Peking University Health Science Center Zhuang HuiDrug resistance is one of the biggest challenges for the treatment of chronic hepatitis B
Peking University Health Science Center Zhuang Hui
Drug resistance is one of the biggest challenges for the treatment of chronic hepatitis B (CHB) with nucleoside (acid). Effective prevention and management of drug resistance is an important measure to improve the efficacy of hepatitis B virus (HBV), shorten the course of treatment, improve the prognosis and reduce the cost of medical treatment. In recent years, Europe, America, Asia Pacific and China's chronic hepatitis B diagnosis and treatment guidelines have been updated to promote the prevention and management of drug resistance.
Recently, the "China virus disease," the magazine "the Journal of infectious diseases", "liver" and "Clinical Hepatology" magazine co sponsored 14 written "nucleoside and nucleotide analogs in the treatment of chronic hepatitis B drug and its management" officially released by the fund, and will carry out the "prevention of hepatitis China face drug resistance and perspective for the future" as the theme of the chronic hepatitis B resistant consensus tour lasted for half a year in the 12 national city.
Drug resistance and its harm
Drug resistance is an important obstacle for the treatment of hepatitis B virus (HBV) drugs. When treated with nucleoside (acid) drugs for a long time, the occurrence of drug resistance is more common. Drug resistance can not only make the treatment effect has been made (such as histological improvement) loss, can also lead to liver disease deteriorated sharply, the progression of the disease (such as hepatitis recurrence, hepatic decompensation and liver failure etc.).
A number of studies have shown that the incidence of liver cirrhosis and liver cancer in patients with drug resistance is significantly higher than that of non drug resistant patients. Cross resistance and multi drug resistance will increase the difficulty of follow-up treatment and limit the choice of retreatment.
The spread of drug-resistant virus strains may lead to serious public health problems, drug resistance caused by rtA181T/sW172* mutations may have potential carcinogenicity, follow-up mutant and non mutant patients, 26 months when the liver cancer incidence rates were 30% and 1.8%. In addition, drug resistance will significantly increase the cost of medical treatment of long-term treatment. Based on the serious harm of drug resistance, it is very important to prevent drug resistance.
In China, the problem of drug resistance to nucleoside (acid) is serious, which is not related to the use of these drugs and the lack of awareness of drug resistance.
A survey shows that our understanding of the importance of physician resistance was significantly lower than that in South Korea and the United States; nucleosides in Europe and Japan and South Korea and other countries and regions (acid) drug naive patients, the use of high efficiency and low resistance to nucleoside (acid) the proportion of patients with drugs for 80%~90%, while China, up to 81% of patients still with low efficiency and high resistance to nucleoside (acid) drugs such as initial treatment, including 30% lamivudine (LAM, 35%) using adefovir dipivoxil (ADV).
At the same time, patients receiving nucleoside (acid) drugs during the treatment of single drug free, casual dressing or sequential frequent dosing, drug resistance is not reasonable dosing or dressing and other irregularities, about half of the patients stop taking the drugs.
Mechanism and detection of drug resistance
The production of HBV resistant strains can be explained in terms of evolutionary theory. Due to the characteristics of hepatitis B virus replication rate, low fidelity, prone to mutation, after a drug pressure (including the target, pharmacokinetics, drug resistance gene barrier barrier, antiviral efficacy and drug resistance pathway) screening, through adaptation to the environment (intrahepatic replication and spatial adaptability) process, culminating in drug-resistant virus strains.
At present, the drug resistance rate of LAM is the highest among the 4 nucleoside (acid) drugs listed in our country, and the lowest in Cave (ETV).
Drug resistance detection
Clinical drug resistance monitoring mainly includes HBV replication level monitoring and follow-up, as well as the detection of liver biochemical indicators.
At present, China is still a lack of genotypic resistance testing method specification, standard, unified, common techniques including nucleic acid sequence analysis and restriction fragment length polymorphism analysis, reverse linear probe hybridization and gene chip technology, which have advantages and disadvantages, need to be standardized.
