The overall goal of chronic hepatitis B treatment is to maximize long-term suppression of HBV, reduce hepatocyte inflammation necrosis and liver fibrosis, delay and reduce the occurrence of liver failure, cirrhosis, HCC and its complications, thus improving quality of life and prolonging survival time.
The treatment of chronic hepatitis B mainly includes antiviral, immunomodulatory, anti-inflammatory and antioxidant, anti-fibrotic and symptomatic therapy, among which antiviral therapy is the key, and standardized antiviral therapy should be administered as long as there is an indication and conditions allow.
General indications for antiviral therapy
General indications include: HBV DNA ≥104 copies/m l (equivalent to 2000 IU/ml); ALT ≥2 × ULN; if treated with interferon, ALT should be ≤10 × ULN and total serum bilirubin should be <2 × ULN; ALT <2 × ULN, but liver histology shows Knodell HAI ≥4, or inflammatory necrosis ≥G2, or fibrosis ≥S2.
Antiviral therapy should also be considered for those who are persistently HBV DNA positive but do not meet the above treatment criteria, but have one of the following conditions
(1) Antiviral therapy should also be considered for those with ALT > upper limit of normal and age > 40 years
(2) For those with persistently normal ALT but older (>40 years old), close follow-up and preferably liver biopsy should be performed; if liver histology shows Knodell HAI ≥4, or inflammatory necrosis ≥G2, or fibrosis ≥S2, antiviral therapy should be actively administered.
(3) If dynamic observation reveals evidence of disease progression (e.g., enlarged spleen), liver histology is recommended, and antiviral therapy should be given if necessary.
Elevated ALT due to drugs, alcohol or other factors should be ruled out 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 structural derivatives, the AST level may be higher than ALT, and the AST level may be used as the main indicator in this case.
Interferon a treatment
Plain interferon a (2a, 2b and 1b) and pegylated interferon a (2a and 2b) have been approved for the treatment of chronic hepatitis B in China.
A meta-analysis showed that patients with chronic hepatitis B treated with plain interferon had better HBeAg seroconversion rates, HBsAg clearance rates, incidence of cirrhosis, and HCC rates than those without interferon treatment . Four randomized controlled trials in HBeAg-negative patients showed response rates of 38% to 90% at the end of treatment, but durable response rates of only 10% to 47% (mean 24%). It has been suggested that a course of at least 1 year of treatment with regular IFN-a is necessary to achieve a good outcome.
International multicenter randomized controlled clinical trials have shown that the HBeAg seroconversion rate was 32% at 24 weeks of discontinuation after 48 weeks of pegylated interferon a-2a (PegIFN-a2a) treatment (87% of Asians) and up to 43% at 48 weeks of discontinuation. Foreign studies have shown that similar rates of HBVDNA suppression, HBeAg seroconversion, and HBsAg disappearance can be achieved with pegylated interferon a-2b (PegIFN-a2b) in HBeAg-positive chronic hepatitis B.
In HBeAg-negative chronic hepatitis B patients (60% Asian) treated with PegIFN-a2a for 48 weeks, the HBV DNA <2´104 copies/ml (equivalent to 2000 IU/ml) was 43% at 24 weeks post-discontinuation and 42% at 48 weeks post-discontinuation; the HBsAg disappearance rate was 3% at 24 weeks post-discontinuation and increased to 8% at 3 years post-discontinuation. The rate of HBsAg disappearance was 3% at 24 weeks of discontinuation and increased to 8% at 3 years of discontinuation.
Nucleoside (acid) analog therapy
(a) Currently there are five anti-HBV nucleoside (acid) analogs that have been used in clinical practice, and four have been marketed in China.
1, lamivudine (lamivudine, LAM)
The results of randomized controlled clinical trials at home and abroad show that 100 mg of lamivudine taken orally once a day can significantly inhibit HBV DNA levels, HBeAg serological conversion rate increases with the extension of treatment time, 16%, 17%, 23%, 28% and 35% at 1, 2, 3, 4 and 5 years of treatment, respectively; the HBeAg serological conversion rate is higher in those with higher ALT levels before treatment. . Randomized double-blind clinical trials have shown that lamivudine treatment for 3 years in patients with chronic hepatitis B with significant liver fibrosis and compensated cirrhosis can delay disease progression and reduce the incidence of liver failure and hepatocellular carcinoma. Patients with decompensated cirrhosis also improved liver function and prolonged survival after treatment with lamivudine. Foreign studies have shown that the efficacy of lamivudine in the treatment of chronic hepatitis B in children is similar to that in adults, with a good safety profile. Clinical studies in China have also shown similar clinical efficacy and safety.
Lamivudine has a low incidence of adverse reactions and a safety profile similar to that of placebo. The incidence of viral resistance mutations increased with the duration of treatment (14%, 38%, 49% and 66% in years 1, 2, 3 and 4, respectively).
