人免疫缺陷病毒-1（HIV-1）感染的初次治疗

This is an overview of initial treatment of HIV-1-infected adults with combination antiretroviral therapy (CART). We have focused on some of the major considerations which govern decision making as to when to commence CART and what to start with. The latter should always take into account other co-morbidities which may negatively affect the likelihood of success through non-adherence, exacerbation of antiretroviral-related toxicities, predisposition to well described toxicities e.g. nevirapine hepatotoxicity and higher CD4+ T-cell count and clinical status e.g. pregnancy. Although this chapter will discuss important considerations in the use of antiretroviral therapy in HIV-infected women of child bearing potential, an in-depth review of the management of HIV in pregnancy and in children is beyond the scope of this review.

本文对利用联合抗反转录病毒治疗（CART）初次治疗HIV-1感染成人进行总述。重点在于指导治疗决策的若干主要问题，如何时开始CART，开始时采用何种方案等。后者需同时考虑可能对成功率产生负面影响的其他并存情况，例如依从性差、抗反转录病毒药物相关毒性的放大、和明确的药物毒性的易感性，如奈韦拉平肝毒性与高CD4+ T细胞计数及临床状态如妊娠。虽然本章会涉及在HIV感染的育龄妇女中使用抗反转录病毒治疗时需要考虑的重要问题，对妊娠期HIV感染和儿童HIV感染控制的深入探讨并不在本章的范围内。

Guideline: Hammer SM, et al. Antiretroviral Treatment of Adult HIV Infection. 2008 Recommendations of the International AIDS Society-USA Panel. JAMA 2008;300(5):555-570.

The hallmark of HIV-immunodeficiency is the inexorable depletion and dysfunction of CD4+ T-cells leading ultimately to the development of AIDS-defining illnesses and death. The mechanisms that underlie this CD4+ T-cell depletion are poorly understood but include direct loss via virus-induced lysis or synctia formation and indirect loss through enhanced immune destruction i.e. “bystander T-cell loss” (reviewed in (141)). The viral reservoir is established early and constantly replenished even when plasma viral load is maximally suppressed (25,26,42). Whilst the host does mount an anti-HIV immune response that partially controls the virus - at least early in the course of the disease – this is insufficient to eradicate the virus.

HIV免疫缺陷症的标志在于CD4+ T细胞的耗竭和功能障碍，最终导致AIDS定义疾病的产生和死亡。目前对这一CD4+ T细胞耗竭的机制知之甚少，但其中包括病毒引发溶解或合胞体形成而导致的直接丢失，以及免疫破坏增强即“旁观者T细胞丢失”（综述见(141)）而导致的间接丢失。病毒储藏库建立很早且不断更新，即使当血浆病毒载量受到最大抑制时也不例外(25,26,42)。虽然感染者体内的确会激发出抗HIV免疫应答，也能部分控制病毒（至少在疾病进程早期），这一应答尚不足以清除病毒。

In 1997, Hammer et al (62) demonstrated the first unequivocal evidence of the superiority, with respect to CD4+ T-cell increase, plasma HIV RNA decline and clinical benefit of using CART consisting of two nucleoside reverse transcriptase inhibitors (NRTI) and a protease inhibitor vs. dual NRTI. Since this time there have been numerous randomised clinical trials and many large long-term observational studies demonstrating the survival advantages that CART affords individuals with HIV infection (39,52,91,93,109,116,140). Details of these clinical studies are discussed later in this review. These benefits have been seen in CART-treated patients with both advanced immunodeficiency and asymptomatic disease (140). Although the long term benefits of CART are less well described in the developing world, as large prospective cohorts have only been set up relatively recently (31), all the indications point to rates of AIDS defining illness decline with CART use which are equivalent to those in the developed world (38,130).

1997年，Hammer等(62)首次以明确证据表明，使用含有两种核苷类反转录酶抑制剂（NRTI）和一种蛋白酶抑制剂的CART，在CD4+ T细胞增加、血浆HIV RNA下降和临床收益等方面都优于含两种NRTI的CART方案。此后，有大量随机临床试验和大型长期观察性研究均证实了CART对于HIV感染者存活的作用(39,52,91,93,109,116,140)。这些临床研究的具体情况本文将稍后讨论。无论是进展期免疫缺陷症患者还是无症状患者，接受CART治疗均有获益(140)。虽然发展中国家对于CART长期作用的研究较少（大型前瞻性队列研究仅在相对近期开始(31)），目前结果表明使用CART可使AIDS定义疾病的发病率下降，与发达国家是一致的(38,130)。

Immune restoration with CART can result in resolution of intercurrent infections e.g. cryptosporidiosis, and improvement in outcomes for other AIDS defining illness for which no specific therapies exist i.e. progressive multi-focal leukoencephalopathy and AIDS dementia complex (14). Moreover, the increase in absolute CD4+ T-cells allow the subsequent withdrawal of primary and secondary prophylaxes against opportunistic infections (OI) with very little risk of disease recrudescence (90). However, in patients starting CART very late in the course of their HIV infection, several immune abnormalities persist (>3 years) despite partial normalisation of peripheral CD4+ T-cell count (reviewed in (81, 82). These abnormalities include a persistent narrowing of the T-cell receptor (TCR) repertoire, dysregulation of CD4+ T-cell cytokine production and dysfunction of antigen-presenting cells including abnormal intracellular killing of pathogens by effector macrophages. The quality of the immune restoration is always poorer and the degree of immune dysregulation greater in patients starting CART at CD4+ T-cell counts less than 200 cells/µL compared to those starting at higher levels. This factor may go part way to explaining why patients starting CART at low CD4+ T-cells counts always have a higher risk of HIV disease progression than those starting with counts ≥200 cells/µL, even though the risk is substantially reduced in both groups. In patients with CD4+ T-cells <100 cells/µL starting CART with or without an active OI there is also a risk of immune restoration disease (reviewed in (114)) and in those being concurrently treated for an active OI, the added problem of drug-drug interactions. The latter is particularly problematical when patients are being treated for mycobacterial disease with rifamycins (14). Collectively, these arguments support a view that treatment should be initiated relatively early in HIV disease before profound immunodeficiency and the onset of symptomatic disease.

CART带来的免疫重建能缓解隐孢子虫病等并发感染，并改善其他尚无特定治疗的AIDS定义疾病的预后，如进行性多灶性白质脑病和AIDS痴呆综合征(14)。此外，CD4+ T细胞绝对计数的增加，允许其后在疾病复发风险很小的情况下停止针对机会性感染（OI）的初级和二级预防(90)。然而，对于那些HIV感染很晚期才开始CART的患者而言，即使外周血CD4+ T细胞计数部分正常化，某些免疫异常也仍然持续存在（>3年）（综述见(81, 82)）。这些异常包括，T细胞受体(TCR)库的持续缩窄、CD4+ T细胞细胞因子产生障碍，以及抗原提呈细胞的功能障碍，包括效应巨噬细胞对病原体的胞内杀灭异常。CD4+ T细胞计数低于200细胞/µL才开始CART的患者与计数水平较高时开始治疗的患者相比，其免疫重建的质量始终较低，免疫失调的程度也更严重。这一因素可以部分解释，虽然在两组人群中HIV疾病进展的风险都显著降低，低CD4+ T细胞计数开始CART的患者HIV疾病进展的风险为何仍高于计数≥200 细胞/µL开始治疗的患者。对于伴有或不伴有活动性OI、CD4+ T细胞数<100细胞/µL开始CART的患者而言，还有发生免疫重建疾病的风险（综述见(114)），而对于那些同时接受活动性OI治疗的患者而言，又增加了药物间相互作用的问题。当患者接受利福霉素治疗分枝杆菌病时，该问题尤其突出(14)。总之，这些论点表明，应当在HIV疾病的相对早期、发生严重的免疫缺陷和机会性疾病之前开始治疗。

The main limitations of CART include failure to eradicate virus (43,152), the probable lack of any long-term impact on viral set-point if CART is ceased (157), and the short, medium and long-term toxicities of CART (23,44,45). Ultimately viral escape can occur due to the development of resistance (reviewed in (27)). Risk factors for treatment failure include transmitted resistance i.e. at primary infection (128) or subsequently i.e. “super-infection” (54,69,135,158), poor drug adherence (12,28,84,112), drug–drug interactions leading to sub-therapeutic levels of antiretrovirals, co-morbidities such as co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) (18,92,129) and variable potency of different CART regimens. These issues are discussed further in section 6 of this review.

CART的主要局限性包括不能清除病毒(43,152)，停止CART后可能缺乏对病毒调定点的任何长期作用(157)，以及CART的短期、中期和长期毒性(23,44,45)。由于耐药性的产生最终可能发生病毒逃逸（综述见(27)）。治疗失败的危险因素包括，原发感染(128)或随后发生如“再感染”的传播性耐药性(54,69,135,158)、药物依从性差(12,28,84,112)、药物-药物相互作用导致抗反转录病毒药物浓度低于治疗水平、共病如共感染乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）(18,92,129)，以及不同CART方案的效力差异。这些问题在本文的第六章予以详细谈论。

As described in the current Department of Health and Human Services guidelines (67) and the British HIV Association antiretroviral guidelines (68) the goals of therapy in the antiretroviral-naïve patient are to:

- achieve maximal and durable viral suppression – with an expectation that at least eighty percent of patients will have a viral load <50 copies/mL by 48 weeks (see section 4);

正如现行《卫生人类服务部指南》(67)和《英国HIV联盟抗反转录病毒指南》(68)所述，在初次抗反转录病毒的患者中治疗目的在于：

Once the decision to initiate CART has been made, the patient must be monitored closely from the perspective of their virological and immunological response, adherence and tolerability. Side-effects which necessitate a switch are those which are life-threatening or interfere significantly with the patient’s QoL. Expected declines in plasma HIV RNA level should be at least a 1 log₁₀ copies/mL after 4 weeks of therapy and patients should have viral load below the level of quantification (generally <400 copies/mL) after 4-6 months of therapy and <50 copies/mL by 48 weeks (67). However, there is a caveat in so much as intermittent plasma HIV RNA “blips” are common and appear to represent biological, sample assay and statistical variations around the mean plasma HIV RNA of <50 copies/mL rather than clinically significant elevations of plasma HIV RNA (104). Factors to consider if these milestones are not being met are primary resistance or on-treatment resistance perhaps related to poor adherence and drug-drug interactions leading to sub-therapeutic drug levels.

