How better to avoid the development of drug resistance? At this stage, there is a saying that nucleoside analogues are less likely to be resistant during the first 6-12 months of treatment, and that getting the HBVDNA as negative as possible during this period determines to a large extent whether drug resistance is likely to occur later. Therefore, before starting treatment, patients must plan a long-term treatment plan with the help of their doctor based on their condition (“major” or “minor”, whether they have cirrhosis, the level of virus, etc.), with the aim of being effective and non-resistant. What is the first principle to prevent drug resistance? To prevent drug resistance, it is necessary to reduce the virus level to the limit (the bottom line of the detection limit, or conversion) in the first 6 to 12 months after starting nucleoside analogs. This is the first and most important thing to do, so it is called the “first principle of drug resistance prevention”. If you are thinking of choosing to treat with nucleoside analogs and have not yet started, then please consider it carefully. Now there are five nucleoside analogues in China, according to the results of clinical trials, although not very accurate, according to the antiviral efficacy that can be achieved within one year, can be roughly arranged as follows: tenofovir can inhibit viral replication 9 times, entecavir 8 times, tipivudine 7 times, lamivudine 6 times, adefovir 5 times. If you are a “major triplet” and your viral level is 8 times, you should of course choose entecavir, which is the most powerful antiviral drug available in China; if you are 7 times, you can use telbivudine; 6 times, lamivudine; and 5 times, adefovir. Most of the treatment results, but the clinical application of individual differences, such as some 7 times the party of patients, with lamivudine within a year, or even less than a year can not detect the virus, the price is much cheaper, the family is not well-off can also be tried for 6 months. What is the basis of the “first principle”? To put it simply, the “first principle” requires that viral replication be brought down to the bottom of the detection limit as soon as possible. The higher the frequency of virus replication, the higher the incidence of drug resistance. The higher the frequency of viral replication, the higher the incidence of drug resistance. The lower the viral replication, the lower the incidence of drug-resistant mutations. 2, nucleoside analogs from the beginning of the administration, a very small number of drug-resistant mutant viral strains will occur from wild strains, they will be transformed into drug-resistant mutant cccDNA, stored in the nucleus of liver cells. As treatment proceeds, more and more drug-resistant cccDNA is accumulated. By reducing the frequency of viral replication as early as possible, less drug-resistant cccDNA will accumulate, and this may reduce the rate of drug resistance that occurs later in treatment. Therefore, the prevention of nucleoside resistance becomes the key to the success or failure of hepatitis B treatment! How can we achieve the “first principle”? If your family is well-off, it is best to use entecavir even if your viral level is not very high when you start treatment. For example, if your viral level is only 5 times higher, whether you use entecavir or lamivudine, you will be able to reduce the virus to the bottom of the detection limit (500 or 1000 copies per milliliter of serum) at 6 months, which may actually make a difference. 2, cirrhosis and “small triple” hepatitis need a longer period of maintenance treatment, if the family is well-off, it is best to also use entecavir. The reason is that entecavir is rarely resistant within 3 years, and later switching to a lower-grade drug is equivalent to an additional 3-year safety period of rare resistance. What if the “first principle” is not met? Because 20% and 5% of lamivudine and telbivudine will be resistant within 1 year respectively, if the treatment has not been reduced enough to 2 times by 6 months, it is estimated that it will not be reduced to the bottom line of the check limit within 1 year, in order to avoid resistance, it is best to switch to higher grade entecavir, if the cost of the drug is not affordable, at least add the domestic drug of adefovir daidine. At present, the mainland economy is not yet developed, some patients with high viral levels, also with adefovir, a few may also be reduced to the bottom of the check limit within a few months, most to 6 months has not been reduced by 2 times, transaminases are sometimes abnormal. Although the effect is not good, because the first use of nucleoside analogues of “major triple-positive” patients, Adefovir will not be resistant in 1 year, you can wait and see. If the bottom of the check limit has not been lowered by 12 months, although Adefovir is rarely resistant in 2 years, it is still not good to continue the single drug, why? Currently, there are 3 types of nucleosides (entecavir, telbivudine and lamivudine) in the nucleoside class of drugs in the domestic market, while nucleotides are temporarily only 1 type of adefovir. Adefovir is needed to prevent resistance to telbivudine and lamivudine, and adefovir is also preferable for final maintenance with a single agent. For any long-term regimen, the longest current dosing period is adefovir. Although adefovir will not be resistant for a short period of time, resistance does not occur suddenly, but gradually accumulates, and although it will not be resistant temporarily, it may accumulate resistance later.