< strong>This article is published with the authorization of Academician Zhuang Hui, please do not reprint without permission.
On May 14, 2022, it will bring together more than 20 top clinical experts and scientific researchers in the field of liver disease in my country The “4th Chronic Hepatitis B Clinical Cure Summit and China School Summit Forum” was held online.
span>At the conference, Academician Zhuang Hui from Peking University School of Medicine gave a presentation on “Expert Opinions on Expanding Antiviral Treatment of Chronic Hepatitis B” Wonderful interpretation, Yimaitong summarizes the main content, and now presents it to you as follows.
>Academician Hui Zhuang
Peking University School of Medicine Professor and doctoral supervisor of the Department of Pathogen Biology, School of Basic Medicine
Former member of the World Health Organization Viral Hepatitis Advisory Committee Member of the Regional Expert Committee on Hepatitis B Immunization Control and Member of the WHO Western Pacific Region Polio Eradication Confirmation Committee< /span>
He is currently a member of the Asia-Pacific Alliance for the Elimination of Viral Hepatitis and an honorary chairman of the Chinese Medical Association Hepatology Branch
Won 3 Second Prizes of National Science and Technology Progress Award
Won 1 US Patent and 2 Chinese Patents , 3 New Drug Certificates
Won the Ministry of Health, Ministry of Education and Beijing Science and Technology Progress Awards
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Published more than 650 papers, edited 5 monographs in English, 30 monographs in Chinese, and translated 1 volume
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1. Why was the Expert Opinion on Expanding Antiviral Therapy for Chronic Hepatitis B proposed?
1. Current guidelines for chronic hepatitis B treatment are too strict
In 2016, 369 hepatitis B surface antigen (HBsAg) positive patients in the United States were followed up for an average of 7 years, and it was found that among the dead patients, those who did not meet the guidelines for treatment developed hepatocellular carcinoma ( HCC) death rate was 40%-80%; non-HCC death rate was 30%-73%. Antiviral therapy in this population can reduce the risk of HCC and non-HCC mortality.
span>2019 Korea Multicenter Cohort Study of 3624 Untreated Chronic Hepatitis B Virus (HBV) Infections(median follow-up time: 4.6 years), the proportion of HCC deaths in patients who did not meet the treatment criteria ranged from 33.5% to 64.0%. Antiviral therapy in this population can reduce the risk of death from HCC.
< span>2. New understanding of the natural history of HBV infection, challenge for immune tolerance and inactive periods without disease progression and without treatment
A study by Kim et al in 2018 showed that the risk of HCC and death or liver transplantation in patients with HBV infection in the immune-tolerant stage without treatment is higher than that in the immune-active stage chronic hepatitis B with treatment patient. If this population is treated, the risk of HCC development and death or liver transplantation can be reduced.
3. To achieve the WHO goal of eliminating the public health threat of viral hepatitis by 2030
In 2016, the World Health Organization (WHO) proposed the goal of eliminating the public health threat of viral hepatitis by 2030: new-onset chronic hepatitis B and chronic hepatitis C Hepatitis decreased by 90%, and deaths related to chronic hepatitis B and chronic hepatitis C decreased by 65%. To achieve this goal, the diagnosis and treatment rates of viral hepatitis need to be improved. According to the report of Polaris on October 4, 2021, the diagnosis rate of hepatitis B in my country is 22%, and the treatment rate is 17%, which is still far from the target proposed by WHO.
4. The price of hepatitis B antiviral drugs has dropped significantly, and the availability of chronic hepatitis B antiviral treatment has improved
5. Chronic hepatitis B antiviral therapy is expanding
In recent years, domestic and foreign guidelines have gradually relaxed the treatment standards for chronic hepatitis B. In 2019, our guideline proposed that for HBV DNA positive + alanine aminotransferase (ALT) > upper limit of normal (ULN) If other causes are excluded, antiviral therapy can be initiated.
In addition, scholars in the UK, India, Greece and other places have also proposed the “Treat All” treatment strategy, which The clinical significance of the strategy includes: reducing the source of infection and HBV transmission; reducing HCC, liver transplantation and death; reducing hepatitis B discrimination;
II. Interpretation of “Expert Opinions on Expanding Antiviral Therapy for Chronic Hepatitis B” strong>
Recommendations1: For the general population, especiallypeople at high risk of HBV, such as people with human immunodeficiency virus (HIV) infection, men who have sex with men, intravenous drug addicts, sexual partners and household contacts of people with HBV infection patients, pregnant women, receiving immunosuppressive or antitumor drugs and anti-hepatitis C virus (HCV strong>)Medical treatment should be carried outHBsAg screening, so that all screening should be done .
For HBsAg screening, qualitative detection reagents are used, not HBsAg quantitative detection reagents. At AASLD 2021, Razavi-Shearer et al. reported that screening and treating HBsAg-positive patients in the general population is cost-effective. CONCLUSIONS: It is more cost-effective to screen high-risk groups for HBV and treat HBsAg-positive patients who meet the expanded treatment criteria.
Recommendations2:< /strong>For HBsAg positive patients, including chronic hepatitis B patients receiving antiviral therapy, high-sensitivity real-time quantitative PCR should be used to detect HBV DNA (LOD 10~ 20 IU/ml).
The quantitative range and detection limit of the reagents currently used to detect HBV DNA are shown in the figure below. The detection limit of highly sensitive real-time quantitative PCR has been reduced to 10-20 IU/ml.