Guideline: Aberg JA, et al. Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2009;49:651-681.

一旦决定开始CART，应当严密监测患者的病毒学和免疫学反应、依从性和耐受性。一旦出现威胁生命或严重干扰患者生活质量的药物副作用，必须更换药物。预期治疗后4周时血浆HIV RNA水平的下降应答至少为1 log₁₀ 拷贝/mL，而治疗后4-6月时患者的病毒载量应低于定量检测下限（通常<400拷贝/mL），48周时<50拷贝/mL(67)。然而，应当注意间断的血浆HIV RNA“波动”很常见，似乎更可能是血浆HIV RNA<50 拷贝/mL附近的生物学、样品测定及统计学差异的表现，而并非出现了临床显著的血浆HIV RNA升高 (104)。如果没有达到以上治疗标准，则应当考虑如原发耐药或治疗中耐药等因素，后者可能与依从性差及药物间相互作用导致药物水平低于治疗阈有关。

Data from multiple cohort studies have irrefutably demonstrated that it is the first CART regimen which has the greatest chance of achieving durable virological suppression (34,110,117, 118) provided it is selected with due care and the factors outlined above are considered. Three-drug combinations with either two NRTI and either a protease inhibitor or non nucleoside reverse transcriptase inhibitor (NNRTI) have become the “standard-of-care” approach for HIV infection (50,56-58,62,64, 65) and it is clear that starting all three drugs simultaneously is associated with a better outcome than a staggered approach (57). The question of whether there is any advantage to using a 4 drug combination from 3 drug classes as first line therapy was addressed in both the INITIO study (30) and ACTG 384 (131) with no benefit demonstrated with the addition of a third class with respect to duration of successful HIV-1 treatment. Boosting protease inhibitors by utilising small doses of ritonavir (/r) i.e. 100 – 200 mg twice a day to increase the levels of the other protease inhibitor in the combination is not universally recommended in ART-naïve patients; The exception to this is the recommended use of Kaletra® (ritonavir boosted lopinavir) as there are data supporting its use in the naïve setting (see later). Both the Department of Health and Human Services and British HIV Association guidelines recommend the use of ritonavir-boosting in ART-experienced patients as ritonavir-boosting is an important component in increasing the area-under the curve for the primary protease inhibitor and either preventing or overcoming viral resistance (reviewed in (46)). The Department of Health and Human Services and British HIV Association guidelines make recommendations on the basis of data from properly conducted, well designed randomised clinical trials in ART-naïve patients with the caveats that:

- These results probably represent the best possible outcomes in a cohort of well selected and presumably adherent patients;

- The outcomes of the majority of these studies are based upon surrogate markers of efficacy i.e. CD4+ T-cell changes and plasma HIV RNA and not on clinical endpoint data.

众多队列研究的数据均证实，只要谨慎加以选择并考虑上述因素，首次采用的CART方案达到长期病毒学抑制的可能性最大(34,110,117, 118)。由两种NRTI类联合一种蛋白酶抑制剂或非核苷类反转录酶抑制剂（NNRTI）的三药联合方案，是HIV感染的“标准治疗方案” (50,56-58,62,64, 65)，并且已经明确，同时开始使用三种药物的临床预后好于先后添加方法(57)。至于以三类药物中的4种药物组合作为一线治疗是否更有优势的问题，在INITIO研究(30)和ACTG384(131)中均有涉及，其结果表明添加第三类药物无助于成功 HIV-1治疗所需的时间。在ART初治的患者中并不普遍推荐利用小剂量的利托那韦(/r)即100-200mg一日两次增强的蛋白酶抑制剂，以提高联合药物中其他蛋白酶抑制剂的水平；但Kaletra® (利托那韦增强的洛匹那韦)的推荐用法是例外，有数据支持将其用于初治患者（见后）。《卫生人类服务部指南》和《英国HIV联盟抗反转录病毒指南》均推荐将利托那韦增强用于ART复治患者，因为利托那韦增强是增加初级蛋白酶抑制剂曲线下面积从而防止或抑制病毒耐药性产生的重要手段（综述见(46)）。《卫生人类服务部指南》和《英国HIV联盟抗反转录病毒指南》的推荐依据是运行良好、设计合理的ART初治患者随机临床研究数据，且遵循以下前提：

- 这些结果很可能代表了由经过挑选且依次性好的患者组成队列中最好的预后可能；

- 这些研究中大部分都以有效性指标衡量预后，即CD4+ T细胞改变和血浆HIV RNA，而不是临床终点数据。

The licensed drugs are shown in Table 1. Regimens have been designated as “preferred” or “alternative” on the basis of existing efficacy and safety data (Tables 2, 3.1, 3.2). All recommended regimens have a “backbone” of two NRTI. There is further discussion regarding the choice of NRTI backbone below. The preferred regimen is always “class sparing”, i.e. preserves at least one class of widely available antiretroviral agent for future use. At present there are insufficient data to make any recommendation on the use of NRTI-sparing regimens including those using fusion inhibitors; the use of dual or triple protease inhibitors, monotherapy with ritonavir-boosted protease inhibitors, four drug combinations or induction-maintenance strategies. It is beyond the scope of this review to discuss the pharmacokinetic and side-effect profile of all available licensed drugs (Table 1), but the reader should refer to the guideline documents carefully (67, 68).

获批准的药物如表1所示。根据现有的有效性和安全性数据，将方案标记为“优选”或“备选”(表2, 3.1, 3.2)。所有推荐的方案均具有两种NRTI类的“主干”。下文中有关于NRTI主干选择的进一步讨论。优选的方案通常“不含某一类别”，即保留至少一类可广泛获取的抗反转录病毒药物以备后用。目前，尚无充分数据可对不含NRTI类药物的方案加以推荐，包括使用融合抑制剂的方案、使用两种或三种蛋白酶抑制剂、利用利托那韦增强的蛋白酶抑制剂进行单药治疗、四药联合或诱导－维持策略。讨论所有可得的获批药物的药代动力学和副作用参数(Table 1)不在本综述的范围内，但读者应当仔细参考指南文件(67, 68)。

The preferred NRTI backbone recommended in both the Department of Health and Human Services and British HIV Association guidelines is zidovudine plus lamivudine emtricitabine or tenofovir plus lamivudine or emtricitabine. In the head-to-head study of tenofovir and emtricitabine versus zidovudine and lamivudine plus efavirenz (47), the tenofovir and emtricitabine arm fulfilled the criteria for non inferiority against the comparator arm at 48 weeks. Moreover, this arm proved superior in terms of virologic suppression (84 percent vs. 73 percent with plasma HIV <400 copies/mL, p=0.002), partly explained by the better tolerability of this arm with less discontinuations. Both can be given as fixed dose combinations i.e. Combivir® (zidovudine with lamivudine) and Truvada® (tenofovir + emtricitabine); the latter is dosed qd. There has been much longer experience with zidovudine - as monotherapy in the days pre-CART - and following the widespread use of CART from 1996 onwards. As a consequence, more is know about the long-term toxicity of this drug compared to tenofovir (reviewed in (105)). The rationale for tenofovir with lamivudine being recommended is the 3 year data from the 903 licensing study for tenofovir (48). In this study, tenofovir plus lamivudine and stavudine plus lamivudine with efavirenz were equivalent at 48 weeks i.e. 80% and 84% respectively had plasma HIV RNA <400 copies/mL and this was sustained to 144 weeks. However, stavudine was associated with more dyslipdaemia and lipodystrophy. In the CNA30024 study (32), abacavir was virologically equivalent to zidovudine at week 48; CD4+ T-cells were significantly higher over the same time period (+209 vs. +155 cells/µL respectively) in those receiving abacavir. However, abacavir is listed as an alternative NRTI with either lamivudine or emtricitabine, because of the 5-8% risk of hypersensitivity associated with this drug. Abacavir may find greater utility as a first-line NRTI if patients with HLA-B*5701 can be screened out of receiving this drug in clinical practice, thereby reducing the risk of abacavir -hypersensitivity (88). Moreover, abacavir with lamivudine is now available as a fixed dose combination (Kivexa® or Epizcom®) - also given once daily and this may have advantages for adherence (100). There is an important need for a proper head-to-head comparison of Truvada® and Kivexa® with either efavirenz or a ritonavir-boosted protease inhibitor in order to determine which has the better long-term safety profile. Both drugs appear not to be associated with lipodystrophy and dyslipidaemia in the same way as the thymidine analogue NRTIs, zidovudine and stavudine (reviewed in (105)). The side-effects of lamivudine and emtricitabine appear similar – at least to date - with respect to haematological, neurological and gastrointestinal side effects; however, hyperpigmentation particularly affecting the palms and soles is reported in two percent of individuals using emtricitabine with higher rates in people of Afro-American origin. Overall, lamivudine and emtricitabine appear to be very similar in potency, patterns of resistance and safety and for this reason these drugs are considered equivalent in the guidelines (124). The factors that govern the recommended NRTI combinations in future will be the relative risks of lipodystrophy with zidovudine-based regimens; any emerging long-term side-effects of tenofovir on renal function and bone mass (3,74,106); twice daily versus once daily dosing and resistance related to the first line NRTI backbone and how this impacts on future options (148,151). The combination of stavudine and didanosine should be avoided because of unacceptable hepatoxicity and lactic acidosis particularly in pregnant women, lipodystrophy syndrome and other manifestations of mitochondrial toxicity including pancreatitis and peripheral neuropathy (73). In addition, there are emerging data that the combination of didanosine and tenofovir (and this is not recommended in the guidelines) should be avoided. The reasons for this include, the risk of toxicity associated with increased levels of didanosine, the negative impact on CD4+ T-cell levels (11, 77, 78) and early virological failure which resulted in the early closure of two clinical trials when this NRTI backbone was combined with efavirenz (85,121).

