抗反转录病毒治疗的并发症

抗反转录病毒治疗的并发症

JoCarol McNabb, Pharm.D, M.P.A.

Assistant Professor

University of Nebraska Medical Center

College of Pharmacy

Omaha, NE 68198-6405

Phone: (402)559-4927

Email: jmcnabb@unmc.edu

Janell Kobayashi, Pharm. D.

Clinical Pharmacist, Pharmaceutical Services

Marin General Hospital

Greenbrae, California

Robert W. Shafer,M.D.

译者：吴鹏博士研究生

北京协和医院感染科

Email：wpnsync@163.com

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

Introduction

简介

Drug toxicity is often the most common reason for prematurely switching antiretroviral therapy (21) and is an important contributor to nonadherence and virologic failure. Antiretroviral drug toxicities can be divided into those that an immediate change in therapy (e.g. lactic acidosis, pancreatitis, severe hypersensitivity), those that can be managed conservatively unless they progress (e.g. peripheral neuropathy, hepatic transaminase elevations, hyperlipidemia, some hematological abnormalities), and those that may not pose serious danger to the patient but may decrease adherence and lead to virologic failure (e.g. headache, dysphoria, gastrointestinal intolerance).

药物毒性是过早更换抗病毒治疗方案(21)的一个最常见原因而且也是导致患者依从性差和治疗病毒学失败的一个重要因素。抗病毒治疗药物毒性的严重程度可以分为以下几种：一种是需要立即更换治疗方案（如乳酸酸中毒，胰腺炎，严重的过敏反应）；另外一种是可以保持继续治疗除非病情进一步进展（如外周神经炎，肝转氨酶升高，高脂血症，一些血液学异常）；还有一种就是不会导致严重疾病但会降低患者的依从性而且导致治疗病毒学失败（如头痛，烦躁不安，胃肠道反应）。

Many of the toxicities associated with NRTIs – including lactic acidosis, peripheral neuropathy, pancreatitis, lipoatrophy, and myopathy – result from NRTI-induced mitochondrial toxicity (8, 19, 73). This toxicity appears to be caused by a combination of nucleoside analog inhibition of mitochondrial gamma polymerase and interference with exonuclease removal of each analog after incorporation (38, 43). In vitro studies demonstrate the following hierarchy of mitochondrial DNA gamma polymerase inhibition: ddC > ddI > d4T > 3TC > tenofovir > ZDV > abacavir (38, 41, 47); however, 3TC, tenofovir, abacavir, and ZDV are efficiently removed after incorporation, reducing DNA gamma polymerase inhibition (7, 38, 43). Tissue-specific mitochondrial toxicity is a function of the cellular dependence on mitochondrial function and perhaps of the varying rates of triphosphorylation of the NRTIs in different cells (73). The molecular basis of the toxicities associated with PIs and NNRTIs is less well understood.

许多与核苷类反转录酶抑制剂有关的毒性，包括乳酸酸中毒、外周神经炎、胰腺炎、皮下脂肪萎缩、肌病都是由于这类药物能够产生线粒体毒性而造成的(8, 19, 73)。这种毒性可能是由于核苷类似物抑制了线粒体γ聚合酶并在该类似物整合到线粒体DNA后干扰了核酸外切酶清除该类似物所造成的(38, 43)。体外研究表明核苷类似物对线粒体DNAγ聚合酶的抑制程度依次排列如下：ddC > ddI > d4T > 3TC > TDF > ZDV >ABC (38, 41, 47)；尽管如此，3TC, TDF, ABC, 以及ZDV在整合入线粒体DNA后还是被及时地清除了，进而减少了对DNAγ聚合酶的抑制(7, 38, 43)，组织特异性的线粒体毒性是不同细胞的功能均依赖其线粒体功能的一种表现，概因核苷类反转录酶抑制剂在不同的细胞内三磷酸化的速率不同而造成的(73)。关于蛋白酶类抑制剂和非核苷类反转录酶抑制剂的毒性作用的分子机制目前还知之甚少。

Hypersensitivity reactions

过敏反应

Hypersensitivity reactions occur in up to 5% of patients receiving nevirapine or abacavir – although higher rates of nevirapine hypersensitivity were reported before the starting dose was lowered to 200 mg per day for the first two weeks. Hypersensitivity reactions to efavirenz and delavirdine also occur, but at a lower rate (26, 80). Of the PIs, skin rash occurs most commonly with amprenavir (78). Although amprenavir is a sulfonamide, the potential of cross-reactivity between amprenavir and sulfa drugs is not known. Idiosyncratic hypersensitivity reactions to the other PIs have rarely been reported.

在接受奈韦拉平或阿巴卡韦治疗的病人中有5%的人发生了过敏反应，但在开始治疗两周内每天使用奈韦拉平200毫克的疗法出现之前，报道中的奈韦拉平过敏反应还是比较高的。在接受依非韦伦和地拉韦啶治疗的病人中也有过敏反应的发生，但是比例要低一些(26, 80)。蛋白酶类抑制剂中，使用安普那韦患者皮疹最为常见(78)。尽管安普那韦是一种磺胺类药物，但是它与其他磺胺类药物的交叉反应还不清楚。其他蛋白酶类抑制剂导致的特殊体质的过敏反应目前报道很少。

Hypersensitivity reactions usually occur within six weeks of starting a new drug. NNRTI hypersensitivity is usually manifested by a maculopapular rash often accompanied by fever, mucosal changes, and elevated hepatic transaminases. Female patients are at a significantly higher risk of nevirapine hypersensitivity. In one study, 15% of women compared with 3% of men had a rash after starting nevirapine (3). Some clinicians have successfully continued treatment or desensitized patients using antihistamines and low doses of corticosteroids, but this practice is considered risky (51, 65, 78). The use of antihistamines and corticosteroids has not been shown to decrease the risk of nevirapine hypersensitivity in patients starting nevirapine. Despite the different chemical classes of each of the NNRTIs, there is some degree of cross-hypersensitivity between them. However, cross-hypersensitivity is not complete and unless a patient has had a life-threatening toxicity with one NNRTI (e.g. Stevens-Johnson Syndrome of toxic epidermal necrolysis), most physicians would be willing to re-challenge a patient with a different NNRTI (11).

过敏反应通常发生在使用一种新药的前6周内。非核苷类反转录酶抑制剂导致的过敏反应通常出现斑丘疹，并伴随发热，黏膜改变和转氨酶的升高。女性患者明显比男性患者更易对奈韦拉平产生过敏反应。在一项研究中，开始奈韦拉平的服药后有15%的女性在使用奈韦拉平后出现了过敏反应，而同组只有3%的男性出现了此反应(3)。一些临床医生用抗组胺药和小剂量的皮质激素类药物成功地维持了治疗或者使患者脱敏，但是仍有风险的(51, 65, 78)。使用抗组胺和皮质激素并没有减少病人在开始奈韦拉平治疗后发生过敏反应的风险。尽管非核苷类反转录酶抑制剂在化学结构上有所不同，但是它们在一定程度上还是存在相互交叉过敏反应。然而，这类药物的交叉过敏反应只在一定的程度上存在，除非这种过敏反应对于病人来说是致命的（如Stevens-Johnson综合征导致的中毒性表皮坏死溶解），否则大多数医生还是情愿给病人换用其他非核苷类反转录酶抑制剂(11)。

Abacavir hypersensitivity differs from many other drug-induced hypersensitivity reactions. Although fever and cutaneous involvement occur, they are often not prominent. In contrast, gastrointestinal symptoms, as well as symptoms compatible with an upper or lower respiratory infection occur commonly (35). Re-challenge with abacavir following a hypersensitivity reaction is absolutely contraindicated and may be fatal.

