Is Hepatitis Virus Resistance to Antiviral Drugs a Threat?

StephenW

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• National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
• INSERM U955, Créteil, France
• Reprint requests Address requests for reprints to: Professor Jean-Michel Pawlotsky, MD, PhD, Department of Virology, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. fax: (33) 1-4981-4831
  

The onset of the acquired immune deficiency syndrome epidemic in the early 1980s led to successful antiviral drug discovery programs, which brought to the market a large number of antiretroviral drugs with different targets and mechanisms of action. However, it soon became apparent that human immunodeficiency virus (HIV) resistance to these drugs would be a problem in long-term antiretroviral therapy.1 A combination of drugs with different viral targets and no cross-resistance (highly active antiretroviral therapy [HAART]) was shown to be a valuable option to prevent HIV resistance in the long-term. Nevertheless, multidrug-resistant viruses emerge in some patients on HAART therapy, generally those who have been on treatment for many years and have received a number of different drugs during their life. These viruses escape the antiviral effect of all available drugs and their outgrowth is responsible for treatment failure, disease progression, and death.1Based on this experience, hepatitis B virus (HBV) and hepatitis C virus (HCV) resistance to direct-acting antiviral (DAA) drugs often is seen as a dreadful threat. The reality is, however, different.

Hepatitis B Virus Resistance to Nucleoside/Nucleotide Analogues Lamivudine, a drug widely used in HAART therapy, was the first nucleoside analogue available for HBV treatment. Its broad use in monotherapy was associated with a high incidence of virologic breakthrough owing to the selection and outgrowth of lamivudine-resistant HBV variants.2 Similar observations were reported after a few years of monotherapy with adefovir, a nucleotide analogue developed for HIV and the second inhibitor approved for HBV therapy.3 Because these 2 drugs select different resistance-associated amino acid substitutions, they were combined to prevent resistance emergence. This strategy proved to be efficient, with very few breakthroughs on de novo or add-on lamivudine–adefovir combination therapy,4, 5 and it still is appropriate in resource-constrained settings. However, viruses bearing an rtA181V/T substitution, which confers cross-resistance to the 2 drugs, occasionally were selected in patients receiving the combination of lamivudine and adefovir.6
Bearing this in mind, some investigators, including myself, were convinced that, similar for HIV, de novo combinations of drugs without cross-resistance were the only valid therapeutic option for chronic hepatitis B treatment with nucleoside/nucleotide analogues, and that even this option probably would not prevent outgrowth of multidrug-resistant viruses after several years of combined therapy. In the meantime, 2 new drugs, entecavir and tenofovir, had been approved for HBV therapy. Surprisingly, long-term follow-up studies of HBV resistance with these drugs showed incredibly low cumulative resistance rates in treatment-naive patients: 1.2% with entecavir at 6 years and 0% with tenofovir at 5 years.7, 8 These results subsequently were confirmed in the real-life setting, in which treatment failures caused by resistance were extremely rare in adherent treatment-naive patients receiving entecavir or tenofovir monotherapy. This led to the conclusion that, unlike HIV, HBV infection can be treated for years with either first-line entecavir or tenofovir monotherapy without a major risk of viral breakthrough owing to resistance selection.9, 10
This favorable situation can be explained by the characteristics of HBV and of the drugs used to block its replication. Indeed, strong conservatory constraints exist on the amino acid sequence of HBV proteins because of the overlapping reading frames that encode different viral proteins that cannot tolerate extensive variations. As a result, the number of possible viable viruses with amino acid substitutions in the reverse transcriptase that confer primary resistance to HBV nucleoside/nucleotide analogues is limited. In addition, although rtM204V/I confers reduced susceptibility to entecavir and rtN236T and rtA181V/T confer reduced susceptibility to tenofovir in vitro,11 the drug concentrations achieved in vivo are high enough to control the replication of HBV variants bearing these substitutions in the long term in treatment-naive patients, preventing the accumulation of additional substitutions that could improve their fitness. Finally, triple mutants that are fully resistant to entecavir do not appear to pre-exist frequently at baseline in patients who have not been exposed previously to lamivudine. Therefore, their selection by first-line entecavir is unlikely, and the antiviral potency of the drug prevents them from being generated on treatment.7
In treated patients, adherence to therapy is a key factor of maintained antiviral efficacy without virologic breakthroughs. Whether viral resistance could emerge after many years in patients likely to receive life-long treatment with these drugs remains unknown. Long-term follow-up studies therefore are needed. For this reason, some experts recommend de novo combination of tenofovir and one of the nucleoside analogues, or tenofovir and emtricitabine in one tablet, in patients with advanced HBV-related liver disease, because resistance emergence would be life-threatening in these individuals.
In patients already exposed to a nucleoside/nucleotide analogue who developed HBV resistance to this drug, the “add-on” strategy was shown to be superior to the “switch” strategy in preventing selection of viral variants that are resistant to lamivudine and adefovir.4 However, the superiority of the add-on vs switch strategy has not been shown with entecavir or tenofovir, which are more potent and have a higher barrier to resistance. Given the number of patients and length of follow-up evaluation needed to answer this question, it is likely that this information will never be available. In this context, it is reasonable to recommend that patients who developed resistance to one of the available HBV drugs be treated with a combination of tenofovir plus 1 of the 3 nucleoside analogues (lamivudine, telbivudine, or entecavir), or with the combination of tenofovir plus emtricitabine in one tablet, because this strategy is the only one that can delay the emergence of multidrug resistance. In this respect, the best combination by far is tenofovir plus entecavir, but long-term tolerance data are lacking and cost may be an issue in certain areas of the world. This approach is particularly important in the absence of any alternative therapy active on viruses that would escape both nucleoside and nucleotide analogues, especially in patients with advanced liver disease.