《卫生人类服务部指南》和《英国HIV联盟抗反转录病毒指南》均推荐的优选NRTI主干为齐多夫定＋拉米夫定及恩曲他滨，或替诺福韦＋拉米夫定或恩曲他滨。在替诺福韦＋恩曲他滨 v.s. 齐多夫定＋恩曲他滨＋依非韦仑(47)的平行对照研究中，替诺福韦＋恩曲他滨组在48周时的治疗效果并不差于对照组。此外，该组抑制病毒效果更好（84% v.s. 73%，血浆HIV< 400拷贝/ml，p=0.002），部分是由于该组药物耐受性较好而中断治疗者较少。两组药物均可按固定计量组合给药，即Combivir® （齐多夫定＋拉米夫定）以及Truvada® （替诺福韦＋恩曲他滨）；后者每日一次给药。不论是在CART实施前作为单药治疗，还是在1996年CART广泛使用后，齐多夫定的使用时间和经验都丰富得多。因此，相对于替诺福韦而言，对于该药物的长期毒性了解更为全面（综述见(105)）。推荐替诺福韦＋拉米夫定的依据来自903替诺福韦注册研究的3年数据(48)。该研究中，替诺福韦＋拉米夫定＋司他夫定组与拉米夫定＋依非韦仑组在48周时的效力相当，即分别有80%及84%的患者血浆HIV RNA< 400拷贝/ml，并且这一效应持续至144周。然而，使用司他夫定伴发的血脂异常和脂肪萎缩更为多见。在CNA30024研究中(32)，阿巴卡韦与齐多夫定在48周时的抗病毒效力相当；但阿巴卡韦组患者的CD4+ T细胞在同时期内显著高于齐多夫定（分别为＋209 v.s. ＋155细胞/ul）。然而，阿巴卡韦仅是作为与拉米夫定或恩曲他滨联合使用的备选NRTI药物，因为该药有5-8%引发过敏反应的风险。如果在临床实践中能筛查排除HLA-B*5701 的患者，从而降低阿巴卡韦过敏的风险，则阿巴卡韦可能作为一线NRTI而发挥更大的作用(88)。此外，目前已有固定剂量组合的阿巴卡韦＋拉米夫定产品(Kivexa® 或Epizcom®)，也是每日一次给药，这可能有助于提高患者依从性(100)。目前非常需要进行合适的平行对照试验对Truvada®和 Kivexa®与依非韦仑或利托那韦增强的蛋白酶抑制剂合用进行比较，从而确定哪种方案的长期安全性能较好。这两种药似乎都不会像胸腺嘧啶类似物NRTI类齐多夫定及司他夫定一样，引起脂肪萎缩及血脂异常（综述见(105)）。至少迄今为止，拉米夫定和恩曲他滨的副作用相似－均为造血系统、神经系统及胃肠道系统副作用；然而有报道称2%使用恩曲他滨的患者出现了手心和脚心的色素沉着，尤其在美洲黑人患者中发生率较高。总体而言，拉米夫定和恩曲他滨的药物效力、耐药类型及安全性能非常相似，因此指南认为这些药物相当(124)。未来影响推荐NRTI组合的因素主要为：基于齐多夫定方案出现脂肪萎缩的相对风险；替诺福韦对肾功能和骨髓的任意长期副作用(3,74,106)；每日两次与每日一次服药的取舍；以及对一线NRTI主干的耐药及其对未来选择的影响(148,151)。应当避免使用司他夫定和去羟肌苷的组合，因为其可能引发严重的肝毒性和乳酸酸中毒（特别是妊娠妇女）、脂肪萎缩综合征以及其他线粒体毒性的表现，包括胰腺炎和外周神经病(73)。此外，有数据说明也应当避免去羟肌苷和替诺福韦的组合（指南中并未推荐）。其原因包括，去羟肌苷水平增高而引发毒性的风险、对CD4+ T细胞计数水平的不良影响(11, 77, 78)以及早期的病毒学失败，后者导致了两项使用该NRTI主干与依非韦仑联用的临床研究的提前终止(85,121)。

The Department of Health and Human Services and British HIV Association guidelines recommend an NNRTI- or protease inhibitor-based regimen as the best choice in ART-naïve patients without making any particular recommendations in favour of either class (Table 2 and 3.1). Original concerns about the potency of NNRTI as first line treatment particularly in patients with high plasma HIV RNA have not been borne out by clinical trials, where if anything they have usually out-performed – in terms of efficacy - the comparator protease inhibitor especially if this was not boosted with ritonavir. The preferred protease inhibitor, is ritonavir-boosted lopinavir (lopinavir/r or Kaletra®) - due largely to there being more data from randomised clinical trials using this ritonavir-boosted protease inhibitor. The preferred NNRTI is efavirenz. The latter is preferred over nevirapine because of a more favourable toxicity profile with respect to rash and hepatitis (especially in those co-infected with hepatitis viruses) (24,89). Moreover, there are some data indicating an increased likelihood of these toxicities with the use of nevirapine if CD4+ T-cell counts are higher than 400 cells/µL for males and >250 cells/µL for females (13,83,144,145). For this reason nevirapine should not be used in patients with CD4+ T-cells counts above these thresholds. Efavirenz has the disadvantage of CNS toxicities leading to insomnia, poor concentration, vivid dreams and vertigo in some individuals. In addition, the drug has been reclassified by the FDA as a category D drug in pregnancy and therefore must be avoided in women of childbearing potential who are planning pregnancy (142).

《卫生人类服务部指南》和《英国HIV联盟抗反转录病毒指南》推荐使用基于NNRTI或蛋白酶抑制剂的方案作为ART初治患者的最佳选择，但并未特别推荐其中某一类(表2和3.1)。对NNRTI作为一线治疗方案的效力（特别是对于血浆HIV RNA载量高的患者）的顾虑并未得到临床试验的证实，NNRTI组的效力通常强于对照的蛋白酶抑制剂组，尤其是当后者缺乏利托那韦增强时。优选的蛋白酶抑制剂是利托那韦增强的洛匹那韦(洛匹那韦/r或Kaletra®)－主要是由于来自使用该利托那韦增强的蛋白酶抑制剂的随机临床试验数据更多。优选的NNRTI为依非韦仑。后者比奈韦拉平优选，因为其引发皮疹及肝炎（尤其是对于共感染肝炎病毒者而言）等毒副作用优于奈韦拉平(24,89)。此外，一些数据表明，若男性CD4+ T细胞计数大于400细胞/ul，而女性大于250细胞/ul，使用奈韦拉平出现上述毒性的可能性更大(13,83,144,145)。因此，不应在CD4+ T细胞计数大于上述阈值的患者中使用奈韦拉平。依非韦仑具有CNS毒性，在某些个体中可能导致嗜睡、注意力分散、多梦及眩晕。此外，该药已被FDA重新划分为妊娠期D类药物，因此在计划妊娠的育龄妇女中应避免使用(142)。

The choice between an NNRTI and boosted protease inhibitor remains largely a matter of opinion although more efficacy data exists for NNRTI-based regimens. The major drawback of the NNRTI class is the low genetic barrier to resistance and cross resistance, such that non-adherence will be associated with the development of resistance and the potential loss of all of the drugs in this class for future use (75,80,111). However, in adherent patients, NNRTI-based combinations have proven long-term durability (48). In favour of efavirenz is the once daily dosing, the very low pill burden (one pill) and it’s relative “lipid friendly” profile compared to most boosted protease inhibitor including Kaletra®. On the other hand, ritonavir boosted protease inhibitors generally have a higher genetic barrier to resistance with less likelihood of developing resistance in those with poorer antiretroviral adherence (9,10). The downside is their well known association with gastrointestinal side effects, dyslipdaemia and lipodystrophy (23,24), generally higher pill burden and until recently, their requirement for at least bid dosing. Ritonavir-boosted atazanavir, which has many of the attributes that favour the use of NNRTI (lipid friendly profile, low pill burden and dosed once daily) without the low genetic barrier to resistance, is not the preferred boosted protease inhibitor in either set of guidelines. This is probably due to the relative paucity of data on boosted atazanavir in this setting. At the present time this protease inhibitor is only licensed in its unboosted form in antiretroviral therapy naïve patients. The exception is when atazanavir is administered with a tenofovir-containing NRTI backbone because tenofovir lowers the levels of unboosted atazanavir and in some cases atazanavir levels may become subtherapeutic (6).

虽然更多的有效性数据支持使用基于NNRTI的方案，对NNRTI及增强的蛋白酶抑制剂的选择仍是见仁见智。NNRTI类的主要缺陷在于其对耐药性和交叉耐药性的遗传屏障低，因此依从性差会导致耐药性的产生，并可能导致所有该类药物将来都不能使用(75,80,111)。然而，对于依从性好的患者而言，基于NNRTI的药物组合具有长期耐受性(48)。依非韦仑的好处在于其每日一次用药、药片负荷很低（一片），以及该药相对于大多数增强的蛋白酶抑制剂包括Kaletra®，对脂质的影响相对较小。另一方面，利托那韦增强的蛋白酶抑制剂一般都具有较高的耐药性遗传屏障，在抗反转录病毒药物依从性不好的患者中产生耐药性的可能性较低(9,10)。其缺点在于众所周知的胃肠道副作用、血脂异常及脂肪萎缩(23,24)、通常较高的药片负荷，及其直到最近为止每天至少两次用药。利托那韦增强的阿扎那韦具有NNRTI类的多种优势（对脂质影响小、低药片负荷及每日一次用药），且对于耐药的遗传屏障不低，却不在任一指南优选的增强型蛋白酶抑制剂之列。这可能是由于增强的阿扎那韦相对缺乏此类情况的数据。目前该蛋白酶抑制剂仅获批以未增强的形式用于初次抗反转录病毒治疗的患者。但当阿扎那韦与含替诺福韦的NRTI主干联用时除外，因为替诺福韦会降低未增强的阿扎那韦的水平，从而使得某些情况下阿扎那韦的水平可能低于治疗水平(6)。

The Gilead 903 study (48) has raised the bar in terms of expected efficacy and safety outcomes in first line CART over several years of follow-up. None of the other prior randomised studies using efavirenz have performed as well, however, differences in study design need to be taken into consideration when interpreting cross study comparisons. A summary of the randomised studies exploring the use of NNRTI is presented below:

- Efavirenz vs. various unboosted protease inhibitors (i.e. indinavir (IDV, Crixivan^®), atazanavir) plus an NRTI backbone (136,137) showed that 64% (136) and 70% (137) of patients had undetectable plasma HIV RNA (<400 copies/mL) at 48 weeks;

- The 2NN (145) was an important multicentre, open-label trial study in antiretroviral naive individuals (n=1216). This study showed, that nevirapine was equivalent to efavirenz over 48 weeks and there was no virological benefit in combining the two drugs in one regimen. Efavirenz only outperformed nevirapine in patients with very low CD4+ T-cell counts. Patients with baseline plasma HIV RNA >100,000 copies/mL were 1•63 times more likely to experience virological failure than those with plasma HIV RNA <100,000 copies/mL; there was no difference between efavirenz and nevirapine in this respect.

