儿童HIV感染

Updated August, 2009

Dr. Mehri S. McKellar, Dr. Sabrina Bakeera-Kitaka, Dr. Robert Colebunders

译者： 张峣 医学博士

             北京协和医院 感染科

             Email: zhangyao1@gmail.com

OVERVIEW

概述 

               Since the introduction of protease inhibitors, HIV mortality in children has decreased by approximately 80-90% (12, 27, 40, 58). Opportunistic infections have likewise decreased since the pre-highly active antiretroviral therapy (HAART) era (26). With data generated from clinical trials and advances in laboratory monitoring including resistance testing, clinicians now have the ability to better select effective initial treatment regimens while preserving new drugs and drug classes for second or third-line regimens. At the same time, the availability of new drugs and drug formulations has led to regimens with less dosing frequency, fewer toxicities, and better palatability. This is very important for children, as the availability of pediatric formulations and solutions has been and continues to be limited. These improvements should lead to better adherence overall and decreased resistance. Given these therapeutic advances, HIV practitioners are now charged with what appears to be a more realistic goal in both pediatric and adult HIV care and treatment – maximal viral suppression in order to preserve immunological function, prevent disease progression and avert the development of resistance.

　　自开始使用蛋白酶抑制剂以来，儿童HIV的死亡率下降了约80-90％ (12, 27, 40, 58)。随着高效抗逆转录病毒治疗(HAART)的出现，机会性感染也出现了同样显著下降(26)。 临床试验研究和实验室监测进展（包括耐药性检测）提示，医生在更好地选择初步有效的治疗方案的基础上，现在已经有能力研究新的药物和二线、三线药物。新的药物和试剂研究可以产生剂量更小，毒性更小，口感更好的方案。对于儿童来说，这是非常重要的。有关儿童的配方和解决方案一直比较有限，而且这种情况还将继续。但通过以上这些进展，儿童治疗有更好的依从性，并可能减少耐药的发生。随着治疗技术不断改进，在儿童和成人HIV感染者的护理和治疗中，艾滋病医疗工作者面临更现实的目标---最大限度地抑制病毒，以维护免疫功能，防止疾病进展，避免产生耐药。

DIFFERENCES BETWEEN ADULTS AND CHILDREN

成人与儿童的差异

               Although the pathogenesis of HIV infection and the general virologic and immunologic principles are similar for all HIV-infected persons, there are some unique considerations for HIV-infected infants and children. One of these differences is that HIV virologic tests (HIV RNA or DNA) are necessary in order to diagnose HIV infection in infants less than 18 months due to the crossover of the maternal HIV antibody. Another significant difference in children is that plasma HIV RNA levels are markedly higher and persist at high titers, reaching steady-state values seen in adults only after approximately 5 years of infection. With regard to laboratory monitoring, CD4 cell counts are age-specific; typically CD4 percentages are used to monitor children < 5 years old. Another noteworthy difference is that drug dosing needs to be frequently revisited in pediatric patients given the changes in the pharmacokinetic parameters with age and development.

　　尽管所有HIV感染者具有类似的发病机理、病毒学和免疫学总体特征，但是感染HIV的婴幼儿和儿童与成人却有不同之处。其中一个不同之处是儿童可以从母体获得HIV抗体，因此HIV病毒学检测（HIV RNA或DNA）对于18个月龄以下婴幼儿HIV感染的确诊是十分必要的。另一个重要差异是儿童血浆艾滋病病毒的RNA水平更高，并保持高滴度，大约5年后达到成人的稳态水平。实验室监测结果显示，CD4细胞计数与特定的年龄相关，通常CD4百分比用来监测5岁以下儿童的感染状况。另外，值得注意的是，不同年龄的药代动力学参数不一样，因此儿童病例的药物剂量也要随之加以调整。

EPIDEMIOLOGY

流行病学

               Worldwide, both the annual number of new HIV infections and the annual rate of AIDS deaths in children have declined since 2002-3 (65). This is in part due to successful prevention of mother-to-child transmission (PMTCT) and treatment scale-up programs. In 2007 the number of children living with HIV infection increased to 2 million – almost 90% of whom live in sub-Saharan Africa (65).

　　2002-2003年，无论是HIV儿童年新发感染人数还是艾滋病儿童年死亡率在世界范围内均有所下降（65）。部分原因是由于成功实施了阻断艾滋病母婴传播(PMTCT)和治疗扩大计划。2007年，儿童HIV感染存活人数增加到200万，其中接近90%的人生活在撒哈拉以南非洲（65）。

               In resource-rich countries, the use of antiretroviral therapy during pregnancy in HIV-infected women has resulted in a dramatic decrease in the transmission rate to infants. The transmission rate is currently less than 2% in the United States; in 2007 there were only 139 reported perinatal HIV infections (36). The number of perinatal infections in the U.S. continues to decline in part due to the 2006 recommendations by the Centers for Disease Control (CDC) for a “universal opt-out” policy, in which all pregnant women are tested for HIV as part of the routine panel of prenatal tests unless the patient declines the test (6).

　　在一些资源比较丰富的国家，感染HIV的孕妇经过抗逆转录病毒药物的治疗后，母婴传播几率发生了大幅度的下降：目前美国艾滋病母婴传播率低于2%；2007年围产期HIV感染者只有139例（36）。围产期HIV感染者人数不断下降，部分原因是源于2006年美国疾病预防控制中心（CDC）建议采纳的“常规知情不拒绝” 检测策略，除非主动提出拒绝，否则所有怀孕妇女在例行产前检查时需要检测HIV（6）。

               In resource-limited countries, where access to prevention, testing and treatment is difficult, perinatal infection continues to represent a major and overwhelming global health problem, requiring its own solutions. It is estimated that 90% of children living with HIV acquired the virus during pregnancy, birth or breastfeeding – all of which are forms of HIV transmission that can be prevented (65). The impact of PMTCT has not yet been realized in sub-Saharan Africa; as one tragic example, it was recently announced that 30% of children admitted to the hospital pediatric ward in Mozambique have HIV(54).

　　而在资源比较有限的国家，要想获得艾滋病的预防、检测和治疗都是很困难的，围产期HIV感染依然是一个重要的全球健康问题，需要各国自己寻求适合的解决方法。据估计，儿童HIV感染者中，90%是在其母亲怀孕、分娩或哺乳时感染的。所有这些传播艾滋病病毒的途径都是可以预防的（65）。在撒哈拉以南非洲，还没有充分地认识到艾滋病母婴传播阻断的作用，这里有一个悲惨的例子，据估计莫桑比克住院儿童中有30%的儿童感染有HIV（54）。

               Growing older, perinatally-infected children will bring new challenges of adherence issues, drug resistance and management of multiple drugs. Adherence is a key issue for sustainable virologic suppression. When a child gets older, it will become essential to explain in an appropriate way why he/she has to take antiretrovirals. Full disclosure should be reached when the child and parents are both ready for it, but preferentially before adolescence as other issues such as reproductive health will come up during this time period.