HCV Resistance to DAA Drugs The virologic characteristics of HCV suggested that HCV resistance would be an issue when DAA drugs become available. Indeed, HCV is a highly variable positive-strand RNA virus, with large populations and a very short half-life of free virions in peripheral blood.12, 13 Mathematic modeling predicted that, in every infected patient, all possible single, double, and possibly triple mutants are generated each day and can be selected by DAA administration.14 The pre-existence of viral variants bearing amino acid substitutions that confer resistance to the different classes of drugs in treatment-naive patients has been shown by means of ultra-sensitive, pyrosequencing-based methods.15 In vitro, all DAAs currently in development select resistant, generally fit variants after multiple passages.16 Monotherapy studies with DAAs with a low barrier to resistance, including NS3/4A protease inhibitors and non-nucleoside inhibitors of HCV RNA–dependent RNA polymerase and NS5A inhibitors, have shown early virologic breakthroughs owing to the selection and outgrowth of fit-resistant viral populations. Other classes of drugs appear to have better resistance profiles, such as, for instance, the nucleoside/nucleotide analogue inhibitors of HCV RNA-dependent RNA polymerase, which select resistant variants that are poorly fit and grow slowly in the presence of the drug, or the cyclophylin inhibitors, which target a host protein involved in HCV replication, not a viral structure.16
To prevent resistance emergence, a DAA must be combined with one or several other, non–cross-resistant antiviral molecules. Three options currently are being explored: triple combinations with a DAA, pegylated interferon (IFN)-alfa, and ribavirin; quadruple combinations with 2 non–cross-resistant DAAs, pegylated IFN-alfa, and ribavirin; and all-oral, IFN-free drug regimens. Clinical trials with these strategies have been reassuring thus far. Indeed, in contrast to HIV and HBV, HCV infection is curable, and cure is easily achievable provided that virus production is profoundly inhibited in a sustained manner, to ensure progressive cure of infected cells, most likely through the action of intracellular responses linked to innate immunity, which are no longer suppressed by viral protein expression. Therefore, the use of combinations of drugs that prevent the emergence of drug-resistant HCV variants over weeks to months is probably sufficient to eradicate all viruses from a patient's liver. The choice of the drugs administered and of treatment duration are thus of the utmost importance.
What was learned from phase II and III triple combination trials is that, not surprisingly, cure of HCV infection is achieved easily in patients who respond to pegylated IFN-alfa and ribavirin; in contrast, treatment failures are seen in poor IFN responders.17, 18, 19 In all patients who fail on this therapy, the population of viral variants resistant to the protease inhibitor grows relative to the wild-type virus that efficiently is inhibited. Indeed, in phase II and III trials, resistant viruses were the dominant population at the time of failure (virologic breakthrough or relapse) in approximately 50%–70% of cases, as detected by population sequencing. When treatment is stopped, the wild-type, protease inhibitor–sensitive viral population was shown to grow back and become dominant again in all patients within a few months, for up to 2 years, as assessed by population sequencing.20 