- In ACTG 5095 (59), efavirenz with an NRTI backbone of either Trizivir® or Combivir® vs. Trizivir® was discontinued early because of unacceptably high failure rates in the Trizivir® arm. The time to virologic failure was significantly shorter in the triple-nucleoside group (p<0.001). Whilst Trizivir® does not appear equipotent to efavirenz containing regimens it remains listed as an alternative CART in patients unable to tolerate or access protease inhibitor or NNRTI containing regimens (Table 3.2). Moreover, there is still some debate about the place of Trizivir® in clinical practice and there is renewed interest in its use in induction-maintenance strategies (87);

- The INCAS study was one of the earliest studies of nevirapine as part of CART and clearly demonstrated the superiority in terms of virological suppression of triple therapy using this NNRTI (95).

- In the COMBINE study (120) nevirapine and nelfinavir with a Combivir® backbone over 12 months were virologically equivalent. However, discontinuation due to toxicity was high in both arms i.e. 21% with nelfinavir and 25% with nevirapine;

- In the Atlantic study (143), indinavir (IDV, Crixivan^®), nevirapine and lamivudine with a didanosine and stavudine backbone were compared. ATLANTIC demonstrated that nevirapine was equivalent to unboosted indinavir (IDV, Crixivan^®) and both arms were superior to the triple NRTI arm. There was no excess of liver toxicity or elevation of hepatic transaminases in the didanosine, stavudine, nevirapine arm.

Gilead 903研究(48)提高了对一线CART数年随访的预期效力和安全性结果的标准。以前还没有哪项对依非韦仑的随机研究得到这么好的结果，然而在解释不同研究间比较时，应当考虑在研究设计上的不同之处。以下显示了对使用NNRTI进行的随机研究概要：

? 依非韦仑vs.多种不增强的蛋白酶抑制剂（即茚地那韦 (佳息患,Crixivan^®)、阿扎那韦）加上NRTI主干(136,137)，显示48周时分别有64% (136)和70% (137)的患者血浆HIV RNA低于检测低限（<400拷贝/ml）；

? 2NN (145)是对抗反转录病毒初次治疗患者的一项重要的多中心、开放标记的试验研究(n=1216)。该研究显示，48周内奈韦拉平与依非韦仑相当，而在同一方案中使用两药没有任何病毒学益处。依非韦仑仅在CD4+ T细胞计数极低的患者中作用胜于奈韦拉平。与基线血浆HIV RNA<100,000拷贝/ml的患者相比，基线血浆HIV RNA>100,000拷贝/ml的患者出现病毒学失败的可能性是其1.63倍；依非韦仑和奈韦拉平在这方面没有区别。

? 在ACTG5095(59)中，依非韦仑加NRTI主干（Trizivir® 或Combivir®）vs. Trizivir®被提前中断，因为在Trizivir®组中病毒学失败率非常高。其出现病毒学失败的时间显著短于三种核苷类药物组(p<0.001)。虽然Trizivir®与含依非韦仑的方案并不等效，它仍被列为无法耐受或得到含蛋白酶抑制剂或NNRTI方案患者的备选CART(表3.2)。此外，对于Trizivir®在临床实践中的地位仍有争议，对其在诱导－维持策略中的用途又有新的关注(87)；

? INCAS研究是对奈韦拉平作为CART一部分进行的最早期研究之一，明确证实了使用该 NNRTI的三药联合在病毒学抑制上的优越性(95)。

? 在COMBINE研究(120)中，奈韦拉平＋奈非那韦以及奈韦拉平＋Combivir®主干在12个月内病毒学等效。然而，由于毒性而中断治疗者在两组中比例都很高，即奈非那韦组21%，奈韦拉平组25%；

? 在Atlantic研究中(143)，比较了茚地那韦、奈韦拉平以及拉米夫定与去羟肌苷和司他夫定主干联用的效果。ATLANTIC证实，奈韦拉平与无增强的茚地那韦等效，两组均优于三种NRTI联用组。在茚地那韦、司他夫定和奈韦拉平组未出现过度肝毒性或肝转氨酶升高情况。

The nine protease inhibitors that are currently approved by the Food and Drug Administration for the treatment of HIV infection are shown in Table 1. There is no doubt that the genetic barrier to resistance to protease inhibitors has been raised through the use of boosting doses of ritonavir (29). This effect is explained in part by the relationship between plasma drug concentrations and virological response to several agents. The ratio of drug concentration at trough (C_min) to a measure of susceptibility to a drug is referred to as the inhibitory quotient. Several studies have now shown a correlation between the normalised inhibitory quotient of ritonavir-boosted protease inhibitors and virological outcomes (150). In addition, ritonavir boosting has allowed bid dosing and reduced pill burden for patients – advantageous in terms of adherence and QoL. One of the previously most commonly used protease inhibitors, nelfinavir, is no longer the preferred the protease inhibitor in the Department of Health and Human Services and British HIV Association guidelines, largely because of the superior efficacy of both Kaletra® and efavirenz in clinical trials, as well as its high pill burden and gastrointestinal side-effects. The M98-863 study (146) showed that Kaletra® outperformed nelfinavir with 67% vs. 52% (p<0.001) of patients having plasma HIV RNA <50 copies/mL respectively at 48 weeks. Protease inhibitor-resistance mutations (D30N and L90M) appeared in 45% subjects receiving nelfinavir who experienced virologic rebound (n=96) compared to none in the Kaletra®-treated patients with virologic rebound (79). Moreover, in the five year follow-up data, in those remaining on their original Kaletra® randomization showed sustained virological suppression and immunological benefit (41).

目前，食品和药品监督局批准用于治疗HIV感染的9种蛋白酶抑制剂列于表1。无疑，使用增强剂量的利托那韦，提高了蛋白酶抑制剂对耐药性的遗传屏障(29)。该效应部分是由于药物血浆浓度与若干药物病毒学应答的关系所致。药物的谷浓度（C_min）与药物敏感性测量值的比值为抑制商。已有若干研究表明利托那韦增强的蛋白酶抑制剂的标准化抑制商与病毒学结局间具有相关性(150)。此外，利托那韦的增强使用药成为每日两次，并降低了患者的药片负荷－对于依从性和生活质量有利。曾经最常用的一种蛋白酶抑制剂奈非那韦，已不再是《卫生人类服务部指南》和《英国HIV联盟抗反转录病毒指南》优选的蛋白酶抑制剂，主要是由于Kaletra® 和依非韦仑在临床试验中的有效性均表现出色，而奈非那韦药片负荷重并具有胃肠道副作用。M98-863研究(146)显示，Kaletra®效果优于奈非那韦，48周时分别有67%及52%的患者血浆HIV RNA<50拷贝/ml（p<0.001）。在45%奈非那韦治疗但出现病毒学反弹的患者(n=96)中出现了蛋白酶抑制剂的耐药突变(D30N和L90M)，而Kaletra®治疗出现病毒学反弹的患者中无一出现这些突变(79)。此外，根据5年随访数据，那些仍在接受其初始Kaletra®随机方案的患者，仍表现出持续的病毒学抑制和免疫学受益(41)。

The data for the other protease inhibitors licensed for initial treatment are summarized below:

- Atazanavir is only licensed for use in ART-naïve patients when used unboosted (unless combined with tenofovir). The licensing studies showed the drug were equivalent to nelfinavir (101,127) and efavirenz (136). There are insufficient data on the use of ritonavir-boosted atazanavir in ART-naïve patients at the present time to recommend its use;

- Several studies suggest that twice daily combinations of indinavir (IDV, Crixivan^®) and boosting doses of ritonavir are tolerable and may be efficacious as part of CART (2,20,70,94,125), however, this combination is listed as an alternative regimen (see Table 3.2) because there are now better tolerated ritonavir-boosted protease inhibitors available. Daily dosing has fallen from favour as it appears to be associated with greater risk of renal toxicity;

- The MaxCMin1 study (36) enrolled a heterogeneous population of patients with respect to prior antiretroviral treatment, and 39% were protease inhibitor-naïve. This study compared twice daily ritonavir-boosted saquinavir to ritonavir-boosted indinavir (IDV, Crixivan^®). Both regimens were equivalent at 48 weeks; with 27% and 25% of 148 patients in the ritonavir-boosted indinavir (IDV, Crixivan^®) and ritonavir-boosted saquinavir arms respectively considered virological “failures” at 48 weeks. However, there were more discontinuations due to toxicity in the ritonavir-boosted indinavir (IDV, Crixivan^®) arm. In the MaxCMin2 study (37), Kaletra® was compared to ritonavir-boosted saquinavir (1000/100 mg bid). The population was heterogenous; 27% were ART-naïve, 32% were prior protease inhibitor failures. At 48 weeks treatment failure in the ritonavir-boosted saquinavir arm was significantly higher (p=0.002) than in the Kaletra® arm, due largely to more early discontinuations in this arm i.e. 30% compared to 14% in the Kaletra® arm. The primary reasons for premature discontinuation were non-fatal adverse events and patients' choice. There are data to support once daily dosing of ritonavir-boosted saquinavir (4) although hard gel saquinavir appears better tolerated than soft gel saquinavir with respect to gastrointestinal side-effects. To this end, a hard gel saquinavir formulation of 500mg per tablet which will also reduce pill burden has been developed;

- Fosamprenavir is licensed for use un-boosted in ART-naïve patients and can be given once daily; it is given boosted twice daily in ART-experienced patients. In the SOLO study (51), 69% of patients in the ritonavir-boosted fosamprenavir once daily group and 68% in the nelfinavir twice daily group had plasma HIV RNA <400 copies/mL. More patients in the nelfinavir twice daily group (17%) experienced virological failure than in the ritonavir-boosted fosamprenavir group (7%). In the NEAT study (123), 66 percent of fosamprenavir recipients compared to 51 percent of nelfinavir recipients with an abacavir and lamivudine backbone achieved a plasma HIV RNA <400 copies/mL at week 48.

