曾经抗反转录病毒治疗的病人

Rami Kantor, M.D., Karen T. Tashima, M.D.

译者：阮桂仁 博士

      北京协和医院 内科

      Email：ruanguiren@yahoo.com.cn

审阅者：卢洪洲 教授博士生导师

        上海市公共卫生临床中心感染一科

               Antiretroviral treatment failure may be caused by drug toxicity or virologic failure. Virologic failure may occur because an antiretroviral treatment regimen fails to reduce plasma HIV RNA levels to undetectable levels (<20-50 RNA copies/ml) or because plasma HIV RNA levels rebound following an initial decrease to undetectable levels. The success rate of antiretroviral therapy is lower in patients who have already experienced virologic failure on an earlier treatment regimen than in previously untreated persons.

        药物毒性或病毒学治疗失败均可导致抗反转录病毒治疗失败。病毒学治疗失败包括两种情况：一种是抗反转录病毒治疗方案无法将血浆HIV RNA载量降至可检测水平以下（<20-50 RNA 拷贝/毫升）；第二种情况是血浆HIV RNA载量在降至可检测水平以下后出现反弹。与未治疗过的病人相比，经治病人出现病毒学治疗失败后再次治疗的成功率较低。

               The goals of management of treatment-experienced patients with virologic failure differ according to circumstances related to prior treatment exposure and drug resistance. In limited or intermediate prior drug exposure, with adequate or some treatment options, the goal is to re-establish maximal virologic suppression. In extensive prior drug exposure, with few or no adequate treatment options, the goal is preservation of immune function and prevention of clinical progression, and expert advice is critical (4). If two or more fully active drugs can be identified, however, the goal of treatment for the patient with highly resistant virus is to achieve viral suppression to below 50 copies/mL (7). This goal is more readily achievable with the use of enfuvirtide and new protease inhibitors designed with activity against multiply PI-resistant virus (7, 27).

        经治病人出现病毒学治疗失败后的治疗目标因其既往治疗方案及耐药性不同而异。仅接受过有限的抗病毒药物治疗的患者，可以有足够的或部分的其他敏感药物供选择，其治疗目标是重新达到最大程度的病毒抑制。而既往接受过很多种抗病毒药物治疗的患者，没有或者很少有敏感药物可供选择，其治疗目标是尽可能保留其免疫功能、避免临床症状加重，此时，专家的意见较为关键。对于带有高度耐药病毒株的患者，如果能找到两种或两种以上完全敏感的抗病毒药物，其治疗目标是将血浆病毒载量控制在50 拷贝/毫升以下；随着恩夫韦地（enfuvirtide）及对多蛋白酶抑制剂耐药病毒敏感的新型蛋白酶抑制剂的研制，这种治疗目标将会更容易达到。

               In patients experiencing drug toxicity, it is appropriate to substitute one or more drugs of similar potency but with different side effects. Often it will be possible to substitute drugs of the same class but occasionally it may be necessary to substitute an equally potent drug from a different drug class. Drug toxicity must be anticipated and recognized early because it is a common cause of non-adherence leading to virologic failure. When toxicity cannot be confidently attributed to a single drug and is severe enough to require temporary discontinuation of therapy, all agents in the combination should be stopped (7).

        对于出现药物毒性的患者，应将相关药物替换为等效的毒副作用不同的一种或多种药物。这种替换通常在同类药物中进行，但必要时也可在等效的不同种类药物中进行。医师必须预测并尽早发现药物的毒性，因为这是导致依从差的常见原因并进而导致病毒学治疗失败。当毒性反应无法归因于某一种药物且毒性很严重而需暂停治疗时，所有的抗病毒治疗药物均需停用。

Causes of Virologic Failure

病毒学治疗失败的原因

               In patients with continued HIV replication despite antiretroviral therapy, it is essential to determine whether virologic failure is due to non-adherence, pharmacological factors, or pre-existing or acquired HIV drug resistance. This requires a detailed history of drug-taking behavior and possibly drug-resistance testing. Drug resistance testing is particularly important in patients who have been partially adherent or have received a drug to which drug resistance can emerge rapidly, such as 3TC or an NNRTI.

        对于接受抗反转录病毒治疗同时仍持续有病毒复制的患者，首先须明确病毒学治疗失败的原因，是由于依从性差、药理学因素，还是由于预先存在的或获得性的病毒耐药？这需要获得患者服药行为的详细情况，必要时还需做耐药性检测。对于服药依从性不佳的患者，或服用很快会产生耐药的药物如拉米夫定、非核苷类反转录酶抑制剂（NNRTI）的患者，耐药性检测尤为重要。

               Drug resistance testing is not necessary in patients who have not taken any of their prescribed antiretroviral drugs, and may or may not be necessary in patients who have discontinued all of their drugs simultaneously. In patients receiving a protease inhibitor-based regimen, resistance is unlikely to develop if all drugs are discontinued simultaneously. However, in patients receiving an NNRTI-based regimen, simultaneous discontinuation of all drugs may lead to prolonged exposure of the patient's virus to the NNRTI alone at subtherapeutic levels, since the two most commonly used NNRTIs – nevirapine and efavirenz – each have a much longer half-life than those of the NRTIs.

