Differences of YMDD Mutational Patterns, Precore/Core Promoter Mutations, Serum HBV DNA Levels in Lamivudine-Resistant Hepatitis B Genotypes B and C

X.P. Pan; L.J. Li; W.B. Du; M.W. Li; H.C. Cao; J.F. Sheng


J Viral Hepat. 2007;14(11):767-774. 

In This Article

Summary and Introduction

The aims of this study were to investigate the viral differences among lamivudine-resistant hepatitis B virus (HBV) genotypes B and C in vivo. Fifty-three patients carrying lamivudine-resistant HBV were enrolled in this study. HBV genotypes, Levels of alanine aminotransferase (ALT), HBV DNA levels were monitored during therapy. The polymerase and precore/core promoter genes were amplified by polymerase chain reaction and their products were sequenced directly. Among 53 patients resistant HBV genotypes B and C accounted for 41.50% and 58.50%, respectively. The occurrence of reverse transcriptase rt204I mutants was lower in genotype B (36.36%) than that in genotype C (87.10%), whereas rt204V mutants was higher in genotype B (63.64%) than that in genotype C (12.90%). The occurrence of precore mutation (nt1896A) was higher in genotype B (77.27%) than that in genotype C (32.26%). Serum HBV DNA levels after emergence of lamivudine resistance were higher in genotype C (7.71 ± 0.80 Log copies/mL) compared with genotype B (6.97& ± 0.77 Log copies/mL). Multivariate analysis identified pretreatment HBV DNA levels, HBeAg status and HBV genotype as independent factors associated with a shorter time to lamivudine resistance(P = 0.035, P = 0.006 and P = ;0.001, respectively). Multivariate analysis showed that HBV genotype (P = 0.004) and pretreatment ALT levels (P = 0.01) was independently associated with YMDD mutational patterns. The results showed that the YMDD mutational patterns, precore mutation and serum HBV DNA levels differ between lamivudine-resistant HBV genotypes B and C in vivo. It is valuable for treatment of lamivudine-resistant HBV in clinic.

Hepatitis B virus (HBV) infection is one of the major causes of hepatic cirrhosis and hepatocellular carcinoma in endemic areas.[1,2] Lamivudine, a potent inhibitor of HBV replication by interfering with HBV reverse transcriptase activity, has become the main therapeutic option for the treatment of chronic hepatitis B. It has been demonstrated that lamivudine could lead to a marked decrease in serum HBV DNA levels, a significant increase in the rate of e-seroconversion,[3,4] as well as improvements in serum alanine aminotransferase (ALT) levels[5] and liver histopathologic parameters.[4,6] However, the major concern is the emergence of lamivudine-resistant HBV during the treatment of chronic hepatitis B, which is characterized by amino acid variations in the reverse transcriptase domain of the HBV polymerase,[7,9] especially an exchange of the methionine within the YMDD motif by an isoleucine or a valine (named YIDD variant and YVDD variant, respectively). These lamivudine-resistant mutants caused virological and biochemical breakthrough,[7,10,13] represented as re-elevation of serum HBV DNA levels and ALT levels. Moreover, acute exacerbation of hepatitis and fatal hepatic failure may occur after the emergence of YMDD mutants.[14,15]

Hepatitis B virus genotypes are potential factors that influence the outcome of antiviral therapy for chronic hepatitis B. Previous studies indicated that HBV genotypes B and C influenced the response during treatment with interferon-α.[16,17] Similarly, HBV genotypes have played an important role on the response to lamivudine in the treatment of patients with chronic hepatitis B.[18,20] Recent study proved that the YMDD mutational patterns differed between genotypes A and D after emergence of lamivudine resistant HBV strains.[21] However, there is little information on the differences of YMDD mutational patterns, and precore/core promoter mutations in lamivudine-resistant hepatitis B genotypes B and C.

In the present study, we examined YMDD motif mutants, precore/core promoter mutations, serum HBV DNA levels in patients with chronic hepatitis B resistant to lamivudine so as to explore the viral characteristics of lamivudine-resistant HBV genotypes B and C.


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