Hepatitis B virus rtCYE/rtCYEI mutations may contribute limited tenofovir resistance: Analysis of a large sample of Chinese patients

Figure 1 The evolution of drug-resistant hepatitis B virus mutants and clinical responses during the antiviral therapy of six representative patients. The duration (months) of therapy is indicated by bars above the graph and serum samples from the patient are indicated by the time-points of sampling shown by arrows on the graph. Two dashed lines show the lower limit of detection of hepatitis B virus (HBV) DNA (100 IU/mL) and normal alanine aminotransferase (ALT) level (40 U/L). Proportions of wild-type and mutant HBV strains in the viral reverse-transcriptase of each sample are depicted by a series of pie charts. P1-1, serum sample 1 from patient 1; P2-1, serum sample 1 from patient 2; P3-1, serum sample 1 from patient 3; P3-2, serum sample 2 from patient 3; P3-3, serum sample 3 from patient 3; P4-1, serum sample 1 from patient 4; P5-1, serum sample 1 from patient 5; P6-1, serum sample 1 from patient 6. A: The dynamic changes in serum HBV DNA and ALT levels are shown along with the antiviral therapy for patient 1; B: The dynamic changes in serum HBV DNA and ALT levels are shown along with the antiviral therapy for patient 2; C: The dynamic changes in serum HBV DNA and ALT levels are shown along with the antiviral therapy for patient 3; D: The dynamic changes in serum HBV DNA and ALT levels are shown along with the antiviral therapy for patient 4; E: The dynamic changes in serum HBV DNA and ALT levels are shown along with the antiviral therapy for patient 5; F: The dynamic changes in serum HBV DNA and ALT levels are shown along with the antiviral therapy for patient 6. LAM: Lamivudine; ADV: Adefovir dipivoxil; ETV: Entecavir; TDF: Tenofovir disoproxil fumarate.

Figure 2 Assessment of the natural replication capacity of hepatitis B virus. The data are presented as the mean ± SD. Relative replication capacities of rtCYE/rtCYEI-containing mutants and rtWT (laboratory-modified) strain compared to the rtWT strain are presented. ^aP < 0.05 vs rtWT; ^bP < 0.05 vs rtCYE; ^cP < 0.05 vs rtCYEI+M204I. HBV: Hepatitis B virus; rtCYE: rtS106C+H126Y+D134E; rtCYEI: rtS106C+H126Y+D134E+L269I.

Figure 3 Three-dimensional structures of tenofovir disoproxil fumarate-binding domains of viral reverse-transcriptase. The effects of rtS106C+H126Y+D134E (rtCYE), and rtS106C+H126Y+D134E+L269I (rtCYEI) mutations on the binding ability of the hepatitis B virus (HBV) reverse transcriptase (RT) region to tenofovir disoproxil fumarate (TDF) were evaluated using a homology model constructed based on the crystal structure of human immunodeficiency virus RT. A: The binding domains of the wild-type with TDF; B: The rtCYE mutant with TDF; C: The rtCYEI mutant with TDF. TDF ligand and interacting residues are shown in stick format. rtCYE: rtS106C+H126Y+D134E; rtCYEI: rtS106C+H126Y+D134E+L269I.