Tenofovir is a more suitable treatment than entecavir for chronic hepatitis B patients carrying naturally occurring rtM204I mutations

Abstract

BACKGROUNDHepatitis B virus (HBV) DNA polymerase mutations usually occur to long term use of nucleos(t)ide analogues (NAs), but they can occur spontaneously in treatment-naïve chronic hepatitis B (CHB) patients. The naturally occurring HBV DNA polymerase mutations might complicate antiviral therapy with NAs, leading to the generation of drug-resistant viral mutants and disease progression. The most common substitutions are known to be YMDD-motif mutations, but their prevalence and the influence on antiviral therapy is unclear.AIMTo investigate prevalence of the naturally occurring rtM204I mutations in treatment-naïve CHB genotype C2 patients and their influence on antiviral therapy.METHODSA total of 410 treatment-naïve CHB patients infected with HBV genotype C2 strains were enrolled in this retrospective study. Among the 410 patients, 232 were treated with NAs for at least 12 mo. Significant fibrosis was defined as fibrosis-4 index > 3.25 or aspartate aminotransferase to platelet ratio index > 1.5. Complete viral response (CVR) during NAs was defined as undetectable serum HBV DNA (< 24 IU/mL). The rtM204I variants were analyzed by a newly developed locked nucleotide probe (LNA probe) based real-time PCR (LNA-RT-PCR) method.RESULTSThe LNA-RT-PCR could discriminate rtM204I mutant-type (17 patients, 4.2%) from rtM204 wild-type (386 patients, 95.8%) in 403 of 410 patients (98.3% sensitivity). Multivariate analysis showed that naturally occurring rtM204I variants were more frequently detected in patients with significant fibrosis [odd-ratio (OR) 3.397, 95% confidence-interval (CI) 1.119-10.319, P = 0.031]. Of 232 patients receiving NAs, multivariate analysis revealed that achievement of CVR was reversely associated with naturally occurring rtM204I variants prior to NAs treatment (OR 0.014, 95%CI 0.002-0.096, P < 0.001). Almost patients receiving tenofovir achieved CVR at 12 mo of tenofovir, irrespective of pre-existence of naturally occurring rtM204I mutations (CVR rates: patients with rtM204I, 100%; patients without rtM204I, 96.6%), whereas, pre-existence of naturally-occurring rtM204I-mutations prior to NAs significantly affects CVR rates in patients receiving entecavir (at 12 mo: Patients with rtM204I, 16.7%; patients without rtM204I, 95.6%, P < 0.001).CONCLUSIONThe newly developed LNA-RT-PCR method could detect naturally occurring rtM204I mutations with high-sensitivity. Theses mutations were more frequent in patients with liver fibrosis. Tenofovir is a more suitable treatment than entecavir for CHB patients carrying the naturally occurring rtM204I mutations.

Global prevalence and molecular characteristics of three clades within hepatitis B virus subgenotype C2: Predominance of the C2(3) clade in South Korea

“…Indeed, our previous study using a cohort of treatment-naïve patients with chronic HBV infection revealed a higher prevalence of naturally occurring NAr mutations in Korea compared to other areas, including China ( Kim et al, 2017 ). Our previous LNA-based RT–PCR assay also showed a higher prevalence of rt204I region YMDD variants, particularly in Korean HCC patients ( Choe et al, 2019 ). Higher rates of relapse in Korean chronic HBV infection patients with HBeAg seroconversion after lamivudine treatment have also been found, supporting the above hypothesis ( Song et al, 2000 ).…”

Tenofovir is Superior to Entecavir in Patients with Treatment-naïve Hepatitis B e-Antigen–Positive Chronic Hepatitis B

“…22 Another South Korean study demonstrated that TDF achieved significantly more complete viral response in rtM2041 variants than ETV treatment. 23 Adherence to treatment protocol was strictly supervised; hence the poor response to ETV as compared with tenofovir among HBeAg-positive patients could be attributable for some unknown reasons. HBV genotyping with mutation analysis are needed to accredit the better efficacy of TDF over ETV in HBeAg-positive CHB patients.…”