Akamatsu S, Hayes C N, Tsuge M, Murakami E, Hiraga N, Abe H, Miki D, Imamura M, Ochi H, Chayama K
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
J Viral Hepat. 2015 Feb;22(2):166-74. doi: 10.1111/jvh.12275. Epub 2014 Jun 16.
Treatment success of chronic hepatitis C virus genotype 1 infection has improved with the advent of telaprevir plus peg-interferon/ribavirin triple combination therapy. However, the effect of inosine triphosphatase (ITPA) polymorphism on dose reduction during triple therapy, especially during the postmarketing phase, has not been sufficiently evaluated. We analysed 273 patients with genotype 1 infection who were treated with triple therapy and assessed the effect of the ITPA polymorphism on dose reduction. ITPA and IFNL4 SNP genotypes were determined by the Invader assay. A stepwise multivariate regression analysis was performed to identify factors associated with outcome of the therapy. The overall sustained viral response (SVR) rate 12 weeks after the end of therapy was 80.2% (219/273). Decline of haemoglobin was significantly faster, and ribavirin was more extensively reduced in patients with ITPA SNP rs1127354 genotype CC than CA/AA. Extensive reduction of ribavirin resulted in mild reduction of telaprevir and peg-interferon, but no significant increase in viral breakthrough. Although the amount of telaprevir given was slightly higher in CA/AA patients, the total dose of peg-interferon and the SVR rate did not differ between the two groups. Multivariate analysis showed that IFNL4 but not ITPA SNP genotype, platelet count and peg-interferon adherence were significantly associated with outcome of therapy. Postmarketing-phase triple therapy resulted in a high SVR rate in spite of extensive ribavirin dose reduction in a diverse patient population, indicating the importance of treatment continuation and appropriate management of adverse events.
随着特拉匹韦联合聚乙二醇干扰素/利巴韦林三联疗法的出现，慢性丙型肝炎病毒1型感染的治疗成功率有所提高。然而，肌苷三磷酸酶（ITPA）多态性对三联疗法期间剂量减少的影响，尤其是在上市后阶段，尚未得到充分评估。我们分析了273例接受三联疗法治疗的1型感染患者，并评估了ITPA多态性对剂量减少的影响。通过Invader检测法确定ITPA和IFNL4单核苷酸多态性（SNP）基因型。进行逐步多因素回归分析以确定与治疗结果相关的因素。治疗结束后12周的总体持续病毒学应答（SVR）率为80.2%（219/273）。与ITPA SNP rs1127354基因型为CA/AA的患者相比，CC基因型患者的血红蛋白下降明显更快，利巴韦林减少得更广泛。利巴韦林的大量减少导致特拉匹韦和聚乙二醇干扰素轻度减少，但病毒突破无显著增加。虽然CA/AA患者的特拉匹韦给药量略高，但两组之间聚乙二醇干扰素的总剂量和SVR率并无差异。多因素分析表明，与治疗结果显著相关的是IFNL4而非ITPA SNP基因型、血小板计数和聚乙二醇干扰素依从性。尽管在不同患者群体中利巴韦林剂量大量减少，但上市后阶段的三联疗法仍取得了较高的SVR率，这表明持续治疗和妥善处理不良事件的重要性。
