Author: Chief Physician Wang MingmingShandong Public Health Clinical Center (formerly Jinan Infectious Disease Hospital)
This article is published with the authorization of the author, and please do not reprint without authorization.
Introduction
Nucleoside drugs and alpha-interferon have brought new hope to chronic hepatitis B patients. With more than 20 years of accumulated experience, while effectively controlling the virus and improving the condition, clinical treatment has new and higher goals and requirements, which are clinical cure and complete cure. However, the road to antiviral treatment is long. To achieve this goal, correct understanding and practical efforts are required.
New concepts of clinical cure and complete cure
Clinical cure and complete cure are concepts updated in recent years. More than 20 years ago, when there were no hepatitis B antiviral drugs, patients could be clinically cured as long as they received liver-protecting and enzyme-lowering therapy and their liver function reached stable and normal levels. At that time, there were no five quantitative and DNA tests for hepatitis B. Current clinical cure means that is undetectable in serum HBsAg, with or without HBsAg seroconversion after antiviral therapy; HBV DNA remained below the lower limit of detection; HBeAg-positive patients also had HBeAg-negative conversion; liver inflammation was relieved and liver histopathology improved, and liver function remained stable and normal, but cccDNA remained in the nuclei of liver cells. Complete cure means after antiviral therapy, the serum HBsAg is undetectable, with or without HBsAg seroconversion, and the HBV in vivo DNA was completely cleared (including cccDNA and integrated HBV DNA in the hepatocyte nucleus), and serum HBcAb remained positive.
The continuous development of medical science has given new concepts of “clinical cure” and “complete cure”. Clinical cure and complete cure are the ideal and ultimate goals of antiviral therapy for chronic hepatitis B, but the achievement of these goals is related to many factors, including transmission mode, viral genotype, antiviral strategy and the patient’s physical status, etc.. For the advantaged population with the possibility of clinical cure, we can strive to pursue this goal by optimizing the treatment, but the non-dominant population should not blindly pursue clinical cure, especially complete cure.
cccDNA response to antiviral drugs
From above It can be seen that the fundamental difference between clinical cure and complete cure is whether HBV cccDNA is cleared in vivo. The full name of cccDNA is covalently closed circular DNA (covalently closed circular DNA). HBV invades the host hepatocytes through the sodium ion-taurocholic acid-cotransporter on the hepatocyte membrane as a receptor. The plus strand is extended to mend the cleft region in the plus strand, forming cccDNA. The biological significance of cccDNA is that it can be used as a template for viral transcription, and it can be transcribed under the action of RNA polymerase to generate three subgenomic RNAs, which can be used to synthesize viral proteins and supplement the source of viruses. Each infected hepatocyte nucleus contains 30-50 copies of cccDNA. Although the number is not large, the half-life is long. Most studies believe that the half-life of cccDNA is about 2 months, and a few studies believe that it is more than half a year. Natural decay time is long. At present, nucleoside drugs have no inhibitory effect on cccDNA, so it is difficult to fundamentally remove HBV DNA. Alpha-interferon can promote clinical cure by enhancing the degradation of HBV pregenomic RNA (pgRNA) and core particles, or through epigenetic modification of cccDNA to inhibit HBV transcription and reduce the expression of viral proteins such as HBsAg. cccDNA is the main cause of chronic hepatitis B, and also the root cause of chronic hepatitis B difficult to cure.
Optimized treatment of dominant populations
To achieve clinical To cure, it is necessary to select the dominant population for optimal treatment. evaluation factors for the dominant population should include: ① The physical status of the patient, including age (18-60 age), no underlying diseases (such as diabetes, kidney disease, chronic obstructive pulmonary disease, mental illness, etc.), and the functional status of various organs is good; ② baseline level and antiviral response.
Take the baseline level as an example: The New switch study showed that patients with chronic hepatitis B positive for e antigen received nucleoside (acid) analog therapy for 1~ 3 years, e-antigen clearance and HBV DNA <200 IU/mL, combined with peginterferon for 48 weeks, HBsAg quantification at baseline <1500 IU/ml, at the end of 48 weeks, 26.5% of patients achieved clinical cure, HBsAg at baseline Quantitative >1500 IU/ml, 4.7% of patients achieved clinical cure at the end of 48 weeks. The OSSTOSST study showed that after 9-36 months of treatment with nucleoside drugs in chronic hepatitis B patients, HBV DNA ≤103 copies/mL, e-antigen <100 PEIU /mL, combined with peginterferon for 48 weeks, HBsAg quantification at baseline <1500 IU/ml, at the end of 48 weeks, 20% of patients achieved clinical cure, HBsAg quantification at baseline >1500 IU/ml, at the end of 48 weeks, 1.6 % of patients achieved clinical cure.
Several studies have shown that baseline levels of HBsAg and HBV DNA and their The magnitude and speed of decline in is an important indicator for evaluating the dominant population and predicting clinical cure.
Currently, the combination therapy of nucleoside drugs and peginterferon mainly includes initial combination therapy strategy and sequential combination therapy strategy. These include “switching” strategies (that is, switching nucleosides to pegylated interferon) and “adding” strategies (that is, adding polyglycols to nucleosides).Glycol Interferon). To optimize the treatment of the dominant population, the current clinical application is the sequential combination therapy strategy, that is: the long-term use of nucleoside drugs On the basis of switching or adding peginterferon therapy. Both “switching” and “additional” treatment strategies can improve the clinical cure rate of patients. The “switching” strategy can achieve continuous HBsAg negative conversion and facilitate the safe withdrawal of nucleoside drugs, but the “switching” strategy may cause virological relapse, and attention should be paid to follow-up and monitoring during treatment; the “additional” strategy is relatively It may be safer and more secure, but it increases the economic and psychological burden of patients. Regular review and evaluation, and timely adjustment of treatment strategies to obtain the best curative effect are the soul of optimal treatment.
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