Hepatitis B virus (HepatitisBvirus, HBV) infection is a serious global hazard, of the 6 billion people in the world, about 2 billion people have HBV infection, 300. 500 million people have chronic HBV infection, of which 25-40% will eventually die of cirrhosis or hepatocellular carcinoma, 15-20% of chronic hepatitis B patients with active viral replication have cirrhosis within 5 years, and chronic The 5-year survival rate for patients with liver cirrhosis is only 55%. The risk of hepatocellular carcinoma is 200 times higher in hepatitis B patients than in non-hepatitis B patients [1. 1]. There is a consensus that antiviral therapy is the key to the treatment of chronic hepatitis B.
1. Indications for antiviral therapy and its new developments.
1.1 Viewpoint 1: The American Association for the Study of Liver Diseases (AASLD) guidelines represent the viewpoint [1. 2]: antiviral decisions should be based on evidence-based medicine. scholars represented by Lok believe that while new data and information should not be ignored when selecting or changing antiviral regimens, the most important thing is to base them on the quality of evidence-based medicine that the available clinical evidence has. Such guidelines fully embody the principles of evidence-based medicine and thus provide authoritative guidance for antiviral treatment decisions. These guidelines are not without flaws. First, they are too restrictive for antiviral treatment of HBV infection, resulting in denial of treatment for patients who might benefit from the latest antiviral strategies, leading experts to urge that they should not be confined to the guidelines.
1.2 Viewpoint 2: A scholarly viewpoint represented by Dieterich [2.1]: argues that antiviral decisions should be based on the maximum biological benefit available to the patient, and that the maximum biological benefit of antiviral therapy should enable the preventive effect on liver damage and primary hepatocellular carcinoma (HCC) after complete suppression of HBV. Therefore, the primary therapeutic goal for HBV infection is aggressive and complete suppression of viral replication. For HBsAg-positive and HBVDNA-positive patients, regardless of HBVDNA and ALT levels, efforts should be made to achieve complete suppression of HBV, rather than a “wait and see” attitude, passively waiting for the increase in viral titers, liver function damage or even decompensation, and HCC before giving treatment.
1.3 The similarities and differences between the two views are the same for the fundamental interests of patients, both hope to obtain the desired effect of prevention and treatment with the rational application of antiviral strategies. However, they have different perspectives on the interpretation of evidence and patient benefits, and thus may differ in their treatment opinions. For chronic hepatitis B (CHB) with elevated ALT, the two management opinions are largely consistent. However, for HBV carriers with positive HBVDNA and persistently normal ALT, the guidelines focus on prevention and control of hepatitis activity and do not recommend administration of antiviral therapy because.
(i) HBV does not cause significant impairment of liver function at this time.
(ii) the host is in a state of immune tolerance to HBV and responds poorly to IFN, making it difficult to obtain effective viral suppression and HBeAg/anti-HBe serological conversion.
(iii) Nucleoside analogs are difficult to completely clear HBV, and long-term treatment may in turn cause drug resistance and stimulate liver damage. In contrast, Dieterich focuses on the prevention of HCC, preferring to give antiviral therapy, because the persistence of HBV is likely to cause hepatitis activity, cirrhosis and even HCC; in addition, the integration of viral genes into the host chromosome, viral mutation, and trans-activation of HBsAg can activate oncogenes and/or inhibit the expression of oncogenes, which can occur directly without hepatitis activity or cirrhosis. Therefore, the maximum “benefit/cost” ratio suitable for different patients should be clinically agreed with the patient.
2. New perspectives on several antiviral reference markers
2.1 alanine aminotransferase (ALT) elevated serum ALT often reflects hepatocellular injury, suggesting that patients have some immunity to HBV and may respond better to antiviral therapy. Almost all guidelines recommend that antiviral therapy for CHB needs to be based on liver disease activity [3], especially when ALT exceeds 2 times the upper limit of normal (ULN) and HBVDNA levels exceed 105 copies/ml. However, recent studies have found that. About 20-30% of HBV carriers with so-called normal ALT have moderate or even severe necrotizing inflammation in the liver, and a few patients have significant liver fibrosis confirmed by liver biopsy [4]. In addition, the factors of ALT elevation besides viral factors include alcohol, drugs, autoimmune and other Og factors. Therefore, it is believed that a normal ALT is not equal to the absence of inflammatory liver tissue damage, and some scholars even suggest that ALT should not be used as a judgment indicator for antiviral therapy.
2. 2HBVDNA load HBVDNA titer at baseline level is associated with the occurrence of cirrhosis, and there is a “dose-effect relationship” between HBVDNA level of 104~105/ml or more, and the risk ratio of HCC for those with less than 104 copies/ml is as high as 2.6. There is a tendency for a high incidence of HCC in those with less than 104 copies/ml, but it is not statistically significant [5]. It is believed that there is a “safe domain value” for HBVDNA in humans, which supports the identification of those who need antiviral therapy based on HBVDNA cut-off values. However, Dieterich does not fully agree with this interpretation, and it cannot be assumed that infected patients with low HBVDNA levels (less than 105-104 copies/ml) will not develop HBV-associated HCC; as long as HBVDNA is detectable in the body, despite its low level, appropriate antiviral therapy should be administered [2.2] to minimize the likelihood of HCC.