　　随着年龄的增长，围产期感染HIV儿童面临新的问题：依从性，耐药性和多种药物的管理。依从性对于持续抑制病毒是至关重要的。当一个小孩子不断长大，最基本的问题就是，要以恰当的方式向他/她解释为什么需要采取抗逆转录病毒治疗。当孩子和家长都准备好了的时候，向孩子说明实情，通常要在青春期前，因为此后其他问题如生殖健康等问题会随之出现。

TESTING

检测

               HIV infection can be definitively diagnosed in most non-breastfed HIV-infected infants by age one month and in virtually all infected infants by age 4 months through the use of virologic assays (92). Early diagnosis of infection is important, given the potential for rapid disease progression in infants. In an analysis of data from 7 randomized MTCT intervention trials in Africa, 35% of infected children were estimated to have died by age 1 year and 52% by 2 years of age, without treatment (55). In this same study, children with evidence of early infection (before 4 weeks of age) were at higher risk of death within 12 or 24 months of becoming infected than those who acquired infection after 4 weeks of age through breastfeeding (55).

　　大多数1个月龄非母乳喂养和几乎所有4个月龄的婴幼儿， HIV感染可以通过病毒学检测明确诊断（92）。由于婴幼儿患病有快速进展的可能，HIV感染的早期诊断就显得相当重要。非洲有一项对随机抽取的7个地区的艾滋病母婴传播阻断情况进行研究发现，在没有治疗的情况下，35%感染HIV的儿童预计会在1岁时死亡，52%的儿童在2岁时死亡（55）。同样也是在这个研究中，早期（出生4周以内）出现HIV感染症状的儿童，比出生4周后有感染症状的母乳喂养儿童在12或24个月内有的死亡风险高（55）。

               In infants under 18 months, HIV antibody tests such as the ELISA, Western blot and the recently approved rapid tests are not used due to the transplacental transfer of maternal HIV antibodies. Close to 100% of infants born to HIV-positive mothers will have a positive antibody test at birth (45). The median age for the disappearance of antibodies in uninfected children is 10 months (16), although the antibodies may persist until 18 months (64). As a result, virologic tests should be utilized. This includes either detection of HIV by DNA or RNA polymerase chain reaction (PCR). A positive virologic test indicates infection and should be confirmed by a repeat virologic test (92). Of note, the antibody test may be helpful and less costly than PCR for assessing if an infant is “at risk” for HIV, such as in the case when the infant is transported to another institution from the mother whose HIV status is unknown. If the ELISA is positive, the infant would then need to undergo virologic testing.

　　由于母亲HIV抗体可穿过胎盘传给胎儿，因此酶联免疫吸附试验（ELISA），蛋白印迹法（WB）以及最近批准的快速检测法等艾滋病病毒抗体检测方法均不适用于18个月龄以下的婴幼儿。如果母亲HIV抗体阳性，婴儿在出生时抗体阳性率接近100%(45)。未感染HIV儿童的抗体可能会持续到18个月（64），抗体消失的年龄中位数是10个月(16)。其结果就是，HIV的检测应当依靠病毒学检测，包括检测艾滋病病毒的DNA或RNA聚合酶链反应（PCR）。HIV病毒检测阳性提示可能存在感染，需要重复一次病毒学检测予以确认(92)。值得注意的是，如果评估一个婴儿感染HIV的“危险性”，抗体检测可能会有帮助，而且成本要低于PCR技术。比如，其HIV感染状况不明母亲所生的婴儿，如果ELISA初筛阳性，这个婴儿便需要进行病毒学检测。

               The p24 antigen is no longer recommended due to its lower sensitivity in the neonatal period (30). However, in recent years an ultrasensitive p24 technique has been developed, which yielded an overall sensitivity and specificity of 91.7% and 98.5%, respectively, in 802 plasma specimens from 582 Malawian infants and children of 0 to 180 days (20). After exclusion of infants less than 7 days of age, the sensitivity and specificity were 93.7% and 98.3 %, respectively, which is still below the current World Health Organization’s (WHO) guidelines for diagnostic tests for HIV(20, 24). In Haiti a simplified test was performed using overnight (16 hours) p24 antigen solid-phase incubation ELISA without amplification which attained comparable diagnostic accuracy to the ultrasensitive p24 assays (24). The test was also adapted to be used on dried blood spots on filter paper, with similar results to the ultrasensitive p24 assay (43).

　　新生儿期p24抗原检测不再建议使用，因为其敏感性较低(30)。然而，近年来开发的超敏p24技术，在马拉维582名出生0至180天儿童的802份血标本中，其整体敏感性和特异性分别为91.7%和98.5%（20）。当剔除小于7天的婴幼儿标本后，其敏感性和特异性分别为93.7%和98.3%，但仍然低于目前世界卫生组织的（WHO）指南中的要求（20，24）。在海地进行的研究显示，利用一种简化的夜间（16小时）p24抗原无扩增固相酶联免疫吸附法可以达到与超敏p24检测技术相当的准确率（24）。这个实验还试用于滤纸上的干血斑，与超敏p24技术的结果也类似（43）。

               Of the virologic assays, HIV DNA PCR is often recommended as the preferred test for infants. This technique is used to detect HIV DNA within the peripheral blood mononuclear cells (PBMCs). The sensitivity of a single HIV DNA performed at < 48 hours of age is less than 40% but increases to over 90% by 2 weeks (13). By age 28 days, the sensitivity and specificity has been reported as high as 96% and 100% respectively (11).

　　艾滋病病毒的DNA聚合酶链反应(PCR)通常被推荐作为婴幼儿病毒学检测的首选。这项技术是用来检测外周血单核细胞（PBMCs）中艾滋病病毒的DNA。出生48小时内，一次检测的敏感性不到40%，但在2周后增加到90％以上（13）。28天时，其敏感性和特异性分别高达96%和100% (11)。

               HIV DNA PCR is also measurable using heel-stick dried blood spots, from which HIV DNA can be extracted and amplified. In one study in South Africa which included 206 heels sticks, the sensitivity and specificity of dried blood spots was 98.3% and 98.9%, respectively. The majority of the children tested were approximately 6 weeks old (59). This may a cheaper and more practical solution for countries lacking laboratory resources.

        HIV DNA聚合酶链反应也可以用足跟血干血斑进行检测。在南非，一个关于206例足跟血检测的研究，足跟血检测的敏感性和特异性分别为98.3%和98.9%。大多数参加检测的儿童大约为出生后6周（59）。这对于实验室资源有限的国家来说，可能会是更便宜和更实用的解决方法。

               Although data is more limited regarding its use, RNA PCR appears to be equally sensitive and specific for early diagnosis of HIV infection. HIV RNA assays detect extracellular viral RNA in the plasma. Several studies have demonstrated sensitivities of 25-40% during the first weeks of life, increasing to 90-100% by 1-3 months of age (11, 44, 73, 76). Similarly, specificity is comparable between the two tests, although with low levels of HIV RNA (< 10,000 copies/mL) the test should be repeated before being interpreted as positive in infants as it may not be reproducible (92). Some clinicians use the HIV RNA assay as the confirmatory test for infants who have an initial positive HIV DNA PCR test. In addition to providing virologic confirmation of infection, the expense of a repeat HIV DNA test is spared, and RNA viral loads can be used to guide treatment decisions (92).