阿巴卡韦引起的超敏反应和很多其他种类药物引起的超敏反应有所不同。尽管发热和皮疹等皮肤改变也会发生，但常不是主要表现。相反，胃肠道症状和上下呼吸道感染的症状却经常发生(35)。如果发生了超敏反应后则禁止再使用该药进行治疗，并且很可能会导致生命危险。

Two groups have recently published data linking abacavir hypersensitivity to the HLA-B57 allele. In one study consisting predominantly of Caucasian patients from Western Australia, HLA typing had a nearly 100% positive predictive value for the development of abacavir hypersensitivity (45). A case control study in a more genetically diverse North America population confirmed a weaker association between HLA-B57 and abacavir hypersensitivity (34) and makes it unlikely that HLA typing can currently be used to decide who should receive abacavir or to confirm a suspected hypersensitivity reaction.

最近有两个研究小组发布关于阿巴卡韦引起超敏反应与HLA-B57等位基因关系的数据。其中由主要来自澳大利亚西部的高加索人组成的受试者的研究表明，HLA型别几乎可以百分之百地成功预测该病人在使用阿巴卡韦后是否会出现超敏反应(45)。另外一个病例对照研究则选取了来自北美的遗传背景多样的受试者，结果发现HLA-B57与阿巴卡韦引起的超敏反应(34)关系并不是那么密切，所以使得用HLA型别判定阿巴卡韦适应人群或者判断可疑的超敏反应的结果不那么可靠了。

Pancreatitis

胰腺炎

HIV-infected patients have much higher rates of pancreatitis than the general population (20, 55). The cause of this increase is multifactorial but the NRTIs are important contributory factors. The strongest association within the NRTI class is with ddI, particularly when administered at a high dose or together with hydroxyurea (20, 40, 55). d4T also appears to increase the risk of pancreatitis but to a lesser degree than ddI. 3TC showed a strong association with pancreatitis in one pediatric study but this observation has not been observed in other studies. The high triglyceride levels observed with certain PIs, particularly ritonavir, would be expected to also increase the risk of pancreatitis, but this has not yet been documented.

HIV感染者比一般人群更容易发生胰腺炎(20, 55)。导致该现象的原因是多种多样的。但是使用核苷类反转录酶类抑制剂是一个重要的诱因。核苷类反转录酶抑制剂药物中最容易引起胰腺炎的是DDI，特别是服用了大剂量或者是合并使用羟基尿的时候(20, 40, 55)。D4T也可能会增加胰腺炎的危险性但没有DDI的危险性高。曾有一个以儿童为受试者的研究中发现，3TC与胰腺炎的发生有关，但是这种现象并没有被其他的研究所证实。某些蛋白酶类抑制剂可能与高脂血症有关，特别是利托那韦，这同样也可能增加了发生胰腺炎的危险性，但这些相关性亦尚未被证实。

The diagnosis of pancreatitis is based on a combination of clinical criteria and laboratory tests. Serum lipase is the most sensitive and specific blood test; abdominal CT scan, MRI, and sonogram are useful radiological tests. The diagnosis of pancreatitis requires the immediate discontinuation of all pancreatotoxins and in some cases all medications until the patient is once again able to take oral medications. ddI is absolutely contraindicated in patients who have had pancreatitis. The threshold for using other NRTIs in such patients depends on the circumstances. For example, patients should probably not be given the same drugs they were receiving at the time pancreatitis developed if antiretroviral therapy is the likely cause. Patients who have had lactic acidosis at the time of their presentation should not be given d4T. Some investigators believe that lipase levels should be monitored in patients at risks for pancreatitis and that persistent high levels of lipase – even in the absence of symptoms – should prompt a change to NRTIs with a lower risk of pancreatitis.

胰腺炎的诊断基于临床标准和实验室检查。血清脂肪酶是最有效也是最特异的血液检查；腹部CT扫描、MRI、超声图都是有价值的放射学检查。对胰腺炎诊断后就需要立即停止使用一切有胰腺毒性的药物，对于一些情况严重的病人，甚至需要停用所有的药物直到病人可以重新开始口服药物。已有胰腺炎的病人绝对不能再使用DDI。在这类病人中使用核苷类反转录酶抑制剂要视情况而定。如果胰腺炎的发生可能是由抗病毒治疗引起的则病人不应继续该药治疗。如果病人在用抗病毒治疗期间出现乳酸酸中毒则不能使用D4T。一些研究者认为，应当对发生胰腺炎风险较高患者的脂肪酶水平进行监测，如果患者有持续高脂肪酶，即使没有症状出现也应当更换胰腺炎发生率较低的核苷类反转录酶抑制剂。

Lactic acidosis and hyperlactatemia

乳酸酸中毒与高乳酸血症

Hyperlactatemia is defined as a venous lactate level >18 mg/dL (2 mmol/L). Lactic acidosis is defined as an elevated venous lactate and low arterial pH (<7.30) (69). The clinical features of lactic acidosis include weight loss, fatigue, abdominal pain, tender hepatomegaly, nausea, vomiting, and respiratory distress. Recently it has been recognized that NRTI-associated lactic acidosis may present with a profound motor weakness resembling Guillain-Barré Syndrome (46). Accompanying laboratory abnormalities include increased anion gap and elevated hepatic transaminases, lipase, amylase, and CPK. Abdominal imaging studies show diffuse fatty infiltration of the liver. Liver biopsy shows severe microvesicular and macro vesicular steatosis (52). Severe lactic acidosis accompanied by lactate levels >10 mmol/l has a mortality of >50%.

高乳酸血症是指静脉血中乳酸盐的含量>18 mg/dL (2 mmol/L)。乳酸酸中毒是指高静脉血乳酸根含量以及低动脉血PH值(<7.30) (69)。乳酸酸中毒的临床特征包括体重下降、疲倦、腹痛、轻度肝肿大、反胃、呕吐以及呼吸窘迫。最近发现核苷类反转录酶抑制剂引起的乳酸酸中毒可以呈现出与格林巴利综合征相似的运动虚弱症状(46)。实验室检查的异常包括阴离子间隙增大，以及转氨酶、脂肪酶、淀粉酶、CPK升高。影像学呈现出肝脏弥漫性脂肪浸润。肝脏活检显示出现严重的肝微小囊状和大泡状脂肪变性(52)。严重的乳酸酸中毒在伴有乳酸根含量超过>10 mmol/l时，患者病死率高达>50%。

Lactic acidosis associated with hepatic steatosis has an incidence between 0.1%-2.0% per patient per year depending on the patient population and on how the syndrome is defined (10, 44). It was first reported with ZDV monotherapy (15) but has since been reported with each of the NRTIs and it is strongly linked to NRTI-induced mitochondrial toxicity (19). Female sex, pregnancy, obesity, long-term NRTI use, d4T administration, and ddI administration are associated with an increased risk of this toxicity (11, 19, 44, 46, 52, 58).