        未服用过处方上所规定的抗反转录病毒药物的患者则无需行耐药性检测；但对同时停用所有药物的患者，则情况有所不同。在接受以蛋白酶抑制剂（PI）为基础的治疗方案的患者中，同时停药产生耐药性的可能性不大，所以没有必要行病毒耐药性检测。而在接受以NNRTI为基础的治疗方案的患者中，常用的两种NNRTI奈韦拉平、依非韦仑的半衰期远长于同时应用的核苷类反转录酶抑制剂（NRTI）的半衰期，同时停药会导致患者体内的病毒暴露于治疗剂量以下的NNRTI之中，此时耐药性检测应是必要的。

Management of Virologic Failure Due to Nonadherence or Pharmacokinetic Factors

由依从性差或药理学因素导致病毒学治疗失败的处理

               The absence of detectable drug resistance in a patient failing an antiretroviral regimen strongly suggests inadequate drug levels due either to non-adherence or interfering pharmacological factors. Decreased drug levels increase the risk for resistance, particularly if the virus is exposed to some but not all of the drugs in a treatment regimen. Decreased drug activity is often correctable by improving adherence or by modifying therapy to increase bioavailability. Strategies to improve adherence are outlined in "Initial Treatment of HIV Infection".

        在病毒学治疗失败的患者中若未检测到耐药性，则强烈提示体内药物浓度不足。这或者是由依从性差所致，或者是由其他药理因素的干扰。药物浓度的降低增加耐药性产生的风险，特别是当病毒暴露于治疗方案中某些而非全部的治疗药物时。此种药物疗效的降低可以通过增加依从性或者修改治疗方案以提高生物利用度而改善。增加依从性的策略参见《HIV感染的初始治疗》一章。

Antiretroviral Drug Resistance 

抗反转录病毒药物耐药性

               The presence of resistance to one or more of the drugs in a regimen before starting therapy is an independent predictor of virologic response to that regimen. In addition, several prospective controlled studies have shown that patients whose physicians have access to drug resistance data, particularly genotypic resistance data, respond better to therapy than control patients whose physicians do not have access to these assays. The accumulation of such retrospective and prospective data has led expert panels to recommend the use of resistance testing in the treatment of HIV-infected patients.

        治疗前体内是否存在对治疗方案中一种或多种药物的耐药毒株是预测该方案病毒学疗效的独立因素。此外，多个前瞻、对照性研究显示医师能获得其所治疗的病人耐药性资料，特别是基因型耐药资料时，病人的治疗效果要好于不能获得资料的病人。随着类似前瞻性及回顾性研究的积累，专家组推荐在治疗HIV感染的病人时采用耐药性检测。

               Drug resistance tends to be cumulative for a given individual and reliance on a single test can result in an underestimation. Thus all prior treatment history and resistance test results should be taken into account when determining a sequential regimen (4,8).

        对一个特定的病人而言，耐药性会逐渐累积，仅靠一次耐药性检测就下结论则会导致对耐药性的低估，所以在确定后续治疗方案时应参考既往所有的治疗经过及耐药性检测结果。

Management of Virologic Failure Caused by Drug Resistance

耐药性导致病毒学治疗失败后的策略

               There are several strategies for managing antiretroviral therapy in treatment-experienced patients with detectable plasma viremia and drug resistance. These include: 1) maintaining the failing treatment until clinical or immunologic progression force a change in therapy, 2) intensifying the current regimen with the addition of a single drug, or 3) changing the entire regimen. When the decision to change therapy is based on viral load determination, the viral load result should be confirmed with a second test. Clinicians have also often opted to temporarily discontinue therapy in some patients to reduce the level of resistance in an attempt to maximize the response to subsequent therapy but the risks and potential benefits of this strategy are controversial.

        经治病人出现可检测的病毒血症及耐药性时，抗反转录病毒治疗可行的策略包括：1）维持原方案直至临床或免疫学有了进展而推动治疗方案进行更换；2）在目前方案的基础上新加一种药物以强化治疗；3）改变整个治疗方案。当依据病毒载量测定决定更改治疗方案时，病毒载量测定的结果需要再次测定确认。有些临床医师倾向于在部分病人中暂停抗病毒治疗一段时间，以降低其耐药性水平，从而希望后续的抗病毒治疗能达到最佳的效果，此种策略的风险及潜在效益仍有争议。

Maintaining Treatment in Persons with Transient Low-Level Viremia

短暂性低水平病毒血症病人中的维持治疗

               Transient low-level viremia, now referred to as a "blip", is defined as the occurrence of a plasma HIV RNA level >50 copies/ml on at least one occasion followed by a subsequent measurement of <50 copies/ml. Blips occur in up to 40% of patients receiving antiretroviral therapy. The causes of blips are likely to be heterogeneous and may include a temporary decrease in drug exposure (e.g. due to decreased drug absorption, increased drug metabolism, or a change in plasma binding proteins), a temporary increase in release of virus caused by activation of the latent virus reservoir, or a higher steady state of low-level virus replication because of a weak antiretroviral regimen or pre-existing drug resistance.