        HIV RNA检测血浆中细胞外的RNA病毒，虽然数据使用较为有限，但RNA聚合酶链反应与DNA聚合酶链反应在诊断HIV感染时，似乎具有同样的敏感性和特异性。许多研究表明，出生后第一周HIV RNA检测的敏感性为25-40%，而在1-3个月龄时提高到90-100%的（11，44，73，76）。同样，两种检测方法的特异性相当。低水平的HIV RNA（<10000拷贝/毫升）时，在确定婴幼儿检测结果为阳性之前需要进行重复检测（92）。有些临床医生把HIV RNA检测用作HIV DNA PCR初筛结果为阳性婴幼儿的确认检测。除了作为HIV感染检测的确认方法，节省了重复HIV DNA PCR检测的费用外，RNA病毒载量还可用于指导治疗方案的决策（92）。

               Prophylactic antiretroviral therapy could theoretically affect the predictive value of virologic testing in neonates by lowering the viral load to undetectable levels. Zidovudine (AZT) monotherapy, however, did not delay detection of HIV by culture technique in infants in the PACTG protocol 076 (9). As HIV DNA PCR detects PBMC infection and not plasma levels, this test will remain positive in individuals receiving antiretroviral treatment (ART) [26], and false negatives should not occur. Interestingly, in several studies maternal antenatal treatment with ART and/or with infant antiretroviral prophylaxis did not appear to have a profound effect on the sensitivity or specificity on RNA levels (73, 93).

        抗逆转录病毒预防性用药在理论上可以通过降低新生儿的病毒载量水平直至检测不到，从而影响病毒学检测的预测值。但是，齐多夫定（AZT）单独用药并没有延缓婴幼儿HIV的检测（PACTG076研究使用培养技术）（9）。因为HIV DNA聚合酶链反应用于检测外周血单核细胞而不是血浆水平的感染，个人在接受抗逆转录病毒治疗（ART）的时候，检测结果不受影响（26），不会出现假阴性。在几个研究中孕产妇的产前抗逆转录病毒治疗和/或与婴幼儿的抗逆转录病毒预防用药似乎没有影响RNA水平的敏感性或特异性（73，93）。

               For non-subtype B, HIV RNA assays may be more sensitive than HIV DNA PCR (56, 93). In situations where non-subtype B perinatal exposure is suspected and the HIV DNA PCR is negative, repeat testing using the RNA assay should be performed.

        对于非B亚型，HIV RNA的聚合酶链反应检测可能会比HIV DNA聚合酶链反应更加敏感（56，93）。在怀疑围产期暴露于非B亚型，而且HIV DNA聚合酶链反应是阴性的情况下，应当使用HIV DNA聚合酶链反应进行重复检测。

CLINICAL MANIFESTATIONS

临床表现

Opportunistic Infections

机会性感

               Since the introduction of HAART therapy, there has been a substantial reduction in the incidence of opportunistic infections (26). The natural history of opportunistic infections in children may differ from that observed in HIV-infected adults (52). Many opportunistic infections in adults are secondary to reactivation of previously-acquired opportunistic pathogens, often acquired before being infected with HIV when host immunity was intact (52). Opportunistic infections among HIV-infected children more often reflect primary infection with the pathogen, occurring at a time when the child’s immune system may already be compromised (52). This can lead to different manifestations of disease among children when compared to adults. For example, young children with Mycobacterium tuberculosis are more likely to have extra-pulmonary and disseminated infection than adults, even without concurrent HIV infection (52).

        自引入高效抗逆转录病毒治疗(HAART)后，机会性感染的发生率出现了大幅度的下降（26）。儿童的机会性感染可能不同于成人的情况（52）。成人的许多机会性感染往往是先前感染的激活。在宿主免疫系统未受破坏，在未感染HIV之前，宿主先有机会感染的致病菌（52）。儿童的机会性感染在大多数情况下是初发感染，发生在免疫系统可能已经受到损害时（52）。儿童可能会出现不同于成人的疾病。例如，即使没有合并感染HIV，婴幼儿比成人更可能有肺外结核和传播结核（52）。

               It is important to remember that an important mode of acquisition of opportunistic infections is from an infected mother to her child, both perinatally and in the home once the child is born. Multiple difficulties exist in making laboratory diagnoses of various infections in children. Diagnosis is often compounded by a child’s inability to describe their signs and symptoms. Diagnosing lung infections, for example, is difficult because children generally do not produce sputum, and more invasive procedures may be needed. For infections where the primary diagnostic modality is the presence of antibody, the ability to make a diagnosis in infants may be complicated by transplacental transfer of maternal antibody that can persist in the infant for 12-15 months (52).

        重要的是要记住，获得机会性感染的一个主要方式是从感染HIV的母亲传给她的孩子，一旦孩子出生，不管是在围产期还是在家里，实验室诊断儿童的各种感染也存在多种困难。儿童常无法描述他们的症状和体征，例如诊断肺部感染非常困难，因为儿童通常不会吐痰，可能需要更多有创性的手段。传染病的主要诊断方法是检测抗体的存在，能够对婴幼儿作出诊断可能比较复杂，因为母源转移的抗体在婴幼儿体内能够持续12到15个月（52）。

               Similar to antiretrovirals, treatment for opportunistic infection can be made difficult due to drug pharmacokinetics and the lack of pediatric dosing in children, particularly when < 2 years of age.

        与抗逆转录病毒治疗类似，由于药物代谢动力学和缺乏儿童用药，治疗儿童机会性感染也很难，尤其是2岁以下的婴幼儿。  

               In the pre-HAART era, the most common opportunistic infections among children in the U.S. (event rates >1.0/100 child-years) were serious bacterial infections (with pneumonia and bacteremia being most common), herpes zoster, disseminated Mycobacterium avium complex (MAC), Pneumocystis jivoreci (formerly carinii) pneumonia (PCP), and oral candidiasis (26). Although the majority of infections occurred among children who were substantially immunocompromised, HIV-positive children from all levels of immune strata suffer more bacterial infections, herpes zoster, and tuberculosis than children without HIV. Since the onset of HAART, the number of infections has significantly decreased (26). Bacterial pneumonia, herpes zoster, dermatophyte infections and oral candidiasis are now the most common first-time infections (26).