- there are insufficient data on the use of tipranavir in initial treatment of HIV infection to recommend it at this time.

? MaxCMin1研究(36)募集了以前抗反转录病毒治疗不同的患者人群，其中有39%未使用过蛋白酶抑制剂。该研究比较了每日两次利托那韦增强的沙奎那韦与利托那韦增强的茚地那韦。两种方案在48周时作用相当；利托那韦增强的沙奎那韦组和利托那韦增强的茚地那韦组的各148名患者中，分别有27%和25%在48周时被认为病毒学“失败”。然而，在利托那韦增强的茚地那韦组中因毒性而中断治疗者更多。在MaxCMin2研究中(37)，将Kaletra®与利托那韦增强的沙奎那韦(1000/100 mg bid)进行比较。该患者人群也具有异质性：27%从未接受过ART，32%曾有蛋白酶抑制剂治疗失败。48周时，托那韦增强的沙奎那韦组治疗失败者多于Kaletra®组(p=0.002)，主要是由于该组中早期中断者更多，达到30%，相对而言Kaletra®组仅为14%。提前中断的主要原因在于不致命的不良事件及患者选择。数据支持每日一次使用托那韦增强的沙奎那韦(4)，但是就胃肠道副作用而言，硬胶囊沙奎那韦的耐受性似乎优于软胶囊沙奎那韦。为此，已经研制出每粒500mg的硬胶囊沙奎那韦制剂，这也降低了药片负荷；

? 夫沙那韦获批可以未增强形式用于初次ART患者，且每日用药一次；在ART复治患者中，以增强形式用药每日两次。在SOLO研究中(51)，69%每日一次利托那韦增强的夫沙那韦组患者以及68%每日两次奈非那韦组患者血浆HIV RNA<400拷贝/ml。在奈非那韦组中出现病毒学失败的患者(17%)多于利托那韦增强的夫沙那韦组(7%)。在NEAT研究中(123)，使用阿巴卡韦和拉米夫定主干，有66%夫沙那韦组患者在48周时实现了血浆HIV RNA<400拷贝/ml，而奈非那韦组为51%。

? 目前还缺乏足够数据推荐将替拉那韦用于HIV感染的初次治疗。

Many studies used for the development of new protease inhibitor have used nelfinavir as the comparator arm. Given that Kaletra® seems to outperform all the unboosted protease inhibitors and even some other ritonavir boosted ones in the antiretroviral naïve setting, it appears that in future Kaletra® will become the gold standard comparator for all new protease inhibitors. In addition, the contribution of boosting doses of ritonavir to lipodystrophy, insulin resistance and dyslipidaemia associated with the long term use of protease inhibitors has been reported (24,29, and reviewed in (53)).

许多研制新型蛋白酶抑制剂的研究均使用奈非那韦作为对照组。考虑到Kaletra®组在初次抗反转录病毒治疗上似乎优于所有未增强的蛋白酶抑制剂甚至一些利托那韦增强者，也许今后Kaletra®会成为所有新型蛋白酶抑制剂的金标准对照。此外，随着蛋白酶抑制剂的长期使用，利托那韦增强剂量的使用对脂肪萎缩、胰岛素抵抗以及血脂异常的影响已有所报道(24,29, 且综述于(53))。

There has been keen interest in exploring the use of protease inhibitor and NNRTI-sparing strategies in the treatment of ART-naïve individuals. This approach has been to some extent encouraged by the appearance of fixed dose combinations of NRTI in the armamentarium of licensed drugs. However, several studies have shown Trizivir® to be inferior to either a protease inhibitor or efavirenz-based regimen. However, there is still interest in this drug in the naïve setting especially when the concurrent treatment of tuberculosis is needed. In addition, studies using this fixed dose combination in induction-maintenance showed that maintenance with Trizivir® for 48 weeks following a 48-week induction period with abacavir, lamivudine, zidovudine and efavirenz resulted in both virologic control and immunologic response, reduced fasting lipids and antiretroviral-associated adverse events, and improved adherence (87). Further research is required to explore other NRTI combinations that might be more robust with respect to the development of resistance, have minimal to low risk of lipodystrophy and other long-term side effects, low pill burden and a favourable safety profile. One such combination is Combivir® or Trizivir® with tenofovir. The rationale for this combination is that the presence of thymidine analogue mutations (TAMS) and the most common tenofovir mutation, K65R, appear to be incompatible in the same virus – however, these mutations may co-exist in the same person (86,148). It is unclear whether combining these drugs as part of first treatment may prevent the development of one or other of these pathways of resistance and preserve efficacy of these agents.

研究不含蛋白酶抑制剂和NNRTI的方案在初次ART患者治疗中的应用，吸引了众多注意力。固定剂量组合的NRTI出现于获批药物中，在某种程度上鼓舞了该方法。然而，一些研究显示，Trizivir®不如基于蛋白酶抑制剂或依非韦仑的方案。不过，对将这一药物用于初次治疗尤其是需同时治疗伴发结核时，仍有很多关注。此外，在诱导－维持治疗中使用该固定剂量组合的研究表明，在使用阿巴卡韦、拉米夫定、齐多夫定和依非韦仑进行48周诱导期治疗后，使用Trizivir®维持48周，具有病毒控制和免疫学应答效果，降低了空腹血脂及抗反转录病毒治疗相关的不良事件，且提高了患者依从性(87)。需要进一步研究来寻找其他NRTI组合，使其更不易诱导耐药性、产生脂肪萎缩及其他长期副作用的风险很低或较低、药片负荷低并且具有很好的安全性能。此类组合之一为Combivir®或Trizivir®与替诺福韦联用。该组合的原理在于胸腺嘧啶类似物突变（TAMS）以及最常见的替诺福韦突变K65R，在同一病毒中似乎不相容－但这些突变可共存于同一患者(86,148)。尚不明确使用这些药物组合作为初次治疗的一部分，是否能防止一种或其他这些耐药性路径的产生并维持这些药物的有效性。

There are a number of important factors to consider when starting CART, and some of these are compromised where there is limited access to CART. Achieving treatment goals is a balance. Considerations that will increase the likelihood of success are:

- choosing a combination that is potent, and well tolerated in the short, medium and long-term;

- taking into consideration other co-morbidities in particular active opportunistic infections, hepatitis B and C co-infection, depression and active illicit drug or alcohol use that increase the risk of treatment failure through non-adherence and increased risk of CART-related toxicities.

开始CART时需要考虑一系列重要因素，其中某些由于获得CART的途径有限而不得不折衷。达到治疗目标是寻求平衡。提高治疗成功可能性的因素包括：

The CD4+ T-cell count - at the time of treatment initiation - is a stronger predictor of AIDS free survival than plasma HIV RNA level (39) and all current guidelines advise commencement of CART based upon levels of CD4+ T-cells as described below. In addition, the CD4+ T-cell count is also an independent predictor of all cause mortality, including deaths which are probably HIV-related but are not officially classified as AIDS defining illness e.g. Hodgkin’s lymphoma (39,93). Within the existing guidelines (67,68,156) there is consensus that all patients with symptomatic HIV disease or an AIDS defining illness in the setting of chronic HIV infection should receive CART irrespective of their CD4+ T-cell count.

与血浆HIV RNA水平(39)相比，开始治疗时的CD4+ T细胞计数是无AIDS生存的更强预测因素，所有的现行指南均建议如下所述根据CD4+ T 细胞水平开始CART。此外，CD4+ T细胞计数也是所有原因死亡（包括很可能为HIV相关但并未正式归为AIDS定义疾病所致的死亡，如Hodgkin’s淋巴瘤）(39,93)的独立预测因子。现有指南(67,68,156)公认，慢性HIV感染的所有症状性HIV疾病或AIDS定义疾病患者，不论其CD4+ T细胞计数如何均应接受CART。

- the timing of the introduction of CART in patients with an active opportunistic infections – although CART is definitely indicated in this setting;

- the point at which CART should be initiated in patients with asymptomatic, chronic HIV infection;

The initial hope that treatment during primary infection followed by treatment interruption with or without vaccination would alter the viral set point and clinical course of HIV has not been borne out in several clinical trials (reviewed in (134)). As such, treatment of primary HIV infection is not currently recommended. However, patients should be encouraged to participate in clinical trials in order to better understand the role of CART in this setting (153).

开始认为，在原发感染时治疗后使用或不用疫苗并中断治疗，会改变病毒调定点和HIV的疾病进程，但一些临床研究并未证实这一观点（综述见(134)）。因此，目前不推荐治疗原发HIV感染。然而，应当鼓励患者参与临床研究以更好地了解该情形下CART的作用(153)。

All patients with CD4+ T-cells ≤ 200 cells/µL should commence CART. The rationale for this is the strong cohort data supporting treatment in this group (39,52,91,93,116,140) in order to improve survival and prevent the development of symptomatic HIV infection including AIDS defining illnesses.