It is possible that protease inhibitor–resistant variants have acquired additional substitutions that further improve their fitness in the presence of a protease inhibitor. Nevertheless, 2 years after a triple combination treatment failure, a situation close to the pretherapeutic one has been restored, with a dominant wild-type viral population and the presence of minor variants bearing amino acid substitutions conferring resistance to protease inhibitors. Selection of resistant HCV variants in these patients does not appear to be harmful, and a new treatment with a first-generation protease inhibitor sharing cross-resistance with telaprevir and boceprevir is not contraindicated, provided that this drug is combined with another drug or several drugs that potently inhibit HCV replication while sharing no cross-resistance with protease inhibitors (thus, excluding re-treatment in combination with pegylated IFN-alfa and ribavirin only).
A recent study, based on a small number of null responders to a first course of pegylated IFN-alfa and ribavirin, has shown viral eradication in all cases with a quadruple combination of pegylated IFN-alfa, ribavirin, and 2 DAAs with no cross-resistance, including an NS3/4A protease inhibitor and an NS5A inhibitor.21 Because the frequency of viral breakthroughs caused by multidrug-resistant viruses was high with these 2 DAAs in the absence of pegylated IFN-alfa and ribavirin for subtype 1a, this result indirectly suggests that sustaining HCV inhibition and preventing early re-increase of viral replication may have restored IFN responsiveness in these patients.
Based on these data, there is no reason to think that an IFN-free regimen would not be able to eradicate HCV in virtually all cases if no resistant HCV variants are selected during treatment. Such a DAA combination must have a high barrier to resistance, and treatment must be administered for long enough to ensure that every infected cell is cured. In a recent proof-of-concept study, 9 of 10 prior null responders to pegylated IFN-alfa and ribavirin infected with HCV subtype 1b achieved viral eradication after 24 weeks of treatment with an NS3/4A protease inhibitor and an NS5A inhibitor, a DAA combination with a high barrier to resistance in this subtype. No patient broke through owing to selection of resistant HCV variants.22 In another study, 10 of 10 treatment-naive patients infected with HCV genotype 2 or 3 achieved an SVR after 12 weeks of a combination of a nucleotide analogue and ribavirin.23
The challenge now will be to identify the optimal IFN-free, all-oral DAA combination that can become the universal first-line therapy for chronic hepatitis C. This combination ideally must have pan-genotype coverage and a high enough barrier to resistance to yield very high cure rates within a reasonable time frame. Given the properties of the drugs currently in development, such a combination could be available within the next 5–7 years. In the meantime, treating physicians should be cautious when using nonoptimal IFN-free combinations because some of them will yield frequent selection of multidrug-resistant viruses. However, these viruses are unlikely to be more aggressive to the patient's liver than wild-type viruses and probably will be replaced by the latter within a few months after treatment failure and discontinuation. Given the current routes of transmission of HCV, such resistant viruses also are unlikely to spread in newly infected individuals.

