Study On Optimization Therapy For Chronic Hepatitis B

Chronic hepatitis B (CHB) influences peoples'health in the world. Antiviral therapy is necessary to prevent the progression of CHB to cirrhosis, hepatic failure, hepatocellular carcinoma. HBsAg clearance and sero- conversion, characterized by the loss of serum HBsAg without or with development of anti-HBs antibody, are the main markers of a successful immunological response to HBV infection and the closest outcome to clinical cure.Nucleos(t)ide analogues were recommended as first-line options for CHB treatment, due to their stronger inhibition on HBV DNA duplication, more convenient and safer administration than interferons. However, some literatures indicated that interferon based therapy, especially pegylated interferon alpha (peginterferonα, PEG-IFNα), obviously outstripped nucleos(t)ide analogues in achieving HBsAg clearance and seroconversion. The weekly administration of PEG-IFNαis likely to improve patients'compliance rate, while obtains much better pharmacokinetics.We evaluated the efficacy and safety of four kinds of nucleos(t)ide analogues in HBeAg-positive or negative CHB patients, and conducted a meta-analysis to estimate the effect of pegylated interferon alpha (peginterferonα, PEG-IFNα) based therapy on HBsAg clearance or seroconversion in CHB. It might provide reliable evidences for CHB treatment.Part 1 Optimization strategy of nucleos(t)ide analogues for chronic hepatitis BObjective: To evaluate the efficacy and safety of four kinds of nucleos(t)ide analogues in HBeAg-positive or negative chronic hepatitis B (CHB) patients and optimize therapeutic strategy of nucleos(t)ide analogues for CHB. Methods: 94 CHB patients were recruited from Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University from February 2005 to February 2010, according to the Chinese guidline of chronic hepatitis B prevention and treatment revised in 2010. The number of CHB patients treated with lamivudine (100mg daily), adefovir dipivoxil (10mg daily), entecavir (0.5mg daily), telbivudine (600mg daily) were 31, 25, 16, 22, respectively. The course of antiviral treatment was 48 weeks. Serum alamine transaminase (ALT), HBV DNA and HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc were determined at pretreatment and weeks 4, 12, 24, 48, as well as side effects and antiviral resistance. The data were analyzed by statistical software SPSS 13.0.Results: The efficacy and safety of four kinds of nucleos(t)ide analogues in HBeAg-positive or negative CHB patients were as followed:1 Biochemical response: There was no significant difference in the ALT normalization rates by compared lamivudine, adefovir dipivoxil, entecavir and telbivudine treated groups (P>0.05).2 Virological responses:2.1 At the 4th, 12th, 24th, 48th week, the HBV DNA undetectable rates were 32.3%, 61.3%, 61.3% and 71% in lamivudine group, 8%, 20%, 40% and 72% in adefovir dipivoxil group, 12.5%, 81.3%, 81.3% and 87.5% in entecavir group, 18.2%, 54.5%, 77.3% and 77.3% in telbivudine group. There were significant diferences in adefovir dipivoxil group and the other three groups at the 12th week (P=0.002, 0.000, 0.014, respectively), and there were marked diferences between adefovir dipivoxil group and entecavir or telbivudine groups at 24th week (P=0.009, 0.010, respectively), but no significant diferences were found by comparing the other groups (P>0.05).2.2 At the 4th, 12th, 24th, 48th week, the HBV DNA undetectable rates of HBeAg positive CHB patients were 29.2%, 58.3%, 58.3% and 66.7% in lamivudine group, 0%, 0%, 33.3% and 50% in adefovir dipivoxil group, 10%, 70%, 70% and 80% in entecavir group, 11.8%, 52.9%, 76.5% and 76.5% in telbivudine group. There were significant diferences between adefovir dipivoxil group and the other three groups at the 12th week (P=0.001, 0.001, 0.003, respectively). And there were significant diferences between adefovir dipivoxil and telbivudine groups at 24th week (P=0.029), but no significant diferences were found by comparing the other groups (P>0.05).2.3 At the 4th, 12th, 24th, 48th week, the HBV DNA undetectable rates of HBeAg negative CHB patients were 42.9%, 71.4%, 71.4% and 85.7% in lamivudine group, 15.4%, 38.5%, 46.2% and 92.3% in adefovir dipivoxil group, 16.7%, 100%, 100% and 100% in entecavir group, 40%, 60%, 80% and 80% in telbivudine group. At 12th and 24th week, there were significant diferences between adefovir dipivoxil