98.
(II) Predictors of IFN-α antiviral efficacy
Predictors of pre-treatment
HBeAg-positive chronic hepatitis B patients with the following factors had higher HBeAg serologic conversion rates on PegIFN-α treatment: 1) HBVDNA <2x108IU/ml; 2) high ALT levels; 3) genotype A or B; 4) low HBsAg levels at baseline; 5) liver tissue inflammation necrosis G2 or higher; and HBeAg-negative chronic hepatitis B patients also had no valid predictors of virologic response prior to treatment.78 Among patients with antiviral indications, PegIFN-α therapy may be prioritized in relatively young patients (including adolescent patients), patients who wish to have children in recent years, patients who expect to complete treatment in the short term, and patients who are receiving antiviral therapy for the first time.
Predictive factors in the treatment process
Quantitative levels of HbsAg and HBVDNA at 24 weeks of treatment in HBeAg-positive patients with chronic hepatitis B are predictors of treatment response.78 Treatment with PegIFN-α results in higher HBeAg serologic conversion rates if HBsAg is <1500 IU/ml at 24 weeks and continued monotherapy up to 48 weeks.87 For patients with genotypes A and D, if after 12 weeks PegIFN-α treatment does not result in a decrease in HBsAg quantification, it is recommended to discontinue treatment (negative predictive value 97%-100%). For patients with genotype B and C, if HBsAg quantification remains greater than 20,000 IU/mL after 12 weeks of PegIFN-α treatment, discontinuation of treatment is recommended (negative predictive value 92%-98%). Regardless of genotype, if HBsAg quantification is still greater than 20,000 IU/mL after 24 weeks of treatment, it is recommended to discontinue PegIFN-α therapy (101,102).
The decline in HBsAg and HBVDNA levels during treatment in HBeAg-negative patients with chronic hepatitis B are predictors of sustained virologic response after discontinuation.89 If HBsAg does not decline after 12 weeks of treatment and HBVDNA decreases <2Log10IU/ml from baseline, discontinuation of PegIFN-α therapy should be considered.103,104 For details, see "Recommendations for Antiviral Therapy".
(C) Adverse reactions to interferon and their management
1.Influenza-like syndrome manifested as fever, headache, myalgia and malaise can be treated by injecting IFN-α at bedtime or taking antipyretic and analgesic drugs at the same time of injection.
2, transient peripheral cytopenia absolute neutrophil count ≤ 0.75×109/L and/or platelets < 50×109/L, the dose of IFN-α should be reduced; recheck after 1~2 weeks, if recovered, gradually increase to the original amount. IFN should be suspended for absolute neutrophil counts ≤0.5×109/L and/or platelets <25
3. Psychiatric abnormalities can be manifested as depression, delusions, severe anxiety and other psychiatric symptoms. For those with severe symptoms, IFN should be discontinued in a timely manner, and if necessary, further consultation with a specialist in psychiatric psychiatry.
Some patients with autoimmune diseases may develop autoantibodies, and only a few patients with thyroid disease, diabetes mellitus, thrombocytopenia, psoriasis, leukoplakia, rheumatoid arthritis and systemic lupus erythematosus-like syndrome, etc. should be consulted and treated together with physicians from relevant departments, and the drug should be discontinued in serious cases.
5, other rare adverse reactions include renal damage, cardiovascular complications, retinopathy, hearing loss and interstitial pneumonia, etc. Interferon therapy should be discontinued.
(D) Contraindications to IFN-α therapy
Absolute contraindications to IFN-α therapy include pregnancy or short-term pregnancy plans, history of psychiatric disorders (with a history of schizophrenia or major depression, etc.), uncontrolled epilepsy, decompensated cirrhosis, uncontrolled autoimmune disease, with severe infection, retinal disease, heart failure, chronic obstructive pulmonary and other underlying diseases.
Relative contraindications to IFN-α therapy include thyroid disease, previous history of depression, uncontrolled diabetes mellitus, hypertension, pre-treatment neutrophil count <1.0
XIII. Treatment and monitoring of NAs
Five NAs drug efficacy
1. entecavir (ETV)
The phase III randomized controlled double-blind clinical trial showed that in HBeAg-positive chronic hepatitis B patients, the rate of HBVDNA conversion (<300 copies/mL) at 48 weeks of ETV treatment was 67%, the rate of HBeAg serological conversion was 21%, the rate of ALT normalization was 68%, and the rate of hepatic histological improvement was 72%.105 In HBeAg-negative chronic hepatitis B patients, ETV The rate of HBVDNA conversion (<300 copies/mL) at 48 weeks of treatment was 90%, the rate of ALT normalization was 78%, and the rate of hepatic histological improvement was 70%.106
Studies of long-term treatment follow-up with ETV have shown that HBeAg-positive chronic hepatitis B patients treated with ETV for 5 years have a 94% rate of HBVDNA regression (<300 copies/mL) and an 80% rate of ALT normalization.107 In patients with primary hepatitis B from NAs (HBeAg-positive or negative), the cumulative incidence of resistance at 5 years of ETV treatment is 1.2%, however, in patients who have developed However, in patients who had developed lamivudine (LAM) resistance, the cumulative incidence of resistance at 5 years of ETV therapy increased to 51% (108). Histological studies of the liver treated with ETV for 5 years showed that 55/57 (88%) achieved improvement in liver fibrosis and 4/10 (40%) reversal of cirrhosis (70,109). The occurrence of lactic acidosis has been reported in patients with severe liver disease and should be a cause for concern.
