The Effect Of Alternating Lamivudine And Adefovir Dipivoxil Antiviral Therapy In Patients With Hepatitis B Virus

Introduction Chronic hepatitis B virus (HBV) infection is a global health problem, and carries a risk of serious and even life-threatening complications. The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver diseases. The ultimate goal is to prevent cirrosis, hepatic failure and hepatocellular carcinoma (HCC).Nucleoside/tide analogues have revolutionized therapy for chronic hepatitis B.These agents suppress HBV replication effectively, and improve liver disease and reduce rates of liver cirrhosis and HCC. However, antiviral resistance has become an increasingly common problem during long-term treatment with nucleoside/tide analogues. Viral breakthrough associated with selection of drug resistance is usually followed by biochemical breakthrough and in some instances hepatitis flares and liver failure. In addition, resistance to one antiviral agent may confer resistance to other agents and may limit future treatment options.Drug resistance of nucleotide analogues is an increasing clinical problem. To date, most studies on the therapy in CHB have focused on patients with Lamivudine (LVD) resistance.Antiviral-resistant mutations are assoication with long-term nucleoside/tide analogues treatment, so we presumed that a short course of each agent treatment would be an attractive option to reduce frequency of drug resistant mutants. This study was performed to reduce the incidence of drug-resistance by alternating LVD and adefovir dipivoxil (ADV) treatment, which means choice reasonable drug at the right time. It is therefore possible to maintain the initial antiviral response long-time frames, optimizing the clinical effect. The patients would get the best cost-effectiveness ratios, and might achieve the desired objectives. It is important to prevent the transmission of drug-resistant strains, and to provide benefit for management of patients with chronic hepatitis B.Part 1 Study on the alternating lamivudine and adefovir dipivoxil therapy in patients with chronic hepatitis BObjective To determine the time span and the overlapping time of LVD or ADV during the alternating lamivudine and adefovir dipivoxil therapy in patients with chronic hepatitis B. Methods This study including two trails: Trailâ… Thirty-five patients with chronic hepatitis B were enrolled.They received lamivudine (LVD) 100 mg/d for 52 weeks. Serum HBV DNA, alanine aminotransferase (ALT), HBV M and YMDD were measured at 0wk, 12wk, 20wk, 24wk, 36wk and 52wk of LVD treatment.Trialâ…¡Forty patients with non-YMDD variant chronic hepatitis B were enrolled who were randomized (1:1) to overlap group and non-overlap group. Patients in the overlap group were received LVD 100 mg/d for 12 weeks, added 10 mg of ADV for 4 weeks, and then accepted ADV alone to 52 weeks. Patients in non-overlap group were administrated LVD 100mg/d for 12 weeks, then switch to ADV monotherapy to 52 weeks. Serum HBV DNA levels, ALT and HBV M were tested at 0wk, 12wk, 16wk, 20wk and 52wk.Results The YMDD mutation emerged at week 20 of LVD treatment in trialâ… , at week 52, the rates of undetectable HBV DNA, ALT normalization and HBeAg seroconversion are 74.3%, 71.4% and 42.9%. In trialâ…¡, there was no significant difference in the rates of undetectable HBV DNA, ALT normalization and HBeAg seroconversion between two groups (P>0.05), whereas the levels of ALT and HBV DNA flare up after 4 weeks of ADV monotherapy were seen in 2 of the non-overlap patients.Conclusions The ideal treatment is that receiving LVD for 12 weeks, adding ADV for 4 weeks and then ADV monotherapy for 4 weeks, repeat the cycle. Part 2 The efficacy of alternating lamivudine and adefovir dipivoxil therapy in patients with chronic hepatitis BObjective To investigate the therapeutic effect and influence on drug resistance by therapy of alternate lamivudine(LVD)and adefovir dipivoxil (ADV) in patients with chronic hepatitis B. Methods 100 patients with non-YMDD variant chronic hepatitis B were enrolled who were randomized (1:1) to trial group and control group. Patients in the trial group were received LVD 100mg/d for 12 weeks, added 10 mg of ADV for 4 weeks, and then accepted ADV alone for 4 weeks, repeated the cycle to week-52. Patients in control group were administrated only LVD 100mg/d for 52 weeks. During the treatment, YMDD was tested by mismatched-PCR. HBV DNA levels were measured by quantitative PCR, alanine aminotransferase(ALT)and HBeAg were conducted.Results After 52 weeks, serum HBV DNA turned negative (fewer than 1000 copies per milliliter) was 45 cases of 50 patients in the trial group and 38 cases of 50 patients in the control group (90 percent vs 76 percent,P>0.05), normalization of ALT was 43 cases of 50 patients in the trial group and 36 cases of 50 patients in the control group (86 percent vs 72 percent,P>0.05) and HBeAg seroconversion rate was 45.9 percent in the trial group and 42.9 percent in the control group (P>0.05). However, the YMDD mutation rate was remarkably declined in the trial group as compared with that of the control group (P=0.0455).Conclusions Alternation therapy showed no better effects on the clearance of serum HBV DNA, HBeAg seroconversion and normalization of ALT than that of LVD monotherapy, but could reduce the incidence of YMDD mutation obviously.Part 3 HBV DNA clonal analysis of Lamivudine-resistance patients treated with Entecavir for 24 weeksObjective To observe the efficacy and the drug-resistance for patients received ETV in patients with genotypic resistance.Methods Two patients of the trial group and eight patients of the control group received ETV treatment. At 24 weeks, the serum levels of HBV DNA, ALT and HBV M were tested according to manufacturer's instructions. If HBV DNA>103 copies / ml, serum samples were cloned and analyzed additionally to examine the evolution of HBV mutations and the distribution of drug-resistant strains in vivo.Results Two cases in the trial group achieved complete response (HBeAg positive chronic hepatitis B patients: ALT normalization, undetectable HBV DNA by PCR assay and HBeAg seroconversion.HBeAg-negative patients: ALT normalization and undetectable HBV DNA). There were five patients achieved complete response, and three cases occured genotypic resistant in the control group, which are multiple point mutant strains.Conclutions The finding showed that the effect is better in alternation treatment group than in LVD monotherapy group at 24 weeks, alternation treatment is benefical to following therapy.