依据病人数量以及综合征的定义，每年每个病人发生伴随有肝脂肪变的乳酸酸中毒比例在0.1%-2.0%之间(10, 44)。关于核苷类反转录酶抑制剂的伴有肝脂肪变的乳酸性酸中毒的副作用报道是始于ZDV的单一疗法(15)，至今，所有核苷类反转录酶抑制剂介导的此类良反应均有报道并且认为此与NRTI介导的线粒体毒性有明显相关性（19)。女性、孕妇、肥胖、长期使用核苷类反转录酶抑制剂、服用D4T或DDI，都是此药物毒副作用的高风险因素 (11, 19, 44, 46, 52, 58)。

Treatment of acute lactic acidosis requires discontinuation of all NRTIs and supportive care. Bicarbonate infusions and hemodialysis (16), along with vitamin coenzymes (thiamine and riboflavin), electron acceptors (vitamin C), antioxidants (co-enzyme Q), and L-carnitine have been tried without definitive evidence of utility (9, 10, 78). Patients recovering from NRTI-associated lactic acidosis should either be changed to a non-NRTI containing regimen (e.g. a regimen containing an NNRTI and 1-2 PIs) or re-challenged cautiously after recovery with a NRTI with less mitochondrial toxicity (19).

对急性乳酸酸中毒的治疗包括停止使用所有的核苷类反转录酶抑制剂以及进行支持性治疗。输入碳酸氢盐和血液透析(16)，同时服用维他命和辅酶（硫胺和核黄素），电荷接受体（维他命C），抗氧化剂（辅酶Q），L-肉毒碱的疗法已经用于尝试但并没有确切的证据表明其有效性(9, 10, 78)。当病人从核苷类反转录酶抑制剂相关的乳酸酸中毒恢复之后，应当使用不含核苷类反转录酶抑制剂的用药方案（比如，一种非核苷类反转录酶抑制剂加一到两种的蛋白酶类抑制剂）或者谨慎使用线粒体毒性较小的核苷类反转录酶抑制剂(19)。

Lactate levels about 2-3 times the upper limit of normal may be associated with a compensated form of hyperlactatemia (4, 11, 36). This syndrome has been reported in 1%-10% of patients receiving NRTIs, particularly d4T, but it is difficult to define because lactate levels, particularly those obtained from venous blood, are difficult to measure accurately. Routine monitoring of lactate levels in asymptomatic patients is generally not recommended. But in patients with elevated lactate levels, some physicians choose to replace ddC, ddI, d4T, and ZDV with less mitochondrial-toxic NRTIs such as abacavir, 3TC and tenofovir (19, 44).

乳酸根高于正常标准上限的两到三倍可能是高乳酸血症的一种代偿形式(4, 11, 36)。这种综合征在使用核苷类反转录酶抑制剂的患者特别是使用D4T的患者中发生率约为1%-10%，但此数值来源于患者静脉血，而静脉血里的乳酸根含量很难精确测得，所以，给出高乳酸血综合征的诊断非常困难。因此，不推荐对无症状患者进行乳酸根的常规监测。但是如果患者出现乳酸根升高的情况，一些医生会选择线粒体毒性较小的核苷类反转录酶抑制剂如阿巴卡韦，3TC和替诺福韦来代替DDC，DDI，D4T，ZDV等药物(19, 44)。

Venous lactate levels are highly dependent on collection techniques. Proper collection procedures include (i) having the patient avoid dehydration or exercise for 24 hours prior to venipuncture, (ii) having the patient sit relaxed for 5 minutes prior to venipuncture, (iii) avoiding fist clenching and the use of a tourniquet, (iv) collecting the sample in a chilled gray-top (sodium fluoride-potassium oxalate) tube, (v) placing the sample on ice and sending it to the laboratory for processing within 30 minutes of collection, (vi) repeating elevated levels after providing additional instructions including the avoidance of alcohol for 24 hours and food or drink for four hours prior to venipuncture. If proper collection procedures are not possible and hyperlactatemia or lactic acidosis are likely, arterial lactate levels should be measured.

静脉乳酸根含量的测定与血样本采集技术流程有关。合理的收集技术包括(1)使病在静脉穿刺的前24小时避免脱水和运动；(2)在穿刺前让病人坐下放松5分钟；(3)避免病人握拳并且不使用止血带，(4)使用低温的避光管（氟化钠--草酸钾管）收集样本；(5)将收集的标本置于冰上并在取血30分钟内送检，(6)要提高检测重复性，则要求病人在穿刺前的24小时内避免饮酒，4小时内不进食饮水。如果无法进行恰当的采集程序而又可能是发生高乳酸血症或乳酸酸中毒的情况，则应测量动脉血的乳酸根水平。

In a recent study, the ratio of mitochondrial to nuclear DNA in peripheral blood mononuclear cells was significantly reduced in patients with symptomatic hyperlactatemia (19). All eight patients in this study were receiving d4T and six of these were also receiving ddI. Discontinuation of NRTIs was associated with improvement in lactic acid levels and in mitochondrial to nuclear DNA ratios. Improvements were sustained for up to three months even after the patients were switched to other NRTIs. If these results are reproduced, measuring the ratio of mitochondrial to nuclear DNA may become a useful means of identifying patients at higher risk of symptomatic lactic acidosis.

在最近的研究中发现，出现了有症状乳酸血症的患者外周血单核淋巴细胞中的线粒体DNA与核DNA的比例是显著降低的(19)。该研究中全部8名患者都使用了D4T，其中6人使用了DDI。停用核苷类反转录酶抑制剂与患者乳酸水平和线粒体DNA与核DNA比例的改善有相关性。尽管有些患者已经改用其他的核苷类反转录酶抑制剂，改善仍可持续3个月的时间。如果这个结果是可重复的，那么测量线粒体DNA与核DNA比例将成为一种有效的发现存在有症状乳酸中毒的高风险患者的方法。

Hepatitis

肝炎

Asymptomatic elevations of hepatic transaminases occur in 6%-30% of patients receiving combination antiretroviral therapy. The main risk factors for hepatitis appear to be chronic infection with HCV or HBV, alcohol ingestion, and the administration of nevirapine, ritonavir, or ddI+d4T — particularly in pregnant women (31, 48, 75, 76, 82). However, each of the NNRTIs and PIs can cause hepatitis.