所有CD4+ T-细胞 ≤ 200 细胞/µL的患者必须开始CART。其原因在于队列研究的数据强烈支持在该组人群中开始治疗(39,52,91,93,116,140)，以改善存活率并防止产生症状性HIV感染包括AIDS定义疾病。

Asymptomatic HIV infection with CD4+ T-cells ≥ 201 cells/µL to <350 cells/µL

Both the British HIV Association and Department of Health and Human Services guidelines (67, 68) advise commencing treatment in asymptomatic patients with CD4+ T-cells in this range. However, as there is a paucity of randomised clinical trial data regarding clinical outcomes in this patient group. The British HIV Association guidelines at least, suggest that the slope of CD4+ T-cell decline, hepatitis B or C co-infection, symptomatology, patient preference and level of viral load should also be used to guide the start of CART. At best, the risk of progression based upon age, baseline CD4+ T-cell count and HIV plasma RNA level can be estimated from pooled cohort data (39,115). The CASCADE Collaboration (115) – which collects pooled data from 22 cohorts - reported that during 5126 person-years of follow-up, 219 individuals developed an AIDS defining illness. For those with CD4+ T-cells between 200-349 cells/µL risks were 0.5 percent (plasma HIV RNA <10,000 copies/mL), 1.6 percent (plasma HIV RNA 10,000-29,999 copies/mL), 3.2 percent (plasma HIV RNA 30,000-99,999 copies/mL) and 4.7 percent (plasma HIV RNA ≥100,000 copies/mL); for those with CD4 T-cell count ≥350 cells/µL the corresponding progressions rates for the same viral load ranges were 0.2 percent, 0.5 percent, 0.9 percent and 2.2 percent, respectively. Egger et al (39), described the risk of progression in a pooled analysis of 13 cohorts across North America and Europe. In this analysis, although CD4+ T-cells still remained the strongest predictors of clinical progression, patients with plasma HIV RNA >100,000 copies/mL, who were older, infected through injecting drug use (IVDU) and had prior AIDS defining illness were at greater risk of progression. The 3 year probability of AIDS defining illness in those with CD4+ T-cells of 200-349 cells/µL and ≥350 cells/µL was 4.7% (6.1% if plasma HIV RNA was >100,000 copies/mL) and 3.4% (4.4% if plasma HIV RNA was >100,000 copies/mL) respectively. In addition, CD4+ T-cell percentage may be predictive of disease progression in HIV-infected patients initiating highly active antiretroviral therapy with CD4 lymphocyte counts ≥350 cells/µL (71). ). In summary, in making the decision whether to commence antiretroviral therapy in asymptomatic patient’s with CD4+ T-cell counts of 201-349 cells/ µL, the authors advice that other factors that influence more rapid HIV progression should be considered. These include older age, infection through IVDU, and plasma HIV RNA over 100,000 copies/mL.

《英国HIV联盟指南》及《卫生人类服务部指南》(67, 68)均建议CD4+ T细胞计数处于该范围内的无症状患者开始治疗。然而，由于缺乏有关该组患者临床预后的随机临床试验数据，英国HIV联盟指南至少还建议，也可参考CD4+ T细胞下降的速度、乙型或丙型肝炎共感染、临床症状、患者意愿及病毒载量水平以指导CART的开始。最好能根据荟萃队列数据，基于年龄、基线CD4+ T细胞计数及HIV血浆RNA水平估计疾病进展风险(39,115)。CASCADE协作组(115)收集了22个研究队列的荟萃数据，报道在5126病人-年的随访量中，219人出现了AIDS定义疾病。CD4+ T细胞处于200-349细胞/µL的患者，其风险分别为0.5%（血浆HIV RNA <10,000拷贝/mL）、1.6%（血浆HIV RNA 10,000-29,999拷贝/mL)、3.2%（血浆HIV RNA 30,000-99,999拷贝/mL)及4.7%（血浆HIV RNA ≥100,000拷贝/mL)；而CD4+ T细胞计数≥350细胞/ul的患者相应风险分别为0.2%、0.5%、0.9%及2.2%。Egger等人(39)对北美及欧洲的13项队列研究进行荟萃分析，描述了疾病进展的风险。在该分析中，虽然CD4+ T细胞仍为临床进展最强的预测因子，血浆HIV RNA>100,000拷贝/ml、年龄较大、通过静脉吸毒途径(IVDU)感染并具有AIDS定义疾病病史的患者进展的风险更大。CD4+ T 细胞计数为200-349 细胞/µL及≥350细胞/µL的患者3年进展至AIDS定义疾病的概率分别为4.7% （血浆HIV RNA>100,000 拷贝/mL者为6.1%）及3.4% （血浆HIV RNA>100,000 拷贝/mL者为4.4%）。此外，在CD4淋巴细胞计数≥350细胞/µL就开始高效抗反转录病毒治疗的患者中，CD4+ T细胞百分比可以预测疾病进展(71)。总之，决定是否在CD4+ T细胞计数为201-349/µL的无症状患者中开始抗反转录病毒治疗，作者们建议应当考虑其他影响HIV更快进展的因素。包括年长、IVDU途径感染以及血浆HIV RNA>100,000拷贝/mL。

At the present time, neither the British HIV Association nor Department of Health and Human Services guidelines recommend CART in asymptomatic patients with CD4+ T-cells ≥350 cells/µL. The potential benefits of deferred therapy include preservation of treatment options and reduced risk of toxicity because of less drug exposure. However, the downside is the probable irreversible loss of components of the immune system – the long term effects of which are unknown - increased risk of death and AIDS defining illnesses and from a public health perspective, increased potential for HIV transmission. Moreover, deferring CART might be associated with other deleterious effects including neurocognitive disease as a consequence of ongoing immune dysregulation in the central nervous system (19). Whether the rationale for deferral of CART because of the risk of irreversible long-term toxicities of ART is as valid today as 3 years ago is a subject of intense debate - especially as newer and apparently less toxic drugs are now available (17,66). Patients whose therapy is deferred should have their CD4+ T-cell count and plasma viral load measured every 2 to 4 months (1).

目前，《英国HIV联盟指南》及《卫生人类服务部指南》均不推荐在CD4+ T细胞≥350细胞/µL的无症状患者中使用CART。推迟治疗的潜在益处包括保留治疗选择、由于减少药物暴露而降低毒性风险。然而，其缺点在于可能会不可逆丢失免疫系统组成部分（其长期作用尚不明确）、增加死亡及AIDS定义疾病的风险，且从公共卫生角度而言还会增加HIV传播的可能性。此外，推迟CART还可能会造成其他不良作用，包括由于中枢神经系统中进行性免疫失调而引发的神经认知性疾病(19)。由于ART不可逆的长期毒性而推迟CART的理由在今天是否还与3年前一样正确，是争论的焦点之一－尤其是现在已经出现了更新的且毒性较小的药物(17,66)。推迟治疗的患者应当每2-4月检测其CD4+ T细胞计数及血浆病毒载量(1)。

Co-existent medical conditions must be considered when commencing CART. These include, in particular, pre-existing ischaemic heart disease (44,45), renal disease (see below), psychiatric illness and viral hepatitis co-infection (see below). Women of childbearing potential should be offered optimal CART regimens taking into consideration that some antiretroviral drugs may decrease the effectiveness of oral contraceptives (154). In addition, CART should be selected such that if pregnancy does occur, there is the least chance of teratogenicity and harm to the mother. Hence where possible efavirenz should be avoided. If there is no suitable alternative, women must be counselled about the need to avoid pregnancy whilst taking this drug and suitable alternatives offered should they wish to become pregnant. CART is recommended for all pregnant women (67,68), irrespective of their clinical status, CD4+ T-cell count or plasma HIV RNA in order to minimize the risk of perinatal transmission. For ARV-naïve women who become pregnant, CART should commence by week 20 at the very latest. The drugs that are recommended are zidovudine, lamivudine and twice daily nelfinavir or ritonavir-boosted saquinavir (67). Drugs that must be avoided in pregnancy include efavirenz, didanosine and stavudine, amprenavir and nevirapine (especially if commencing for the first time during pregnancy and/or if the CD4+ T-cells count is ≥250 cells/µL). However, if there really is no alternative then the latter can be used with very close monitoring especially during the first 18 weeks of treatment. Women exposed to single dose nevirapine in the intra-partum period may well have developed NNRTI resistance (75,80). This has implications for the future use of CART when the woman needs to start combination therapy which might include an NNRTI (see below) especially if access to protease inhibitors is limited.

开始CART时必须考虑共存的医疗情况。其中具体包括，既往的缺血性心脏病(44,45)、肾脏疾病（见下）、精神疾病以及病毒学肝炎共感染（见下）。对于育龄妇女而言，应考虑到某些抗反转录病毒药物可能会降低口服避孕药的药效，从而提供最佳CART方案(154)。此外， CART的选择应考虑如果真出现妊娠，药物致畸性以及对母亲产生的危害为最小。因此，若有可能应尽量避免依非韦仑。如果没有合适的备选药物，应当建议妇女服用此药时避免妊娠的必要性以及希望妊娠时合适的替代药物。不论其临床状况、CD4+ T细胞计数或血浆HIV RNA水平如何，对于所有妊娠期妇女均建议其接受CART(67,68)以最大程度地减小围产期传播的风险。对于初次使用ARV的怀孕妇女而言，最迟应在20周时开始CART。推荐使用的药物为齐多夫定、拉米夫定以及每日两次奈非那韦或利托那韦增强的沙奎那韦(67)。孕期需避免使用的药物包括依非韦仑、去羟肌苷和司他夫定、安普那韦和奈韦拉平（尤其在妊娠期首次开始使用和/或CD4+ T细胞计数≥250 细胞/µL时）。然而，如果确实不存在替代方案，也可在严密监测下使用后者，尤其是在治疗的第一个18周内。产时使用单剂奈韦拉平的女性很可能会产生NNRTI耐药性(75,80)。这会对以后CART的使用产生很大限制性，因为当该妇女需要开始联合治疗时，其中可能含有NNRTI（见下，尤其是无法使用蛋白酶抑制剂时）。

Increasingly, genotypic and phenotypic testing is being performed in treatment-naïve patients with chronic infection, especially if the patient was infected in a geographical location where levels of transmitted drug resistance are high i.e. ≥5% (128). Physicians should be aware that these results, especially if testing takes place years after HIV seroconversion, may not accurately reflect any archived mutations due to reversal of mutations in the absence of drug-related selection pressure. In addition, clinicians should be aware of prior receipt of single dose nevirapine to prevent vertical transmission of HIV-1 in female patients or the perinatally or infected breastfeeding children of women treated with short course antiretroviral regimens. This issue is applicable in the developing world, where single dose nevirapine has been the mainstay of prevention of mother-to-child-transmission. If primary resistance mutations exist (75,80), the antiretroviral naïve patient should be treated as if they have had prior drug exposure and the genotype (if available) utilised to guide the best choice of CART. However, even if NNRTI mutations are not detected following single dose nevirapine exposure, there are data showing a poorer response to CART containing NNRTI presumably due to the presence of archived NNRTI mutations (75). In future, antiretroviral strategies which effectively reduce mother-to-child transmission without compromising future prevention of vertical transmission in subsequent pregnancies or response to CART once maternal treatment starts need to be developed. Such approaches are the subject of ongoing studies in the developing world and include the use of nucleoside analogues such as Combivir® or a protease inhibitor based regimen to cover the decay kinetics of single-dose nevirapine (reviewed in (61)).