2. adefovir dipivoxil (ADV)
Domestic and foreign randomized double-blind clinical trials have shown that oral adefovir in HBeAg-positive chronic hepatitis B patients can significantly inhibit HBV DNA replication, promote ALT normalization, and improve dry tissue inflammation necrosis and fibrosis. In HBeAg-positive patients treated for 1, 2 and 3 years, HBV DNA <1000 copies/mL was 28%, 45% and 56%, respectively, and HBeAg serological conversion rate was 12%, 29% and 43%, respectively; resistance rate was 0%, 1.6% and 3.1%, respectively. At 5 years of treatment in HBeAg-negative patients, the rate of HBV DNA <1000 copies/mL was 67% and the rate of ALT normalization was 69%; at 4 and 5 years of treatment, 83% and 73% had improved liver inflammatory necrosis and fibrosis, respectively; at 5 years of treatment, the incidence of cumulative drug resistance mutations was 29%, the incidence of virologic resistance was 20%, and the incidence of clinical resistance was The incidence of cumulative resistance mutations was 29%, virologic resistance was 20%, and clinical resistance was 11% at 5 years of treatment; the rate of mild creatinine elevation was 3%.
Adefovir alone or in combination with lamivudine was effective in suppressing HBV DNA and promoting ALT normalization in lamivudine-resistant chronic hepatitis B. However, the incidence of resistance to adefovir was lower in those who used the combination. The results of several studies have shown that combination therapy with adefovir is effective in patients with compensated and decompensated cirrhosis who have developed lamivudine resistance.
3. entecavir (ETV)
A randomized, double-blind controlled clinical trial showed that in HBeAg-positive patients with chronic hepatitis B, 67% of those with HBV DNA down to PCR levels (300 copies/mL) or less at 48 weeks of entecavir treatment, 68% of those with normalized ALT, and 72% of those with improved liver histology were better than those treated with lamivudine; however, HBeAg seroconversion rates were similar in both groups ( 21% and 18%). In HBeAg-negative patients, the rate of HBV DNA reduction below PCR levels at 48 weeks of entecavir treatment was 90%, the rate of ALT normalization was 78%, and the rate of hepatic histological improvement was 70%.
Long-term follow-up studies have shown that continued treatment maintains a high level of HBVDNA suppression in those who achieve virologic response. A Japanese study showed a 3-year cumulative resistance rate of 1.7% to 3.3% for entecavir. The results also suggest that entecavir 1.0 mg daily in patients who failed lamivudine treatment can also suppress HBV DNA and improve biochemical parameters, but the efficacy is lower than in primary treatment and the incidence of virological breakthrough is significantly higher. The results of clinical trials in China are basically similar to those reported above.
4, tebivudine (telbivudine, LdT)
A 2-year global multicenter clinical trial showed that at 52 weeks of treatment in HBeAg-positive patients, HBV DNA in the telbivudine group decreased to below the level detected by PCR in 60.0%, the ALT normalization rate was 77.2%, the incidence of drug resistance was 5.0%, and the liver histological response rate was 64.7%, all better than the lamivudine treatment group, but its HBeAg seroconversion rate ( The HBeAg seroconversion rate (22.5%) was similar to that of the latter; the HBV DNA suppression, ALT normalization rate and drug resistance rate of HBeAg-negative patients at 52 weeks of treatment were also better than those of the lamivudine group. At 2 years of treatment, the overall efficacy (except for the disappearance of HbeAg and seroconversion rate) and the incidence of drug resistance were also better than those of the lamivudine group. A multicenter clinical trial in China also showed that its antiviral activity and incidence of drug resistance were better than those of lamivudine. Clinical studies in China and abroad suggest that HBeAg-positive patients with baseline HBV DNA <9log and ALT³2ULN or HBeAg-negative patients with HBV DNA <7log have better efficacy and lower incidence of drug resistance at 1 and 2 years of treatment if they reach 300 copies/mL of HBVDNA at 24 weeks of treatment with telbivudine.
The overall incidence of adverse events was similar to that of lamivudine, but the incidence of grade 3-4 creatine kinase (CK) elevation at 52 and 104 weeks of treatment was 7.5% and 12.9%, respectively, which were higher than that of the lamivudine group (3.1% and 4.1%, respectively).
5.Tenofovir disoproxil fumarate (TDF)
TDF is structurally similar to adefovir, but with less nephrotoxicity and a therapeutic dose of 300 mg daily. this drug has not been approved for marketing in China.
In a randomized, double-blind, controlled clinical trial, the HBVDNA rates in HBeAg-positive patients treated with TDF or ADV were 76% and 13% for HBVDNA <400 copies/mL, and 68% and 54% for sexual eALT reversion, respectively; the HBVDNA rates in HBeAg-negative chronic hepatitis B patients treated with ADV were 93% and 63% for HBVDNA <400 copies/mL at 48 weeks, respectively; the study showed that HBV inhibition was superior to that of ADV, and no tenofovirate-related resistance mutations were identified. At 3 years of continuous treatment with tenofovir, 72% of HBeAg-positive patients and 87% of HBeAg-negative patients had serum HBVDNA <400 copies/mL, and no resistance mutations were detected.