Study On Transaminase Elevation Of Six Subjects In The Phase Ⅰ Clinical Trial Of Hepatitis B Virus Core Protein Assembly Regulator After 28 Days Of Continuous Administration

Objective:To study the baseline characteristics of 126 subjects in6 hepatitis B virus core protein allosteric modulator(HBV Cp AM)trials,the incidence of elevated transaminases and clinical characteristics after treatment;to analyze the risk factors affecting elevated transaminases;study the relationship between virological decline and transaminase elevation;provide experience related to the occurrence of transaminase elevation for future clinical trials of new HBV Cp AM drugs and anti-HBV treatment.Methods:From 2015 to 2021,126 patients with chronic hepatitis B virus who were successfully enrolled in the phase I clinical trials of six HBV core protein allosteric modulators in the phase I drug clinical trial center of the First Hospital of Jilin University,completed the trials and had complete records.Subjects with hepatitis B were the subjects of the study.The research contents include:the clinical characteristics of elevated transaminases by using class I and class II hepatitis B core protein assembly regulators respectively;the relationship between the decline of virological indicators and the increase of transaminases;the influencing factors of the occurrence of elevated transaminases.Evaluation indicators include:subjects’gender,age,BMI,ALT,AST,GGT,ALP,TBil,blood lipids(TC,TG),quantitative changes of HBV DNA,HBV RNA,HBs Ag,HBe Ag,HBCr Ag on D28-D-1 Volume,abdominal B-ultrasound,etc.,use Excel table for data entry,use Two-way ANOVA、T test for statistical analysis,and include baseline and 28 days after treatment ALT,GGT,ALP,TBIL,TC,TG,gender,age and other factors to construct multiple factors Logistic regression equation,the software uses SAS 9.4 software,drawing software uses Prism9.0.In this study,the six test items of allosteric modulators of hepatitis B core protein included were coded as A,B,C,D,E,and F,and only the increase of transaminase during administration was studied.We give the definition of ALT flare according to the DILI guidelines for clinical trials and the fluctuation characteristics of transaminases in this trial:if the ALT baseline is<1.5 times ULN,and the maximum value of ALT fluctuations during the trial is>3 times ULN,it is defined as flare;if the ALT baseline is≥1.5 times ULN,the maximum value of ALT fluctuation≥2 times baseline during the test was defined as flare.Flare=2 means:ALT rises to the defined range during the test;Flare=1 means:ALT rises during the test,and the maximum value of the rise does not reach the above defined range;Flare=0 means:ALT rises during the test decline.Result:(1)A total of 126 subjects were enrolled in our center in 6 clinical trials,of which 107 subjects were treated with experimental drugs.Among the 107 subjects,a total of 28 cases received type I drugs,accounting for about 26.2%,a total of 79 cases received type II drugs,accounting for about 73.8%;a total of 68 cases of male subjects,accounting for about 63.6%;female subjects A total of 39 cases,accounting for about 36.4%;a total of 22 cases of subjects with fatty liver,accounting for about 20.6%,a total of 85 cases of subjects without fatty liver,accounting for about 79.4%.All subjects had a body mass index(BMI)between 18.0 and 32.0 kg/m2(including the critical value).Enrollment baseline 1×ULN<ALT≤10×ULN;HBe Ag positive,HBV DNA≥2×10~4IU/m L;HBe Ag,HBV DNA≥2×10~3IU/m L.(2)Among the 107 subjects who applied the test drug,the incidence rate of Flare=2 group was 8.4%(9 cases);the incidence rate of Flare=1 group was 69.2%(74 cases);the incidence rate of Flare=0 group was 22.4%(24 cases);the incidence of elevated transaminases was 77.6%(83 cases).Among them,the incidence of Flare=1 was higher than that of the other two groups.The peak ranges of transaminase ALT and AST of 9 subjects in Flare=2 group were between 117.3-515.9 IU/ML and 129.9-344.3IU/ML respectively,and the increase of transaminase was not accompanied by the increase of bilirubin.The elevation of transaminases begins on the3rd-8th day and reaches the peak on the 15th-22nd day.Three of the four Flare cases underwent clinical intervention,and the transaminase value fell back to the normal range on days 9-35.(3)After 28 days of continuous administration,HBV DNA,HBV RNA,HBs Ag,and HBCr Ag all showed a downward trend compared with the baseline,and the difference was statistically significant(P<0.0001).Among them,the quantitative decrease of HBV DNA and HBV RNA was more obvious than that of HBs Ag and HBCr Ag(P<0.0001).(4)When Flare=2,HBV DNA and HBV RNA decreased most significantly(R~2=0.7823 and R~2=0.7838),when Flare=1,HBV DNA and HBV RNA decreased significantly(R~2=0.6583 and R~2=0.6525)When Flare=0,the decrease of HBV DNA and HBV RNA was generally obvious(R~2=0.5215 and R~2=0.5739).The higher the degree of transaminase elevation,the more obvious the decline of HBV DNA and RNA.(5)The higher the baseline ALT,the greater the incidence of ALT flare during drug administration,which was statistically significant(OR=1.025,95%CI,1.001—1.049 P=0.0415).(6)The higher the baseline HBV RNA level,the greater the incidence of ALT flare during drug administration,which was statistically significant(OR=1.986 95%CI 1.019—3.870,P=0.0440).Conclusion:(1)The 83 cases of elevated transaminases in this study were considered to be"good flare",and most of them did not require drug withdrawal and drug intervention.(2)The increase and decrease of transaminases corresponded to the decrease of HBVDNA and HBV RNA quantification.(3)The baseline transaminase level has a certain influence on the increase of transaminase during the antiviral process.(4)The baseline virological level has a certain influence on the increase of transaminase during the antiviral process.