2. tenofovirdisoproxilfumarate (TDF)
Phase III randomized controlled double-blind clinical trial showed that in HBeAg-positive chronic hepatitis B patients, the rate of HBVDNA conversion (<400 copies/mL) at 48 weeks of TDF treatment was 76%, the rate of HBeAg serological conversion was 21%, and the rate of ALT normalization was 68%. In HBeAg-negative chronic hepatitis B patients, the rate of HBVDNA conversion (<400 copies/mL) at 48 weeks of TDF treatment was 93% and the rate of ALT normalization was 76%110,.
Histological studies of the liver showed a histological improvement rate of 87% and a reversal of fibrosis rate of 51% at 5 years of TDF treatment; among patients diagnosed with cirrhosis before treatment (Ishak score of 5 or 6), the Ishak score decreased by at least 1 point after 5 years of treatment in 71% of patients71.
The recently completed TDF long-term follow-up study showed that after 8 years of TDF treatment, HBeAg-positive patients had a 98% rate of HBVDNA conversion (<400 copies/mL), a 31% rate of HBeAg serologic conversion, and a 13% rate of HBsAg disappearance. 99.6% of HBeAg-negative patients had a rate of HBVDNA conversion (<400 copies/mL). No TDF-related drug resistance was detected. During long-term treatment, blood creatinine elevation ≥0.5 mg/dL occurred in 2.2% of patients and creatinine clearance less than 50 mL/min occurred in 1% of patients, and patients on long-term medication should be alerted to the development of renal insufficiency and hypophosphatasia.111
Studies of TDF in treated patients with NAs from 48 weeks to 168 weeks showed that TDF demonstrated a high virologic response and was well tolerated, whether LAM-resistant, ADV-resistant, ETV-resistant, or poorly responding to ADV or combined LAM and ADV resistance112-115.
3. telbivudine (LdT)
The 52-week results of a domestic randomized, double-blind, multicenter phase III clinical trial and the 104-week results of a global multicenter study showed that LDT had better antiviral activity than LAM and a lower incidence of drug resistance than LAM (116,117), but the overall resistance rate was still high. Domestic and international clinical studies suggest that HBeAg-positive patients with baseline HBVDNA <109
4. adefovirdipivoxil (ADV)
Domestic and foreign randomized double-blind clinical trials have shown that oral administration of ADV to HBeAg-positive chronic hepatitis B patients can significantly inhibit HBVDNA replication, promote ALT normalization, and improve liver tissue inflammation necrosis and fibrosis. In HBeAg-positive patients treated for 1, 2, 3 and 5 years, HBVDNA <1000 copies/mL was 28%, 45%, 56% and 58%, respectively, and HBeAg serological conversion rate was 12%, 29%, 43% and 48%, respectively.
The rates of drug resistance were 0%, 1.6%, 3.1%, and 20%, respectively.119,120 After 5 years of treatment in HBeAg-negative patients, 67% of those with HBVDNA <1000 copies/mL and 69% of those with ALT normalization; 83% and 73% of those with improvement in liver inflammatory necrosis and fibrosis, respectively, at 5 years of treatment; and the cumulative incidence of drug-resistant mutations in patients at 5 years of treatment. The incidence of drug-resistant mutations was 29%, virologic resistance was 20%, and clinical resistance was 11%; the incidence of mild creatinine elevation was 3% (121).
ADV in combination with LAM was effective in suppressing HBVDNA and promoting ALT normalization in LAM-resistant chronic hepatitis B, and the incidence of resistance to ADV was lower in those on the combination122.
At 5 years of long-term treatment with ADV, serum creatinine increased by more than 0.5 mg/dL in 3% of patients, but the increase in serum creatinine was reversible.119,121 Patients on long-term medication should be alerted to the occurrence of renal insufficiency and hypophosphatous bone disease.
5.Lamivudine (lamivudine, LAM)
The results of randomized controlled clinical trials at home and abroad showed that 100 mg of LAM administered orally once daily significantly suppressed HBVDNA levels; the rate of HBeAg serological conversion increased with the duration of treatment and was 16%, 17%, 23%, 28%, and 35% at 1, 2, 3, 4, and 5 years of treatment, respectively.123 Randomized double-blind clinical trials showed that patients with chronic hepatitis B with significant liver fibrosis and patients with compensated cirrhosis treated with lamivudine for 3 years delayed disease progression and reduced the incidence of hepatic decompensation and hepatocellular carcinoma.124 Patients with decompensated cirrhosis also improved liver function and prolonged survival after lamivudine treatment.125
The incidence of viral resistance mutations increased with longer treatment duration (14%, 38%, 49%, and 66% at years 1, 2, 3, and 4, respectively)123.