        短暂性低水平病毒血症，也称作“微波（blip）”，是指至少一次血浆HIV RNA水平>50 拷贝/毫升，而紧接着下一次检查<50 拷贝/毫升。在接受抗反转录病毒治疗的患者中，高达40%的患者会出现病毒载量微波。其产生的原因不一，可能的原因包括：暂时性药物浓度减低（例如由药物吸收降低、药物代谢加快或药物的血浆结合蛋白水平改变）、潜伏病毒库激活所致的暂时性病毒释放增加、抗反转录病毒方案效力较弱或预先存在的耐药性所致的病毒复制水平略高的稳定状态等。

               Viral blips can provide therapeutic dilemmas for clinicians, however their biological significance remains unclear with conflicting data. Patients with persistently detectable low-level viremia (>50 copies/ml) have been observed to be at increased risk of virologic rebound (i.e. viral load >5,000 copies/ml with subsequent return of viral load towards baseline). Frequent blips may be associated with the accumulation of new drug-resistance mutations and the risk of frank relapse may be higher in patients receiving drugs such as the NNRTIs, to which resistance can develop by the acquisition of a single mutation. However, Isolated blips were not associated with virologic failure in a short-term study of patients receiving Zidovudine (ZDV)-Lamivudine (3TC)-indinavir. Moreover, in an intensive study of a small group of patients most blips appeared to represent normal biological and statistical variation around mean levels that are below 50 copies/ml rather than clinically significant elevations in the level of viral replication (24).

        对临床医师而言，病毒载量微波是一个治疗难题，但这种现象的生物学意义仍不明确，目前的研究资料也不统一。有观察显示具有持续性可检测水平以上的低水平病毒血症（>50 拷贝/毫升）的病人出现病毒反弹（即病毒载量>5000 拷贝/毫升，随后再次降至基线水平）的风险增加。频繁的微波可能与新的耐药突变的累积有关，在接受NNRTI治疗的病人中，频繁的微波使出现明显病毒复燃的风险增加，因为单一的突变即可导致对此类药物的全部耐药。但在一个以齐多夫定-拉米夫定-茚地那韦方案治疗的患者为受试对象的短期研究中发现，孤立的病毒载量微波与病毒学治疗失败并无相关性。此外，一个小样本病人的集中研究显示大多数的病毒载量微波更象是围绕50 拷贝/毫升以下的平均病毒复制水平的生物学及统计差异，而非具有临床意义的病毒复制水平的升高。

               A patient experiencing frequent blips should be counseled about the importance of adherence although is has been suggested that its importance is negligible (22). It may also be necessary to assess the potency, dosing schedule, and pharmacokinetics of the drug regimen, and to consider whether the patient could have pre-existing resistance to one or more of the drugs in the combination. Treatment intensification is an option for those patients believed to be at risk for virologic failure, but the selection of an additional drug may have to be made in the absence of drug susceptibility results, since most resistance assays may not be able to detect resistance when the viral load is very low.

        对出现频繁病毒载量微波的病人，医师应向其强调依从性的重要性（尽管有研究显示其作用可能微乎其微）；并需进一步评估治疗方案的效力、药物剂量、药代动力学、是否在治疗前即存在对用药方案中一种或多种药物耐药的毒株。对于有可能出现病毒学治疗失败的患者，可以选择强化治疗方案，但新治疗药物的选择只能在没有药物敏感性资料的情况下作出决定，因为在病毒载量较低时大多数耐药性检测都得不出阳性结果。

Maintaining Treatment in Persons with Persistently Elevated Plasma HIV RNA Levels

血浆HIV RNA水平持续升高的患者中的维持治疗

               It is often possible to select a second completely suppressive regimen for patients experiencing their first virologic failure. However, because patients with more treatment experience are less likely to respond fully to a new regimen, many clinicians base their changes on the patient's clinical and immunologic status and the extent, rather than the presence, of virologic failure. Even a partial virologic response can increase CD4 counts and substantially decrease the rate of clinical progression. Many patients with virologic rebound also continue to maintain elevated CD4 counts — a phenomenon of unknown durability that has been referred to as RNA-CD4 discordance.

