Di Marco Vito, Di Stefano Rosa, Ferraro Donatella, Almasio Piero Luigi, Bonura Celestino, Giglio Maria, Parisi Pietro, Cappello Maria, Alaimo Giuseppe, Craxì Antonio
Cattedra e Unità Operativa Complessa di Gastroenterologia ed Epatologia, University of Palermo, Palermo, Italy.
Antivir Ther. 2005;10(3):431-9.
In hepatitis B virus (HBV) cirrhosis patients on long-term lamivudine (LAM), the relationships between HBV suppression, development of viral resistance and disease outcome are unclear. We analysed the dynamic of serum HBV-DNA and its relationship with the clinical course of 59 patients (52 males, mean age 51.4 +/- 8.4 years, 12 HBeAg positive and 47 HBeAg negative, and 57 genotype D and two genotype A) with cirrhosis (45 in Child-Turcotte-Pugh class A) and high levels of serum HBV-DNA (median 14.7 x 10(7) genomes/ml) treated with LAM [median (range): 44 (15-78) months]. A total of 50 patient (84.7%) achieved a virological response (serum HBV-DNA negative by PCR) during the first 6 months of therapy, and nine (13.3%) achieved a reduction in viral load of > 3 log10. Mutations in the YMDD motif of HBV polymerase were documented in 26 patients [median (range) 18: (7-42) months]. At the time of the emergence of mutants, 22 patients had HBV-DNA < 10(5) genomes/ml and normal alanine aminotransferase (ALT) levels. The appearance of virological resistance was followed by an increase of HBV-DNA to > 10(5) genomes/ml and of ALT values in 19 out of 26 patients [median (range): 8 (3-19) months]. Event-free survival was significantly longer (P = 0.001) in patients who maintained virological suppression than in those who did not have a complete virological response or suffered a breakthrough. Patients with advanced cirrhosis were more likely to develop liver failure after the emergence of YMDD mutants. The risk of development of hepatocellular carcinoma in patients with compensated cirrhosis and YMDD mutations was maintained, regardless of HBV-DNA serum levels. Profound and maintained HBV-DNA suppression correlates with a better outcome. Early identification of LAM resistance mutations allows switching to other antivirals before liver decompensation or hepatocellular carcinoma development.
在长期服用拉米夫定（LAM）的乙型肝炎病毒（HBV）肝硬化患者中，HBV抑制、病毒耐药性的产生与疾病转归之间的关系尚不清楚。我们分析了59例肝硬化患者（52例男性，平均年龄51.4±8.4岁，12例HBeAg阳性，47例HBeAg阴性，57例为D基因型，2例为A基因型）（45例Child-Turcotte-Pugh A级）血清HBV-DNA的动态变化及其与临床病程的关系，这些患者血清HBV-DNA水平较高（中位数为14.7×10⁷基因组/ml），接受LAM治疗[中位数（范围）：44（15 - 78）个月]。共有50例患者（84.7%）在治疗的前6个月达到病毒学应答（PCR检测血清HBV-DNA阴性），9例（13.3%）病毒载量下降>3 log₁₀。26例患者检测到HBV聚合酶YMDD基序突变[中位数（范围）18：（7 - 42）个月]。在突变体出现时，22例患者的HBV-DNA<10⁵基因组/ml，丙氨酸氨基转移酶（ALT）水平正常。在26例患者中的19例[中位数（范围）：8（3 - 19）个月]，病毒学耐药出现后，HBV-DNA升高至>10⁵基因组/ml，ALT值也升高。病毒学抑制得以维持患者的无事件生存期显著长于那些未获得完全病毒学应答或出现病毒突破的患者（P = 0.001）。晚期肝硬化患者在YMDD突变体出现后更易发生肝衰竭。代偿期肝硬化且有YMDD突变患者发生肝细胞癌的风险持续存在，与血清HBV-DNA水平无关。深度且持续的HBV-DNA抑制与较好的转归相关。早期识别LAM耐药突变可在肝脏失代偿或肝细胞癌发生之前换用其他抗病毒药物。
