Vincenti Donatella, Piselli Pierluca, Solmone Mariacarmela, D'Offizi Gianpiero, Capobianchi Maria R, Menzo Stefano
National Institute for Infectious Diseases, INMI, "Lazzaro Spallanzani", Rome, Italy.
Università Politecnica delle Marche, Department of Biomedical Sciences and Public Medicine, Ancona, Italy.
Antiviral Res. 2017 Jul;143:62-68. doi: 10.1016/j.antiviral.2017.03.008. Epub 2017 Mar 18.
Antiviral therapy has revolutionized treatment of chronic HBV infections. First generation compounds, lamivudine and adefovir, displayed a high rate of treatment failures, and have been replaced by more potent compounds with high genetic barrier to resistance. However, the evolution of the virus towards resistance due the use of first generation compounds may still provide useful information for a better management of current antivirals. A single center sequence database including 705 HBV reverse transcriptase sequences from patients failing antiviral treatments (2002-2012) has been statistically analyzed to highlight viral evolution in relationship to the use of antiviral compounds and to their associations/sequencing in those years. The influence of viral genotypes and polymorphisms on resistance-related mutational patterns was also investigated. This study documents how, after the first years of antiviral therapy, the use of adefovir as an add-on strategy allowed a consistent reduction treatment failures. It also documents the effects of the initial misuse of entecavir in lamivudine experienced patients. In the latest years, the correct use of entecavir and the introduction of tenofovir allowed further curbing of resistance-related treatment failures, which virtually disappeared. Furthermore, the study allows a better understanding of how viral genotype (A vs D) conditions specific mutational pathways to resistance against lamivudine and entecavir, and demonstrates that the use of adefovir in lamivudine experienced patients is associated to peculiar mutational patterns, in particular A181V + F/Y221L. Despite some concern may arise for patients previously treated with lamivudine/adefovir, in sequence or combination, where the virus may have developed a lower genetic barrier against resistance to tenofovir, the outlook of antiviral treatment of HBV infection should be quite optimistic.
抗病毒疗法彻底改变了慢性乙型肝炎病毒（HBV）感染的治疗方式。第一代化合物拉米夫定和阿德福韦治疗失败率较高，已被对耐药具有更高基因屏障的更有效化合物所取代。然而，由于使用第一代化合物导致病毒向耐药性演变，这仍可能为更好地管理当前的抗病毒药物提供有用信息。对一个单中心序列数据库进行了统计分析，该数据库包含705条来自抗病毒治疗失败患者（2002 - 2012年）的HBV逆转录酶序列，以突出与抗病毒化合物使用及其在那些年中的关联/测序相关的病毒演变。还研究了病毒基因型和多态性对耐药相关突变模式的影响。这项研究记录了在抗病毒治疗最初几年后，使用阿德福韦作为附加策略如何使治疗失败率持续降低。它还记录了在拉米夫定治疗过的患者中恩替卡韦最初的不当使用所产生的影响。近年来，恩替卡韦的正确使用和替诺福韦的引入进一步遏制了与耐药相关的治疗失败情况，这种情况几乎消失了。此外，该研究有助于更好地理解病毒基因型（A与D）如何决定针对拉米夫定和恩替卡韦的耐药性的特定突变途径，并表明在拉米夫定治疗过的患者中使用阿德福韦与特殊的突变模式相关，特别是A181V + F/Y221L。尽管对于先前接受过拉米夫定/阿德福韦序贯或联合治疗的患者可能会有些担忧，因为病毒可能对替诺福韦产生较低的耐药基因屏障，但HBV感染抗病毒治疗的前景应该相当乐观。