and entecavir groups (P=0.018, 0.044), but no significant diferences were found by comparing the other groups (P>0.05).3 Serological response: At 24th and 48th week, the HBeAg clearance rates of HBeAg positive CHB patients were 12.5% and 25% in lamivudine group, 0% and 25% in adefovir dipivoxil group, 50% and 30% in entecavir group, 11.8% and 17.6% in telbivudine group. At 24th week, the rate in enticavir group was markedly greater than that in lamivudine or adefovir dipivoxil groups (P<0.05), while no significant differences were found in other group comparisons (P>0.05). At 24th and 48th week, the HBeAg serconversion rates of HBeAg positive CHB patients were 4.2% and 8.3% in lamivudine group, 0% and 8.3% in adefovir dipivoxil group, 20% and 30% in entecavir group, 5.9% and 11.8% in telbivudine group. And there were no significant diferences in the HBeAg seroconversion rates (P>0.05).4 Safety: One case occurred impairment of renal function (serum creatinine increase) with adefovir dipivoxil treatment for 12 week. One patient appeared peripheral nerves damage after four weeks and one had myalgia by 48 week telbivudine administration. No adverse reaction was found in lamivudine and entecavir treated patients. 6 (18.75%) patients in lamvudine group developed resistance mutation, and none happened in other groups.Conclusions:1 Entecavir, telbivudine and lamivudine showed rapidly and powerful suppression of HBV DNA to below the detectable level, and could be used for the patients with high HBV DNA load.2 Adefovir Dipivoxil performed antiviral effects more slowly, however, it still a good choice for the patients with lower HBV DNA level at base line, especially for HBeAg negative patients.3 No significant differences in the antiviral effect were found among the nucleos(t)ide analogues treatment groups as the course prolonging.4 The efficacy and prognosis could be improved by resistance prevention and treatment optimization.Part 2 Peginterferon alpha based therapy for chronic hepatitis B focusing on HBsAg clearance or seroconversion: a meta-analysis of controlled clinical trialsObjective: To estimate the effect of pegylated interferon alpha (peginterferonα, PEG-IFNα)-based therapy on HBsAg clearance or seroconversion in Chronic hepatitis B (CHB) by a meta-analysis.Methods: All available controlled clinical trials, published from 2004 to 2010, with the following antiviral therapies for CHB patients: PEG-IFNαcombined with lamivudine (LAM), PEG-IFNαonly, conventional IFNαand LAM, with a course≥24 weeks, were meta-analysed for HBsAg clearance and seroconversion.Results: Fourteen trials (involving a total of 2,682 patients) were identified, including seven high-quality and seven low-quality studies. The analysis results of the different antiviral therapies on HBsAg clearance or seroconversion were as follows:1 No significant difference in HBsAg clearance or seroconversion was observed between the combination therapy group and PEG-IFNαmonotherapy group [odds ratio (OR) = 1.16, 95% confidence intervals (CI) (0.73-1.85), P = 0.54 and OR = 1.07, 95% CI (0.58-1.97), P = 0.82, respectively];2 HBsAg clearance and seroconversion rates in patients with combination therapy were markedly higher than in those with LAM monotherapy [OR=9.41, 95% CI (1.18-74.94), P = 0.03, and OR=12.37, 95% CI (1.60-95.44), P = 0.02, respectively];3 There was significant difference in HBsAg clearance between the PEG-IFNαgroup and IFNαmonotherapy group [OR=4.95, 95% CI (1.23-20.00), P = 0.02], but not in seroconversion [OR=2.44, 95% CI (0.35-17.08), P = 0.37];4 PEG-IFNαwas superior to LAM in HBsAg seroconversion [OR=14.59, 95% CI (1.91-111.49), P = 0.01].Conclusions: PEG-IFNαfacilitated HBsAg clearance or seroconversion in CHB patients. PEG-IFNα-based therapy was more effective than LAM monotherapy in achieving HBsAg clearance or seroconversion for both HBeAg-positive and HBeAg-negative CHB patients. There was no significant difference in HBsAg clearance or seroconversion between PEG-IFNα/LAM combination therapy and PEG-IFNαmonotherapy. PEG-IFNαwas obviously superior to conventional IFNαin HBsAg clearance, but not in HBsAg seroconversion. Although PEG-IFNαproduced significantly higher rates of HBsAg clearance and seroconversion, the absolute change in the proportion of HBsAg clearance and seroconversion was low (about 3-6%). Therefore, additional interventions are needed to improve the rate of positive outcomes.