        经历初次病毒学治疗失败的病人常有可能选择出第二个对病毒有完全抑制作用的治疗方案。但因为治疗经历越多的病人新方案完全起效的可能性越低，所以许多临床医师主要依据病人的临床及免疫学状态而不是病毒学治疗失败的表现来决定是否更改治疗方案。即使有部分抗病毒效果也可以使CD4淋巴细胞计数升高并显著降低疾病临床进展的速度。许多出现病毒载量反弹的病人仍可以继续维持CD4淋巴细胞计数在较高的水平，这种现象称为RNA-CD4不一致，其持续期目前尚不清楚。

               Physicians may be hesitant to change therapy in patients with stable CD4 counts despite detectable viremia because of the risk of new toxicities, adverse reactions, or new problems with adherence. However, patients with ongoing viremia on failing therapy may develop higher levels of resistance to the drugs in their regimen and cross-resistance to other drugs within the same class. If resistance testing indicates that options are available to fully suppress HIV replication, then a change in therapy is indicated as early as possible (13). However, if few or no active drugs are available, it may be most appropriate to continue current therapy while weighing the patient's prognosis, the degree of HIV resistance, and the prospect of new drug availability to determine whether the benefit of RNA-CD4 discordance outweighs the risk of additional resistance. It may not be appropriate to use NNRTIs in any non-suppressive regimen, in part because most of the cohorts in whom RNA-CD4 discordance has been described have been receiving protease inhibitor-based therapy.

        对于出现可检测的病毒血症而CD4淋巴细胞计数稳定的病人，临床医师可能不愿主动去更改治疗方案，因为新方案可能有新的毒性、副反应，或者出现新的依从性问题。但若仍继续原来无效方案，随着病毒水平的持续升高，病人对原方案中药物的耐药性也会增加，并对其同类药物产生交叉耐药。如果耐药性检测显示有可能组成对病毒有完全抑制作用的新方案，就尽快更改方案。若耐药性检测显示没有或仅有少数敏感药物可供使用，则可以继续目前治疗方案，同时仔细权衡病人的预后、病毒耐药程度以及获得新治疗药物的机会来决定RNA-CD4不一致的益处与产生额外的耐药性的风险孰轻孰重。任何一种对病毒未完全抑制的方案都不应再使用NNRTI，部分是因为在大多数观察到RNA-CD4不一致现象的研究队列中使用的均是以蛋白酶抑制剂为基础的治疗方案。

Intensification

强化治疗

               Intensification is the addition or substitution of a single antiretroviral agent to a regimen on which a patient has measurable viremia. It has been studied primarily in heavily treated patients with established virologic failure and plasma HIV RNA levels >1,000 copies/ml. Intensification should be considered for patients with low-level plasma viremia, in whom either resistance testing or low plasma HIV RNA levels suggest that most of the administered drugs are still active. For example, patients who have developed the 3TC-associated mutation M184V may have low-level viremia on 3TC-containing regimens without developing resistance to other components of the regimen. Blind intensification (i.e. without resistance testing) is necessary in patients with low viral loads (e.g. <1000 copies/ml), in whom resistance testing often cannot be obtained, but should be avoided in patients failing therapy with higher viral loads, since resistance testing in these patients can provide specific information about resistance to the drugs in the failing regimen.

        强化治疗是指在病人接受抗反转录病毒治疗出现可检测到的病毒血症时,在原方案的基础上增加或替换某一抗反转录病毒药物。这项研究最初针对经过反复治疗后出现明确病毒学治疗失败且血浆HIV RNA>1000拷贝/毫升的患者。目前，应考虑强化治疗用于具有低水平病毒血症的病人，在此类病人中，无论是耐药性检测还是低血浆HIV RNA水平均提示以往方案中的大多数药物仍有效。例如，具有拉米夫定相关的耐药突变M184V的病人接受含有拉米夫定的治疗方案时会有低水平病毒血症，但并不会产生对方案中其他药物的耐药性。盲法强化治疗（即无耐药性检测结果）在低病毒载量（如<1000拷贝/毫升）的病人中是必需的，因为在此类病人中常无法获得耐药性检测的结果。而在高病毒载量的治疗失败的病人中，应避免使用盲法强化，因为在这些病人中耐药性检测可以提供对失败方案中药物的耐药性的详细资料。

               If intensification proves ineffective, it can lead to resistance not only to the drugs in the original regimen, but also to the drug used for intensification. To minimize this risk, clinicians should avoid adding drugs that would be key components of future regimens, such as drugs from entirely new classes. Intensification is usually considered only in two situations, neither of which is associated with extensive resistance: (i) HAART has recently been initiated and plasma HIV RNA levels have decreased but remain detectable; (ii) a patient has developed low-level virologic rebound after having already achieved an undetectable viral load. In these situations, drug resistance, if present, is likely to be minimal, and usually affects only one component of the regimen.