< span>Recommendations3:For serumHBV DNA positive,ALT consistently above the therapeutic threshold(male strong>30 U/L, Female 19 U/L), 1 year continuous follow-up3more than one , at least every time3 months apart, excluding other causes, Antiviral therapy is recommended.
A study in the United States included 59 patients with chronic HBV infection with ALT<40 U/L, liver biopsy The results showed that the liver histological lesion rate in the group with high normal ALT value (26-40 U/L) was significantly higher than that in the group with low normal value (≤25 U/L). A prospective cohort study of 94,533 males and 47,522 females with health insurance in South Korea showed that the relative risk of death from liver disease increased with increased baseline serum ALT levels. A study in Hong Kong, China showed that the risk of complications and HCC in HBV patients increased with elevated ALT levels.
In recent years, many international guidelines, including those in Asia, have recommended lowering the ALT threshold for starting antiviral therapy. Among them, the 2007 and 2016 AASLD guidelines, the 2013 NICE guidelines, and the 2020 East Asian expert opinion all recommended that the ALT threshold for initiating antiviral therapy be 30 U/L for men and 19 U/L for women.
Recommendations4:< /strong>For serum HBV DNA positive, no matter the level of ALT, as long as one of the following conditions is met, < /strong>Recommended antiviral therapy:( >1) Family history of hepatitis B cirrhosis or HCC;( 2) Age >30 years old ;(3) non-invasive indicators Or liver histological examination, suggesting significant liver inflammation (G≥2) or fibrosis (F≥2).
This recommendation is different from the 2019 edition of my country’s 2019 Guidelines for the Prevention and Treatment of Chronic Hepatitis B. The 2019 Guidelines It was pointed out: “For those with positive serum HBV DNA, normal ALT, and family history of hepatitis B cirrhosis or hepatitis B liver cancer and age>30 years old, antiviral therapy is recommended” . However, many recent studies and published foreign guidelines have pointed out that family history of HBV-related liver cirrhosis or HCC or age > 30 years are two independent risk factors for disease progression, and those who meet one of them can be used as the initiation of anti-inflammatory drugs. Indications for viral therapy.
Taiwan and mainland China reported that the mortality rate of HCC, viral hepatitis and chronic liver disease was significantly increased in people over 30 years old. A study in Taiwan, China showed that the cumulative incidence of HCC in patients with a family history of HCC and HBsAg positive was higher than that in those without a family history. An Italian study showed that HBsAg and/or anti-HCV positive patients with a family history of HCC had a higher risk of HCC than those without a family history. Explain that as long as one of them is present, it is recommended to start antiviral treatment.
Recommendations5:< /strong>For follow-upmore than 1 year, HBV DNA and ALT patterns are difficult to determineand strong>Untreated“indeterminate period” chronic hepatitis Bpatients, recommendedantiviraltreatment.
The “uncertain period” refers to a 1-year follow-up of untreated patients with chronic HBV infection, Its HBV DNA and ALT patterns were inconsistent with traditional chronic HBV infection staging.
In Nanjing, my country, 4759 patients with chronic HBV infection (2016.1~2020.8) were staged according to the “AASLD 2018 Hepatitis B Guidance”. 27.8%; the disease stage distribution of 791 patients with hepatitis B e antigen (HBeAg) positive or negative chronic HBV infection with ALT detection more than twice and liver biopsy in 6 months of follow-up showed that patients with indeterminate stage accounted for 37.4%.
The risk of chronic hepatitis B disease progression remains high during the “uncertain period”. According to reports from the United States, Singapore, and Taiwan, the cumulative incidence of HCC in patients with indeterminate period was significantly higher than that in inactive period. Therefore, antiviral therapy should also be performed for the population with a high incidence of such HCC.
Recommendations6:For ART1years with hypoviremia For patients with chronic hepatitis B, it is recommended to switch to or add a potent and low-resistance nucleoside analog (entecavir, tenofovir disoproxil or tenofovir alafenamide) therapy, or combined with pegylated interferon therapy.
Low viremia (LLV) refers to: receiving entecavir, tenofovir disoproxil, or In patients with chronic hepatitis B treated with tenofovir alafenamide and good compliance, HBV DNA can still be detected by high-sensitivity quantitative PCR method (minimum detection limit of 10-20 IU/mL) after treatment for at least 48 weeks , but <2000 IU/mL.
Multiple studies at home and abroad suggest that LLV is closely related to the progression of chronic hepatitis B after antiviral therapy. A study in my country showed that persistently low levels of HBV DNA can promote the progression of liver fibrosis in patients with chronic hepatitis B. A Korean study reported that a retrospective cohort study of 875 patients with newly diagnosed chronic hepatitis B, followed up for 8 years, the cumulative incidence of HCC in LLV patients was higher than that in patients with sustained virological response (MVR), and the cumulative incidence of LLV in patients with or without cirrhosis. The incidence of HCC was higher than that of MVR patients.
span data-brushtype=”text”>III. Summary
To sum up, the current treatment trend for chronic hepatitis B is to gradually transition from expanding the standard of care to “complete treatment” (“expanding the standard of care strong>Treat All”) strategy, if new drugs are developed in the future to enable us to clear HBV within a limited time, the treatment of chronic hepatitis B can be “total cure” ( “Treat All”) strategy.
Reference: Chronic Hepatology Branch of Chinese Medical Association. Expert opinion on antiviral treatment of hepatitis B[J]. Chinese Journal of Hepatology, 2022,30(02):131-136.