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Antiviral drug resistance: clinical consequences and molecular aspects.
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Semin Liver Dis. 2006 May;26(2):162-70. Antiviral drug resistance: clinical consequences and molecular aspects. Bartholomeusz A, Locarnini SA. Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia. Antiviral drug resistance now poses a major problem for the management of patients with chronic hepatitis B. In theory, resistance may be prevented if a sufficiently potent antiviral drug, or combination of antiviral agents, is used that prevents viral replication and thereby the ongoing selection of hepatitis B virus quasispecies. Emergence of drug resistance in patients with hepatitis B generally results in progression of liver disease and in some cases, significant clinical deterioration if hepatic reserve is compromised. Currently, there are two major patterns of resistance mutations found in the viral reverse transcriptase (rt) that can be selected during monotherapy: (1) those that include the codon rtM204, which is part of the catalytic domain (YMDD) of the enzyme; (2) and those that do not include the codon. The rtM204I/V is selected by lamivudine and L-nucleosides. It is also part of the entecavir resistance profile and the tenofovir-lamivudine combination resistance profile. In contrast, resistance to adefovir is associated with mutations at rtN236T +/- rtA181V. A reasonable clinical goal is to develop an overall strategy that prevents the selection of resistance. These strategies have yet to be optimized for hepatitis B, but may include multiple therapies such as immune-based therapies in combination with one or more nucleoside analogue treatments. Future treatment protocols can be modeled on the use of multiple agents comprising highly active anti-retroviral therapy regimens that have been developed for the successful management of patients infected with human immunodeficiency virus. 抗病毒药物耐药：分子学和临床后果 抗病毒药物的耐药是目前困扰慢性乙肝治疗的一个主要问题。理论上，如果一个药物有足够强的抗病毒能力或者抗病毒药物联合治疗可阻止病毒复制从而不断选择乙肝病毒准种。乙肝患者出现耐药常导致肝病进展，在一些肝脏储备差的病例中可见明显的临床恶化症象。目前在单药治疗中发现的病毒逆转录酶（rt）耐药变异有两者主要方式：1、密码子rtM204，酶催化区（YMDD）的一部分；2、不包括此密码子。rtM204I/V被拉米夫定和L-核苷选择，同时也是恩替卡韦以及替诺福韦（tenofovir）拉米夫定联合耐药的部位。阿德福韦的耐药突变不同，发生在rtN236T±rtA181V。合理的临床治疗目的是开发预防耐药选择的总体策略。这些策略应使乙肝治疗最佳化，可能包括多种治疗，如基于免疫的治疗与一个或多个核苷类似物联合应用。将来的治疗模式应采用多种药物，包括已在HIV中成功应用的高活性的抗逆转录病毒的药物 |
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