        强化治疗若无效，则可能导致毒株对原方案中药物及新加药物的耐药。为了使这种风险降至最低，临床医师在进行强化治疗时应避免使用在未来的治疗方案中可以起关键作用的药物，例如一种完全不同种类的药物。强化治疗通常在无广泛耐药产生的两种情况下考虑使用，包括：1）刚开始HAART治疗，血浆HIV RNA水平已经降低，但仍在可检测水平以上；2）病人在将病毒载量控制在可检测水平以下后出现低水平的反弹。在这些情况下，如果出现耐药性，通常都是轻微的，且仅涉及到治疗方案中的一种药物。

               Most studies of intensification have involved the addition of a third NRTI or tenofovir DF to a HAART regimen already containing two NRTIs, or the addition of a second protease inhibitor to a HAART regimen already containing one protease inhibitor. Intensifying a protease inhibitor-based regimen with an NNRTI or vice versa has not been studied and is generally not advised. The most commonly studied NRTIs used for intensification are abacavir and tenofovir. Abacavir has been shown to mostly benefit NRTI-experienced patients with limited resistance to NRTIs. It is notably highly effective for patients who have a dominant virus with only the M184V mutation (16). Intensification of partially suppressive regimens with tenofovir can achieve both a sustained virologic response and reduction in the emergence of new resistance mutations (21,23,26). When used as a single protease inhibitor, indinavir is associated with wide variations in Cmax and Cmin, and intensification with ritonavir, a potent inhibitor of cytochrome P450, in patients on long-term indinavir regimens has been shown to improve virologic response. With the exception of nelfinavir, all available PIs should be pharmacologically enhanced with ritonavir boosting, providing consistently higher drug levels over the dosing interval (4, 5, 7).

        强化治疗的大多数方案涉及到在含有两种NRTI的HAART方案中加用第3种NRTI或替诺福韦（tenofovir TDF），或在含有一种蛋白酶抑制剂的HAART方案中加用第二种蛋白酶抑制剂。对在以蛋白酶抑制剂为基础的治疗方案中加用NNRTI或者在以NNRTI为基础的治疗方案中加用蛋白酶抑制剂则尚未有过研究，通常也不建议使用。最常见的应用于强化治疗的NRTI是阿巴卡韦和替诺福韦。研究显示阿巴卡韦对接受过NRTI治疗且仅对其有限耐药的病人益处最大，特别是对于以仅含有M184V耐药突变的病毒株为主的病人。对病毒仅有部分抑制作用的方案应用替诺福韦进行强化治疗可以获得持续的病毒学应答，并减少新耐药突变的产生。作为单一的蛋白酶抑制剂使用时，茚地那韦的Cmax及Cmin变异很大，而当应用作为一种有效的细胞色素P450酶抑制剂的利托那韦（ritonavir）进行强化治疗时，长期接受茚地那韦方案治疗的病人的病毒学疗效有改善。除了奈非那韦（nelfinavir），目前所有可用的蛋白酶抑制剂都应使用利托那韦强化，以使在给药间隔内仍维持较高的药物浓度。

Choosing a New Regimen

选用新方案

               Before the widespread use of resistance tests, it was commonly assumed that virologic failure signaled resistance to all drugs in the regimen. However, several recent clinical trials have shown that most patients developing virologic failure on their first HAART regimen usually have resistance to only one of the drugs in the regimen, usually those with the lowest genetic barrier to resistance. A resistance test, which should be performed while patients are still on the failing regimen or within 4 weeks after regimen discontinuation (4), can help determine which drugs are no longer likely to be effective and which may retain antiretroviral activity.

        在耐药性检测广泛应用以前，通常的假设是病毒学治疗失败预示对方案中的所有药物产生耐药。但近期多个临床研究表明对首个HAART方案出现病毒学治疗失败的病人通常仅对原方案中抵御耐药的能力最差的一种药物耐药。耐药性检测应该在病人仍在使用原方案或停药后4周内进行，以帮助确定何种药物可能无效，而何种药物仍敏感。

               The standard approach to managing virologic failure to an initial HAART regimen is to use at least two or three new drugs, including at least one drug belonging to a new class (4, 7). The relative lack of resistance in patients with early virologic failure on their first HAART regimen suggests that a less complete change in therapy may be possible. The DHHS guidelines currently advise that a single drug substitution (made on the basis of resistance testing) can be considered, but is unproven at this setting. When resistance to and toxicity of NRTIs or NNRTIs limits the availability of non-protease inhibitor drugs, use of a double-boosted PI (2 active PIs and low-dose ritonavir) has been proposed for study, without much available data (2, 7).