Conclusions A good story never happens twice, and those who thought that the HIV resistance adventure would start again with hepatitis viruses may be disappointed. Most, if not all, situations in HBV-infected patients now can be controlled with entecavir and/or tenofovir. In resource-constrained areas, tenofovir generally is accessible through HIV programs at a reasonable cost and thus can be used as first-line therapy or in combination with lamivudine in treatment-exposed patients. If tenofovir is not available, the combination of lamivudine and adefovir (often available as a generic drug in these countries) was shown to be efficient in the long term, with a modest risk of selection of resistance owing to rtA181V/T substitutions. Thus, HBV resistance no longer appears as a major threat, at least in the short term to midterm, provided that patients are adherent to therapy. On the other hand, the failure of DAA-containing therapies to cure HCV infection is associated with selection of DAA-resistant viral populations. However, outgrowth of resistant variants is not harmful, and the wild-type virus generally grows back as the dominant species within a few months after therapy. HCV remains curable in these patients, who will have access to better combinations in the midterm future. A pan-genotype, highly efficient, all-oral, IFN-free treatment regimen most likely will be available within a few years. As a result, the rising tide of HIV resistance specialists moving to the hepatitis field might end up as an ebb tide.

StephenW

在20世纪80年代早期获得性免疫缺陷综合症疫情爆发导致成功的抗病毒药物的研究计划，这给市场带来大量的抗逆转录病毒药物，不同的目标和行动机制。然而，它很快变得明显，人类免疫缺陷病毒（HIV）到这些药物的耐药性，将是一个长期的抗逆转录病毒therapy.1不同病毒目标和无交叉耐药性（高活性抗逆转录病毒疗法[鸡尾酒疗法的药物组合问题）被证明是一个有价值的选择，以防止艾滋病毒在长期阻力。然而，多药耐药的病毒出现在一些患者对鸡尾酒疗法治疗，一般是那些已多年，并已收到他们的生活在不同的药物治疗。这些病毒逃避所有可用药物的抗病毒作用及其产物是负责治疗失败，病情恶化，death.1

基于这方面的经验，B型肝炎病毒（HBV）和丙型肝炎病毒（HCV）的电阻直接作用抗病毒药物（的DAA）的药物常常被看作是一种可怕的威胁。然而，现实是不同的。


乙肝抗病毒核苷/核苷酸类似物

拉米夫定，广泛用于鸡尾酒疗法的药物，是第一个可用于乙肝治疗的核苷类似物。其在单一的广泛使用，与高发病率的病毒学突破，由于拉米夫定耐药HBV variants.2类似意见的选择和生长相关报道后，艾滋病毒的核苷酸类似物阿德福韦单一几年和第二抑制乙肝therapy.3批准，因为这2种药物选择不同抗性相关的氨基酸替换，他们结合起来，以防止出现抗药性。这种策略被证明是有效的，很少从头突破或添加拉米夫定，阿德福韦联合治疗，4，5，它仍然是在资源有限的设置适当的。然而，病毒rtA181V / T替换，这2种药物的交叉耐药性赋予轴承，偶尔接收患者拉米夫定adefovir.6组合选择

铭记这一点，一些研究者，包括我自己在内，相信，艾滋病毒类似，从头药物无交叉耐药性的组合是唯一有效的核苷/核苷酸类似物治疗慢性乙型肝炎的治疗选择，而且即使此选项可能不会阻止多药耐药病毒的产物，经过几年的综合治疗。在此期间，恩替卡韦和替诺福韦，2个新的药物，已被批准用于乙肝治疗。令人惊讶的是，长期跟踪与这些药物的抗乙肝病毒的研究表明，低得令人难以置信，在治疗过的患者累积耐药率：替诺福韦与恩替卡韦在6年的1.2％和0％5 years.7，这些结果随后被在现实生活中的设置确认，其中由电阻引起的治疗失败的粘附治疗初治患者接受恩替卡韦或替诺福韦单药治疗极为罕见。这导致了，不像艾滋病毒，乙肝病毒感染可以治疗无论是第一线的恩替卡韦或替诺福韦单药治疗的主要风险抵抗selection.9的一个病毒的突破，由于多年没有结论，10

