Analysis Of Variation After Treatment With Nucleos(t) Ide Analogue In Patients With Chronic Hepatitis B

Object:Chronic HBV infection is a global epidemic,and there is still no complete cure,and no drug with a higher cure rate has been found.Therefore,nucleos(t)ide analogues are still the main treatment.With the popularization of nucleos(t)ide analogues,drug resistance has become an issue that needs urgent attention and solution.With the strong support of the country,the first-line drugs,such as entecavir and tenofovir,have not only high drug resistance barriers,but also greatly reduced prices,even lower than the price of second-line drugs.However,some patients in Northeast China still take lamivudine and other non first-line drugs for a long time due to various reasons,and have doubts about changing antiviral therapy.This study analyzed the drug resistance of patients with chronic hepatitis B in Jilin Province after treatment with nucleos(t)ide analogues,explored the relevant factors affecting drug resistance,and provided a reference for patients and doctors in selecting drugs.Methods:A total of 1,211 chronic hepatitis B patients who had a poor response or a virological breakthrough after treatment with nucleos(t)ide analogues and were tested for the hepatitis B mutation site were collected from December 2015 to December 2018,and 271 patients were detected with mutation sites.144 patients who met the inclusion criteria and had complete case data were selected as the study.The subjects were divided into groups with mutations(64 cases)and groups without mutations(80 cases)according to the presence or absence of mutation sites;according to taking NAs type and quantity,divided into single drug treatment group(90 cases)and multi drug treatment group(54 cases);divided into regular medicine group(89 cases)and irregular medicine group(55 cases)according to whether the medicine was used regularly.Collected the general data of the patients included sex,age,family history,smoking history,drinking history,hypertension,diabetes history,and clinical data including detection results of hepatitis B mutation sites(detection sites include rt I169,rt V173,rt L180,rt A181,rt T184,rt A194,Rt S202,rt M204,rt N236,rt M250),quantitative detection of hepatitis B virus(HBV DNA),alpha-fetoprotein(AFP),liver function(AST,ALT,?-GT,ALB,TBIL),coagulation function(PT,INR,PTA),Creatinine(Cr),blood routine(WBC,Hb,PLT),medication history,compliance,complications(cirrhosis,liver failure,liver cancer).SPSS 23.0 software was used for data analysis,and Excel was used for chart drawing.Result:(1)In this study,a total of 1,211 patients with poor response or virological breakthrough were found,and 271 patients were detected with mutation sites,with a total mutation rate of 22.4%.Among the 144 patients included,44 patients took LAM,accounting for 31%,and the drug resistance rate was the highest at 52.3%.There were 15 patients taking ADV,accounting for 10%,and the drug resistance rate was 46.7%.There were 5 patients taking Ld T,accounting for 3%,and the drug resistance rate was 40.0%.A total of 26 patients took ETV,accounting for 18%,with the lowest drug resistance rate of 30.8%.A total of 54 patients were combined,accounting for 38%,and the drug resistance rate was 44.4%.(2)64 cases of hepatitis B mutation sites were detected.The average HBV DNA was 6.67 ± 0.95 log10 IU/ml,the median AFP was 10.50(4.50,111.20)ng/ml,and the median ALT was 100.80(36.75,274.75)U/L,the average Hb was 129.23 ± 24.73 g/l;there were 80 cases without mutation sites,the average HBV DNA was 4.20 ± 1.57 log10 IU/ml,and the median AFP was 6.13(2.29,23.89)Ng/ml,median ALT was 50.40(29.60,162.40)U/L,and average Hb was 118.62 ± 31.33 g/l.The levels of HBV DNA,AFP,ALT,and Hb in patients with mutation sites were significantly higher than those without mutation sites,and the differences were statistically significant(P <0.05).(3)A total of 20 mutation sites were detected,of which the L180 M site appeared the most frequently,36 times,followed by the M204 I,M204V,and A181 T sites.Among the two site mutations,L180 M + M204 I appeared the most frequently.11 times,followed by L180 M + M204 V.Of the 64 patients with drug resistance,17 had mutations at the M204 I site,11 had mutations at the L180 M + M204 I site,and 5 had mutations at the L180 M + M204 V site,all of which were caused by long-term oral LAM.A total of 14 patients with three or more site mutations,most of them were sequential or irregular combined with multiple NAs drugs.(4)In patients with long-term oral LAM,L180 M,M204I,M204 V,M204V/I alone or L180 M + M204 combination mutation is the main variation.In patients with longterm oral ADV treatment,the A181 + N236 was the dominant mutation.In patients with long-term oral ETV,the L180 ± M204 mutation is combined with other site mutations such as one or more of S202 G,T184I,and M250 V.(5)Among the 64 patients,25 patients were detected with one site mutation,accounting for 39.1%;22 patients with two site mutations,accounting for 34.4%;17 patients with 3 site mutations,Accounted for 26.6%.(6)The levels of HBV DNA,AST,and ALT in patients in the regular medication group were significantly lower than those in the irregular medication group,and the differences were statistically significant(P <0.05).(7)The significant increase in HBV DNA levels(OR 0.179,95% confidence interval 0.101-0.316,P < 0.05)and poor compliance(OR 8.748,95% confidence interval 2.191-34.921,P < 0.05)during treatment were independently associated with the occurrence of genotypic resistance in patients.Compared with ETV,oral LAM(OR 0.020,95% confidence interval of 0.001-0.338,P <0.05)and ADV(OR 0.060,95% confidence interval of 0.005-0.806,P <0.05)are more prone to drug resistance.Conclusion:(1)In the past three years,the majority of chronic hepatitis B patients with poor response or virological breakthrough are still taking LAM orally,while the number of patients taking first-line drugs is relatively small.(2)With the prolonged treatment time of nucleos(t)ide analogues,the resistance rate increased significantly.Among patients with poor response and virological breakthrough,LAM resistance rate was highest and ETV resistance rate was lowest.(3)The occurrence of genotypic resistance in patients is closely related to the HBV DNA level,compliance,and type of medication during treatment.The higher the HBV DNA level,the worse the compliance,and oral LAM and ADV,the more prone to drug resistance.When HBV DNA ?6 log10 IU / ml,the mutation rate is higher.(4)At present,drug-resistant patients are mainly at one site.The most mutated are the L180 M and M204 I sites,which are mostly caused by long-term oral LAM.The patients with three or more loci are the least mutated,mainly by long-term oral ETV.Or caused by sequential and irregular oral multiple NAs.