        在前HAART时代，美国儿童最常见的机会性感染（儿童事件发生率>1.0/100人年）是严重的细菌性感染（以肺炎和菌血症最为常见），带状疱疹，播散性鸟分枝杆菌复合感染（MAC），卡氏肺囊虫肺炎（PCP）和口腔念珠菌病（26）。虽然大多数感染发生于免疫功能严重受损的儿童，但是无论免疫功能如何，HIV检测结果呈阳性反应的儿童比HIV阴性的儿童容易患有更多的细菌性感染、带状疱疹和肺结核。开始使用高效抗逆转录病毒治疗后，感染人数已出现明显的下降（26）。细菌性肺炎，带状疱疹，皮肤真菌感染和口腔念珠菌病是目前最常见的初发感染（26） 。

               Antibiotic prophylaxis against PCP with co-trimoxazole is recommended for infants with indeterminate HIV status starting at 4-6 weeks of age until they are determined to be HIV-uninfected. Children who are HIV-positive should continue to receive prophylaxis for the first year of life regardless of their immune status. Need for subsequent prophylaxis after 12 months of age should be determined on the basis of CD4 percentages or overall clinical status. The CDC recommends prophylaxis for all children aged 1 to 5 years with CD4 counts of <500 cells/mm3 or CD4%<15, and for all children aged >6 years with CD4 counts <200 cells/mm3 or CD4%<15 (8). When the child is > 5 years, adult guidelines can essentially be followed. Children with a history of PCP should continue to receive chemoprophylaxis regardless of their CD4% in order to prevent recurrence. Of note, the World Health Organization recommends PCP prophylaxis in children aged 1-5 with a CD4%<25 or who are symptomatic (WHO clinical stages 2,3, or 4) . Once a child is started on co-trimoxazole, the WHO recommends that treatment is continued until 5 years of age regardless of symptoms or CD4%. The WHO also proposes offering co-trimoxazole prophylaxis to all children living with HIV irrespective of their age or CD4 level in countries with high burden of morality and morbidity due to other infectious diseases such as malaria and bacterial infections (88).

　　当婴儿的HIV感染状况不确定时，建议从出生后4-6周开始使用复方新诺明来预防卡氏肺囊虫肺炎（PCP），直到HIV检测结果确定为阴性。而对于HIV检测结果为阳性的儿童，无论其免疫状态如何，在随后的第一年里应继续采取预防性用药。12个月以后儿童是否需要继续预防用药取决于CD4细胞百分比或者其总体临床状态。疾病预防控制中心建议，所有1岁至5岁的儿童在CD4细胞计数<500 个/mm3或CD4％<15时，所有6岁以上儿童CD4细胞计数<200 个/mm3或的CD4％<15时，需要采取预防性用药（8）。5岁以上的儿童可以参照成人的用药标准。曾患有卡氏肺囊虫肺炎（PCP）的儿童，无论他们的CD4%如何，应继续接受预防性服药以防止复发。值得注意的是，世界卫生组织建议1-5岁的儿童在CD4%<25或者出现临床症状（WHO的临床分类为2，3，4期）时，应进行卡氏肺囊虫肺炎（PCP）的预防性用药。世界卫生组织建议，一旦儿童开始使用复方新诺明后，无论其有无症状或CD4%如何，这种治疗要一直持续到5岁。由于其他传染性疾病如疟疾和细菌性感染的存在，导致这些国家的死亡率和发病率很高，世界卫生组织还建议，不论其年龄或CD4计数的水平，应对所有感染艾滋病病毒的儿童提供复方新诺明的预防性用药（88）。

TIMING OF TESTING

检测时间

               The current U.S. National Institutes of Health (NIH) guidelines recommend that virologic testing be performed at age 14-21 days; 1-2 months; and 4-6 months. Some experts will also perform virologic testing at birth (92). The WHO guidelines suggest that virological testing is performed at age 4-6 weeks or any time subsequently in infants known to be exposed to HIV (89).

　　目前美国国立卫生研究院（NIH）的指导原则是，建议在出生后14-21天，1-2个月和4-6个月时进行病毒学检测。一些专家认为在出生时也可以进行病毒学检测（92）。世界卫生组织指南中则建议，在出生后4-6周或其后任何时候提示婴儿有暴露可能时应该进行病毒学检测（89）。

               HIV is diagnosed by two positive HIV virologic tests performed on separate blood samples, regardless of age. A positive HIV antibody test with confirmatory Western blot (or IFA) at age >18 months also confirms HIV infection.

　　不论年龄大小，不同血液样本艾滋病病毒学检测两次阳性，即可诊断HIV阳性。大于18个月龄的儿童HIV抗体初筛阳性，并经WB或者IFA确认阳性时，也可以作出诊断。

               HIV infection can be presumptively excluded in non-breastfed infants with two or more negative virologic tests with one test obtained at > 14 days of age and one obtained at > 1 month of age; or one negative virologic test result obtained at age > 2 months; or one negative HIV antibody test result obtained at > 6 months of age (92). HIV infection can be definitively excluded in a non-breastfed infant with two or more negative virologic tests with one obtained at age > 1 month and one at > 4 months; or 2 negative HIV antibody tests from separate specimens obtained at > 6 months (92). Loss of HIV antibody in a child with a negative virologic test confirms that the child is HIV-uninfected (92).

　　非母乳喂养的婴儿两次或两次以上病毒学检测为阴性，出现以下几种情况可作出假定排除HIV感染的诊断：出生14天后，1个月内第一次病毒学检测阴性，出生1个月后第二次检测也是阴性；或出生2个月后病毒学检测为阴性；或出生6个月后HIV抗体检测为阴性。非母乳喂养的婴儿两次或两次以上病毒学检测为阴性，出现以下几种情况可明确作出排除HIV感染的诊断：出生1个月后，4个月内第一次病毒学检测阴性，出生4个月后第二次检测也是阴性；或出生6个月后血液样本HIV抗体检测两次均为阴性（92）。HIV抗体检测阴转，病毒学检测阴性，也可以证实儿童未感染HIV。（92）。

               In the 2008 revised surveillance case definition of HIV infection (64a), laboratory-confirmed evidence of HIV infection is now required for all reported cases of HIV infection among children aged 18 months to <13 years. Laboratory criteria for children aged <18 months at the time of diagnosis include revisions to one category: presumptively uninfected with HIV. No substantial changes have been made to the remaining three categories (definitively HIV infected, presumptively HIV infected, and definitively uninfected with HIV). Because diagnostic laboratory testing for HIV infection among children aged <18 months might be unreliable, children in this age group with perinatal HIV exposure whose illness meets the AIDS case definition on the basis of clinical criteria are considered presumptively HIV infected when the mother has laboratory-confirmed HIV infection. No changes have been made to the conditions listed under the AIDS criteria in the 1987 pediatric surveillance case definition for AIDS for children aged <13 years.