在既往未治疗的慢性感染患者中已逐渐开展了基因型及表型检测，尤其是如果该患者感染的地理区域发生传播性耐药的水平很高即≥5% (128)。医生应意识到这些结果可能并不能准确反映任何发生的突变，尤其是在HIV血清转化后多年进行的检测，因为当缺乏药物相关的选择压力时突变会发生回复。此外，医生也应当注意女性患者以前是否使用过单剂奈韦拉平以阻断HIV-1的垂直传播，或曾接受抗反转录病毒方案短期治疗妇女生育的围生期感染的母乳喂养的孩子。该问题在发展中国家很有现实意义，因为单剂奈韦拉平仍是那些地区预防母婴传播的主要方法。如果存在原发的耐药性突变(75,80)，治疗时应当将这些初次治疗的患者视同既往具有药物暴露史的患者，并利用基因型检测（如有可能）指导CART的最佳选择。然而，即使在单剂奈韦拉平暴露后没有检测到NNRTI突变，也有数据显示其对含NNRTI的CART反应不佳，很可能是由于既往存在NNRTI突变(75)。今后需要发展抗反转录病毒策略，既能有效降低母婴传播，又不致于影响再次妊娠时垂直传播的预防或母亲治疗开始后对CART的应答。此类方法是目前在发展中国家进行研究的课题，包括使用核苷类似物如Combivir®或基于蛋白酶抑制剂的方案，以覆盖单剂奈韦拉平的衰减动力学（综述见(61)）。

Co-morbidities that require ongoing drug treatment may impact on the choice of antiretroviral medication because of the potential for drug-drug interactions (154). While the place of therapeutic drug monitoring (TDM) in clinical practice has not yet been established, it may find a place in the management of patients where drug-drug interactions are predicted e.g. tuberculosis-HIV- co-infection (15).

由于能发生药物相互作用，需要持续药物治疗的共病可能会影响对抗反转录病毒药物的选择(154)。虽然治疗药物检测（TDM）在临床实践中尚未得到应用，它在管理药物相互作用明确的患者（如结核-HIV共感染）中可能具有一定作用(15)。

Assessment of a patient’s willingness to adhere to CART is critical to the success of the treatment in terms of a durable virological and immunological responses and preservation of future treatment options by minimising the risk of resistance. Outcomes appear to be better in those with higher adherence as discussed below (8,55,63,72). Adherence assessments should be taken prior to commencement and repeatedly whilst on therapy, the key strategic approaches are outlined in the October 2005 Department of Health and Human Services guidelines (67). The cornerstone of success is the correct timing of CART introduction (“patient readiness”), simplification of the regimen without sacrificing potency, education (“what to expect” and “what to do”) and a supportive healthcare environment. Paradoxically, however, the risk of resistance seems to rest not only upon the level of adherence but other factors including elimination half life, potency of the drugs and genetic barriers to resistance. For example, those who are poorly adherent on a non- nucleoside reverse transcriptase inhibitor (NNRTI) have a relatively high risk of resistance (111). In contrast those who adhere better have a greater risk of resistance when using an unboosted protease inhibitor (7,8,49,147), than those who are poorly adherent. The long term correlations between levels of adherence and resistance with ritonavir-boosted protease inhibitors is unknown although the development of resistance is less likely with the use of the latter (7,9,10).

评估患者对CART的依从性意愿，能够获得持久的病毒学和免疫学应答并通过最小化耐药产生的风险而保留未来的治疗选择，对于治疗的成功至关重要。如下所述，依从性较高的患者其预后也较好(8,55,63,72)。应当在治疗开始前进行依从性评估，并在治疗期间不断重复，其关键策略方法列于2005年10月《卫生人类服务部指南》中(67)。治疗成功的关键在于引入CART的正确时机（“患者准备情况”）、在不牺牲效力的前提下简化方案、教育（“期望什么”以及“做什么”）以及支持性的卫生保健环境。然而，矛盾之处在于产生耐药性的风险不仅取决于依从性水平，也与其他因素包括清除半衰期、药物效力以及对耐药性的遗传屏障有关。例如，对非核苷类反转录酶抑制剂（NNRTI）依从性差的患者产生耐药性的风险相对较高(111)。与之相对，当使用未增强的蛋白酶抑制剂时，依从性较好的患者产生耐药的风险比依从性差的患者更大(7,8,49,147)。对于依从性水平与利托那韦增强的蛋白酶抑制剂耐药性的长期关系尚不明确，不过使用后者出现耐药性的可能性较小(7,9,10)。

Patients with HIV infection should always be screened for hepatitis B (HBV) and C (HCV) co-infection as part of routine standard-of-care practice (1). Viral hepatitis co-infection has a considerable impact on the choice of antiretroviral therapy and may influence the timing of CART commencement especially if treatment of hepatitis C with pegylated interferon and ribavirin is available and warranted (18,35,103,129,132). Guiding principles include:

- avoidance of antiretrovirals with a high risk of hepatotoxicity and/or lactic acidosis i.e. didanosine, stavudine, nevirapine, high dose ritonavir;

- avoidance of drugs which may interact with ribavirin i.e. zidovudine, didanosine and stavudine;

- where possible avoidance of monotherapy for hepatitis B in co-infected patients who are commencing CART which contains drugs with anti-HBV activity i.e. lamivudine alone. At the present time tenofovir alone or in combination with lamivudine or emtricitabine is recommended.

必须将筛查HIV感染患者的乙型肝炎（HBV）及丙型肝炎（HCV）共感染，作为常规标准护理实践的一部分(1)。病毒性肝炎共感染对于抗反转录病毒治疗的选择具有很大影响，并可能会影响CART的开始时机，尤其在能够且必须使用聚乙二醇干扰素及利巴韦林治疗丙型肝炎的情况下(18,35,103,129,132)。指导原则包括：

? 避免使用引发肝毒性和/或乳酸酸中毒风险高的抗反转录病毒药物，如去羟肌苷、司他夫定、奈韦拉平、高剂量利托那韦；

? 避免使用可能与利巴韦林相互作用的药物，如齐多夫定、去羟肌苷及司他夫定；

? 如有可能，避免在 CART 含有抗HBV活性药物的共感染患者中使用单药治疗乙型肝炎，如单独使用拉米夫定。目前推荐替诺福韦单药或与拉米夫定或恩曲他滨联用。

Immune restoration disease (IRD) has been described in the setting of many opportunistic infections (reviewed in (114)) and is a particular risk for patients with an active opportunistic infections with a CD4+ T-cell count of <100 cells/µL starting CART. There are no objective data to guide the timing of CART in such patients. However, CART should not be deferred for several months in patients with such low CD4+ T-cells and clinicians should closely observe patients in this situation. Clinicians should refer to specific treatment guidelines for guidance on the treatment of tuberculosis in the HIV-infected person (14,67).

免疫重建疾病（IRD）被描述出现于多种机会性感染中（综述见(114)），对于CD4+ T细胞计数<100细胞/µL、患有活动性机会性感染同时开始CART的患者尤其危险。对于此类患者中CART的时机尚无客观数据加以指导。然而，在CD4+ T细胞如此之低的患者中不应将CART推迟数月，临床医生应当严密观察这类患者。医生应当根据特定的治疗指南治疗HIV感染者的结核感染(14,67)。

There is increasing awareness of the renal axis in HIV-infected individuals especially as the population of individuals currently being treated in the developed world is now ageing. Consideration should be given to the recent IDSA guidelines (60) which specifically suggest the use of regular estimates of creatinine clearance (although none have been specifically validated in the setting of HIV-infection) and urinalysis in those with a normal creatinine or creatinine clearance for the detection of proteinuria. Those at higher risk of renal disease i.e. African American patients, those with a CD4+ T-cell count of <200 cells/µL or plasma HIV RNA ≥4000 copies/mL and those with hypertension, diabetes mellitus and hepatitis C co-infection should undergo annual screening for proteinuric renal disease. In addition, the guidelines give directives on how to dose adjust antiretroviral drugs that undergo renal excretion in patients with chronic renal disease or end-stage renal disease. These drugs include didanosine, lamivudine and tenofovir. However, anxiety re the potential nephrotoxicity of tenofovir in patients who do not have overt renal disease do not appear to be have manifested – at least in the short term (74,106,149) - although tenofovir levels are increased by 32% and 22% in patients concomitantly treated with ritonavir-boosted lopinavir and a newer protease inhibitor, ritonavir-boosted darunavir respectively. This potential interaction needs to be monitored carefully as suggested above.

