A Prospective Randomized Clinical Study,Antiviral Therapy With Nucleoside Analogues On Patients Of Early-to-mid Stage HBV-Associated Acute-on-Chronic Liver Failure(HBV-ACLF)

ObjectiveTo clinically study the antiviral effects of lamivudine and entecavir on patients with early-to-mid stage HBV-associated acute-on-chronic liver failure(HBV-ACLF), to investigate the prognostic factors in these patients and to explore the roles that peripheral NK cells play in HBV-ACLF.MethodsA prospective, randomized, open and parallel controlled clinical trial was designed to observe the antiviral effects of nucleoside analogues on patients with early-to-mid stage HBV-ACLF. Three groups were set for controlled study, i.e. basic treatment group, lamivudine(100mg/d) plus basic treatment group and entecavir(0.5mg/d) plus basic treatment group.From May 2006 to March 2009,316 patients admitted to 302 Hospital of the Chinese PLA were enrolled in this study. The data from 279 patients in total were analyzed at the end of 24 weeks after administration. Patients'clinical and biochemical indices were expressed as mean±SD. Analysis of variance was used for comparisons between different treatment groups, and significant differences were assessed using F-tests and Student-Newman-Keuls tests, x2 tests were used for comparisons between the rates of liver cirrhosis, complications, and sex. The Kaplan-Meier method was used to estimate the overall survival rates. The log-rank test was used to compare the death rate between groups. We also performed multivariate Cox regression analysis and calculated the relative risk ratios (RR) and 95% confidence intervals (95% CI). P value<0.05 was considered statistically significant.A cross-sectional analysis of the immunological features (phenotype and functional characteristics) of peripheral NK cells was conducted in patients with HBV-ACLF.Results1.4 weeks after treatment, the total survival rate was 81.2%, and there were no significant difference between three groups (p>0.05). However, the cumulative survival rates were 69.2% at 12 weeks and 65.8% at 24 weeks in group of patients with the lamivudine antiviral treatments,67% at 12 weeks and 60.1% at 24 weeks in group of patients with the entecavir antiviral treatments, both significantly higher than those that were 42% at 12 weeks and 42% at 24 weeks in group of patients without the antiviral treatment(p=0.045, p=0.04 respectively). There were no significant difference between two antiviral treatment groups (p>0.05)2. After 4 weeks of treatment, the proportion of patients with HBVDNA decrease of more than 21og was 72.4% in entcavir group, and 62.0% in lamivudine group, which showed no significance difference between these two groups, but signifcantly higher than that (26.1%) in the basic treatment group (x2=34.0186 p =0.000). The most frequent complications during the 4-week treatment for patients with early-to mid-acute on chronic liver failure were ascites with an occurrence rate of 79.45%, hepatic encephalopathy with 47.67%, spontaneous peritonitis with 32.19%, hepatic-renal syndrome with 10.27% and hemorrhage of digestive tract with 0.04%. The incidences of those complications showed no significant difference between groups (p>0.05).3. The mortality rate of patients with MELD scores over 30 was 52.2%, much higher than that with MELD≤30 (x2=3.920 p=0.048). Moreover, For the patients with MELD scores over 30, the mortality rate would be significantly decreased by antiviral treatments (x2=4.323, P=0.038). For the patients with pretreatment HBV DNA>103, the cumulative survival rate in patients with antiviral treatments group was higher than that of patients in basic treatment group (x2= 5.014 p=0.025).4. According to the COX model, patients not treated with antiviral drugs had a significantly higher mortality (relative risk (RR)=0.597, P=0.030). The highest risk of death in patients with ACLF was associated with hepatorenal syndrome (RR=2.186, P=0.021), while other significant factors were electrolyte disturbances (RR=2.075, P=0.000), and hepatic encephalopathy (RR=1.864, P =0.000).5. Out of the 279 patients,118 cases had certain inductive factors of ACLF recorded, accounting for 42.63%. The first three causes were:physical and/or mental stress 39 case (33.05%), infection 22(18.64%) and withdrawal of nucleoside analogues 21 (17.79%). Of the 21 cases, one changed the medication for interferon due to virological breakthrough, other two patients stopped antiviral treatment also because of virological breakthrough and the remaining 18 patients discontinued the drug while it was effective due to a variety of reasons, including financial problem, doctor's advice, or incompliance. Among patients with liver failure due to drug withdrawal,15 cases had liver cirrhosis of above Child B level before first-time antiviral treatment, accounting for 71.43%.6. In patients with HBV-ACLF, Peripheral NK cells were dominated by activation receptor (NKp30, NKp44, and NKp46) expression, whereas inhibitory receptor (CD158a/b) expression was largely decreased.Conclusions1.Administration of lamivudine or entecavia demonstrates significant positive effect on the survival rate of patients with early-to-mid stage HBV-ACLF when the antivirus therapy is carried on longer than 12 weeks.2. Patients with either higher HBVDNA level or MELD> 30 prior to treatment might response to antiviral treatment better than those with lower HBVDNA level or MELD<30.3. Besides antiviral therapy with NAs, hepatorenal syndrome, electrolyte disturbances, and hepatic encephalopathy are also independent factors that affected the prognosis of patients with HBV-ACLF.4. Improperly dealing with the NAs, especially withdrawing them, increases the risk of patient developing HBV-ACLF. Therefore hepatitis B patients, especially those with liver cirrhosis, shoud be expected to adopt long-term NAs administration.5. In HBV-ACLF patients, peripheral NK cells were activated and might play an important role in liver damage.