　　2008年修订了有关HIV感染者的病例监测定义（64a），需要报告所有出生18个月龄到13岁之间儿童的HIV实验室确认结果。对18个月龄以下儿童在作出诊断前，实验室诊断标准的修订包涉及一个分类：假定未感染HIV。其余三类（确定HIV感染者，假定HIV感染者，确定HIV阴性者）的实验室诊断标准未作出重大变更。由于18个月龄以下儿童的HIV感染的实验室诊断检测结果可能是不可靠的，当母亲HIV实验室确认检测结果为阳性时，而在这一年龄段儿童有围产期的暴露，其疾病状态又达到临床诊断艾滋病病例的定义标准，可认为假定存在HIV感染。1987年的13岁以下儿童艾滋病监测病例定义没有改变。

LABORATORY MONITORING

实验室监测

               In HIV-infected children, as in infected adults, the CD4 count and percentage declines with the progression of disease. In children under 5 years, CD4% is the preferred test for monitoring immune status as it varies less with age than the absolute count and provides a more stable marker (14, 35, 92). CD4% and absolute count should be measured at the time of diagnosis of HIV infection to establish a baseline and then at least every 3-4 months thereafter, whether the child is on or off antiretrovirals, in order to monitor immune function.

　　感染艾滋病病毒的儿童，与成年人一样，随着疾病的进展，CD4细胞计数和百分比也不断下降。对于5岁以下的儿童，CD4百分比是首选监测免疫状态的检测，因为CD4百分比相对于CD4细胞绝对数来说，更不容易随着年龄的增长而发生改变，可作为一个更稳定的标志（14，35，92）。在进行HIV感染诊断时，需要检测CD4百分比和绝对计数以确定基线水平。无论儿童是否接受抗逆转录病毒药物的治疗，然后至少每3-4个月以后再次检测CD4百分比和绝对计数，以便监测其免疫功能。

               Plasma HIV RNA viral loads should likewise be measured at baseline and then every 3-4 months when on therapy. Viral loads in perinatally-infected infants generally remain higher than in adults (1). In one prospective study, viral loads increased rapidly after birth, peaked at 1 month of age (median 318,000 copies/mL), and then slowly declined to a median of 34,000 copies/mL at 24 months (73). This is in contrast to the rapid decline seen in adults after primary HIV infection (37). Over the next few years, the HIV RNA load in children continues to decline (53). This pattern most likely reflects an immature but developing immune system that has some difficulty with initial containment of the virus but then improves with age.

　　血浆HIV RNA病毒载量同样也应在基线时进行检测，采取治疗后，每3-4个月还要进行检测。一般来说，围产期感染HIV儿童的病毒载量要持续高于成人（1）。在一项前瞻性研究中，婴儿出生后病毒载量迅速增加，1个月龄时达到了高峰（中位数为31.80万拷贝/毫升），然后缓慢下降，到24个月龄时中位数为3.4万拷贝/毫升（73）。这与成年人感染HIV后病毒载量迅速下降有所不同（37）。在接下来的几年内，儿童HIV RNA病毒载量继续下降（53）。这种模式最有可能反映了尚未发育成熟，但仍在发育中的免疫系统最初在抑制病毒复制时遇到了一定的困难，但随着年龄增长，免疫力也逐渐提高的现象。

               The prognostic value of CD4% and viral load testing was assessed in the HIV Pediatric Prognostic Markers Collaborative Study, a large meta-analysis of 17 studies including 3,941 children, which looked at the 12 month risk of developing AIDS or death based on age and baseline CD4% and viral loads (10). Infants in the first year of life experience proportionately higher risk than older children for any given CD4 stratum. These risk profiles have gone on to form the rationale for recommendations on when to initiate therapy in a treatment-naïve HIV infected child (92). CD4 counts are best checked when patients are clinically stable.

　　在HIV儿童预后标志物研究（一项大型Meta分析）中对CD4%和病毒载量检测的预后判断价值进行了评估，研究纳入了17个研究报告中的3941名儿童，根据年龄和基线CD4%和病毒载量判断这些儿童具有在12个月内进展为艾滋病或死亡风险（10）。无论CD4计数如何，婴儿在出生后的第一年要比年龄较大的儿童历经更高比例的风险。这些风险状况为没有参加过抗病毒治疗的HIV感染的儿童何时开始治疗提供了依据（92）。CD4计数通常应在患者病情稳定时检查。

               High HIV RNA levels in infants age < 12 months have been correlated with disease progression and death, but RNA levels overlap considerably in young infants with rapid disease progression and those without (73), and this association was more gradual when compared with CD4% (14). In a recent study of Kenyan infants, infants who experienced acute primary HIV infection syndrome had higher RNA loads later in infection than did infants who did not experience symptoms. However, there was no association between the acute syndrome and increased mortality, although the overall mortality of the group was very high (> 40% by 24 months of age) (66). High RNA levels (i.e. levels of > 100,000 copies/mL) in older children, similar to adults, have been associated with high risk of disease progression and mortality, particularly if the CD4 percentage is < 15% (53).

　　12个月龄以下婴幼儿的HIV RNA水平较高，与疾病进展和死亡相关，但那些出现疾病迅速进展的婴幼儿与没有出现疾病迅速进展婴幼儿的RNA水平存在交叉重叠（73），而这种关系与CD4%的情况相比则更为缓和（14）。在最近一份肯尼亚的研究报告中，出现急性原发性HIV感染综合征婴幼儿的RNA载量要高于没有出现综合征的婴幼儿。虽然这个研究中儿童总体的死亡率非常高（24个月龄时死亡率>40%），急性HIV感染综合征与死亡率上升之间并未见关联（66）。与成年人中观察到得现象相似，年龄较大的儿童中高水平的HIV RNA（即> 10万拷贝/毫升），与高风险的疾病进展和死亡相关，特别是对于那些CD4百分比<15％的婴幼儿（53）。

               More frequent CD4% and RNA monitoring should be considered in infants less than age 12 months, as young infants may have rapid disease progression, which is typically defined as CDC class C clinical event or death (73). More frequent monitoring should also occur in children with suspected clinical, immunologic or virologic deterioration, to confirm an abnormal value; or when initiating or changing therapy.

　　年龄小于12个月的婴幼儿要考虑经常性监测CD4%和RNA，因为婴幼儿可能有时疾病进展迅速，也就是美国CDC定义的C类临床事件或死亡（73） 。当儿童发生可疑的临床、免疫学或病毒学恶化时，或者当启动、改变治疗方案时，也应进行经常性的CD4%和HIV RNA监测，以确定异常值。

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. 

