Hepatitis B virus wild‐type and rtN236T populations show similar early HBV DNA decline in adefovir refractory patients on a tenofovir‐based regimen

Abstract

Hepatitis B virus (HBV) pol/RT mutations that confer clinical resistance to tenofovir disoproxil fumarate (TDF) have not been detected to date. In vitro, the rtN236T adefovir dipivoxil (ADV)-associated resistance mutation confers low-level cross-resistance to tenofovir: 3- to 13-fold changes in EC(50) from wild type. This study evaluated the clinical response of rtN236T mutant viruses by comparing their early viral load decay kinetics to wild-type viruses in chronic HBV monoinfected patients harbouring rtN236T prior to initiating TDF or emtricitabine (FTC)/TDF therapy. Baseline samples (n = 105) from adefovir refractory patients were tested for the presence of rtN236T using a highly sensitive allele-specific PCR assay with an rtN236T detection cut-off of 0.5%. The rtN236T mutation was detected at baseline in 14.3% (14/98) of analysable patient samples (0.5-93.2%, rtN236T percentage range). The median change in total HBV DNA at week 24 was comparable for patients with rtN236T detected at baseline (-3.7 log(10) copies/mL, n = 14) as compared to patients with wild-type HBV (-3.2 log(10) copies/mL, n = 90). In patients with rtN236T, wild-type and rtN236T mutant virus showed similar rates of HBV DNA decline with no statistically significant difference observed at week 4. Moreover, the proportion of rtN236T remained unchanged in patients in either arm of the study during treatment. In conclusion, the rtN236T mutant virus showed similar HBV DNA decline kinetics to wild-type virus in adefovir refractory patients who switched to TDF or FTC/TDF. Despite low levels of cross-resistance in vitro, TDF similarly suppresses wild-type and rtN236T mutant viruses in vivo.

Efficacy of tenofovir disoproxil fumarate therapy in Chinese chronic hepatitis B patients after multiple antiviral failures

“…Several studies have already reported that TDF therapy exhibited satisfactory virological and biochemical responses in LMV‐resistant patients. However, clinical data regarding its efficacy in ADV and multiple NA resistance are quite limited . Most importantly, there is no clinical study conducted in Chinese CHB patients, which consists of the majority of the HBV‐infected population in the world.…”

No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B

“…For patients on TDF shown to harbor the rtN236T mutation by population sequencing, the rtN236T mutant percentage was determined with MultiCode RTx allele‐specific PCR modified for HBV rtN236T detection as described previously …”

“…For patients on TDF shown to harbor the rtN236T mutation by population sequencing, the rtN236T mutant percentage was determined with MultiCode RTx allele-specific PCR modified for HBV rtN236T detection as described previously. 21 Adherence to Study Medication. For patients qualifying for genotypic analysis, adherence was assessed by evaluation of plasma tenofovir levels (liquid chromatography/mass spectroscopy) and by analysis of drug accountability records associated with case report forms or included in clinical deviation logs.…”

Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment

“…It should be noted that due to a high error rate during replication of HBV DNA, these variants may have emerged spontaneously and may not have been acquired at the time of infection. Although we found a higher prevalence of HBV‐DR variants by NGS, the clinical significance of these variants present as a minor species is unclear, and most studies reported no impact of these minor variants on response to NUC therapy . Of the eight participants with DR variants detected by NGS who subsequently started NUC therapy, five had primary DR variants detected by NGS but none by Sanger sequencing.…”