1, CCCDNA stubbornly exists in the nucleus of hepatocytes: hepatitis B virus adsorbed in the hepatocyte membrane, after the decapitation of HBV DNA into the hepatocyte plasma, further into the nucleus of hepatocytes, polymerase repair the cleft zone of positive DNA, forming the early CCCDNA of hepatitis B virus (covalent closed-loop DNA), CCCDNA conformational changes and nuclear protein binding, it becomes the template for HBV replication for a long time. CCCDNA has a long half-life and can enter new hepatocytes as the hepatocytes divide, and HBV continues to invade hepatocytes, forming new intranuclear CCCDNA and increasing the CCCDNA pool. To date, there is no direct anti-CCCDNA drug. The existing antiviral drugs mainly act on the replication phase below CCCDNA. Although it has been reported that a certain drug can reduce CCCDNA, the effect is mostly indirect. Therefore, it is difficult to cure chronic hepatitis B before the template for replicating hepatitis B virus is removed. Recently, it has been reported that when HBsAg is cleared in a few patients with chronic hepatitis B, HBV DNA cannot be detected in the serum, and inflammation of liver tissue has disappeared, but 37% of recovered hepatitis B patients still have low levels of CCCDNA expression in liver tissue, indicating the persistence of CCCDNA. Current treatment can only inhibit viral replication, reduce liver damage, promote repair and improve liver function. 2, HBV genotype: based on HBV whole gene nucleotide sequence heterozygosity ≥ 8%, or S gene region nucleotide sequence heterozygosity ≥ 4% as the standard, HBV can be divided into 8 genotypes: namely, A, B, C, D, E, F, G, H. China is mainly B and C type, C more than B, these two types of anti-hepatitis B virus than other types, C type and worse than B type, from a statistical point of view, C type than Statistically, type C has a higher degree of liver tissue damage than type B; has more variants in the pre-C and C promoters; has a worse response to antivirals; and has a worse prognosis. That is why hepatitis B is more difficult to treat in China and Asia than in other regions. 3, HBeAg-negative chronic hepatitis B is increasing year by year: Currently, chronic hepatitis B can be divided into HBeAg-positive chronic hepatitis B and HBeAg-negative chronic hepatitis B. It is reported that HBeAg-negative chronic hepatitis B has accounted for about 21% of the slow hepatitis B in mainland China, mainly because HBV is replicated using its own reverse transcriptase and polymerase, but the lack of self-correcting effect of this enzyme, the annual nucleotide substitution rate of up to 2.1×10-4/nt in the replication process, the patient’s body in addition to the dominant virus strains, there are many quasi-species, when the body’s immune system to their own infected When the body’s immune system produces a strong and specific immune response to the wild strain (natural strain) of HBV, the wild strain of HBV is suppressed, while the mutant strain can escape from the formed antiviral immunity, gradually becoming the dominant strain from the inferior, the body will also produce an immune response to the high titer of the mutant strain to remove the virus, resulting in liver damage again. Under natural conditions, it is common to have pre-C gene and C promoter mutation, which cannot replicate HBeAg, but can still replicate C antigen, so HBeAg negative occurs, while HBV DNA is still replicating significantly, becoming HBeAg negative chronic hepatitis B. Because HBV DNA genes B and C, are prone to pre-C gene and C promoter mutation, both of which are more likely to occur in type C than type B, Therefore, among the chronic hepatitis B in China, HBeAg negative but anti-HBe positive, HBV DNA still obviously replicates about 1/5 of the slow hepatitis B. This type of hepatitis has a prolonged course, resulting in a higher rate of heavy hepatitis and cirrhosis, and is more difficult to treat, making clinical treatment difficult. 4, the body’s immune tolerance to HBV infection: HBV in mother-to-child transmission and early childhood infection, often causing the body’s immune system to HBV immune tolerance and partial tolerance, it is difficult to activate the body’s specific immunity to HBV to clear the virus, it is estimated that about 40% of the existing HBV infection is this type, to gradually enter the immune clearance period in adulthood, the course of the disease is prolonged, there is a lack of enhance the body’s anti It is estimated that about 40% of existing HBV-infected patients are of this type and gradually enter the immune clearance period in adulthood. 5, occult hepatitis B: occult hepatitis B is mainly due to S gene mutation, commonly the S gene codon 145 glycine replaced by alanine, it is still replicating HBsAg, because of the mutation, with the current enzyme immunoassay anti-HBs can not bind, a negative reaction, can appear other hepatitis B virus indicators, even anti-HBs can also be positive, the main difference is that HBV DNA The main difference is that the level of HBV DNA replication is still high and ALT/AST is elevated. The prevalence of HBsAg-negative HBV variants in the population ranges from 1.9% to 3.4%. This makes diagnosis difficult and delays rational treatment, and is estimated to account for more than half of non-B and non-C chronic hepatitis.