TREATMENT

治疗

               One of the many challenges in treating HIV is that it is a relatively new infection, identified just over 20 years old, with dynamic treatment guidelines and new data continuously evolving from clinical trials. In children, this is more complicated as most antiretrovirals are approved for use in pediatrics based on efficacy data extrapolated from adult studies, with limited pediatric pharmacokinetic and pharmacodynamic data. As with other medications used in pediatrics, adult dosages often do not directly translate to pediatric doses, which can lead to inadequate dosing and decreased efficacy in children. For example, in the CHIPS cohort in the U.K. and Ireland, children were estimated to be underdosed 6-62% of the time when the total daily dose was compared to the current recommended dose (51). A recent study evaluating the use of lopinavir/ritonavir, the recommended protease inhibitor for children, found that significantly more children less than two years old had inadequate minimum concentrations (Cmin) at the recommended dose of 230/57.5 mg/m2 twice daily (83). Pharmacokinetic data differs in children based on their growth and development and should be made available for the different age groups. Failing to account for growth and to change the dose with increases in height or weight will lead to suboptimal dosing. Rounding down doses is another contributing factor for underdosing (51).

　　治疗艾滋病其中一个挑战是在于艾滋病是一个相对较新的感染，从出现到现在仅仅只有20几年，治疗方案不断变化，临床试验不断出现新的数据。儿童艾滋病的治疗就更加复杂，因为大多数抗逆转录病毒治疗的药物获得批准用于儿童是建立在成年人疗效数据的研究基础之上，药代动力学以及药效数据有限。与儿童使用其他药物一样，成人剂量往往不能直接转为小儿剂量，因为这可能会导致不适当用药和降低儿童用药的疗效。例如，在英国和爱尔兰的CHIPS队列研究中，估计有6-62%的儿童每日用药总剂量要低于目前的推荐剂量（51）。最近的一项研究评价了建议儿童使用的蛋白酶抑制剂（洛匹那韦/利托那韦）的使用情况，发现相当大部分不到2岁儿童的最低药物浓度（Cmin）不足，即使在推荐的每日两次给药剂量（230/57.5 mg/m2）下（83）。随着儿童的成长和发育，药代动力学数据也不一样，应给不同年龄组提供合适的剂量。如果没有考虑到身高或体重的增加因素，而且没有改变相应的剂量将导致达不到最佳给药剂量。不精确的给药是剂量不足的另一个影响因素（51）。

               As of February, 2009, there are 25 antiretrovirals approved for use in HIV-positive adults and adolescents: 17 of them have an approved pediatric treatment indication, and 16 are available in a pediatric formulation (92). In children, antiretroviral treatment with at least 3 drugs from 2 different classes is recommended; such regimens have been associated with enhanced survival and reduction in opportunistic infections and other complications of HIV infection. Treatment has also resulted in improved growth and neurocognitive function, as well as improved quality of life in children (7, 72, 78). In the U.S. and United Kingdom, an 81% decline in mortality was reported in HIV-infected children between 1994 and 1999, concomitant with increased use of ART (71). Significant declines in HIV-related hospitalizations in children have been observed in the U.K. and Europe over the same time period (25, 85).

　　截至2009年2月，已有25种抗逆转录病毒药物获得批准用于治疗HIV抗体阳性的成人和青少年：其中17种已获得批准可用于儿童治疗，16种已被用于儿童配方（92）。儿童抗逆转录病毒治疗至少需要从两种不同种类的推荐药物中选择3种，这种方案可以提高存活率，减少机会性感染，以及其他HIV感染的并发症。抗病毒治疗也可以促进改善成长和神经认知功能，以及改善儿童的生活质量（7，72，78）。据报道，1994年至1999年，美国和英国儿童艾滋病的死亡率下降了81%，主要原因是使用抗逆转录病毒药物的治疗(ART)（71）。同一时期，英国和欧洲发现因艾滋病有关原因而住院的儿童也出现大幅度减少（25，85）。

               Treating children is associated with the same challenges as with adults. Some of these challenges include preserving effective regimens for the future and avoiding short and long term toxicities, such as lipodystrophy and other metabolic complications (3, 69), which are starting to be identified in children. Resistance can develop in children who receive regimens containing 1 or 2 drugs that incompletely suppress viral replication. Additionally, drug resistance may be seen in drug-naïve children who were exposed to maternal/infant antiretroviral prophylaxis (15, 39) or from circulating resistant strains in the community that led to the infection of the mother. Previous ART history or exposure thus becomes an important factor in selecting a treatment regimen.

　　儿童艾滋病的治疗也面临同成年人一样的挑战，其中包括坚持有效的治疗方案，以及避免短期和长期的毒性，如脂肪代谢和其他代谢性并发症（3，69），这些并发症一般在儿童病例中先被发现。有些儿童接受包括1种或2种药物的治疗方案，在不能完全抑制病毒复制的时候，就会产生耐药。此外，曾经接受产妇/婴儿抗逆转录病毒预防的儿童（15，39），或者母亲感染的是共同循环耐药株，虽然从未使用过抗病毒药物，也可能出现耐药。先前接受的抗病毒治疗或者暴露史都是选择治疗方案的考虑因素。

               Additional factors to consider when choosing treatment include other co-morbidities such as tuberculosis, hepatitis B, chronic renal or liver disease. This has become particularly true in co-infection with hepatitis B, which shares some of the same antiviral treatments with HIV.

　　在选择治疗方案时，还需要考虑的因素包括其他并发症，如肺结核、乙型肝炎、慢性肾脏或肝脏疾病。特别是合并乙型肝炎病毒（HBV）感染，在抗病毒治疗时，药物可以同时作用于两种病原体。

               Given the chronic nature of the infection, once treatment is started in a child, most likely, it will be life-long. In February, 2009, the NIH Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children recommended several preferred and alternative regimens. A combination ART regimen in treatment-naïve children generally contains two classes of drugs – two nucleoside analogue reverse transcriptase inhibitors (NRTIs), either combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). The most appropriate regimen for a child, however, depends on multiple factors, including the child’s age, the availability and palatability of the appropriate drug formulations, the child’s social support system, the child and caregiver’s ability to adhere to the regimen, and the previous antiretroviral treatment history.

　　由于艾滋病是一种慢性传染性疾病，儿童一旦开始抗病毒治疗时，这种治疗将是终身的。2009年2月，美国国立卫生研究院（NIH）HIV感染儿童抗逆转录病毒治疗和医疗管理工作组提出了若干首选和备选方案。对从未使用过药物的儿童采用抗逆转录病毒治疗组合方案，其主要包含两类药物: 两种核苷逆转录酶抑制剂（NRTIs），要么与非核苷逆转录酶抑制剂（NNRTI）结合，要么与蛋白酶抑制剂（PI）相结合。然而，对儿童最适合的方案取决于多种因素，包括儿童的年龄、可行性和可口的适当药物制剂、儿童的社会支持系统、儿童和看护者的依从性体制、以及之前抗逆转录病毒治疗的情况。

When to Initiate Therapy (Table 1)

何时开始治疗（表1）

               The choice of whether to start early while an individual is still asymptomatic versus delaying therapy until symptoms develop continues to generate controversy among HIV experts. Starting aggressive therapy early may result in a lower viral set point and control of viral replication prior to the onset of rapid genetic mutation and potential evolution of resistance. Early therapy would also slow immune system destruction, thus preserving immune function and preventing clinical disease progression. Now that the drugs have become more advanced with less toxicities and lower pill burden, the trend appears to be more toward early treatment.