        病毒学治疗失败后组成新的HAART方案的标准方法是采用至少两个或三个新药物，其中至少包括一种新的药物种类。病人接受初次HAART方案早期出现病毒学失败后耐药性相对较少，这就提示不一定要彻底改变原方案。DHHS指南目前建议在此种情况下可以在耐药性检测的基础上考虑使用单个药物替换，但尚未获得此类临床背景资料的证实。当对NRTI或NNRTI的耐药性及NRTI或NNRTI的毒性反应限制了非蛋白酶抑制剂类药物的可选择性时，有研究采用双蛋白酶抑制剂的强化治疗（两种敏感的蛋白酶抑制剂及低剂量的利托那韦），但目前相关资料不多。

               The success of salvage therapy decreases with increasing antiretroviral experience because of the high levels of cross-resistance within each of the three drug classes. Preliminary data suggest that patients switching from one dual NRTI combination will generally have some virologic response as long as high-level resistance to the first combination has not yet emerged. Because of the high-level of cross-resistance between ZDV and d4T, it is unlikely that substituting one drug for the other will be highly effective. There appears to be less clinical cross-resistance between ddI and 3TC, and a regimen that involves the substitution of one of these drugs is likely to have some activity. Although there have been several studies describing the use of abacavir and tenofovir for intensification, there are fewer data on the use of these drugs as part of salvage therapy. Nonetheless, because of the potency of these drugs — in untreated persons, they reduce plasma HIV RNA levels by 1.5 logs — they should be considered for use in salvage therapy.

        接受多重抗反转录病毒治疗的病人常有对三类抗反转录病毒药物每一类中都存在高度交叉耐药性，从而使挽救性治疗的成功率降低。目前的资料显示接受含两种NRTI方案治疗的病人只要没有产生高度耐药性，挽救性治疗将都会有一定的病毒学治疗效果。齐多夫定和司他夫定之间存在高度交叉耐药性，所以两者之间的替换通常无效。而临床上去羟肌苷和拉米夫定之间的交叉耐药性较少，所以由两者相互替换的方案可能有一定的治疗作用。尽管多个研究显示了阿巴卡韦和替恩夫韦在强化治疗中的作用，但关于两者在挽救性治疗方案中的作用目前的资料仍较少。因为两者都有抗反转录病毒作用（在未治疗的病人中，阿巴卡韦和替恩夫韦可以使血浆HIV RNA水平下降1.5log值），所以应当考虑用于挽救性治疗方案。

               Because of the high-level of cross-resistance within the NNRTI class, patients developing virologic failure during treatment with one NNRTI are unlikely to benefit from any of the other currently available NNRTIs. However, the NNRTI efavirenz has proved to be useful in the salvage of NNRTI-naïve patients.

        因为NNRTI之间存在高度交叉耐药性，所以接受含有一种NNRTI的方案治疗的患者出现病毒学治疗失败后不太可能从含有目前已有的另一种NNRTI的方案中获益。研究显示依非韦伦在未接受过NNRTI治疗的患者的挽救性治疗中有仍一定的作用。

               For patients who have multiple genotypic resistance mutations in the NRTI and PI classes, a phenotypic resistance test should be considered. The phenotypic resistance test measures the ability of the virus to grow in the setting of different concentrations of drug and can show which antiretroviral agents may have relatively more activity. For example, patients in whom nelfinavir-resistant isolates arise after nelfinavir therapy often respond to a regimen containing another protease inhibitor, because D30N, the most common nelfinavir-resistance mutation, confers little cross-resistance to other protease inhibitors. However, because as many as 15%-25% of nelfinavir failures may be associated with other mutations, including L90M, which is associated with protease inhibitor cross-resistance, virologic failure on nelfinavir does not guarantee susceptibility to other protease inhibitors. Enfuvirtide or T-20 (Fuzeon), the first of fusion inhibitors, has received FDA approval. T-20 has been shown to have potent antiretroviral activity in both phase I, II, and III clinical trials (17,19,27). Adverse reactions associated with T-20 include injection site reactions following subcutaneous administration. The optimal time to initiate T-20 is when a strong and sustained virological response can be predicted on the basis of treatment history, resistance data and viro-immunological parameters, and is best considered at the time of the second, third, or fourth failure, depending on the number of active drugs that remain as options. Maximum sustainable response may best be achieved in patients whose virus retains at least partial activity to two drugs or more, ideally from different antiretroviral classes, and who present with CD4>100 and VL<105. The availability of only a single agent deemed active should not be considered a contraindication for T-20 use. Weighing the risks and benefits of using a single active drug in the heavily treatment-experienced patient is complicated, and consultation with an expert is advised (1,7).

