The Predictive Value Of Baseline Characteristics On Efficacy Of Nucleos(t)ide Analogues In Patients With Chronic Hepatitis B

Part1Predictors of HBeAg Seroconversion after Nucleos(t)ide AnaloguesTreatment for Chronic Hepatitis BObjective: Satisfactory treatment endpoints in HBeAg-positive chronichepatitis B (CHB) patients is HBeAg seroconversion, which is defined as theloss of HBeAg and the subsequent development of anti-HBe, as well ascomplete viral suppression (undetectable levels of HBV DNA replication) andnormalization of ALT, because it is often followed by sustained suppression ofHBV and remission of liver inflammation activity. The purpose of this studywas to evaluate the rate of HBeAg seroconversion in routine clinical practiceand explore its predictors and optimize therapeutic strategy of nucleos(t)ideanalogues (NAs) for CHB.Methods:251patients were recruited from February2001to September2009, according to the Chinese guideline of chronic hepatitis B prevention andtreatment. The numbers of CHB patients treated with lamivudine (100mgdaily), adefovir dipivoxil (10mg daily), telbivudine (600mg daily), entecavir(0.5mg daily), and combination of lamivudine (100mg daily) and adefovirdipivoxil (10mg daily) were71,53,7,29and91, respectively. Serum HBVmarkers, HBV DNA load, ALT level, alpha fetoprotein, abdomenultrasonography and liver histology were determined before and duringtreatment. The primary endpoint of our study was HBeAg seroconversion. Thedata was analyzed by SPSS17.0.Results:1HBeAg seroconversion rates in routine clinical practice. In routineclinical practice, the cumulative HBeAg loss rates were39.0%,54.6%,63.7%,70.7%and74.4%after1,2,3,5and8years of NAs therapy, respectively. Butthe cumulative HBeAg seroconversion rates were only14.3%,32.7%,43.0%, 46.9%and50.5%in1,2,3,5and8years, respectively. In addition, among thepatients with duration of treatment beyond3,5and8years, the total rates ofHBeAg loss were65.4%(70/107),73.8%(76/103) and75.6%(31/41). But thetotal rates of HBeAg seroconversion maintained approximately47.6%–50.5%.2Adherence to NAs treatment for CHB.45patients (17.9%) werereported to be non-adherent. The most common reasons for non-adherencewere forgetful (60%), financial difficulties (16%) and adverse effects (14%).3Predictors of HBeAg loss during NAs therapy. After univariate andmultivariate Logistic regression analysis, lower baseline HBV DNA load(<108copies/ml, OR=3.062, P=0.013), adherence (OR=2.602, P=0.002),higher baseline ALT level (≥200IU/L, OR=2.336, P=0.009) and non-cirrhosis(OR=2.116, P=0.034) was the predictors of HBeAg loss. In38patients withbaseline histologic diagnosis, adherence (OR=38.38, P=0.016), increasedlobular inflammation grade (G≥3, OR=31.81, P=0.027), earlier fibrosis stage(S<3, OR=21.21, P=0.024) and lower baseline HBV DNA load (OR=9.83,P=0.034) was found to be predictors of HBeAg loss.4Predictors of HBeAg seroconversion in patients with NAs inducedHBeAg loss. Of177patients achieved HBeAg loss,61accompanied by thedevelopment of anti-HBe;62developed anti-HBe after a median consolidationtherapy of48weeks; while the other54maintained anti-HBe negative after amean treatment and follow-up of245weeks. Cox proportional hazards modelanalysis showed adherence (OR=2.203, P<0.001), higher baseline ALT level(OR=2.049, P<0.001) and non-vertical transmission (OR=1.656, P=0.006)was predictors of HBeAg seroconversion.Conclusions:1In routine clinical practice, the cumulative HBeAg seroconversion ratesduring NAs therapy were14.3%,32.7%,43.0%,46.9%and50.5%in1,2,3,5and8years, respectively.2Though increased with treatment duration，the increases of HBeAg lossand HBeAg seroconversion might be not parallel. Research on HBeAgseroconversion mechanism and therapy in patients with NAs induced HBeAg loss might be warranted.3Baseline intrahepatic inflammation activities might have predictivevalue for HBeAg loss and seroconversion.4Adherence might be another consideration while treating CHB patientswith NAs for its predictive value on HBeAg loss and seroconversion. Part2The Efficacy and Safety of Nucleos(t)ide Analogues in Patients withSpontaneous Acute Exacerbations of Chronic Hepatitis B: ASystematic Review and Meta-AnalysisObjective: Acute exacerbation (AE) of chronic hepatitis B (CHB), whichis defined as an elevated ALT level to more than200U/L, is often detrimentalbut sometimes leads to sustained immune control and disease remission. Theefficacy and safety of nucleos(t)ide analogues (NAs) in patients withspontaneous AE of CHB remains unclear. We performed a systematic reviewand meta-analysis of the NAs in patients with spontaneous AE of CHB withrespect to the efficacy and safety.Results:15studies were included and substantial heterogeneity wasnoted in the inclusion/exclusion criteria and controls.1Pooled data showed no benefit of lamivudine (LAM) vs. untreatedcontrols for transplant-free survival in patients with spontaneous AE of CHB(OR=0.98(95%CI,0.50–1.92; P=0.956)), hepatic decompensation (OR=0.94(95%CI,0.47–1.88; P=0.862)) and liver failure owing to AE (OR=2.30(95%CI,0.35–15.37; P=0.387)) at3months. Entecavir (ETV) achieved evenhigher short-term mortality than LAM. NAs led to rates of ALT normalization,undetectable HBV DNA, HBeAg loss, HBeAg seroconversion and drugresistance at1year in88%,61%,46%,35%and5%. Pooled data also showedbenefit favoring LAM vs. untreated controls for ALT normalization (OR=1.98(95%CI,1.03–3.80; P=0.039)) and undetectable HBV DNA (OR=38.50 (95%CI,7.68–192.99; P<0.001)) at3months. However, the HBeAg loss ratein LAM-treated patients was similar with no treatment control group(OR=1.100(95%CI,0.312–3.877, P=0.882)).2None of the studies of LAM or ETV reported any serious adverseevents associated with these agents. Elevations in creatine kinase (CK) levelsthrough1year were observed in5out of40(12.5%) LDT-treated patients.The pooled rates of drug resistance with LAM were9%at1year,16%at2years and26%at3years, respectively. M204I mutation also developed in only2.9%of LDT-treated patients at1year. All the NAs were relatively safe andwell tolerated.Conclusion: NAs had no obvious impact on short-term survival andclinical outcomes in patients with AE of CHB, though they were likely toachieve better antiviral responses. It might be rational to carefully start to treatthese patients without evidence of development or deterioration of hepaticdecompensation. We suggest additional studies to evaluate the efficacy ofother NAs.