An analysis on the characteristics of Entecavir resistance mutation in patients with chronic hepatitis B

Abstract

Abstract: Objective To explore the entecavir resistance mutation pattern and its clinical characteristics in patients with chronic hepatitis B.Methods Between October 2020 and May 2023, 121 patients were diagnosed with CHB and treated in Wuxi Branch of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. Drug-resistant mutations need to be positive for rtL180M, rtM204V (or only rtM204I) and any one or more of rtV173, rtT184, rtS202, rtV169 and rtV250; After at least 12 months of oral treatment with at least one antiviral drug such as lamivudine (LAM), telbivudine (Ldt), adefovir dipivoxil (ADV), entecavir (ETV) and tenofovir dipivoxil fumarate (TDF), HBV DNA is at least in a low viral load status. In the study, the antiviral regimen received NAs treatment including single drug therapy, combined therapy and sequential therapy.Results Among 121 patients, there were 46 cases of ETV drug-resistant mutation, and the drug-resistant rate was 38.0%. Specific drug-resistant mutation sites and their mutation patterns include 9 cases of rtT184A/M204V/L180M (19.6%), 8 cases of rtT184L/M204V/L180M (17.4%), 1 case of rtT184S/M204V/L180M (2.2%), 18 cases of rtS202g/M204V/L180m (39.1%), 3 cases of rtS202G/M204I/M240I (6.5%), 3 cases of rtM250V/M204V/L180M (6.5%), 2 cases of rtM250L/M204V/M204I (4.3%) and 2 cases of rtT184/S202/M204V/L180M (4.3%). In patients with drug-resistant mutations of ETV, 17 cases were shift to LAM (37.0%), 15 cases were shift to ADV (32.6%), 4 cases were shift to LDT (8.7%), 3 cases were shift to ETV (6.5%), 2 cases were shift to TDF (4.3%), and the remaining 5 cases (10.7%) were shift to combined or sequential therapy. There were 11 cases (64.7%) with rtT184 mutation in LAM-resistant patients, which was significantly higher than that in ADV-resistant patients [3 cases (20.0%)], and the difference was statistically significant (P<0.05).Conclusion The main gene mutation pattern of entecavir-resistant patients is rtS202G/L180M mutation. Patients should receive careful clinical evaluation during treatment with NAs to prevent the emergence of drug-resistant strains.

Key words: Chronic hepatitis B, Entecavir, Drug resistance

WANG Zhang-yun, WANG Yan-li, HE Xing-chang. An analysis on the characteristics of Entecavir resistance mutation in patients with chronic hepatitis B[J]. Chinese Hepatolgy, 2024, 29(12): 1472-1475.

References

[1] Schreiner S, Nassal M. A role for the host dna damage response in hepatitis b virus cccdna formation-and beyond?[J]. Viruses,2017,9(5).
[2] Shirvani-Dastgerdi E, Winer BY, Celia-Terrassa T, et al. Selection of the highly replicative and partially multidrug resistant rts78t hbv polymerase mutation during tdf-etv combination therapy[J]. J Hepatol,2017,67(2):246-254.
[3] Tacke F, Kroy DC. Treatment for hepatitis b in patients with drug resistance[J]. Ann Transl Med,2016,4(18):334.
[4] Su K, Jin Y, Miao Z, et al. Phenotypic and genetic analysis of dysprothrombinemia due to a novel homozygous mutation[J]. Hematology,2017,22(6):380-385.
[5] 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2022年版)[J]. 实用肝脏病杂志,2023,26(3):后插1-后插22.
[6] Sayan M, Senturk O, Akhan SC, et al. Monitoring of hepatitis b virus surface antigen escape mutations and concomitantly nucleos(t)ide analog resistance mutations in turkish patients with chronic hepatitis B[J]. Int J Infect Dis,2010,14 Suppl 3:e136-141.
[7] Lok AS, Ganova-Raeva L, Cloonan Y, et al. Prevalence of hepatitis b antiviral drug resistance variants in north american patients with chronic hepatitis B not receiving antiviral treatment[J]. J Viral Hepat,2017,24(11):1032-1042.
[8] Hermans LE, Svicher V, Pas SD, et al. Combined analysis of the prevalence of drug-resistant hepatitis b virus in antiviral therapy-experienced patients in europe (capre)[J]. J Infect Dis,2016,213(1):39-48.
[9] Shao J, Liu Y, Liu LM, et al. Multiple drug-resistant hbv mutation may contribute to poor response of adefovir + entecavir in entecavir-resistant patients[J]. J Infect Dev Ctries,2021,15(1):131-140.
[10] Chantratita W, Song KS, Pongthanapisith V, et al. Hbv/4dr 9g test and its comparison with inno-lipa hbv multi-dr test for the detection of drug-resistant hepatitis B virus[J]. J Virol Methods,2016,237:58-63.
[11] Ahn HJ, Song MJ, Jang JW, et al. Treatment efficacy and safety of tenofovir-based therapy in chronic hepatitis B: a real life cohort study in Korea[J]. PLoS One,2017,12(1):e0170362.
[12] Liu Y, Li W, Jia T, et al. Sustained responses in chronic hepatitis B patients with nucleos(t)ide analogue drug-resistance after peg-interferon alfa-2a add-on treatment: a long-term cohort study[J]. J Clin Transl Hepatol,2018,6(1):18-24.
[13] Aydogan S, Ergunay K, Balaban Y, et al. Detection of resistance mutations in chronic hepatitis B patients receiving antiviral therapy for over one year[J]. Mikrobiyol Bul,2013,47(3):472-481.
[14] Bottecchia M, Madejon A, Puente S, et al. Detection of hepatitis B virus genotype a3 and primary drug resistance mutations in african immigrants with chronic hepatitis B in Spain[J]. J Antimicrob Chemother,2011,66(3):641-644.
[15] Ramasubban G, Therese KL, Lakshmipathy D, et al. Detection of novel and reported mutations in the rpob, katg and inha genes in multidrug-resistant tuberculosis isolates: a hospital-based study[J]. J Glob Antimicrob Resist,2015,3(1):1-4.
[16] Abdel-Hamid MS, Ismail MF, Darwish HA, et al. Molecular and phenotypic spectrum of aspm-related primary microcephaly: identification of eight novel mutations[J]. Am J Med Genet A,2016,170(8):2133-2140.
[17] Jamshidi J, Abdollahi S, Ghaedi H, et al. A novel mutation in smoc1 and variable phenotypic expression in two patients with waardenburg anophthalmia syndrome[J]. Eur J Med Genet,2017,60(11):578-582.
[18] Zhao L, Li X, Cheng Y, et al. Hepatitis B virus rta181t/sw172non-stop mutation may increase resistance fold to adefovir- and entecavir-resistant mutants compared to rta181t/sw172* mutation[J]. Antiviral Res,2018,154:26-34.
[19] Wang T, Qin Y, Zhang J, et al. An antiviral drug-resistant mutant of hepatitis b virus with high replication capacity in association with a large in-frame deletion in the pres1 region of viral surface gene[J]. Virus Genes,2020,56(6):677-686.
[20] Huang BX, Liu Y, Fan ZP, et al. Investigation of immune escape-associated mutations of hepatitis B virus in patients harboring hepatitis B virus drug-resistance mutations[J]. World J Gastroenterol,2020,26(35):5314-5327.