The morbidity and mortality of chronic hepatitis B is closely related to persistent viral replication and disease progression to cirrhosis or hepatocellular carcinoma. Longitudinal studies of patients with chronic hepatitis B have shown that the cumulative 5-year incidence of cirrhosis is 8% to 20% and the cumulative 5-year incidence of liver decompensation is approximately 20% after the patient is diagnosed. The 5-year survival rate for patients with compensated cirrhosis is approximately 80% to 86%, and patients with decompensated cirrhosis have a poor prognosis with a 5-year survival rate of 14% to 35%. The annual incidence of HBV-associated hepatocellular carcinoma is high in patients with chronic hepatitis B. The incidence is 2% to 5% in patients with established cirrhosis, although the incidence of HBV-associated hepatocellular carcinoma is correlated with both geographic location and liver disease stage.
The new guidelines address 10 important issues in the diagnosis and treatment of chronic hepatitis B.
1. How is liver disease evaluated prior to treatment?
2. What are the treatment goals and treatment endpoints?
3. How is response to treatment defined?
4. What is the most optimal choice of first-line therapy?
5.What are the predictors of efficacy?
6.What is the definition of drug resistance-related and how to deal with drug resistance?
7. How is treatment monitoring performed?
8.When to stop the drug?
9.How to treat special populations?
10.What are the current unresolved issues?
1.Pre-treatment assessment
The first step should be to determine the causal relationship between liver disease and HBV infection and to evaluate the severity of liver disease. Not all patients with chronic hepatitis B have persistently elevated alanine aminotransferase (ALT). ALT may remain normal in immune tolerant patients and intermittently normal in a subset of HBeAg-negative chronic hepatitis B patients. Therefore, appropriate, longitudinal long-term follow-up is important.
(1) Biochemical indicators to assess the severity of liver disease include: aspartate aminotransferase (AST) and ALT, gamma glutamine transferase (GGT), alkaline phosphatase (ALP), prothrombin time (PT), serum albumin, and blood cell count. Usually, ALT is higher than AST; however, when the disease progresses to cirrhosis, the AST/ALT ratio reverses and, in addition, a decrease in serum albumin, a prolongation of PT, and a decrease in platelet count are observed. Liver ultrasound may also be used for evaluation.
(2) Detection of HBV-DNA levels is necessary for disease diagnosis, treatment decisions, and late monitoring. The real-time quantitative polymerase chain reaction (PCR) method is strongly recommended for follow-up, primarily because of its higher sensitivity, specificity, accuracy, and its wider dynamic range. The World Health Organization has established an international normal standard for the expression of HBV-DNA levels. Serum HBV-DNA levels should be expressed in IU/ml to ensure that the values measured are comparable. One measurement should be used for the same patient in order to assess the antiviral effect.
(3) The presence of other causes of chronic liver disease including HDV, HCV or HIV mixed infection, coexisting alcoholic, autoimmune, metabolic and fatty liver disease should be thoroughly examined.
(4) Morphologic findings of the liver can help determine whether to initiate treatment, so liver tissue biopsy is recommended for patients with elevated ALT or HBV-DNA greater than 2000 IU/ml (or both) to determine the inflammatory response and degree of fibrosis. Liver tissue biopsy is also often used to evaluate other possible causes of liver disease such as steatosis or fatty liver. Although liver puncture is an invasive procedure, the risk of serious complications is small (1 in 4000 to 10,000), and the size of the liver puncture needle should be such that an accurate analysis of the extent of liver damage and fibrosis can be achieved.
Hepatic puncture is usually not required in patients with clinical evidence of fibrosis, or in patients with indications for treatment without consideration of inflammatory activity or fibrosis stage. The application of non-invasive methods including serological indicators and transient elastography to assess liver fibrosis is gaining attention, and these methods are complementary to liver biopsy, which can be avoided.
2.The purpose of treatment
The aim of treating hepatitis B is to stop the progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, hepatocellular carcinoma, and death, to improve the patient’s quality of life, and to prolong survival. If the hepatitis B virus can be suppressed durably, the histological activity of chronic hepatitis, the risk of cirrhosis, and the risk of hepatocellular carcinoma are reduced, and the goal of treating hepatitis B is achieved. However, HBV infection cannot be completely cleared due to the presence of covalent closed-loop DNA (cccDNA) in the nucleus of infected hepatocytes.
3.Treatment endpoint
HBV-DNA must be reduced by treatment to the lowest possible level, ideally below the low limit of PCR detection (10-15 IU/ml), and the virus should be suppressed to a degree that ensures that biochemical parameters are normalized, histology improves, and complications are prevented. Reduction of HBV-DNA to low levels with interferon and nucleoside analogue therapy is associated with disease remission.