对于HIV感染者肾轴的关注日益增加，尤其是随着发达国家目前接受治疗的感染人群逐渐步入老年。近期的IDSA指南(60)值得注意，其中特别建议使用肌酐清除率的常规估计（虽然无一在HIV感染中进行过特别校准）及尿检检测肌酐或肌酐清除率正常的患者的蛋白尿。肾疾病发病风险较高的患者，即美洲黑人、CD4+ T细胞计数<200细胞/µL或血浆HIV RNA ≥4000拷贝/mL，以及患有高血压、糖尿病及丙型肝炎共感染患者，应当每年接受蛋白尿性肾疾病的检查。此外，指南说明应怎样调节慢性肾病或终末期肾病患者者使用经肾排泄的抗反转录病毒药物的剂量。这些药物包括去羟肌苷、拉米夫定及替诺福韦。然而，替诺福韦可能对无严重肾脏疾病的患者产生肾毒性的顾虑尚未经证实－至少短期而言是如此(74,106,149)，但在同时使用利托那韦增强的洛匹那韦及一种较新的蛋白酶抑制剂－利托那韦增强的地瑞那韦的患者中，替诺福韦的水平分别增加了32%及22%。应如上所述严密监测这一可能的相互作用。

Much of the evidence underpinning CART has been obtained from clinical trials and cohort studies in male subjects in developed world countries, and as a consequence there has been a relative paucity - by comparison - of data in women. Data from a number of studies have been conflicting, with some showing that plasma HIV RNA levels are lower in women at equivalent CD4+ T-cell levels to those in men (33,97-99,102,113,122,133). Although this may be the case early in the course of infection, the differences dissipate over time such that at 5-6 years, there are no gender differences (138,139). Moreover, rates of clinical progression are equivalent (139). Hence there are no gender differences in the current treatment recommendations. There is little evidence to suggest that the immunological and virological response to CART is affected by ethnicity. However, patients from minority ethnicities in developed world countries may do less well for social and cultural reasons - including not having been tested for HIV infection - and as a consequence presenting late in the course of HIV infection with or without an active AIDS defining illness (16,67,108,126).

支持CART的大部分证据来自发达国家男性受试者的临床试验和队列研究，因此，相对而言女性数据比较缺乏。一些研究的数据彼此矛盾，有研究显示当CD4+ T细胞水平相同时女性的血浆HIV RNA水平低于男性(33,97-99,102,113,122,133)。虽然感染病程初期可能如此，随着时间推移这一差别逐渐消失，而到5-6年时已不存在性别差异(138,139)。此外，临床进展概率也是相当的(139)。因此，在目前的治疗推荐中并无性别差异。几乎没有证据表明CART的免疫学及病毒学应答受种族的影响。然而由于社会和文化因素，发达国家少数民族患者的治疗效果可能稍逊（包括未进行过HIV感染的检测，因此在HIV感染病程后期才表现为患有或不患有AIDS定义疾病）(16,67,108,126)。

There is a paucity of long-term data on genotypic resistance and treatment outcomes for many of the non-clade B viruses and new recombinant viruses. The dominant clades globally are A and C, however, current NRTI and protease inhibitors have been developed using sequences of clade B reverse transcriptase and protease enzymes due to the predominance of clade B HIV-1 virus in the developed world (76). Until more definitive information on the long term effects of this genetic diversity on treatment outcomes becomes available, initiation of CART for non-clade B virus should follow the same guidelines as for clade B virus with the caveat that there may be relatively few antiretroviral drugs available where non-clade B viruses predominate anyway.

对于许多非B亚型病毒及新的重组病毒而言，目前还缺乏其基因型耐药及治疗效果的长期数据。全球范围内主要的毒株为A和C亚型，但是目前的NRTI和蛋白酶抑制剂都是基于B型反转录酶和蛋白酶序列研发的，因为B亚型HIV-1病毒是发达国家致病的主要病毒(76)。除非得到有关该遗传多样性对治疗效果长期影响的更明确信息，对非B亚型病毒开始CART仍应遵从与B亚型病毒相同的指南，而且很可能非B亚型为主的地区可使用的抗反转录病毒药物相对较少。

The driving factors behind consideration of an “induction-maintenance approach” and structured treatment interruption (STI) have been to reduce pill burden, simplify dosing regimens, reduce the risk of chronic toxicity by reducing drug exposure and preserve future drug options. Examples of successful induction-maintenance strategies in other therapeutic areas include the treatment of tuberculosis with an important caveat, that the aim of tuberculosis treatment is eradication in contrast to HIV infection where eradication is not possible. However, induction-maintenance has failed in prior trials in HIV-infected persons (119) probably because the one or other regimen for “maintenance” was simply not potent enough. Data from an induction-maintenance study using Trizivir® in the maintenance phase looks promising (87), however, more data are required on the long-term potency of Trizivir® and what Trizivir®-failure means in terms of future efficacy of other agents within the NRTI class. The combination of zidovudine, lamivudine and tenofovir or Trizivir® with tenofovir might find a place in further studies of induction-maintenance. In addition, use of Kaletra® monotherapy in antiretroviral naïve patients is the subject of ongoing study and it is foreseeable that Kaletra® may be explored in large randomised studies of induction-maintenance (5,21). However, with the advent of new fixed dose combinations, better tolerated formulations of older and new protease inhibitors or NNRTI with a more favourable toxicity profile, the rationale for exploring this strategy is less pressing. Overall STI has fallen from favour largely because immune responses during the period of viral rebound during STI have not translated into immunological benefit as was once hypothesized (107). Moreover, there are dangers inherent to stopping CART especially in patients with prior low nadir or AIDS defining illnesses and if the decay half-life of the drugs being ceased is not carefully considered (22,96,111). The SMART study (155) has recently demonstrated that patients remaining on continual CART with the aim of viral suppression (VS arm) had fewer clinical endpoints (p= <0.001) and fewer non-AIDS related deaths (p=0.04) than patients receiving CART guided by their current CD4+ T-cell count (DC arm) i.e. starting CART when the T-cells count was ≤250 cells/µL and stopping when the CD4+ T-cell count was ≥350 cells/µL. The relative risks of both AIDS defining illness and death was higher in the DC arm than the VS arm even when matched for baseline and nadir CD4+ T-cell count without any benefit in terms of reduced cardiovascular events in the DC arm. Although only 4.9% of the patients enrolled in SMART were antiretroviral naïve at baseline, these findings are highly significant and patients starting CART for the first time should be told that clinical outcomes will probably be better if they remain on CART continuously without any treatment interruptions.

“诱导－维持方法”以及计划性间断治疗（STI）考虑的驱动因素在于减少药片负荷、简化剂量方案、通过减少药物暴露而降低产生慢性毒性的风险并保留未来的药物选择。在其他治疗领域成功的诱导－维持策略包括结核的治疗，但值得注意的是结核治疗的目标在于清除，而对于HIV感染达到清除则是不可能的。然而，以前对HIV感染者使用诱导－维持的试验以失败告终(119)，很可能是由于用于“维持”的某个或其他方案不够强效。维持阶段使用Trizivir®的一项诱导－维持研究的数据似乎有望成功(87)，不过需要更多数据以了解Trizivir®的长期疗效，以及Trizivir®的治疗失败对将来NRTI类其他药物的疗效会有怎样的影响。齐多夫定、拉米夫定和替诺福韦或Trizivir®和替诺福韦的组合在进一步诱导－维持的研究中可能有其作用。此外，将Kaletra®单药治疗用于初次抗反转录病毒治疗患者，是目前研究的课题之一，可以预见将有大量的诱导－维持随机研究探索Kaletra®的应用(5,21)。然而，随着新的固定剂量组合药物、耐受性更好且毒性有所改善的新老蛋白酶抑制剂或NNRTI制剂的出现，对于这一策略需求的紧迫性有所下降。总体而言STI不再受到青睐，很大程度上是由于STI病毒反弹期出现的免疫应答并未如料想那样转为免疫学益处(107)。此外，停止CART有其内在危险，尤其是对于既往滴度低或患有AIDS定义疾病的患者且又未仔细考虑停止药物衰减半衰期的情况而言(22,96,111)。SMART研究(155)近期证实，持续CART、以病毒抑制为治疗目标的患者（VS组）出现临床终点(p= <0.001)及非AIDS相关死亡(p=0.04)者均少于那些根据当时CD4+ T细胞计数指导CART的患者（DC组），即后一组当T细胞计数≤250 细胞/µL时开始治疗，而CD4+ T细胞计数≥350细胞/µL时治疗停止。DC组出现AIDS定义疾病及死亡的相对风险均高于VS组，即使校正了基线和滴定CD4+ T细胞计数对DC组减少心血管事件并无益处。虽然仅有4.9%参加SMART的患者在基线时未接受过抗病毒治疗，这些发现极其显著，因此应当告知初次开始CART的患者，若其坚持CART治疗而不中断，临床预后很可能会更好。

While there are a much larger number of drugs in the existing armamentarium for use in the treatment of HIV infection, all have their pros and cons. In choosing an antiretroviral combination for first-line treatment of HIV, clinicians should have a strategic plan as to what they will use as a second, third, and even fourth line CART when each fails in turn. HIV infection should be considered a chronic, treatable illness and so, in approaching CART in antiretroviral naïve patients, the CART should be individualised as much as possible, whilst using the guidelines in order to maximize the chances of success. In the interim, novel approaches to the use of licensed drugs including monotherapy with ritonavir-boosted PI, NRTI-sparing strategies or antiretroviral deferral strategies i.e. using recombinant interleukin-2 (40), must only be explored in the setting of properly designed, randomised, clinical trials in order to determine their place in the management of initial treatment of HIV infection.

虽然现有的治疗HIV感染药物数量已经大为扩充，这些药物均有其优点和不足之处。选择一种抗反转录病毒药物组合用于HIV的一线治疗，医生应当制定策略性计划，以明确若治疗依次失败，应将哪些药物作为二线、三线甚至四线CART。HIV感染是一种慢性可治疗的疾病，因此在初次抗病毒治疗的患者中开始CART，应当在使用指南的同时尽可能使CART个体化以使成功的可能性最大。目前为止，使用获批药物的新途径包括使用利托那韦增强的PI单药治疗、不含NRTI的策略或推迟抗反转录病毒治疗策略（即使用重组白介素2）(40)，都必须在设计合理、随机设置的临床试验中进行研究，以确定其在HIV感染初次治疗管理中的作用。

表1 美国食品药品监督局（FDA）批准在美国使用的抗反转录病毒药物

表2 初次联合抗反转录病毒治疗（CART）方案，英国HIV联盟(67)

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