在使用联合抗病毒治疗的患者中有约6%-30%的人会出现无症状的转氨酶升高。肝炎的主要风险应该和HCV或HBV的慢性感染、饮酒、使用奈韦拉平、利托那韦或者联合使用DDI与D4T有关---对于孕妇尤其如此。(31, 48, 75, 76, 82)。不过非核苷类反转录酶抑制剂或蛋白酶类抑制剂亦可导致肝炎。

Hepatitis associated with nevirapine usually occurs within the first few weeks of administration whereas hepatitis associated with ritonavir usually occurs with chronic administration. The DHHS recommends that hepatic transaminase levels be closely monitored in persons starting nevirapine: every two weeks for the first month, monthly for the next 12 weeks, and every one to three months thereafter (78).

奈韦拉平相关肝炎多在治疗用药的初期就可能发生，而使用利托那韦发生的肝炎多是慢性用药所致。因此DHHS建议，如果开始服用奈韦拉平就要密切关注肝转氨酶水平，在用药的第一个月要每两周检查一次，之后12周要每月检查一次，再之后要每1--3月检查一次(78)。

Patients with history of chronic viral hepatitis or elevated transaminase levels should be counseled to avoid alcohol and hepatotoxic drugs such as acetaminophen and isoniazid. Most clinicians would discontinue all drug therapy or the drug considered most likely to be causing hepatitis when transaminase levels are ≥5 times the upper limit of normal. Re-challenge with the offending agent is not generally recommended, unless an alternative cause for the elevated transaminase levels is suspected. Transaminases should be measured monthly in patients with levels between 2-5 times the upper limit of normal.

对于有慢性病毒性肝炎病史或有肝转氨酶升高的病人则应劝其避免饮酒、使用肝毒性的药物，如对乙酰氨基酚、异烟肼等。多数的医生会在转氨酶达正常上限的5倍或以上时停止使用所有的药物或者停用最有可能导致肝炎的药物。一般情况下不推荐再次使用导致转氨酶升高的药物除非存在其他的可能导致转氨酶升高的原因。如果病人转氨酶的水平是正常上限的2到5倍则要每月都检查转氨酶的水平。

Unconjugated hyperbilirubinemia occurs frequently with indinavir but does not represent liver toxicity and does not require indinavir discontinuation. Withdrawal of 3TC in patients with chronic HBV can also lead to a flare in hepatitis, therefore, it is important to be aware of HBV serologies in all patients receiving HAART.

高游离胆红素血症经常发生在使用茚地那韦治疗时。因为这并不表示出现肝毒性，所以也不需要停药。停用3TC后，有慢性乙肝的患者会出现肝炎复发，因此在进行HAART治疗中留意HBV的血清学状态是很重要的。

Peripheral neuropathy

周围神经病变

The most common neuropathy in HIV-infected patients is a distal, symmetrical, predominantly sensory axonal neuropathy. Patients complain initially of numbness and then develop burning pain in their feet, which may extend proximally and, in rare cases, involve the distal upper extremities. Neurological examination will reveal depressed or absent ankle reflexes relative to the knees, increased vibratory thresholds and reduced pain and temperature sensations. Although this syndrome was initially recognized in untreated patients with advanced HIV infection, it now occurs most commonly in association with ddC, ddI, and d4T, particularly when they are administered with hydroxyurea (11, 56, 71). Other risk factors for neuropathy are a low CD4+ cell count (<100/mm³), heavy alcohol consumption, nutritional deficiencies (e.g. vitamin B12), use of other neurotoxic drugs (e.g. isoniazid, dapsone), and diabetes mellitus.

在HIV感染者中最常见的神经病变多是末梢性、对称性的感知觉轴突性神经病变。患者的主诉是开始麻木然后发展为足部烧灼感，这些症状可扩散至附近部位，在一些罕见病例里，甚至可能累及上肢末端。神经检查能够发现相对于膝反射，踝反射减退或者消失，震动觉阈值增高，痛温觉减弱。虽然这种综合征最初是在未经治疗的、严重的HIV感染者中发现的，但是现在这种情况更多见于使用DDC，DDI，D4T，特别是同时使用羟基尿的病人身上(11, 56, 71)。其它导致神经病变的危险因素有：低CD4细胞计数(<100/mm³)、酗酒、营养缺乏（如维他命B₁₂）、使用神经毒性药物（如异烟肼，氨苯砜）、以及糖尿病。

Management usually requires substitution or dose reduction of one or more of the neurotoxic drugs. Symptoms may intensify in the first few weeks after drug discontinuation but they will gradually improve. Treatment should begin with non-narcotic analgesics. Tricylcic antidepressants, gabapentin, and carbamazepine have also been tried with minimal success. With severe neuropathy narcotics are often necessary. Each of these measures is temporizing; discontinuing the offending drug is the only measure that reverses the underlying pathology.

解决的办法通常是换药或者减少一种或者多种神经毒性药物的用量。神经病变的症状在停药的最初几周内可能还会加剧，但是随后会逐渐得到改善。治疗开始时要用非麻醉剂的镇痛药。三环类抗抑郁药物加巴喷丁、卡马西平也尝试用于治疗，但疗效有限。如果出现严重的神经病变则麻醉药常常是必需的。这些都是姑息性的措施。只有停用有神经毒性的药物才是唯一能够逆转潜在神经病变的方法。

Lipodystrophy

脂肪异常分布

Changes in body fat distribution occur in a large proportion of HIV-infected patients receiving HAART. Accumulating data suggest that lipodystrophy consists of two different syndromes: lipoatrophy caused by NRTIs and possibly exacerbated by concurrent PI and visceral fat accumulation caused by PIs (37). The lipoatrophy appears to be associated with other NRTI-associated mitochondrial toxicities including lactic acidemia, whereas the visceral fat accumulation appears to be associated with PI-induced hyperglycemia and hyperlipidemia. Patients with lipodystrophy have not been shown to have a worse prognosis than patients without this toxicity, but lipoatrophy, particularly facial lipoatrophy is often felt to be physically stigmatizing. The fat accumulation is often intraabdominal (visceral), dorso-cervical ("buffalo hump"), and in women, may manifest as breast enlargement.

使用HAART治疗的HIV感染者中很多人都出现了体脂分布异常。大量的数据显示脂肪异常分布包括两种不同的症状：核苷类反转录酶抑制剂可以导致脂肪萎缩并可能由于同时使用蛋白酶类抑制剂而加重脂肪萎缩的程度；蛋白酶类抑制剂也导致内脏脂肪的聚积(37)。脂肪萎缩会伴随着核苷类反转录酶抑制剂的线粒体毒性，如乳酸血症，而内脏脂肪聚积则似乎与蛋白酶类抑制剂药物产生的高血糖症、高脂血症相联系。有脂肪异常分布的病人较其他病人预后无明显差别，但面部脂肪萎缩会使得一些患者在生活中感觉到被打上了耻辱的标签。脂肪聚积通常表现为腹部脂肪堆积（内脏），颈背部脂肪堆积（水牛背）；在女性中，可能表现为乳房增大。

There is no uniform definition for lipodystrophy, leading to a wide range of incidence estimates. The fat loss and fat gain are continuous processes; the distinction between symptomatic vs. asymptomatic disease depends on patients' subjective complaints. Dual X-ray absorptiometry (DEXA) scans are accurate for measuring changes in total body, limb, and trunk fat mass. However, because abdominal subcutaneous and visceral fat may change in opposing directions, single-cut L4 CT scans are preferable for analyzing abdominal fat (37, 53), although this is a primarily a research tool. Cheaper techniques such as anthropometry, bioelectric impedance testing, and ultrasonography are less accurate but may be useful for following individual patients.

