Optimization Of Antiviral Therapy And Monitoring Of Fibrosis Changes In Chronic Hepatitis B

1.BACKGROUND AND AIMAntiviral therapy and liver fibrosis assessment are the two critical aspects in the management of chronic hepatitis B(CHB).Low genetic barrier nucleos(t)ide analogues,such as lamivudine,are still widely used.To reduce drug-related resistance and improve antiviral efficacy,a lamivudine-based optimization strategy and combination therapy with adefovir were proposed whereas their efficacy need validation.On the other hand,to improve prognosis and surveillance management,there are needs for improvement of the accuracy of non-invasive cirrhosis diagonsis in treatment naive CHB patients and non-invasive monitoring of liver fibrosis after antiviral treatment.2.METHOD2.1 Lamivudine-based optimization therapyAdult patients without antiviral therapy within 6 months before screening with HBV DNA>105 copies/mL,alanine aminotransferase(ALT)1.3 to 10 times upper limit of normal and compensated HBeAg positive CHB were randomized into three groups with 1:1:1 ratio.COMBO group,lamivudine plus adefovir de novo combination therapy.OPTIMIZE group,initiated with lamivudine 100 mg q.d.,and adefovir 10 mg q.d.was added to suboptimal responders(HBV DNA>1000 copies/mL at week 24)from week 30 to week 104,while patients with early virological response(HBV DNA?1000 copies/mL at week 24)continued lamivudine monotherapy untill week 104.MONO group,lamivudine monotherapy.For all the patients receiving lamivudine monotherapy,adefovir would be added if virological breakthrough was confirmed.All the patients were treated for 104 weeks,with efficacy and safety assessment every 12 weeks.2.2 Liver stiffness measurement based non-invasive cirrhosis diagnosis before antiviral treatmentTreatment naive compensated CHB patients with liver biopsy during 2008 to 2014 were consecutively enrolled.Analysis was performed in patients with normal serum bilirubin level and with liver biopsy samples?20mm.Eligibal patients underwent liver stiffness measurement(LSM),ultrasound and blood tests,and were divided into training set(n=170)and validation set(n=75).2.3 Liver stiffness measurement based non-invasive liver fibrosis monitoring after antiviral treatmentHBeAg positive treatment-naive compensated CHB patients were enrolled and received telbivudine or combination with adefovir treatment for 5 years.Clinical assessment was performed every 3 months,with LSM every 6 months and liver biopsy at baseline and week 104.3.RESULT3.1 At week 104,more patients in COMBO and OPTIMIZE groups achieved HBV DNA<300 copies/mL(53.3%[64/120]and 48.3%[58/120]),with less lamivudine resistance(0.8%and 6.7%)compared with MONO group(HBV DNA<300 copies/mL 34.8%[41/118],lamivudine resistance 58.47%).All regimens were well tolerated.3.2 An algorithm consisting of LSM,international normalization ratio(INR),ultrasonic hepatic vessel and platelet count(named CIR-4)and a LSM-based cirrhosis six-index score(CIR-6)comprised LSM,INR,platelet,albumin,ultrasonic hepatic vessel and liver parenchyma were derived.In training set,area under receiver operating characteristics curve of CIR-6 and CIR-4 to detect cirrhosis was 0.946 and 0.945,respectively,which was superior to that of LSM alone 0.907.CIR-4 could save more liver biopsies.In validation set,CIR-6 detected cirrhosis with accuracy similar to that in training set.However,the sensitivity of CIR-4 and VCTE in validation set dropped to 0.538 and 0.846,respectively.3.3 A total of 534 patients with qualified LSM at baseline and week 104 were analyzed,164 of which had adequate paired liver biopsies.LSM decreased rapidly in parallel with ALT level from baseline to week 24.LSM decreased slowly but continually from week 24 to week 260(6.1[2.2-37.4]vs.4.9[2.3-19.6]kPa,P<0.001)while median ALT maintained stable within normal range.After 104-week treatment,the proportion of patients with no or mild fibrosis(Ishak,0-2)increased from 74.4%(122/164)to 93.9%(154/164).Multivariate analysis revealed that relative decline of 52-week LSM from baseline was independently associated with 104-week liver fibrosis regression(odds ratio,3.74;P=0.016).4.CONCLUSION4.1 Combination therapy of lamivudine plus ADV exhibited effective viral suppression and relatively low resistance in HBeAg positive CHB patients.In lamivudine treated patients with suboptimal virological response at week 24,promptly adding on ADV is necessary to prevent resistance development.4.2 Combining routine markers improved the accuracy of LSM for cirrhosis detection in hepatitis B patients.CIR-6 which comprised LSM,INR,platelet,albumin,ultrasonic hepatic vessel and liver parenchyma may be more valuable.4.3 LSM based monitoring approach could be useful for further evaluation of fibrosis dynamics following improvement of liver inflammation in treated CHB.The relative decline of week-52 LSM is predictive of post-treatment fibrosis regression.