Gilead Sciences Inc., Foster City, CA 94404, USA.
J Viral Hepat. 2013 Feb;20(2):131-40. doi: 10.1111/j.1365-2893.2012.01638.x. Epub 2012 Jul 9.
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.
乙型肝炎病毒 (HBV) pol/RT 突变导致对富马酸替诺福韦二吡呋酯 (TDF) 的临床耐药性尚未被发现。在体外，阿德福韦酯 (ADV) 相关的 rtN236T 耐药突变对替诺福韦具有低水平的交叉耐药性：野生型 EC(50) 变化 3-13 倍。本研究通过比较慢性 HBV 单感染患者在开始 TDF 或恩曲他滨 (FTC)/TDF 治疗前携带 rtN236T 时，rtN236T 突变病毒与野生型病毒的早期病毒载量衰减动力学，评估了 rtN236T 突变病毒的临床反应。使用高度敏感的等位基因特异性 PCR 检测方法检测阿德福韦耐药患者的基线样本 (n = 105)，rtN236T 检测截止值为 0.5%。在可分析的患者样本中，基线时检测到 rtN236T 的比例为 14.3% (14/98) (rtN236T 百分比范围 0.5-93.2%)。基线时检测到 rtN236T 的患者在第 24 周时总 HBV DNA 的中位变化与野生型 HBV 患者相似 (-3.7 log(10) 拷贝/mL，n = 14)，与野生型 HBV 患者相比 (-3.2 log(10) 拷贝/mL，n = 90)。在 rtN236T 患者中，野生型和 rtN236T 突变病毒的 HBV DNA 下降率相似，在第 4 周时未观察到统计学差异。此外，在研究的任何治疗组中，患者的 rtN236T 比例在治疗期间均保持不变。总之，在转为 TDF 或 FTC/TDF 的阿德福韦耐药患者中，rtN236T 突变病毒与野生型病毒的 HBV DNA 下降动力学相似。尽管体外存在低水平的交叉耐药性，但 TDF 同样可以抑制体内的野生型和 rtN236T 突变病毒。