　　当一个人没有临床症状时是否选择开始早期抗病毒治疗，还是推迟抗病毒治疗的时间直到相关症状的出现再采取措施，一直是艾滋病领域方面的专家产生争议的问题。早期开始积极的抗病毒治疗，可能会在耐药变异出现之前，达到较低的病毒设定点和控制病毒的复制。早期开始抗病毒治疗，也可以减缓免疫系统的破坏，从而保持机体的免疫功能，防止临床症状的出现。目前，抗病毒治疗的药物已经更加先进，毒副作用更小，药物负担也更低，这种趋势似乎更倾向于早期采取抗病毒治疗。

               On the other hand, delaying therapy until later in the course of HIV infection, when clinical or immunologic symptoms appear, may result in reduced evolution of drug-resistant virus due to lack of drug selection pressure, greater adherence to the therapeutic regimen when the patient is symptomatic rather than asymptomatic, and reduced or delayed adverse effects of antiretroviral therapy.

　　另一方面，在感染艾滋病病毒的过程中，推迟抗病毒治疗直到出现临床症状或免疫学特征，由于缺乏药物选择的竞争，出现临床症状的患者可能比没有临床症状的患者在加入抗病毒治疗后依从性更好，减少耐药病毒株的出现，以及减少或推迟抗逆转录病毒疗法的副作用。

               CD4 counts and viral loads vary considerably by age in children; consequently, recommendations for when to start therapy are stratified by age. The NIH Working Group has recommendations based on 3 age groups: infants < 12 months, children 1 to < 5 years; and children and adolescents ≥ 5 years old.

　　不同年龄儿童的CD4细胞计数和病毒载量差别很大，因此，何时开始抗逆转录病毒治疗建议按年龄分层。美国国立卫生研究院工作组建议分3个年龄组：12个月龄婴幼儿，1至5岁儿童，5岁以上儿童和青少年。

Infants

婴幼儿

               The NIH Working Group recommends the initiation of antiretroviral therapy for all infants aged <12 months, regardless of clinical status, CD4 percentage or viral load (92). The risk of progression is greatest in the first year of life, and the ability to differentiate children at risk of rapid versus slower disease progression by clinical and laboratory parameters is most limited in young infants (17). In early reports, more than 15% of HIV-infected children progressed to AIDS or death within the first year of life without treatment. By 12 months, approximately 50% of children developed moderate immune suppression and 20% severe immune suppression (28).

　　不论临床状况、CD4百分比或病毒载量如何，美国国立卫生研究院工作组建议对12个月龄以下所有婴幼儿开始抗逆转录病毒治疗（92）。在出生后一年内出现病情进展的可能性是最大的，并且通过临床和实验室参数不易区分是疾病进展迅速的婴幼儿还是疾病进展缓慢的婴幼儿（17）。早期有报告显示，超过15%的儿童HIV感染者在出生后一年内进展为艾滋病或死亡，这些儿童没有采取抗病毒治疗。到12个月龄时，大约50%的儿童出现中度免疫抑制，20%的儿童出现重度免疫抑制（28）。

               Recent data from the CHER (Children with HIV Early Antiretroviral Therapy) trial showed that treating HIV-infected infants as early as the first 6-12 weeks of life significantly decreased risk of early death by 76% and HIV progression by 75% when compared to children who were deferred treatment (until the CD4% fell below 25% if aged < 1 year or below 20% if < 2 years) (86). Other data, although in slightly older infants, supports early treatment with ART as well. The Perinatal AIDS Collaborative Transmission Study which included 260 HIV-infected children in the U.S. showed that infants who received treatment early (prior to age 2 years, with nearly half starting in the first year of life) were significantly less likely to progress to AIDS or death compared with those who received no therapy (2). The French Perinatal Cohort study reported a 70% reduction in the incidence of AIDS-associated events before age 24 months among infants started early on ART; those who started treatment before 6 months had the best clinical outcomes (18).

　　CHER试验近期公布的数据（感染HIV的儿童早期接受抗逆转录病毒治疗）表明，与推迟接受治疗（年龄小于1岁直至CD4%低于25%；年龄大于1岁小于2岁直至CD4%低于20%）的儿童相比，感染HIV的婴幼儿早到在出生后的6到12周开始抗逆转录病毒治疗，死亡风险显著降低了76%，艾滋病病毒进展的风险降低了75%（86）。即使是稍年长的儿童，其他数据还是支持早期接受抗逆转录病毒治疗。美国一项围产期传播艾滋病的合作研究，包括260名感染HIV的儿童，结果表明，与那些没有接受抗病毒治疗的婴幼儿相比，早期接受抗逆转录病毒治疗的婴幼儿（2岁之前，其中近半数在出生后第一年内开始接受治疗），进展为艾滋病或死亡的风险明显降低（2）。法国一项围产期队列研究表明，在24个月龄前开始接受抗病毒治疗的婴幼儿，其艾滋病相关事件的发生率减少了70%；在6个月龄前开始接受治疗的婴幼儿出现最佳的临床结果（18）。

               Studies are conflicting on the durability of viral suppression with early initiation of ART. Studies have demonstrated that long-term suppression of HIV viremia can be achieved in the youngest and most immunologically immature infants. For example, in the PACTG 356 study, 52 infants were treated with 3 and 4 drug regimens. Those who began treatment at ≤ 3 months of age were more than twice as likely to maintain HIV RNA viral loads < 400 copies/mL for 200 weeks than infants who initiated therapy at age > 3 months (60% versus 30%; p=0.03) (46).

　　早期开始抗逆转录病毒治疗对于抑制病毒的持久性的研究还存在争论。有研究表明，，最年轻和免疫最不成熟的婴幼儿长期抑制艾滋病病毒是可能的。例如，在PACTG 356研究中，52例患者接受三四种药物的治疗方案。与在3个月龄以后才开始接受治疗的婴幼儿相比，那些在3个月龄以内开始治疗的婴幼儿，他们维持HIV RNA病毒载量水平在200周时低于400拷贝/毫升的可能性要高出两倍以上（60% vs. 30%；P=0.03）（46）。

               Nonetheless, the percentage of infants with viral load suppression is lower than what is typically reported in older children and adults. Studies in addition to the PACTG 356 study have indicated that the percent of infants with undetectable viral loads after 12-24 months ranges from 18-60% (17, 47). Possible explanations for the poor response in infants may be due to an immature immune system that has not yet developed HIV-specific immune responses (46). Inadequate antiretroviral drug levels may occur due to the lack of pediatric pharmacokinetic data or due to the fact that the child is growing with evolving body composition and drug metabolism (42). Adherence issues and difficulty in administrating oral regimens are also possible factors.

