Clinical Management And Mutational Patterns Of Hepatitis B Virus Polymerase Gene In Patients With Lamivudine Resistance

Chronic hepatitis B virus (HBV) infection is a worldwide health problem affecting an estimated 350 million individuals in the world,China is one of high epidemic regions of HBV infection.There are approximately 120 million HBV-carriers and 30 million patients with chronic hepatitis in China,Chronic HBV infection is a leading cause of cirrhosis and hepatocellular carcinoma.Complete and sustained suppression of viral replication remains the most important goal in the treatment of patients with chronic HBV infection.In this respect.the introduction of the nucleos(t)ide analog largely improved the outcome in these patients, also by preventing hepatitic decompensation or the development of hepatocellular carcinoma.Lamivudine(LAM) is the first nucleoside analog approved in the treatment of chronic hepatitis B,because of potency.safety profile,and relatively low cost, it has been and is still widely applied globally for chronic hepatitis B patients.However, a major disadvantage of nucleos(t)ide analogs is that resistant HBV mutants develop during long-term treatment, limiting the efficacy of these analogs in suppressing viral replication. As demonstrated in recent studies, approximately 70.0% of patients receiving LAM therapy for more than 4 years suffer the emergence of LAM-resistant caused by mutations in the tyrosine-methionine-aspartate-aspartate(YMDD) motif of the HBV polymerase gene,and it is associated with virologic/biochemical breakthrough, hepatitis flare, and even hepatic decompensation or mortality.The management of LAM-resistant chronic hepatitis B patients is a new problem in clinical practice. Adefovir dipivoxil(ADV) is a new nucleotide analog that has been shown to be effective against LAM-resistant HBV in vivo.The aim of this study was to report clinical outcomes and the mutational patterns of the HBV polymerase gene after the emergence of resistance during LAM therapy,and evaluate the efficacy and safety of adding ADV and switching from LAM to ADV in LAM- resistant patients.Partâ… Clinical outcomes and the mutational patterns of the HBV Polymerase gene in patients with lamivudine resistanceObjective Analyze clinical outcomes and the mutational patterns of the HBV polymerase gene after the emergence of resistance during LAM therapy.Methods LAM-resistant mutations were detected by direct sequencing of the HBV polymerase gene in patients after the emergence of resistance during LAM therapy.Clinical outcomes at the baseline after the emergence of clinical resistance were analyzed. Results 195 patients were found LAM-resistance-associated mutations(rtV173/L,rtL180M and rtM204I/V) in the HBV polymerase gene.The results showed that 99.0%( 193/195) of the samples had YMDD mutations.Four major mutational patterns of LAM-resistant HBV were identified:rtM204I(33.3%),rtL180M+rtM204V(25.6%), rtL180M+rtM204I(21.5%),rtV173L+rtL180M+rtM204V(11.3%).the rtM204V mutation always accompanied by the rtL180M mutation compared with the rtM204I mutation (P<0.01).there were no statistically significant differences in ALT or HBV DNA levels after the emergence of resistance among patients with four major mutational patterns(P>0.05).Conclusions This study indicated a strong correlation between the clinical definition of LAM treatment failure and the presence of YMDD mutations.Four major mutational patterns of LAM-resistant HBV were identified: rtM204I , rtL180M+rtM204V , rtL180M+rtM204I , rtV173L+rtL180M+rtM204V.The rtM204V mutation as always accompanied by the rtL180M mutation.This study indicated that mutational patterns of HBV polymerase gene are possibly unrelated to the clinical outcomes of chronic hepatitis B during LAM therapy.Partâ…¡Clinical study on adefovir dipivoxil alone or combination withlamivudine in patients with lamivudine-resistant chronic hepatitis BObjective To evaluate the efficacy and safety between ADV monotherapy and ADV add-on LAM combination therapy in patients with chronic hepatitis B who had developed LAM resistance with virological breakthroughs under long-tenn LAM treatment.Methods 124 chronic hepatitis B patients with LAM-resistant mutations were enrolled in this study,All patients were treated with ADV monotherapy or ADV add-on LAM combination therapy for 24 or 48 weeks and were retrospectively analyzed. Sequencing of the HBV polymerase gene for LAM and ADV mutations was performed at baseline and on any occasion of virological breakthrough under therapy. All patients were followed with clinical examinations and routine laboratory tests during therapy.Results 74 Patients were treated with ADV add-on LAM combination therapy .50 patients switched from LAM to ADV monotherapy. The two groups did not differ in patients' characteristics. After 24 weeks from start of ADV treatment, serum HBV DNA became nondetectable in 70.3% of patients in ADV +LAM group,while in ADV group the rate is 48.0% (P<0.05);ALT normalized in 94.6% and 96% of patients, with no difference between the 2 groups. The log₁₀ reduction of serum HBV DNA was significantly smaller in ADV group patients compared with ADV added to LAM group patients at week 12 and 24 of treatment[week 12 (1.99±0.64)vs2.55±0.74),P<0.01;week 24 (2.61±0.80)vs (3.19±0.82),P<0.01 respectively].Within 24 weeks treatment,in 2 groups, patients with baseline HBV DNA levels less than 10⁶ copies/ml experienced more frequent decline in serum HBV DNA to nondetectable levels as compared with patients with greater than 10⁶ copies/ml at baseline(P<0.05).The log₁₀ reduction of serum HBV DNA was found to be no statistically significant differences among four major mutational patterns patients with same therapy . Within 48 weeks from start of treatment. The response has been maintained in 43 patients with ADV added to LAM. whereas ADV-resistant mutations occurred in 4 of 27 patients (14.8%) on ADV monotherapy (P<0.05).Conclusions This study shows ADV monotherapy or ADV add-on LAM combination therapy is effective and safe in patients with different patterns of LAM -resistant HBV mutations.Our findings suggested that ADV add-on LAM combination therapy might lead to better virological outcomes in patients compared with ADV monotherapy,and without any evidence of development of resistance to ADV in patients followed for 48 weeks. ADV add-on LAM combination therapy may be first-choice for patients with LAM resistance.As the study was retrospectively analyzed, further studies are needed.