HBV和使用的药物，以阻止其复制的特点，可以解释这种有利的形势。事实上，强劲的温室约束上存在氨基酸序列的乙肝病毒的蛋白质，因为重叠的读码框架，编码不同的病毒蛋白无法容忍广泛的变化。因此，在逆转录酶的氨基酸替换，赋予基层抗HBV核苷/核苷酸类似物可能可行的病毒数量是有限的。此外，rtM204V /我虽然恩替卡韦和rtN236T和rtA181V /赋予赋予敏感性降低，减少了体外药敏泰诺福韦，药物在体内达到的浓度高到足以控制在长期的轴承这些替代的乙肝病毒变种的复制在治疗过的病人，防止积累额外的换人，可以提高他们的健身。最后，完全耐恩替卡韦的三突变体没有出现预先存在于基线，经常在那些以前没有接触过拉米夫定的患者。因此，他们选择由第一线的恩替卡韦是不可能的，该药物的抗病毒效力，防止它们产生于treatment.7

在治疗的患者中，坚持治疗是保持抗病毒疗效无病毒学突破的关键因素。是否可能出现病毒耐药可能获得这些药物的终身治疗的患者多年后仍是未知。因此需要长期随访研究。出于这个原因，一些专家建议重新组合泰诺福韦和核苷类似物之一，或替诺福韦和恩曲他滨在一个平板，拥有先进的HBV相关肝病患者，因为耐药性的出现，将在这些人的生命威胁。

在已经暴露在研制乙肝病毒抵抗这种药物核苷/核苷酸类似物的患者，在“附加”的战略被证明是优于“开关”中选择拉米夫定和阿德福韦有抗药性的病毒变种预防战略。 4，附加上与转换策略的优势，但是还没有被证明与恩替卡韦或替诺福韦，这是更有效和有较高的抵抗障碍。鉴于患者的数量和长度需要回答这个问题的后续评价，它是可能的，这些信息将永远可用。在这种情况下，它是合理的建议进行与泰诺福韦加1 3核苷类似物（拉米夫定，替比夫定或恩替卡韦）的组合治疗，谁可用HBV药物产生抗药性的患者，或替诺福韦组合加上恩曲他滨在一个片，因为这种策略是唯一一个能延缓耐药的出现。在这方面，迄今为止的最佳组合是泰诺福韦加替卡韦，但缺乏长期容忍数据和成本可能是一个在世界上某些地区的问题。在没有任何活跃病毒会逃避，特别是在晚期肝病患者，核苷和核苷酸类似物的替代疗法，这种方法就显得尤为重要。


丙型肝炎病毒抗性的DAA药品

丙型肝炎病毒的病毒学特征建议，丙型肝炎病毒的抵抗将是一个问题的DAA药物时可用。事实上，丙型肝炎病毒是一种高度可变正链RNA病毒，与庞大的人口数量和很短的免费病毒颗粒的一半生活在周边blood.12，13数学建模预测，在每一个受感染的病人，所有可能的单人，双人，三重突变可能生成的每一天，和预先存在的轴承氨基酸替换赋予不同类药物在治疗过的患者的抗病毒变种已显示超灵敏的手段，可以选择的DAA administration.14 ，焦磷酸测序技术为基础的在体外methods.15，目前正在开发中的所有DAAS选择耐腐蚀，一般适合多个passages.16单药治疗研究后DAAS低阻力障碍，包括NS3/4A蛋白酶抑制剂和丙型肝炎病毒非核苷抑制剂的变种RNA依赖的RNA聚合酶和NS5A抑制剂，由于选择合适的抗病毒种群的生长早期病毒学突破。其他类药物的出现，有较好的耐型材等，例如，丙型肝炎病毒RNA依赖的RNA聚合酶，它选择差的适应和缓慢增长的药物存在抗药性的变种，或核苷/核苷酸类似物抑制剂cyclophylin抑制剂，目标宿主蛋白参与丙型肝炎病毒复制，不是病毒structure.16的