由于没有一个脂肪异常分布的统一定义，所以关于它的发生率的估计也只是一个很大的范围。脂肪丢失和脂肪聚积是一个连续的过程；有症状和无症状的区别也主要是依靠患者自身的感觉。双重X线吸收(DEXA)扫描是测量整个身体、上肢、躯干脂肪指数的一个准确方法。但由于腹部皮下脂肪和内脏脂肪可以向两个不同方向变化，所以对腹部脂肪测量最好是采用单切L4 CT扫描(37, 53)（这只是一个主要作为研究而使用的工具）。一些较便宜的检查如人体测量、生物电阻抗检测、超声检查虽然都不那么精确但是对单个病人随访却很实用。

The major risk factors for lipoatrophy include long-term NRTI treatment, older age, female gender, Caucasian background, and the simultaneous use of PI therapy. Within the NRTI class, d4T has been associated with the greatest risk in multiple nonrandomized studies (27, 37, 66-68) and in a randomized study (39). ZDV, ddI, and 3TC have also been linked to lipoatrophy (37). Fewer data are available for ddC because it is rarely used. The median time to onset of lipodystrophy in observational studies has been about 68 weeks.

导致脂肪异常分布的主要危险因素有长期使用核苷类反转录酶抑制剂治疗、高龄、女性、高加索人种、以及同时使用蛋白酶类抑制剂。在许多非随机(27, 37, 66-68)和一个随机研究中(39)都发现D4T是核苷类反转录酶抑制剂中最容易导致脂肪异常分布的药物。ADV、DDI、3TC也都与脂肪萎缩有关(37)。由于DDC使用较少所以关于这个药的研究报告也比较少。在关于脂肪异常分布的观察研究中显示，一般脂肪异常分布出现于治疗后的68周左右。

Studies in which PIs have been replaced with an NNRTI or abacavir have found no effect on body habitus changes (37). However, the substitution of abacavir for d4T or ZDV was recently associated with a slight total body fat gain of about 0.5 kg over 24 weeks (13). Physical exercise and dieting may diminish visceral fat accumulation. Metformin, an insulin-sensitizing agent, may also decrease visceral fat accumulation in addition to improving glucose tolerance (33). Recombinant growth hormone has been studied in small trials and may slightly improve both lipoatrophy and visceral fat accumulation (42), although it has potential to cause insulin resistance and glucose intolerance and is therefore not routinely recommended (69). Androgen therapy is also not recommended due to lack of safety and efficacy data (69). There are anecdotal reports of various forms of cosmetic surgery also being used for treating lipoatrophy (e.g. facial implants) and visceral fat accumulation (e.g. surgical resection of dorsocervical fat).

研究发现使用非核苷类反转录酶抑制剂或者阿巴卡韦代替蛋白酶类抑制剂之后对身体形态没有产生影响(37)。而在使用阿巴卡韦代替D4T或ZDV持续治疗24周后，体重仅增加0.5KG(13)。身体锻炼和节食都有助于减少内脏脂肪的堆积。胰岛素的增敏剂二甲双胍除了改善糖耐量之外，或许也具有减少内脏脂肪聚积的作用(33)。小规模研究发现重组生长激素对于改善脂肪萎缩和内脏脂肪聚积可能都有一些积极作用(42)，但它有可能导致胰岛素抵抗和糖耐量降低，因此并不推荐常规使用(69)。雄激素由于缺乏安全和有效的试验数据因此也不推荐常规使用(69)。有趣的是各种形式的美容手术也可用于治疗脂肪萎缩（如面部脂肪植入）和内脏脂肪聚积（如手术切除颈背部脂肪）。

Hyperlipidemia

高脂血症

Untreated HIV is associated with lower cholesterol levels (including HDL) and higher triglyceride levels. Significant increases in triglyceride and LDL cholesterol levels occur during treatment with each of the available PIs (25). These increases are common and often result in cholesterol and triglyceride levels that meet the National Cholesterol Education Program (NCEP) guidelines for treatment (61, 68). Ritonavir has been associated with the greatest increases in triglycerides and cholesterol (24, 64, 69). Nelfinavir and amprenavir appear to have effects that are less than ritonavir but more than indinavir and saquinavir. Atazanavir, an investigational PI in phase III studies, has not been associated with hyperlipidemia.

未经治疗的HIV患者可伴发低胆固醇（包括HDL）和高甘油三酯血症。甘油三酯和LDL的显著增加常发生在用蛋白酶类抑制剂治疗的患者(25)。血脂的这种改变常见并且常引发了甘油三酯和胆固醇水平过高而符合胆固醇全国教育计划中 (NCEP)所制定的治疗指南(61, 68)。在蛋白酶抑制剂中，利托那韦最容易导致甘油三酯和胆固醇增加(24, 64, 69)。奈非那韦与安普那韦这种效应的强度比利托那韦要弱，但要强于茚地那韦和沙奎那韦。阿扎那韦是一种正在进行3期临床试验的蛋白酶类抑制剂，尚未发现该药使用时发生高脂血症。

Anecdotal reports of premature atherosclerotic disease have been reported in patients receiving PIs. Two population-based studies assessed this risk. A retrospective study of HIV-infected male Veterans Administration patients in the U.S. did not show an association between NRTI, PI, and NNRTI use and cardiovascular or cerebrovascular disease over a median period of 17, 16, and 9 months, respectively (6). However, a large prospective European study showed a 27% increased risk of myocardial infarction per year of HAART exposure (30). Taken together these studies suggest that the benefits of HAART greatly outweighs the slight increased risk of cardiovascular morbidity and mortality that is associated with some HAART regimens; but that persons developing metabolic changes associated an increased risk of cardiovascular diseases should be managed to decrease their long-term risk of cardiovascular mortality.

