| BackgroundDrug resistance is an important and key problem for chronic hepatitis B(CHB)patients treated with nucleos(t)ide analogues (NAs) Compared with patients without resistance, patients suffering from resistance were prone to further progress of the disease,e.g. the progression of liver cirrhosis,higher risk of hepatocellular carcinoma(HCC). The difficulty of follow-up treatment and health care costs also increased. At present, the problem of the drug resistance for chronic hepatitis B antiviral treatment is more serious. Such as in the NAs treatment, there were a variety of non-standard treatment, including single-agent sequential at random, in the short term dressing or frequent dosing, and drug resistance after dosing or unreasonable treatment, etc.Compared with no resistance in patients, resistance not only has the therapeutic effect,but also lead to a sharp deterioration in the liver lesions, accelerates a disease progression to liver failure, increase the rate of liver transplantation, HCC incidence and case fatality rate. At the same time,the cross resistance and multi-resistant make subsequent treatments become more complex and difficult, and may increase the risk of end-stage liver disease. Therefore, the prevention and management of these patients could improve the efficacy of drug resistance, shorten the treatment course, an important measure to improve prognosis and reduce the cost of medical care.ObjectiveTelbivudine(LdT) is a chemical synthesis of nucleoside analogues,has strong anti hepatitis B virus effect. HBeAg serum conversion rate of LdT is relatively high and it belongs to the class B pregnancy medication: Therefore,LdT is recommend as an antiviral agents for the treatment of CHB. However, the potential drug resistance in LdT's long-term treatment has become an outstanding issue,which affects the efficacy of antiviral therapy.The purpose of this study is to explore clinical characteristcs and salvage therapy of LdT resistance in HbeAg-positive CHB patients.MethodsWe established a research queue for HBeAg positive CHB patients receiving single LdT antiviral treatment, viral breakthrough and determination of drug resistance mutation, the baseline data of patients' general data and LdT antiviral therapy were analyzed retrospectively and further prospectively followed-up after treatment of drug-resistant mutations . A total of 62 cases of CHB patients with HBeAg positive for LdT were determined by direct sequencing of pyrophosphoric acid sequencing or PCR product, including 40 cases of patients treated first and 22 cases of patients treated again(the patients treated again referred to usage of NAs for more than 3 months prior to LdT treatment ).In the same period, 36 cases of LdT single drug were collected for more than 2 years, the patients with no resistance mutation and the patients with HBeAg turned negative or transformed were treated as the control group. The baseline characteristics of the two groups were analyzed,including HBeAg. HBV-DNA, age, sex, etc., and the characteristics of the information in the 12 weeks and 24 weeks of antiviral therapy were compared.Comparison of baseline, 12 weeks and 24 weeks related data characteristics of patients in drug resistance group at the group of patients treated first and treaed again;Description of the drug resistant mutants and patterns and table drawings. To investigate the baseline characteristics of LdT in patients with LdT resistance mutations, the characteristics of virological response in the 12th and 24 weeks, and the feasibility of the HBV-DNA level of domestic reagent as the prediction index of the route map; The chemical breakthrough of LdT resistance mutation, the characteristics of viral breakthrough and the characteristics of mutant sites. The curative effect of individualized treatment of LdT resistant mutant patients.Results1.Patients with LdT resistance group: 62 patients, of whom 49 were males, and the median age was 29.5 years (17-55 years old). 40 cases of patients were treated first and 22 cases of patients were treaed again.1.1 clinical features: The median time of virology breakthrough in LdT treatment was 78 (24?194) weeks, of which 39 (62.9%) were virological responders, and the median time of the outbreak of virology breakthrough was 84 (40?194) weeks; In 23 cases (37.1%), the median time of the outbreak of virology breakthrough was 76(24?162) weeks; But the difference was not statistically significant (t = 1.547, P =0.127).The serum HBV-DNA level of the patients with drug resistance mutation was lower than baseline ( 6.83 ± 1.29 log 10 copies/mL) at the time of virology breakthrough ( 5.79 ± 1. 18 log10 copies/ml ),and the difference was statistically significant (t = 4.64, P = 0.000); The serum HBV-DNA level ( 6.10 ± 1.22 log10 copies/ml) was slightly higher than the non-ALT elevated patient ( 5.62 ±1.14 log10 copies/ml), but the difference was not statistically significant (t = 1.56, P = 0.125 ).For patients with LdT resistance mutations, the median virologic breakthrough ALT levels was 44 (12-574) U/L, and the median baseline levels was 111 (12?532)U/L. Difference between the two groupswas statistically significant ( u= 887.5,P=887.5 ).After the outbreak of virology, 4 cases of HBeAg hematology conversion patients, HBeAg was still unmeasurable. 3 patients with HBeAg disappeared, HBeAg was restored. The remaining 55 cases of HBeAg were quantitatively reduced and HBeAg rose.1.2 The locus and the mutant site model of LdT resistance mutation: The LdT resistance group detected 8 mutation sites:M204I, L180M/H, V173L, A181V,V207I/L, V214A, P237H, N/H238S, All 62 patients with LdT resistance had M204I site mutation, and 25.8% (19/62) had the mutation of L180M. There are 11 mutant sites.In patients with single locus of drug resistance mutation, the level of HBV-DNA was 5.41 (3.62?7.88) log 10 copies/ml,lower than those with multiple site-resistant mutations6.22( 4.30?7.70) log10 copies/ml. The difference was statistically significant (u = 315.50, P = 0.03).2. The patients in the LdT resistance group were compared with 36 patients in the control group:The baseline data of the control group with better efficacy of LdT resistance group were higher in age, more men, higher quantitative value of HBeAg,lower ALT, and statistically significant difference. There was no statistical difference in level of HBV-DNA.HBV-DNAloss rate?HBeAg conversion rate,and HBeAg conversion rate were lower than those in the control group in 12 weeks and 24 weeks of LdT resistance group, and the difference was statistically significant.3. Follow-up treatment and clinical resection of the drug resistance group: 55 of the 62 patients were treated and followed up for at least 48 weeks.3.1 Patients with LdT plus ADV treatment (n = 43): In the 48th week, the level of HBV-DNA of 41 patients was reduced by > 21og10, and the level of HBV-DNA of 31 patients was lower than the detection limit, and 2 cases of primary non-respondent HBV-DNA level were still < 21ogl0 / mL. The single M204I mutant virological response rate (74.1 %) was higher than that of the multidrug-resistant site ( 37.5% ),and ?2=5.6218, P=0.018.3.2. patients who changing LdT to LAM plus ADV treatment(n=6): In the 48th week, the level of HBV-DNA in 4 patients was reduced by > 21og10, and 3 patients with the level of HBV DNA were lower than the detection limit, which reached the virological response rate. In the other two patients,the level of HBV-DNA decreased< 21og 10 copies/mL.3.3 patients receiving PEG-IFNa treatment (n = 3): All three patients were M204I, L180M, and ALT increased. In the 48th week, the level of HBV-DNA of two patients were lower than the detection limit. One of the patients showed the HBeAg disappeared, and the level of the HBV was. decreased in one patient < 2 log 10 copies/mL.3.4 patients receiving TDF treatment (n = 3): The level of HBV-DNA of all three patients were lower than the detection limit at the end of week 12, and they reached the virological response. |
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