为了防止出现抗药性，必须结合一个或其他几个，无交叉耐药的抗病毒药物分子的DAA。三个选项目前正在探索：三重组合的DAA，聚乙二醇化干扰素（IFN）-α，所有口服，干扰素与非交叉耐药DAAS，聚乙二醇化干扰素-α和利巴韦林利巴韦林;四组合免费的药物治疗方案。这些策略的临床试验已经放心迄今。事实上，在HIV和HBV，丙型肝炎病毒感染是可以治愈的，治愈是很容易实现提供生产病毒正在深刻地抑制持续地，逐步治愈，最有可能受感染的细胞内反应与先天的行动，以确保通过免疫力，不再通过抑制病毒蛋白的表达。因此，使用药物，防止出现的耐药性丙型肝炎病毒变种多星期到几个月的组合可能是足以消灭所有病毒从病人的肝脏。因此，管理的药品和治疗时间的选择至关重要。

什么是第二和第三阶段的三重组合试验学到的是，这并不奇怪，治愈丙型肝炎病毒感染是谁应对聚乙二醇干扰素α和利巴韦林的患者很容易实现，相比之下，在贫困干扰素responders.17治疗失败， 18日，19日，在所有患者，这种疗法失败的蛋白酶抑制剂的抗病毒变种的人口增长，有效地抑制野生型病毒。事实上，在第二和第三阶段的试验中，抗病毒的优势种群，约50％-70％的情况下失败（病毒学突破或复发）时间，人口测序检测。停止治疗时，野生型，蛋白酶抑制剂敏感的病毒人口的增长和在所有患者在短短几个月内再次成为主导，为长达2年，由人口sequencing.20评估它是可能的蛋白酶抑制剂耐药的变异，获得额外的换人，进一步提高他们的健身中存在的蛋白酶抑制剂。然而，三重结合治疗失败后2年内，在治疗前的密切情况已恢复，与占主导地位的野生型病毒的人口和轴承抗蛋白酶抑制剂的氨基酸替换的轻微变种的存在。抗丙型肝炎病毒的变种，在这些患者中选择不出现有害，telaprevir治疗和boceprevir共享与交叉耐药性抑制剂第一代蛋白酶的一个新的治疗方法是没有禁忌，但前提是这种药物与另一种药物或多种药物组合potently抑制丙型肝炎病毒复制的同时，共享无交叉耐药性蛋白酶抑制剂（因此，不包括与聚乙二醇干扰素α和利巴韦林只组合再处理）。

最近的一项研究的基础上，少数的聚乙二醇干扰素α和利巴韦林的第一期培训班的空反应，显示病毒消灭在所有情况下，无交叉与聚乙二醇干扰素α-干扰素，病毒唑，2 DAAS翻两番组合阻力，包括NS3/4A蛋白酶抑制剂和NS5A的inhibitor.21由于多药耐药的病毒引起的病毒突破的频率与这些亚型1A的情况下，聚乙二醇干扰素α和利巴韦林2 DAAS高，这个结果间接建议维持丙型肝炎病毒抑制和防止病毒复制的早期可能恢复再增加在这些患者中干扰素反应。

基于这些数据，也没有理由认为，干扰素疗法不会是能够根除丙型肝炎病毒在几乎所有情况下，如果没有抗丙型肝炎病毒的变种是在治疗过程中选择。这样的DAA组合必须有一个高阻力障碍，治疗必须足够长的管理，以确保每一个受感染的细胞治愈。在最近的一个概念证明型的研究，取得9 10前空反应聚乙二醇干扰素α和利巴韦林感染丙型肝炎病毒亚型1B NS3/4A蛋白酶抑制剂和NS5A的抑制剂，1的DAA治疗24周后病毒根除在此亚型抗高屏障的结合。通过在另一项研究中，由于没有病人发生的抗丙型肝炎病毒variants.22的选择，治疗过的患者感染丙型肝炎病毒基因型2或3 10 10取得SVR的后12周的核苷酸类似物的组合和ribavirin.23

