Why are there so many interferons and nucleoside analogs in combination therapy? Nucleoside analogs and interferon are two different types of drugs: nucleoside analogs act directly on the virus and have a fast onset of action; interferon has a broader surface of action, stimulates immunity, and has a more stable effect. In the 11 years since the clinical application of nucleoside analogs, many doctors and patients expect that combination therapy will combine the advantages of both drugs and have better results. Certain more difficult-to-treat diseases have achieved good results with combination therapy. The familiar tuberculosis is usually treated with four drugs together; AIDS is treated with a combination therapy called cocktail therapy ……. There are also experts now doing clinical trials on the combination of two drugs, which are said to improve efficacy and even help with surface antigen conversion ……. Interferon has more adverse effects, especially transaminases that can be higher, which can be overcome with the addition of nucleosides; because nucleosides work quickly, the combination therapy may work somewhat better than either single drug during and at the end of treatment. With these recent benefits, there are many doctors willing to promote it and many patients willing to accept it. Many of you have asked me questions about this, and I have responded briefly according to the Domestic and International Guidelines for Hepatitis B. But I know that for various complicated reasons, the combination of these two drugs is already more widely used in China. I am too old to get involved in the debate; in fact, the conclusion has already been reached, and there is no need to debate it. What is the prevailing view of this combination therapy in the domestic and international community? In a pre-marketing phase III international clinical trial in 2000, nearly 1,000 patients were divided into three groups: (1) Peroxin alone, (2) lamivudine alone, and (3) the combination of Peroxin and lamivudine. The mean pre-treatment viral levels in the three groups were 9.9, 10.1 and 10.1 times, respectively, which were very similar, and the duration of treatment was 48 weeks in all three groups. At the end of the course of treatment, the mean reduction of virus level from the pre-treatment level was 4.5 times higher in group 1, 5.8 times higher in group 2, and 7.2 times higher in group 3, with the best effect in the combination group, followed by the lamivudine group, and the worst effect in the piroxin group; 24 weeks after stopping treatment, the mean reduction of virus level from the pre-treatment level was 2.4 times higher in group 1, 1.7 times higher in group 2, and 2.7 times higher in group 3, with the worst effect in the lamivudine group, and the worst effect in the combination and piroxin groups. group and the Pyroxine monotherapy group were not statistically significantly different. The virological effects of piroxin, lamivudine and the combination of both in HBeAg(+) chronic hepatitis B. This figure is from the New England Journal of Medicine, 2005, Volume 352, page 2688, and the blogger is the third author of this article The Phase III international clinical trial of piroxin is a classic, and it was preceded and followed by a number of smaller clinical trials with similar results. The European, American and domestic Hepatitis B Guidelines from 2002 onwards do not recommend the combination of interferon and nucleoside analogues. In another article published in January 2011 in the New England Journal of Medicine (Volume 364, Page 328, Figure 1B), chronic hepatitis with HBV and HDV co-infection and similar pre-treatment viral levels (above and below the 6th power) was treated with Pyroxine monotherapy, Adefovir monotherapy, or a combination of both drugs for 48 weeks, with both Pyroxine monotherapy and combination viral levels reduced to the 3.5th power at the end of treatment, and at 24 weeks of discontinuation Pyroxin alone was the same as at discontinuation, and the combination group rebounded to the 5th power. A patient I checked 3 weeks ago: 6 years on entecavir, virus had turned negative in the first year, switched to Paxil for 1 year for fear of rebound from discontinuation, virus rebounded 7 times square 2 months after discontinuation, and was hospitalized with acute hepatitis attack. The virus was already negative before Pyroxin treatment, and 1 year of treatment did not consolidate it. This is an isolated case, but there are many clinical trials mentioned above that clearly indicate the lack of synergistic effect of the two drugs. Why is there no synergy between the two drugs in combination? Nucleoside analogues can only inhibit viral replication, but have no direct effect on viral antigens, and it takes 3 to 5 years to turn negative for “major triplets”, and most of them will relapse soon after stopping the medication. Interferon needs to stimulate immunity to work, and there are obvious individual differences, only half of the patients are effective. Nucleoside analogs and interferon have different treatment philosophies: in layman’s terms, nucleoside analogs are “fire extinguishers”, which quickly inhibit viral replication and control inflammation, so that the hepatitis can be relieved, but there is no immunomodulatory effect, so the efficacy is not stable. Interferon stimulates immunity, which is equivalent to “ignition”, and stimulating immunity requires an inflammatory environment in the liver, so if nucleosides are used at the same time, the “fire” is extinguished, which is not conducive to interferon therapy.