        对于有多个耐NRTI及蛋白酶抑制剂的耐药基因突变的患者，应当考虑表型耐药性检测。表型耐药性检可测衡量病毒在不同浓度药物水平下的复制能力，可以用来比较哪种药物的抗反转录病毒活性相对更强。例如，从接受含有奈非那韦方案治疗的病人体内分离出的耐奈非那韦病毒株常在此方案下载量上升，但此病毒株对含有其他蛋白酶抑制剂的方案敏感，因为奈非那韦最常见的耐药基因突变D30N对其他蛋白酶抑制剂很少有交叉耐药性。但15%-25%的奈非那韦治疗失败病例是由其他类型的基因突变包括L90M所致，这些耐药突变对其他蛋白酶抑制剂有交叉耐药性，此时再应用其他含有蛋白酶抑制剂的方案治疗则可能无效。恩夫韦地（Enfuvirtide）又称作T-20（Fuzeon）是第一种融合抑制剂，已被FDA批准上市。在I、Ⅱ、Ⅲ期临床试验中，T-20均显示出有效的抗反转录病毒活性。其副作用包括皮下注射后注射部位的局部反应。T-20治疗最好在预计病毒可以得到强有力的、持续抑制的时候开始，这一点可以依据既往治疗史、耐药性资料及病毒学-免疫学指标等来判断。依据其它可选择的敏感药物的数量，可以在第2次、第3次或第4次治疗失败时开始T-20治疗。若病人CD4>100 或VL<10⁵，治疗方案中还有两种或以上至少部分敏感的药物（最好是分属不同的抗病毒药物种类），则可以认为此治疗方案达到了最大程度的持续抑制病毒作用。但仅剩一种敏感药物可用也不是T-20使用的禁忌证。在已接受过大量抗病毒治疗的患者中权衡使用单一敏感药物的风险和获益较为复杂，最好征求专家意见。

[Review Article: Cooper DA, Lange JM. Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development. Lancet Infect Dis. 2004 Jul;4(7):426-36.]

               In patients infected with highly multidrug-resistant viruses, the durability of response is usually brief. However, sustained antiviral responses have been observed when T-20 is combined with at least one other active antiretroviral drug. Because of its expense—it has been priced at $20,000 per year—and its requirement for subcutaneous administration, T-20 is used only for salvage therapy.

        有高度多重耐药病毒感染的病人，治疗效果的维持通常很短暂。而T-20与另外至少一种敏感药物合用可以获得持续的抗病毒治疗效果。但因其价格昂贵（20,000美元/年）而且必须通过皮下注射给药，所以目前T-20仅用于挽救性治疗方案。

               Using a single active antiretroviral drug in a new salvage regimen is not recommended because of the risk of rapidly developing resistance to that drug. However, in patients with advanced HIV disease with a high likelihood of clinical progression, adding a single drug may reduce the risk of immediate clinical progression. Weighing the risk (e.g., selection of drug resistance) and benefits (e.g., antiretroviral activity) of using a single active drug in the heavily treatment-experienced patient is complicated, and consultation with an expert is advised (4).

        不推荐在新的挽救性治疗方案中仅采用一种敏感药物，因为有可能很快出现对该药的耐药性。但对于极易出现临床进展的病情严重的HIV患者，增加一种敏感药物可能降低临床迅速进展的风险。在接受过多种抗病毒治疗的患者中权衡这种使用单个敏感药物的风险（如耐药性的发生）和收益（如抗反转录病毒效果）非常复杂，需征求专家意见。

               The success of multi-drug rescue therapy, or "mega-HAART", in patients who have failed several prior antiretroviral drug regimens and have multidrug-resistant HIV strains is limited by large pill burdens and poor adherence, toxicity and pharmacological interactions. Dual protease inhibitor regimens should also be avoided for these same reasons (7).

        在既往多次抗反转录病毒治疗失败并存在多重耐药病毒株的病人中应用多药联合补救治疗（mega-HAART）的成功率，因服药剂量大、依从性差、药物毒性及药理学上相互作用而使得疗效受限。鉴于此，即使是多药联合补救的目的，双蛋白酶抑制剂的方案也应避免使用。

Treatment Interruptions in Patients with Persistent Viremia

持续性病毒血症的患者的间断治疗

               When faced with untreatable drug resistance, many physicians and patients have elected to stop therapy prior to initiating a salvage regimen, presumably to allow replacement of highly resistant virus with wild-type virus. Although this approach has been shown to be beneficial in some studies (4, 11), re-treatment of such patients with drugs to which they were once resistant rapidly selects for the re-emergence of resistant virus. Treatment interruption has been associated with greater disease progression and did not confer immunologic or virologic benefits or improve the overall quality of life and is therefore not recommended (4,7,17,18,25).