一些有趣的报道称在使用PIs的患者中有人出现了早期的动脉粥样硬化疾病。有两组研究对此进行了风险评估。其中，美国的以合理用药的HIV男性患者为观察对象进行的回顾性研究发现，使用核苷类、蛋白酶类、非核苷类反转录酶抑制剂治疗平均17、16、9个月后心脑血管疾病发病并无相应增加(6)。但另一个欧洲大型前瞻性的研究表明，每使用HAART治疗一年，患者心肌梗塞的危险性就增加27%(30)。综合这些研究发现，使用HAART治疗的益处要远远超过某些HAART疗法所带来微弱的心血管病发生率和病死率的增加，但是由于病人用药而出现代谢的改变，进而导致心血管的发病风险的增加，所以应当设法对这种情况进行处理以减少其长期的心血管病死率。

Guidelines for treating HAART-associated dyslipidemias have been published by the ACTG Cardiovascular Disease Focus Group (25) and by the IAS-USA (69). Serum lipids should be evaluated after the patient has fasted for a minimum of 8 and preferably 12 hours. The standard screening lipid profile, including measurement of total cholesterol, HDL cholesterol, and triglycerides, should be obtained before and 3-6 months after starting HAART. If the triglyceride level is less than 400, the LDL cholesterol level can be calculated from the measured values. If the triglyceride level is >400, then LDL cholesterol can be specifically measured. Patients with elevated cholesterol and triglycerides should be screened for other cardiac risk factors such as smoking, hypertension, diabetes, family history of heart disease, menopausal status, obesity, and physical inactivity and for potential exacerbating factors such as excessive alcohol use, hypothyroidism, renal disease, liver disease, hypogonadism, and the use of certain drugs (e.g. corticosteroids, beta-blockers, thiazide diuretics) (25).

HAART相关血脂紊乱的治疗指南已经由ACTG的心血管病组(25)和IAS-USA发布(69)。血脂测量应该在患者最少禁食8小时（最好是12小时）后进行。标准的血脂筛查包括总胆固醇、HDL和甘油三酯的水平，并且应该在患者开始HAART治疗前以及治疗3到6个月后进行测量。如果甘油三酯的水平低于400则LDL要计算在其内，如果高于400，LDL要单独进行计算。病人有甘油三酯和胆固醇的升高时，应当排除其他心脏危险因素如吸烟、高血压、糖尿病、心脏病家族史、更年期、肥胖、缺乏锻炼和其他潜在的威胁因素如酗酒、甲状腺功能低下、肾脏病、肝病、性功能低下，以及使用特殊的药物（如皮质激素、β-受体阻断剂、噻嗪类利尿剂）(25)。

There are three complementary approaches to therapy. The first involves therapeutic life-style changes that include dietary changes, weight loss and increased exercise (60). The second involves switching from a PI to an NNRTI or abacavir. Preliminary data suggests that nevirapine, in particular, may have anti-atherogenic lipid profile (79). Switching is likely to be successful in patients with controlled viremia who have had little previous therapy (12, 18, 22, 62). But patients receiving PIs as part of a salvage therapy regimen may experience virologic relapse if they switch to a drug to which they already harbor some degree of resistance (50, 63). If a patient is receiving ritonavir, lowering its dose by as little as 100 mg may lower cholesterol and triglycerides. The third approach involves lipid-lowering drug therapy, which is recommended for patients with triglyceride levels >500-1000 mg/dL or LDL cholesterol levels as specified in Table 1 (60).

有三种补救性的治疗方法：第一种是有治疗意义的生活方式改变，包括饮食调整、减肥、增加运动量(60)；第二是用非核苷类反转录酶抑制剂或者阿巴卡韦代替蛋白酶类抑制剂进行治疗。初步研究数据表明奈韦拉平很可能存在抗动脉粥样硬化的作用(79)。对于治疗时间并不长而且病毒血症得到控制的患者，换药的成功率较大(12, 18, 22, 62)。如果蛋白酶类抑制剂作为患者挽救性疗法的一部分，那么将其换为对体内毒株已经耐药的药物后，可能会产生病毒载量的反弹。(50, 63)。如果患者使用利托那韦治疗，那么减少到100mg的用量有助于降低胆固醇和甘油三酯水平；第三种是专门降低血脂的药物治疗，对于甘油三酯水平超过500-1000mg/dl或者LDL已达如表一所列出的水平(60)时使用。

Specific medical treatment depends on whether a patient has isolated high-levels of LDL cholesterol, isolated hypertriglyceridemia, or combined hyperlipidemia (Table 2). The 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors (or statins) are the drugs of choice for hypercholesterolemia. In patients receiving PIs, the use of statins is complicated by the fact that most are metabolized by CYP3A4 enzyme, leading to a theoretical increased risk in skeletal muscle toxicity and rhabdomyolysis (Table 3). Lovastatin and simvastatin are the most extensively metabolized by CYP3A4 and should therefore be avoided. Pravastatin and atorvastatin are the preferred statins because they have the fewest interactions with PIs (29). Fluvastatin is an acceptable alternative agent. Patients should be started on a low initial dose of the statin (e.g. 20 mg of pravastatin or 10 mg of atorvastatin daily) and have the dose titrated up gradually to reduce the risk of myopathy. None of the statins are known to be strong inhibitors or inducers of CYP3A4, and they are not expected to influence the levels of PIs or NNRTIs. The fibrates (e.g. gemfibrozil and fenofibrate) are second-line agents for treating isolated hypercholesterolemia.

不论是只有高LDL或高甘油三酯，还是混合性高脂血症，不同情况下患者采取的的治疗方式不同（表2）。对于高胆固醇血症而言要选择3--羟基--3--甲基戊二酰辅酶A还原酶抑制剂（即他汀类）。如果患者正进行蛋白酶类抑制剂的治疗，使用他汀类药物要谨慎，因为大多数他汀类是通过CYP3A4酶进行代谢的，理论上会增加对骨骼肌的毒性而且可以导致横纹肌溶解（表3）。由于洛伐他汀和辛伐他汀都是主要通过CYP3A4进行代谢的，因此不适用于此类病症的治疗。在他汀类药物中，普伐他汀和阿托伐他汀与蛋白酶类抑制剂的相互作用最小，因此是此种病症的首选他汀类药(29)。氟伐他汀可作为上述两种药物的替代品。开始治疗时应当从小剂量开始（如每日20mg普伐他汀或者10mg阿托伐他汀）剂量增加应逐渐调整以减少引起肌病的风险。他汀类药物均不是强效的CYP3A4的抑制剂或者诱导剂，因此这类药物应当不会影响蛋白酶类抑制剂或非核苷类反转录酶抑制剂的浓度。贝特类（如吉非罗齐和非诺贝特）作为治疗单独的高胆固醇血症的二线药物。

In patients with isolated hypertriglyceridemia, the fibrates are the drugs of choice, followed by statins. For patients with combined hyperlipidemia, initial treatment should begin with a statin. If ineffective after three months of therapy, a fibrate can be added (69). This should be done cautiously, however, because combining a statin and fibrate may increase the risk of myopathy and rhabdomyolysis. Niacin is also effective in treating hypertriglyceridemia but is often not recommended because of its propensity to cause insulin resistance. A recent uncontrolled report, however, suggests that niacin may have the added advantage of raising HDL cholesterol levels and reducing intra-abdominal fat in HIV-infected patients with dyslipidemias (28).