Sustained maintenance of low to undetectable levels of HBV-DNA is key to reducing the risk of viral resistance to nucleoside analogs. Consistently maintaining low to undetectable levels of HBV-DNA also increases the likelihood of HBeAg seroconversion in HBeAg-positive patients and HBsAg conversion in HBeAg-positive and HBeAg-negative patients. If the real-time PCR method cannot be used, a sensitive method should be applied to detect HBV-DNA whenever possible.
(1) For HBeAg-positive and HBeAg-negative patients, the most desirable treatment endpoint is the disappearance of persistent HBsAg with or without the appearance of anti-HBs antibodies. This relates to complete and definitive remission of chronic hepatitis activity and improvement in long-term regression.
(2) In HBeAg-positive patients, durable HBeAg seroconversion is a satisfactory endpoint as it has been shown to be associated with improved prognosis.
(3) HBeAg-positive patients who do not achieve HBeAg seroconversion and HBeAg-negative patients who maintain HBV-DNA at undetectable levels after treatment with nucleoside analogs or persistent undetectable HBV-DNA after treatment with interferon are another most satisfactory treatment endpoint.
4. Definition of response
Two classes of drugs are available for the treatment of chronic hepatitis: interferon alpha and nucleoside (acid) analogs (collectively referred to as NUC in this guideline). The definition of response to antiviral therapy varies depending on the treatment approach.
(1) Interferon therapy
● Primary non-response is defined as a reduction in HBV-DNA of less than 1log10IU/ml from baseline after 3 months of treatment.
● Virological response refers to HBV-DNA level less than 2000 IU/ml at 24 weeks of treatment.
●Serological response refers to the occurrence of HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients.
(2) Nucleoside analogue therapy
●Primary non-response refers to the reduction of HBV-DNA by less than 1log10IU/ml from baseline after 3 months of treatment.
● Virological response refers to no detectable HBV-DNA by real-time PCR at 48 weeks of treatment.
● Partial virological response is defined as HBV-DNA reduced by more than 1log10IU/ml but still detectable by real-time PCR assay.
The presence of partial virologic response should be evaluated at 24 weeks when treated with moderate-strength drugs or drugs with low resistance genetic barrier (lamivudine or telbivudine) in order to adjust the treatment regimen. When treated with potent antivirals or drugs with a high genetic barrier to resistance or late emergence of resistance (entecavir, adefovir, and tenofovir), the presence of a partial virologic response should be assessed at 48 weeks to allow adjustment of the treatment regimen.
● Virologic breakthrough is defined as an increase in HBV-DNA levels of more than 1log10IU/ml above the nadir during treatment.
Virologic breakthrough often occurs prior to biochemical breakthrough (elevated ALT levels). The main reasons for virologic breakthrough during nucleoside analog therapy are poor adherence to treatment and the emergence of HBV-resistant strains of virus.
Recent treatment results
Seven drugs are currently available for the treatment of chronic hepatitis B: including plain interferon, pegylated interferon, and nucleoside analogs. There are three classes of nucleoside analogs for the treatment of HBV infection: L-nucleoside analogs (lamivudine, telbivudine and emtricitabine), deoxyguanosine analogs (entecavir) and open-loop phosphate nucleoside analogs (adefovir and tenofovir). Lamivudine, adefovir, entecavir, tipifudine and tenofovir have been approved in the EU for the treatment of hepatitis B, and a combination tablet of tenofovir and emtricitabine has been approved for the treatment of HIV infection.
The efficacy of the above drugs has been evaluated in 1-year (two years for tenbivudine) randomized controlled trials. Long-term treatment results (approaching 5 years) have been obtained for lamivudine, adefovir, entecavir, tipifovir and tenofovir in certain subgroups of patients. Figures 1 and 2 show the response rates for the above drugs in different trials that used different HBV-DNA assays, and all drugs were not compared head-to-head.
(1) For HBeAg-positive patients, the virologic response rates at 1 year of treatment with pegylated interferon alpha-2a/2b, lamivudine, adefovir, entecavir, tipifovir, and tenofovir (the definition of virologic response also varied across trials and different existing guidelines) were 24%, 36% to 39%, 21%, 67%, 60%, and 74%, respectively. The HBeAg seroconversion rate is 30% for regular interferon and pegylated interferon and about 20% for nucleoside analogs, and can increase with longer treatment with nucleoside analogs, but is affected if drug resistance occurs. The disappearance rate of HBsAg at 1 year of application of pegylated interferon is 3% to 4%, while lamivudine, adefovir, entecavir and tipifudine are all 0, and tenofovir is 3%.