2.3 HBV genotypes are commonly found in China as B and C genotypes, which can be used as non-characteristic reference indicators for predicting antiviral therapy, but not as a basis for decision making on antiviral therapy.
2.4HBeAgHBeAg positivity is usually accompanied by positive HBVDNA and is mostly seen in high and low levels, suggesting active viral replication.HBeAg positivity by itself can increase the risk of HCC by 60-fold [6].HBeAg positivity is an indication for antiviral therapy and should be adhered to at least until serological conversion of HBeAg occurs. On the other hand, attention should be paid to whether HBeAg negativity is due to immune clearance or the absence of HBeAg expression due to, for example, the termination mutation of the pre-C gene G1896A. The latter is the target of antiviral therapy.
2.5 HBsAgHBsAg is an indispensable structural protein of HBV, and unless HBVDNA is fully S-gene integrated into the chromosomal DNA of the host hepatocyte and expressed with the replication, transcription, and expression of the latter, there is no doubt that clearance of HBsAg makes the best therapeutic endpoint for CHB.
2.6 Host and environmental factors Age can indicate the length of HBV infection and possible immune status. The risk of HCC in male patients is much higher than in female patients. The risk of HCC in male patients is much higher than that in female patients. The risk of HCC in male patients is much higher than that in female patients, suggesting that gender, environmental and age factors are involved in the regression of hepatitis B.
3. New understanding of antiviral therapy drugs
3.1 About the nucleoside drugs The nucleoside drugs currently on the market are lamivudine, adefovir and entecavir. In addition, the upcoming launch of telbivudine. Lamivudine, which was first marketed and clinically used, has shown unprecedented effects in the treatment of viral hepatitis B. However, the gradual emergence of drug resistance mutations (rtM204V/I and rtM180V/I, etc.) and rebound effects after drug discontinuation have caused unresolved problems in the treatment of hepatitis. Adefovir-associated mutations rtN236T have also been identified. it is currently believed that after viral replication and disease rebound caused by lamivudine resistance mutations, if remediation with adefovir is performed, lamivudine should be continued at the same time to prevent increased adefovir resistance; if remediation with entecavir is performed, lamivudine should be discontinued to reduce the risk of entecavir resistance [7], because there is a certain degree of cross-resistance. The second is the treatment regimen. Nucleoside analogues can significantly inhibit HBVDNA replication, and long-term application not only reduces liver inflammation, but also may reverse liver fibrosis and reduce the risk of liver failure and HCC. Therefore, on the basis of carefully weighing the “benefit/cost” ratio, a long course of treatment, combined or sequential therapy should be made according to the specific conditions of different patients.
3.2 About interferon therapy. Interferon a-2b (IFNa-2b) and pegylated interferon a-2a (PEG-IFN-2a) are currently used in clinical practice. The best choice of interferon should be hepatitis in active phase, short duration of viral infection, female, genetic behavior type B, and especially low level of HBVDNA replication, which are favorable to improve the efficacy of interferon. In contrast, interferon is less effective in those with high levels of HBVDNA replication, those with familial aggregation or mother-to-child vertical transmission, or those with a long duration of viral infection and genetic behavior type C. Currently, the effect of interferon alone is not very satisfactory, yet there are some side effects, so the doctor needs to make the right treatment decision after a detailed and comprehensive comprehensive analysis of all the information of the patient. Avoid the irresponsible attitude of one-sidedness and short-term quick success, which increases the burden of patients and makes the limited medical resources wasteful.
3.3 Regarding the combination of drugs. Studies have shown that lamivudine combined with PEG-IFN, compared with PEG-IFN alone, did not show particular superiority in HBeAg/anti-HBe serological conversion and ALT reversion rate. However, initial treatment i.e. lamivudine in combination with PEG-IFN, adefovir or telbivudine resulted in a resistance rate of only 2-5% after one year compared to 15-30% with lamivudine alone [8]. It seems that the main benefit of the combination is to reduce the rate of drug resistance, although the combination can cause multiple drug resistance.
4, chronic hepatitis B con- viral treatment outlook: it is a basic consensus that chronic HBV infection should be treated with aggressive antiviral therapy. However, a considerable part of the domestic medical staff and the public still “liver protection” “enzyme reduction” as the mainstream of treatment, which is a big cognitive misunderstanding. Long-term antiviral drugs must have no accumulation, safe and low toxicity for long-term use, good affordability and good tolerability. We should actively seek new antiviral drugs, develop a reasonable treatment plan, insist on combined and individualized treatment, combine long-term and intermittent repeated medication, suppress the virus to the lowest level, and actively prevent and treat to minimize the possibility of HCC. The development of new antiviral drugs that are safe for long-term application, well tolerated, economically adaptable, do not cause viral mutation, rebound, do not cause drug dependence, are able to deplete CCC-DNA, and have achieved stable and long-lasting long-term efficacy. In addition, specific immunotherapy such as dendritic cells and cytokines are also the focus of future research and development.