Is it not surprising that the virus rebounded after taking entecavir for 1.5 years and the resistance test found that both lamivudine and entecavir were resistant, but never used lamivudine? Is it also surprising that you had taken lamivudine for only 3 months more than 10 years ago, and now you are taking entecavir for hepatitis onset but it is not effective, and you are tested for lamivudine monoresistance? If you are taking entecavir, do you also need to know about these “surprises”? Case 1 Last week I saw a middle-aged patient with chronic hepatitis B with “major triple-positive” in the outpatient clinic, ALT started to rise in December 2013, ALT 132U/L in April 2014, HBV DNA 2.50 E+07 iu/ml, ALT normalized in 3 months on entecavir, virus turned negative. However, in October the virus rebounded 2.80 E+05 iu/ml, high transaminases and clinical entecavir resistance. Resistance test results 204 loci (lamivudine) and 202 loci (entecavir) mutations. Never took lamivudine, never drank alcohol, and never took other drugs during the same period. Case 2 The patient was a male, 58 years old. He used to take lamivudine for six months more than ten years ago and then stopped taking it. Six years ago, he started to take domestic adefovir, which is the weakest drug, and the virus still fluctuated around three copies. Three months after switching to domestic entecavir, the virus quickly turned negative, and since then the virus has been stable for about two and a half years. Question: If previously lamivudine resistant, how long does it usually take for resistance to occur on entecavir monotherapy? Is this patient a special case? Case 3 32 years old. “I had HBV DNA 1.85E+08 (unitless) and normal liver function for 3 months when I took lamivudine more than 10 years ago and then stopped taking it. I had previously done 3 consecutive resistance tests, 2 of which tested for mutations at locus 204 V/I, indicating lamivudine resistance, and all 3 tests tested for viruses above the 6th power of 10. Now I have been taking entecavir for almost 1 month and the virus has not decreased. Question: I have only been taking entecavir for 1 month and have been taking lamivudine for a short period of time for over 10 years, how can I have lamivudine resistance? Can I continue to use entecavir, or switch to tenofovir now? [Case Study] How can entecavir “replace” lamivudine resistance? As I have said many times, entecavir is rarely resistant. From 2006 when this drug was launched, I have treated countless patients in my clinic so far, and I clearly remember only a few people who are resistant to the drug: a Wenzhou person who took the drug for 2 years and the tests were normal, wanted to stop the drug, in order to avoid rebound, the local doctor asked him to take 1 tablet every other day for the third and fourth years, and 1 tablet every 3 days for the fifth year, and it rebounded; another Xiamen person was in the same situation; the third person was a chronic nephritis who took corticosteroids at the same time and was resistant to the drug at 7 months; there are several other people who are resistant to the drug. The third was a chronic nephrologist taking corticosteroids at the same time and was resistant at 7 months; and several others were resistant after alcoholism. But unexpectedly, I saw a hepatitis patient (case 1) in the clinic last week, who took entecavir after the onset of the disease and had normal liver function and negative virus within 1 year, and then took it for 5 months, and the virus and transaminases rebounded one after another. Because the virus had previously been negative, it was certainly not a poor effect of entecavir. After repeated questioning and denial of alcohol abuse, I did a resistance test full of suspicion and the result was actually dual resistance to lamivudine and entecavir. He was a patient who was scheduled for my clinic, and every aspect of his medical history, regular checkups, and resistance tests were reviewed correctly. Indeed, he had never taken lamivudine, and he was a first-time patient who took entecavir at the onset. Although he had never taken lamivudine, he may have been infected with a virus that was originally resistant to lamivudine (locus 204), and although he took entecavir at first treatment, cross-resistance (locus 202) had already occurred soon afterwards, only because entecavir was very potent and did not rebound significantly, but he only took 1 tablet per day, and the 202 locus of entecavir mutated 2.5 years later (you may not understand this, and it will be made clear later ). The one you are taking is entecavir, how can it be lamivudine resistant which was taken earlier? Case 3 is his own follow up post, his account of the medical history is clear; case 2 is a patient personally treated by a doctor who has forgotten both things, the information should be credible. The two cases are similar, both took 3 or 6 months of lamivudine more than 10 years ago, case three switched to entecavir virus does not reduce, check lamivudine site variation; case two after the onset of the disease with adefovir 6 years, because of its low efficacy, the virus remains low, after switching to entecavir quickly turned negative, but two and a half years later the amount of virus rose again to six copies, the test suggests entecavir, lamivudine, tebivudine resistance. Lamivudine monotherapy is rarely resistant within 3 or 6 months, especially at 3 months, which can only mean that the virus was resistant to lamivudine before treatment. Because the drug has not rebounded for many years after stopping, it may have been a chronic carrier at the time, and hepatitis has only developed in recent years. Even if the resistant virus disappears in the blood, the parent of the resistant strain (cccDNA) lives on in the liver cells. If the disease develops more than 10 years after discontinuation of the drug, it is still caused by the offspring virus of the resistant parent. Possibly, the virus infected in example 2 was resistant before lamivudine treatment and continued to incubate in the liver cells for more than 10 years after a brief 6-month discontinuation of the drug. 7 or 8 years ago the disease was caused by the lamivudine-resistant virus, which was sensitive with adefovir antiviral and was kept at a very low level for 6 years, and gradually after switching to entecavir by cross-resistance (locus 204) and eventually its own (locus 202) as well. How could the hepatitis B virus be resistant before lamivudine treatment? Isn’t it strange that it is resistant to lamivudine without having taken lamivudine, or before taking lamivudine? As you may know, the methods used to study the human genome are very, very sensitive and have been used in recent years to study hepatitis B virus in chronic carriers, and although these individuals have not been resistant to the virus, the major variant loci for resistance to all nucleoside analogues are already present, including loci 204 for lamivudine and telbivudine, loci 236 and 181 for adefovir, and loci 184, 202, and 250 for entecavir. These resistance sites have long existed naturally, but in very, very small numbers, and are not detectable with conventional resistance tests. Long-term treatment with nucleoside analogs removes the sensitive (non-resistant) viruses, and only the resistant ones can replicate in large numbers, so the disease rebounds. Since resistance sites naturally exist for all nucleoside analogs, why is entecavir never resistant? Because the potency is very strong, 1 site variant (one of 184, 202 and 250) is still sensitive, there must be a cross-resistance site variant of lamivudine first before the virus will rebound, the threshold of resistance is too high, so the onset of primary treatment with entecavir is rarely resistant. Tenofovir is more potent than entecavir, and it is still not known where its resistance sites are. The potency of lamivudine is very low, which is why the threshold of resistance is very low. So, why does it take 2 or 3 years of treatment for Adefovir to become resistant when it has the lowest potency? Because there are 2 primary loci (236 and 181), and generally both loci need to be mutated, there is natural resistance to adefovir, but it is also significantly less than lamivudine. What is the importance of clarifying “natural resistance”? Lamivudine is rarely used today because of its high resistance rate, but as the earliest and only oral antiviral drug from 1999-2004, it has saved countless hepatitis B patients and caused countless drug resistance, which has persisted and is still a complex clinical problem. The first treatment of the disease with entecavir is rarely resistant, rarely adverse reactions (including no nephrotoxicity), domestic drugs are equally effective, (Guangzhou’s) medical insurance almost all free. Currently, it may have begun to become the most commonly used oral antiviral drugs in China, chronic hepatitis B disease requires long-term treatment, patients who are now taking entecavir, I hope you can have more relevant knowledge, standardize the use of drugs, cherish entecavir, entecavir can be used until the drug is discontinued.