现在的挑战将是确定最佳干扰素，口服的DAA的组合，可以成为普遍的第一线治疗慢性丙型肝炎这种组合的理想必须有泛基因型的覆盖面和足够高的屏障，以抵抗产量一个合理的时间框架内的治愈率很高。鉴于目前正在开发中的药物的性质，这样的组合可能在未来的5-7年。在此期间，医生治疗时，应谨慎使用非最佳干扰素自由组合，因为他们中的一些会产生多药耐药的病毒频繁选择。然而，这些病毒是不太可能更积极的病人的肝脏比野生型病毒，并可能会被取代后者治疗失败和停药后的几个月内。鉴于目前丙型肝炎病毒的传播路线，如抗病毒也不大可能在新感染者的传播。


结论

一个好故事，从未发生过两次，和那些认为抗艾滋病毒与肝炎病毒再次冒险将启动可能会失望。最重要的是，如果不是全部，在HBV感染患者的情况现在可以控制与恩替卡韦和/或替诺福韦。泰诺福韦在资源有限的地区，一般是通过艾滋病毒方案以合理的成本，从而可以使用拉米夫定作为一线治疗或联合治疗暴露患者。如果不可用替诺福韦，拉米夫定和阿德福韦（通常在这些国家的仿制药）的组合被证明是有效的，在长期的阻力由于rtA181V /换人选择适度的风险，。因此，HBV耐药不再出现作为一个主要的威胁，至少在短期到中期，患者粘附治疗。另一方面，未能治愈的DAA含治疗丙型肝炎病毒感染相关的DAA抗病毒人群的选择。但是，耐药变异的产物是不会对人体有害，治疗后几个月内的优势种，野生型病毒一般长回来。丙型肝炎病毒仍然在这些患者中，将有机会获得更好的组合在中期的将来治愈。泛基因型，高效，口服，干扰素治疗方案极有可能会在几年内提供。因此，艾滋病毒的抵抗运动肝炎领域专家的涨潮可能最终作为一个低潮。

咬牙硬挺

回复 StephenW 的帖子

怎么个意思？使用恩替或者替诺，乙肝短时期不容易耐药？

StephenW

回复 咬牙硬挺 的帖子

This led to the conclusion that, unlike HIV, HBV infection can be treated for years with either first-line entecavir or tenofovir monotherapy without a major risk of viral breakthrough owing to resistance selection.9, 10
HBV的耐药是不同艾滋病毒的耐药 - 恩替卡韦或替诺福韦可作为单一治疗很长一段时间没有产生抗药性的危险.
This favorable situation can be explained by the characteristics of HBV and of the drugs used to block its replication. Indeed, strong conservatory constraints exist on the amino acid sequence of HBV proteins because of the overlapping reading frames that encode different viral proteins that cannot tolerate extensive variations. As a result, the number of possible viable viruses with amino acid substitutions in the reverse transcriptase that confer primary resistance to HBV nucleoside/nucleotide analogues is limited.
原因：可能逆转录酶(reverse transcriptase)的氨基酸(amino acid)替换(substitution)有限制.
In addition, although rtM204V/I confers reduced susceptibility to entecavir and rtN236T and rtA181V/T confer reduced susceptibility to tenofovir in vitro,11 the drug concentrations achieved in vivo are high enough to control the replication of HBV variants bearing these substitutions in the long term in treatment-naive patients, preventing the accumulation of additional substitutions that could improve their fitness.
原因: 恩替卡韦和替诺福韦是非常有效有力的药物，可以控制有一个或两个突变的病毒，防止积累第三突变.
Finally, triple mutants that are fully resistant to entecavir do not appear to pre-exist frequently at baseline in patients who have not been exposed previously to lamivudine. Therefore, their selection by first-line entecavir is unlikely, and the antiviral potency of the drug prevents them from being generated on treatment.7
原因:耐恩替卡韦的三个的突变(triple mutants)不预先存在.

咬牙硬挺

感谢热心的史蒂芬，放心多了，得了乙肝比艾滋病强点哈