(2) For HBeAg-negative patients, the virologic response rates (defined differently by different trials and different existing guidelines) at 1 year of treatment with pegylated interferon alpha-2a (piroxin), lamivudine, adefovir, entecavir, tipifovir, and tenofovir were 63%, 72%, 51%, 90%, 88%, and 91%, respectively. at 1 year, the pegylated interferon HBsAg disappearance rate was 3% for lamivudine, adefovir, entecavir, tipifudine and tenofovir.
Figure 1, Comparison of HBeAg serological conversion rate, HBV-DNA undetectable rate and ALT recurrence rate at 1 year in HBeAg-positive chronic hepatitis B patients treated with pegylated interferon alpha-2a (PEG-IFN), lamivudine (LAM), adefovir (ADV), entecavir (ETV), tipifovir (LDT) and tenofovir (TDF). These studies used different HBV-DNA assays and all drugs were not compared head-to-head.
Figure 2, Comparison of HBV-DNA undetectability and ALT recurrence rates at 1 year in patients with HBeAg-negative chronic hepatitis B treated with pegylated interferon, lamivudine, ADV, ETV, LDT, and TDF. These studies used different HBV-DNA assays, and all drugs were not compared head-to-head.
Indications for treatment
Treatment indications apply equally to both HBeAg-positive and HBeAg-negative chronic hepatitis B patients and are based on three main criteria: serum HBV-DNA levels, serum ALT levels, and histologic grading and staging.
When a patient has an HBV-DNA level above 2000 IU/ml (approximately 10,000 copies/ml) and/or a serum ALT level above one times the upper limit of normal (ULN) and a liver biopsy (or a non-invasive marker that has been proven in patients with HBV infection) shows moderate to severe active necroinflammation and/or fibrosis (using a standard scoring system, such as METAVIR score of at least grade A2 or stage F2) should be considered for treatment. Patient age, health status and the status of antiviral drug use in each country also need to be taken into account.
The following special patient groups should be considered.
Immune-tolerant patients: For most patients under 30 years of age with persistently normal ALT, high HBV-DNA levels (usually more than 10E7IU/ml), without any suspicion of liver disease and without a family history of liver cancer or cirrhosis, immediate liver biopsy or treatment is not required, but follow-up is mandatory.
Patients with mild chronic hepatitis: for patients with mildly elevated ALT (less than 2 x ULN) and histological examination showing mild lesions (METAVIR score below A2F2), no treatment may be required, but follow-up is mandatory.
Patients with compensated cirrhosis: treatment should be considered if HBV-DNA is detected, even if the ALT level is normal and/or the HBV-DNA level is less than 2000 IU/ml (approximately 10,000 copies/ml).
Patients with decompensated cirrhosis: antiviral therapy is urgently needed. Rapid and potent suppression of the virus should be particularly important in such patients, and the development of drug resistance should be effectively prevented. Significant improvement in clinical symptoms is closely related to controlled viral replication, but patients with very advanced liver disease may not benefit from treatment and should be considered for liver transplantation.
Predicting response
A number of baseline characteristics and on-treatment indicators have been identified as predictors of post-treatment response. Predictors of response to antiviral therapy at different time points vary depending on the antiviral agent.
(1) Interferon alpha-based therapy
Pretreatment factors predicting the occurrence of HBeAg seroconversion are low viral load (HBV-DNA below 10E7IU/ml or 7log10IU/ml), high serum ALT level (>3×ULN), and liver biopsy showing a high activity score (at least A2).
During treatment, the probability of HBV-DNA falling below 20,000 IU/ml at 12 weeks was 50% for HBeAg-positive patients and 50% for HBeAg-negative patients to achieve a sustained virological response.
A decrease in HBeAg levels at 24 weeks during treatment is predictive of HBeAg seroconversion.
Further studies are needed to determine the role of HBsAg quantification in predicting the achievement of sustained virologic response and the disappearance of HBsAg.
Patients with genotypes A and B had a better response to interferon alpha compared to patients with HBV genotypes C and D. However, the predictive value of HBV genotype for individuals is poor, and genotype alone cannot currently determine the choice of treatment.
(2) Treatment based on nucleoside analogues
Pretreatment factors predicting the occurrence of HBeAg seroconversion are low viral load (HBV-DNA below 10E7IU/ml or 7log10IU/ml), high serum ALT level (>3×ULN), and liver biopsy showing a high activity score (at least A2).
The production of a virological response (no HBV-DNA measured by real-time PCR) at 24 or 48 weeks during lamivudine, adefovir or telbivudine treatment was strongly associated with a low rate of drug resistance and, accordingly, a higher probability of a sustained virological response and of HBeAg serological conversion in HBeAg-positive patients.
HBV genotype does not affect the response to any nucleoside analogs.