Love and be careful of the liver, pay attention not to get lost.
Hepatitis B virus is a double-stranded DNA virus belonging to the family Hepatophiliac DNAviridae.
HBV infection is a global public health problem.
It is estimated that there are more than 250 million people living with HBV worldwide, of whom about 600,000 die each year from HBV-related liver disease.
China still faces enormous challenges in achieving the WHO Global Health Sector Strategy, which aims to reduce the incidence of viral hepatitis by 90% and viral hepatitis-related mortality by 65% by 2030.
The goal of anti-HBV therapy is to maximize the inhibition of HBV replication, reduce hepatocyte inflammatory necrosis and liver fibrous tissue hyperplasia, delay and reduce the occurrence of liver failure, cirrhosis decompensation, hepatocellular carcinoma (HCC) and other complications, improve the quality of life of patients, prolong their survival time, and pursue clinical cure for some suitable patients.
Clinical cure refers to the absence of HBsAg-negative (with or without anti-HBs), undetectable HBV DNA, normal hepatic biochemistry, and improved liver tissue lesions, but there is a risk of HBV reactivation and HCC because cccDNA in the hepatocyte nucleus is not cleared.
What is cccDND?
During the replication process of hepatitis B virus, viral DNA enters the host nucleus, and under the action of DNA polymerase, the gaps in both strands are filled to form a superhelix covalently closed circular DNA (cccDNA). Extracellular hepatitis B virus DNA is a loose loop of relaxed circular DNA (rcDNA) molecules. cccDNA is the original template for hepatitis B virus pre-genomic RNA replication, although its content is small, only about 5 to 50 copies in each hepatocyte, but it is of great significance for the replication of hepatitis B virus and the establishment of infection status, only by clearing the cccDNA in the nucleus, can we completely eliminate the viral carrying state of hepatitis B patients.
Drugs that have been used in clinical anti-HBV therapy include nucleoside (acid) analogues (NAs) and interferon α (IFNα).
Long-term oral antiviral therapy for oral NAs can be effective in inhibiting HBV replication, and IFNα-based therapy can achieve a sustained virological response in some patients, and even clinical cure in a small number of patients.
However, whether it is NAs or IFNα treatment, the proportion of clinical cures is not high.
So, why is the hepatitis B virus so difficult to remove?
1. Immune factors
If newborns are not vaccinated against hepatitis B in time, after infection with hepatitis B virus, the probability of developing a positive chronic hepatitis B surface antigen in the future is more than 90%. If infected with hepatitis B virus in childhood, about 20% develop chronic hepatitis B, while adults are infected and develop chronic in only about 10%. Mainly because the immune function is not perfect, the hepatitis B virus "takes advantage of the void" when the body's immune function can not recognize them, the immune system can not recognize the virus, nor does it have the ability to clear the virus, which is called "immune tolerance" in medicine.
2. Lack of drugs against cccDNA
After the hepatitis B virus invades the liver cells, it quickly forms cccDNA within the liver cells, which is the "template" of viral replication. This virus gene is difficult to completely remove, and like the "seeds" of the hepatitis B virus, it constantly takes root and sprouts and reproduces offspring.
None of the current antiviral drugs can act directly on cccDNA. Because drugs are difficult to act directly, even if the hepatitis B virus in the outer layer of the liver is cleared, the cyclic DNA rooted inside is not affected in the slightest.
3. Hepatitis B virus is easy to mutate.
Hepatitis B virus is extremely highly variable, each time it mutates, its pathological characteristics and genetic structure will change accordingly, and the antiviral drugs that previously could inhibit the elimination of the virus will lose their effect. When the virus mutates, some drugs may not be effective against them, and the human immune system is more difficult to recognize.
4. The vitality of hepatitis B virus is extremely tenacious
Of all the viruses known so far, the vitality of the hepatitis B virus is quite tenacious. Studies have shown that under storage conditions of 20 °C, hepatitis B virus can survive for 20 years and remain infectious after 20 years. In boiling water at 100 °C, hepatitis B virus is able to survive for 10 min. At room temperature, hepatitis B virus can survive for more than a week.