如果患者是单纯的高甘油三酯血症则贝特类药物是首选治疗药物，其次是他汀类。如果患者是混合性高脂血，开始治疗时应选用他汀类药物。如果治疗3个月后无效，则可用贝特类药物(69)。联合用药时要谨慎，因为这样会使肌病和横纹肌溶解的风险增加。烟酸对于治疗高甘油三酯血症也十分有效但通常并不推荐，这是因为该药有导致胰岛素抵抗的倾向。最近一份非对照的研究报告称，烟酸可能有增加HDL水平的作用并且有助于减少HIV感染者由于血脂紊乱而导致的腹内肥胖(28)。

D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. The Lancet DOI 2008;10.1016/S0140-6736(08)60423-7

Insulin resistance

胰岛素抵抗

Treatment of HIV-infected patients with PIs has been associated with insulin resistance, hyperglycemia, and the development of diabetes mellitus. Insulin resistance has been found in as many as 40% of patients receiving PIs (2, 23, 59, 77, 81) (69). Most of the data linking PIs with insulin resistance have been based on patients receiving indinavir, ritonavir, and saquinavir. There appears to be a lower risk of diabetes with nelfinavir, amprenavir, and lopinavir.

使用蛋白酶类抑制剂治疗HIV会导致患者胰岛素抵抗，高血糖症和糖尿病的进展。在使用这类药物治疗的病人中有40%出现了胰岛素抵抗(2, 23, 59, 77, 81) (69)。绝大多数导致这种情况发生于使用茚地那韦、利托那韦和沙奎那韦的HIV感染者中。而使用奈非那韦、安普那韦和洛匹那韦则发生糖尿病的可能性要小。

Frank diabetes（frank diabetes: an essentially asymptomatic but still potentially pathological stage characterized by mild hyperglycemia）, clinically similar to type 2 diabetes, develops in about 1% - 6% of patients receiving PIs (23). Some experts recommend monitoring fasting blood glucose every 3-4 months in patients receiving PIs and more frequently in pregnant women. Normal fasting plasma glucose should be <110 mg/dL. Impaired fasting glucose is between 110-125 mg/dL. Frank diabetes is defined as a fasting plasma glucose ≥126 mg/dL or a random plasma glucose ≥200 mg/dL.

使用蛋白酶类抑制剂的病人中有大约1% - 6%的病人会出现糖尿病，其临床症状类似于2型糖尿病(23)。一些专家建议对于使用蛋白酶类抑制剂的病人应当每3到4个月就进行空腹血糖检测，而在孕妇中这种检测应该更加频繁。普通空腹血糖应在110mg/dl以下。异常空腹血糖在110-125mg/dl之间。而糖尿病的定义为空腹血糖≥126mg/dl或者随机血糖≥200mg/dl。

Patients who are treated with PIs or who have lipodystrophy should be informed about the warning signs of hyperglycemia: polydipsia, polyphagia, and polyuria. Treatment should follow the established guidelines for treating diabetes in the general population including conservative measures such as diet modifications, weight loss, and exercise. If diabetes persists despite these interventions, insulin-sensitizing agents with or without discontinuation of PI therapy should be considered. Insulin, oral sulfonylureas, and metglitinides may be used in severe cases, but caution is advised to avoid hypoglycemia.

对于使用蛋白酶类抑制剂治疗或者有脂肪异常分布的病人，医生应当提醒他们注意高血糖的表现如多饮、多食、多尿。治疗可以遵循对于普通人群所制定的糖尿病治疗指南包括保守的饮食调整、减肥、运动等。如果保守治疗后仍持续出现糖尿病，那么就应该考虑使用胰岛素增敏剂并且考虑是否停止蛋白酶类抑制剂的治疗。在严重的病例中可以考虑使用胰岛素、口服磺脲类药物、或者metglitinides，但需注意低血糖的发生。

Central nervous system (CNS) toxicity

中枢神经系统（CNS）毒性

Headache is a common complaint in patients initiating therapy with ZDV. ZDV-associated headache resolves in most patients but a small proportion remain intolerant and must change to another NRTI (usually d4T). Approximately one-third of patients receiving efavirenz have some form of dysphoric CNS side effect including poor concentration, dizziness, insomnia, nightmares and rarely hallucinations (1). It is unusual for patients to discontinue therapy for these symptoms, as they usually subside over the first few weeks of therapy (11, 74). If they persist, however, it is common to switch to nevirapine. One study suggests that patients receiving efavirenz who develop CNS symptoms have serum drug levels several times higher than patients without toxicity (49). However, there are currently no guidelines on how to use efavirenz serum levels in clinical settings and reducing the dose of efavirenz is currently not recommended. Patients with a previous history of mental illness may be at a greater risk of serious psychiatric adverse events such as paranoia, aggression, and depression.

当患者开始服用ZDV治疗的时候通常的主诉为头痛。ZDV相关的头痛在大多数患者中都能消退，有很少一部分不能耐受的患者则需要换其他的核苷类反转录酶抑制剂（通常为D4T）。在使用依非韦伦治疗的患者中有大约三分之一会出现烦躁不安的副作用，包括注意力不集中、头晕、失眠、噩梦，部分患者会有幻觉(1)。由于患者在经过最初的几周治疗后副作用都能消退，所以很少患者因为这些副作用而停止治疗(11, 74)。如果这些症状持续存在，一般就要换用奈韦拉平治疗。一个研究显示患者在使用依非韦伦治疗出现CNS症状时，血浆药物浓度高于没有出现毒性反应患者的数倍(49)。尽管如此，在临床背景下对依非韦伦的血药浓度调整并没有一个治疗指南，而且也不推荐减少其用量。对于原来就有精神疾病病史的患者来说，他们出现严重精神不良反应如谵妄、攻击性、抑郁等的危险性就更大。

Hematological toxicity

血液系统毒性

Reversible anemia (uniformly associated with an MCV >100 fL) and granulocytopenia develop in about 5-10% of patients receiving ZDV, particularly in patients with advanced HIV infection (11). Depending on the severity of these toxicities, it is common to either reduce the dose of ZDV, substitute an alternate NRTI such as d4T or abacavir, or, in some cases, to treat the patient with erythropoietin (EPO) or granulocyte-colony stimulating factor (G-CSF). Baseline endogenous EPO levels of <500 IU/L are predictive of a response to EPO (17).

在使用ZDV治疗的患者中，特别是病情严重的患者中有大约5%-10%的人会出现可逆性贫血（表现为MCV>100 fL）和粒细胞减少(11)。由于毒性反应严重，通常不是减少ZDV的用量，就是用核苷类反转录酶抑制剂如D4T或者阿巴卡韦进行替代治疗，或者在一些病例中，会使用促红细胞素（EPO）或者集落细胞刺激因子（G-CSF）。内源性EPO<500 IU/L表示机体对外源性EPO产生了反应(17)。

Increased spontaneous bleeding episodes in patients with hemophilia A and B have been observed with the use of PIs (78). Most of the reported episodes have involved joints and soft tissues. The bleeding episodes have occurred a median of 22 days after starting PI therapy and may require the use of additional coagulation factor (78).