        当面对无法治疗的耐药性时，许多医师及病人选择在开始挽救性治疗方案前停止治疗一段时间，以期让野生病毒株取代高度耐药的病毒株。某些研究显示这种策略有一定的效果，但此类病人一旦接受其以前耐药的药物治疗后，将很快再次筛选出耐药病毒株。间断治疗可导致更严重的疾病进展，而并未能获得免疫学或病毒学疗效，也不能改善生活质量，所以不推荐使用。

Recently Approved and New Drugs

最近获批的药物及新药

               Recently approved drugs that can be considered in treatment-experienced patients include the fusion inhibitor enfuvirtide (see above), and the protease inhibitors atazanavir, tipranavir and darunavir. Atazanavir has a unique resistance profile and does not increase lipids. Although in patients with high level resistance to other PIs, susceptibility to atazanavir is often reduced (9), recently published 48-week results show that in a moderately treatment experienced population, ritonavir-boosted atazanavir appeared comparable to lopinavir plus ritonavir with advantages on lipid changes and pill burden (7).

        最近获得批准的，可考虑在经治病人中应用的药物包括：融合抑制剂恩夫韦地（见上），蛋白酶抑制剂阿扎那韦、替拉那韦 和达如那韦。阿扎那韦具有独特的抗耐药毒株的能力，并且不增加脂质代谢紊乱。而在对其他蛋白酶抑制剂高度耐药的病人中，阿扎那韦的敏感性通常也降低。最近发表的一个48周的研究显示，在接受过中等强度的抗反转录病毒治疗病人中，利托那韦强化的阿扎那韦与利托那韦强化的洛匹那韦在减少脂质代谢紊乱及降低药物负荷方面的优势相当。

               Tipranavir and darunavir (formerly TMC-114) are the two newest protease inhibitors, used only with ritonavir-boosting, designed to have activity against multi-PI-resistant virus. Studies using tipranavir or darunavir in patients with PI-, NNRTI-, and NRTI-class failures showed greater HIV-1 RNA and CD4 cell count responses compared with another PI in optimized background regimens. The responses to either drug were doubled if one of the agents in the background regimen was enfuvirtide, in patients who had not taken enfuvirtide in the past. The percentage of patients achieving viral load below 50 copies/mL was as high as 36% for tipranavir (Farthing et al. 46th ICAAC abstract H-1385) and 60% for darunavir, if enfuvirtide was also used (3,10).

        替拉那韦和达如那韦(以前称为TMC-114)是两种最新的蛋白酶抑制剂，需在利托那韦增效下使用，对多蛋白酶抑制剂耐药的病毒株有抗病毒活性。在对蛋白酶抑制剂、NNRTI及NRTI耐药的病人中应用替拉那韦或达如那韦均较另一种目前可选的最佳的蛋白酶抑制剂取得了更明显的HIV-1 RNA抑制及CD4淋巴细胞计数升高。在既往未使用过恩夫韦地的病人中，若抗病毒方案中同时含有恩夫韦地，则替拉那韦或达如那韦的治疗效果均可增加一倍。若与恩夫韦地合用，替拉那韦治疗的病人中血浆病毒载量降至50拷贝/毫升以下者占36%，而达如那韦为60%。

               These encouraging results, that are presumably due to improved - yet unique - resistance profiles of these new medications, raise the possibility that the highly-experienced patient population may also be likely to achieve complete viral suppression if medications are chosen carefully. Side effects to tipranavir include nausea, diarrhea, hyperlipidemia and liver enzyme elevations, particularly in patients with hepatitis B or C coinfection. Patients with advanced liver disease should not use tipranavir. Fatal and nonfatal intracranial hemorrhage has been reported among patients taking tipranavir. Side effects to darunavir include nausea and diarrhea.

        这些鼓舞人心的结果可能与这些新药的独特的抗病毒的耐药性有关，这提示对于高度耐药的病人，若仔细挑选适合的药物，也有可能达到完全的病毒抑制。替拉那韦的副作用包括恶心、腹泻、高脂血症及肝酶升高（特别是在合并乙型或丙型肝炎病毒感染的患者中）。晚期肝病的患者不应使用替拉那韦。服用替拉那韦的病人有过致命性及一般性颅内出血的报道。达如那韦的负作用包括恶心和腹泻。

               New drugs and drug classes that are being studied include etravirine, for NNRTI-resistant virus, integrase inhibitors, and CCR5 inhibitors, all of which are in advanced stages of clinical development. The integrase inhibitor MK-0518 shows particular promise and lack of toxicity among treatment-experienced patients (6,20). In summary, an increasing number of new regimens will become available for use relatively soon, and together with the recently approved new PIs are very likely to improve the outcomes of treatment for the highly treatment experienced patient.

        目前正在研究的新药及新的药物种类包括etravirine（针对耐NNRTI的病毒）、整合酶抑制剂及CCR5抑制剂。这些药物都处在临床试验的末期阶段。整合酶抑制剂MK-0518在经治病人中显示了良好的前景及极少的毒性反应。综上所述，越来越多的新型治疗方案在不久的将来可望应用于临床，结合近期被批准的蛋白酶抑制剂，极有可能改善高度耐药的病人的治疗效果。

Acknowledgement

               We thank Andrew Zolopa and Joel Gallant for their past contributions to this chapter.