Drug resistance management
Primary nonresponse management
How should confirm the compliance of patients, then to HBV RT gene sequencing to identify the mutation may exist, according to early replacement of more effective drugs, or with potent, non cross resistant drugs.
Partial response management
After confirming the compliance of patients, the therapeutic regimen was adjusted according to the antiviral effect and the resistance gene barrier.
It is important to note that there is still a debate about the treatment of partial virologic response at 48 weeks of treatment with potent, low resistance drugs (e.g., ETV). The HBV level of the patients at baseline and at 48 weeks of treatment, and the dynamic changes of HBV DNA during the course of treatment should be considered comprehensively. For the high baseline viral load, HBV DNA continued to decline can continue to use the original drug, with the extension of treatment time, still can get a virological response, and the drug resistance rate is very low.
Periodic monitoring of HBV DNA during the treatment of nucleoside (acid) drugs for early detection of virological breakthrough. In order to confirm the patient compliance is good, once the occurrence of virological breakthrough, should be timely treatment, choose to add no cross resistance of antiviral drugs.
In addition, can also be considered with pegylated interferon (PEG IFN) treatment, but for security reasons, telbivudine (LdT) combined with PEG IFN.
Prevention of drug resistance
Understanding the past history of treatment
First of all, we should inquire about the type, dosage, efficacy and drug resistance of the nucleoside (acid) drugs in the past.
Initial drug selection
Nucleoside (acid) - based drugs with high efficiency and high resistance gene are the most effective strategies to prevent drug resistance.
Asia Pacific, Europe and the United States Institute of liver diseases diagnosis and treatment of chronic hepatitis B or consensus guidelines recommend, nucleoside (acid) drug naive patients should select potent antiviral drugs, high genetic barrier to resistance, ETV and Nuo Fuwei (for TDF, not yet listed in China) as the preferred first-line monotherapy or. Our guidelines are suggested: "if conditions permit, the initial treatment should choose the antiviral effect of strong resistance and low rate of drug".
Not only can reduce the occurrence of drug resistance of the initial choice of high genetic barrier to resistance, reduce drug resistance related complications, and no mutation detection was before the treatment, reduce the number of treatment monitoring, and reduce the salvage treatment needs and save cost.
Studies have shown that up to 40% of virological breakthrough may have nothing to do with drug resistance, and poor patient compliance. Survey shows that Chinese 22%~27% patients on drug resistance and the severity of the nucleoside (acid) lack of understanding of the importance of drugs for long-term treatment, only 46.3% of the patients with chronic hepatitis B to recognize the importance of antiviral therapy, most patients with antiviral treatment to high expectations, this is an important cause of poor compliance, an important reason for the resistance nearly half of patients self withdrawal is the treatment of LAM. To strengthen the awareness of patients with disease and compliance education, help to improve the understanding of the importance of long-term treatment of patients, reduce the incidence of drug resistance.
Avoid single drug random sequence
Should be strictly to avoid the low resistance gene barrier or cross drug resistance of single drug random sequential therapy, such as LAM sequential LdT or ADV. The risk of multiple drug resistance mutation and cross resistance can be induced by single drug random sequence. Other studies have shown that, after LAM treatment with ETV, virological response is poor, and prone to drug resistance.
Strict treatment indications
In order to reduce the risk of drug resistance, we should strictly grasp the indications of treatment and avoid unnecessary treatment. Such as liver inflammation, slightly difficult to achieve sustained responders (such as alanine aminotransferase levels were normal, high viral load, hepatitis B e antigen positive immune tolerance of patients), should avoid the use of nucleoside (acid) drugs.
In addition, strengthening the medical staff resistance to antiretroviral therapy and prevention and management of education, avoid nonstandard treatment, including single drug free sequential therapy, frequent short-term dressing or dosing, and drug resistance after reasonable dosing or dressing, helps to reduce the occurrence of drug resistance. At the same time, the positive interaction among academic circles, government departments and pharmaceutical enterprises is a necessary condition to reduce the use of nucleoside (acid) drugs.
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