伴发血友病的HIV患者使用蛋白酶类抑制剂会增加自发性出血的概率(78)。大多数病例的出血部位都是在关节和软组织处。这些病例是在开始服用蛋白酶类抑制剂平均22天左右发生的，治疗上或许应该使用更多的凝血因子(78)。

Gastrointestinal complaints

胃肠道不适

Nearly all antiretrovirals can cause nausea, vomiting, and diarrhea. These symptoms tend to be worse at the start of therapy and to improve over time. However, drug substitution becomes necessary in many patients. Persistent ZDV-induced nausea often requires a change to d4T. ddI-induced nausea has become less of a problem with the development of the enteric-coated (EC) formulation. Nausea and diarrhea with ritonavir have become less of a problem since lower doses of ritonavir are now often used in combination with other PIs. Diarrhea is particularly common with nelfinavir and amprenavir. It is usually treated by dietary modifications, bulking agents, or loperamide.

几乎所有的抗病毒药物都会导致反胃、呕吐和腹泻。在开始治疗时症状一般比较严重但随着时间推移会有所缓解。尽管如此，还是有很多患者需要换药。由ZDV导致的持续反胃通常用D4T替代治疗。DDI引起的反胃由于改用肠溶剂（EC）后得到了相当大的改善。由于联合使用蛋白酶类抑制剂，利托那韦的用量减少，所以其所引起的反胃和腹泻也改善了很多。腹泻常见于使用奈非那韦和安普那韦的患者，而其治疗通常是改变饮食结构，使用膨胀剂或者是洛哌丁胺。

Renal toxicity

肾毒性

Indinavir is poorly water-soluble and can crystallize in the urine causing obstruction anywhere between the renal tubules and urethra (11). This can lead to renal colic, painless hematuria, and, rarely, an asymptomatic rise in serum creatinine (5). Clinically symptomatic nephrolithiasis occurs in about 10% of patients, although it may be more common in patients receiving ritonavir-boosted indinavir (72). If it is not associated with permanent renal or urologic damage, therapy can be continued provided the patient consumes sufficient liquids (preferably ≥1.5 liters above baseline). Recurrences occur in about 50% of patients.

茚地那韦水溶性不好，因此，会在尿中形成结晶而堵塞在肾小管和尿道中(11)。这会导致肾绞痛、无痛性血尿以及罕见的无症状血肌酐升高(5)。临床上有症状的结石病人在患者中的比例大概占10%左右，并且在使用利托那韦作为增效剂的茚地那韦治疗中，此类病人更为多见(72)。如果不引起永久的肾脏或者尿路损伤，治疗可以继续，同时要让病人多喝水（最好是在平时饮水基础上多饮1.5公升以上）。但约50%的病人都会复发肾脏或者尿路损伤。

Musculoskeletal disease

骨骼肌肉疾病

Up to 15% of patients receiving long-term ZDV may develop myopathy resembling idiopathic polymyositis (11). Patients present with myalgias, muscle tenderness, proximal muscle weakness, and prominent muscle atrophy. CPK levels are usually elevated and a muscle biopsy demonstrates "ragged red fibers". Mitochondrial toxicity is believed to be the basis for this toxicity, which may rarely also present as a cardiomyopathy. Treatment involves substituting a different NRTI for ZDV.

长期使用ZDV治疗的病人中有多达15%的人会出现类似于特发性多发性肌炎的肌病(11)。病人会出现肌痛，肌肉松弛，近端肌肉无力以及明显的肌肉萎缩。CPK水平通常升高而且肌肉活检显示破布样的红色纤维。造成这种现象的主要原因是线粒体毒性，而且它还可能呈现出心肌病的表现。治疗上主要是使用其他核苷类反转录酶抑制剂来代替ZDV进行治疗。

Osteonecrosis is an increasingly recognized disorder associated with long-term HIV infection and antiretroviral therapy. The areas most often affected are the femoral and humeral heads, femoral condyles, proximal tibia, and small bones in the hand and wrist (69). A recent cross-sectional study using MRI detected avascular necrosis of the hip in 15 (4.4%) of 339 patients (54, 69). Osteopenia and osteonecrosis have been linked to past corticosteroid use but not to any particular class of antiretroviral drug (32, 57, 70). Reduced bone mineral density is usually first observed 18 months after the initiation of antiretroviral therapy. Other risk factors for osteopenia and osteonecrosis include heavy alcohol consumption, smoking, hyperlipidemia, malnutrition, and inactivity.

骨坏死是一种日渐被重视的、由于长期HIV病毒感染和进行抗病毒治疗后所引起的机能紊乱。最常受累的部位有股骨头和肱骨头、股骨突起、胫骨近躯干部，以及一些在手上和腕部的小骨头(69)。最近一个横向研究用MRI发现股骨缺血性坏死在339名病人中占到4.4%共有15人(54, 69)。骨量减少和骨坏死都认为是由于曾经使用了皮质激素而不是由某类抗病毒药物引起 (32, 57, 70)。骨密度下降通常最初发现于开始抗病毒治疗的18个月。其他造成骨量减少和骨坏死的风险因素有酗酒、吸烟、高脂血症、营养不良和缺乏锻炼。

The first signs of decreased bone mineral density are likely to be fracture or new-onset skeletal pain. Avascular necrosis of the hip is the most severe manifestation of HIV-associated bone disease and often requires hip replacement. Other sites of involvement are the ankle, shoulder, clavicle, and elbow. Radiographs may show reduced bone mineral density but DEXA scans are more sensitive for this purpose. Treatment involves correcting possible risk factors for osteoporosis, insuring adequate intake of vitamin D and calcium, and weight-bearing exercise. Other forms of therapy traditionally used for osteoporosis (e.g. raloxifene, biphosphonates, calcitonin, and hormonal replacement) and surgical intervention may be necessary for symptomatic disease.

骨密度下降的首要症状是骨折或者是新近出现的骨痛。股骨缺血性坏死是HIV相关骨病中最严重的一种，通常需要进行股骨置换。其他受累的部位有踝关节、肩部、锁骨和肘部。X线片能够反应出骨密度的下降，但双能X-线吸收仪（DEXA）更为敏感。治疗则通常是纠正可能引起骨质疏松的一些危险因素、确保服用足够的维他命D和钙、进行负重练习。其它传统治疗骨质疏松的方法(如雷洛昔芬、二磷酸盐、降钙素和激素疗法)也被采用，手术可用于有症状的患者。

Ectodermal dysplasia

体表症状

Alopecia, paronychia, dry skin, and cheilitis occur rarely after about 2-6 months of treatment with indinavir. These manifestations are due to perturbations of retinoic acid metabolism and usually resolve after the discontinuation of indinavir.

脱发、甲沟炎、皮肤干燥、唇炎罕见于使用茚地那韦治疗的2到6个月后。这些症状都是由于维生素A酸代谢波动引起的，通常在停用茚地那韦后会得以消退。

Tables and Figures

图表与数据

Table 1. National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III Treatment Recommendations Based on LDL Cholesterol (Adapted from (60))

Table 2. Choice of Therapy for Hyperlipidemia (adapted from (61, 69))

Table 3. Drug Interactions of Lipid Lowering Agents with Antiretroviral (ARV) Agents

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