　　然而，婴幼儿病毒抑制的比例通常低于年龄较大的儿童和成年人的比例。除PACTG 356研究之外，有其它研究表明，12-24个月龄后，婴幼儿检测不到病毒载量的比例范围是18-60%（17，47）。对婴幼儿低反应的可能解释是由于尚不成熟的免疫系统还不能产生HIV特异性免疫反应（46）。抗逆转录病毒药物的水平不够，可能是由于缺乏儿童药代动力学资料，或者是由于儿童随着身体成分和药物代谢的变化而成长（42）。依从性问题和口服药物方案的管理困难也是可能的因素。

ARV-Naive HIV-Infected Children Age 1 Year or Older

1岁或以上HIV感染的儿童

Due to the lower risk of disease progression in children > 1 year, the option of deferring treatment can be considered for older children. Children with clinical AIDS or significant symptoms (CDC clinical categories B or C) are at higher risk of disease progression, and treatment is recommended for all ages, as with adults. However, children age > 1 year with mild clinical symptoms (CDC clinical category A or N) or who are asymptomatic are at lower risk of disease progression than those with more severe clinical symptoms.

　　由于1岁以上儿童疾病进展的风险较低，年龄较大的儿童可以考虑选择推迟抗病毒治疗。儿童出现艾滋病临床表现或重要症状（CDC，临床分类为B或C）存在疾病进展的高危险性。此时，与成年人一样，应建议各年龄儿童接受抗病毒治疗。然而，1岁以上儿童临床症状比较温和（CDC，临床分类为A或N），或者那些无症状儿童存在疾病进展的风险要低于那些更严重临床症状的儿童。

               The prognostic significance of a specific CD4 percentage or count varies with age (14). Younger children (ages 1-<5 years) with a CD4% of < 25% should be treated, regardless of symptoms or HIV RNA levels; likewise, older children (> 5 years) with an absolute CD4 count of <350 cells/mm3 should be started on therapy. For children who have higher CD4% or absolute counts but are mildly symptomatic and have high viral loads (>100,000 copies/mL) should also be considered for therapy.

　　随着年龄的变化，CD4百分比或细胞计数的预后意义也发生改变。1至5岁的年幼儿童CD4%<25%时，不论是否有临床症状或HIV RNA水平如何，都应该接受抗病毒治疗。同样，5岁以上较大年龄的儿童CD4细胞绝对数的<350 个/mm3应开始接受治疗。而对于那些有更高的CD4%或绝对计数，症状较轻，病毒载量很高的儿童（>10万拷贝/毫升），也应考虑抗逆转录病毒治疗。

TREATMENT RECOMMENDATIONS (Table 2)

治疗建议（表2 ）

               The guidelines developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children (convened by the National Resource Centers at the Francois-Xavier Bagnoud Center, UMDNJ; the Health Resources and Services Administration, and the National Institutes of Health) are utilized here. These guidelines, also referred to as the NIH guidelines, were updated on February, 2009, and can be accessed at the following website: http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf.

　　这里运用的治疗指南是由HIV感染儿童抗逆转录病毒治疗和医疗管理工作组制订的（由在弗朗索瓦格扎维巴尼奥中心的国家资源中心UMDNJ，卫生资源和服务管理组织，以及美国国立卫生研究院召集）。这些指南，也被称为美国国立卫生研究院的指南，更新于2009年2月，并可以通过以下网址获得：http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf.

               Given their complexity, treatment-resistant patients are not specifically discussed here; genotype and phenotype resistance testing are typically utilized to manage these patients. Children who are failing treatment should be managed in consultation with a pediatric HIV specialist. More information about treatment-resistant patients is available in the NIH guidelines.

　　由于耐药患者的复杂性，在这里不作具体讨论。基因型和表型耐药检测通常被用于这些患者。儿童抗病毒治疗失败应咨询儿童艾滋病领域的专家。欲了解更多有关耐药患者的信息可以在美国国立卫生研究院的指南中找到。

NNRTI-Based Regimens

基于NNRTI的方案

               For NNRTI-based regimens, choices would include: efavirenz in combination with 2 NRTIs for children age ≥ 3 years; or nevirapine with 2 NRTIs for children < 3 years or who require a liquid formulation. An alternative regimen would be nevirapine with 2 NRTIs for children age > 3 years.

　　基于非核苷类逆转录酶抑制剂(NNRTI)的方案选择包括：3岁及以上年龄儿童可以选择依非韦伦，加2种核苷类逆转录酶抑制剂(NRTIs)；3岁以下或需要液体配方的儿童可以选择奈韦拉平，加2种核苷类逆转录酶抑制剂(NRTIs)。3岁以上儿童的另一种方案是奈韦拉平加2种核苷类逆转录酶抑制剂(NRTIs)。  

               Both nevirapine and efavirenz have approved pediatric indications. Nevirapine is available in a liquid formulation, while efavirenz is currently not, although that formulation is currently under study. There is also a pediatric fixed-dose combination tablet of lamivudine, stavudine and nevirapine which was approved by the U.S. Food and Drug Administration (FDA) in 2007 and is mainly used in developing countries by the President’s Emergency Plan for AIDS Relief (PEPFAR) treatment programs. This combination pill can be swallowed or dissolved in water for children who can not swallow tablets.

　　奈韦拉平和依非韦伦均已获得儿童用药的批准。奈韦拉平具有液体配方，而依非韦伦目前还没有，这种配方目前正在研究。儿童还有固定剂量复合剂片拉米夫定，司他夫定和奈韦拉平，这几种药物是获得美国食品和药物管理局（FDA）2007年认证的，主要用于发展中国家总统防治艾滋病紧急救援计划（PEPFAR）治疗项目。这些组合药片可以吞服，对于不能吞服药物的儿童，还可以溶于水中服用。

               Advantages of using a NNRTI-based regimen include preservation of the PI class for future use, improved palatability, less pill burden, and perhaps less dyslipidemia and insulin resistance (48). The major disadvantage is that a single viral mutation can confer drug resistance, and cross-resistance often develops across the entire class.

　　使用基于NNRTI的方案的优点包括为将来的蛋白酶抑制剂( PIs)使用留有余地，改良了口味，减少药物负担，以及减少可能出现的血脂异常及胰岛素抵抗（48）。主要的缺点在于单个病毒突变往往发展成为整个类别药物的耐药和交叉耐药。

               Efavirenz is the preferred NNRTI for children age ≥ 3 years who can swallow capsules based on clinical trial experience in children. Results of efavirenz in children are comparable to those in adults (49, 70). Nevirapine is recommended only as an alternative in this age group, mainly due to the higher rate of toxicities observed in adult clinical trials. Rare but serious skin rash (including Stevens-Johnson syndrome) and hepatotoxicity can occur with both drugs but more frequently with nevirapine (4, 79, 82).

　　参照儿童临床研究经验，依非韦伦是3岁及以上可以吞咽胶囊儿童的首选NNRTI治疗药物。儿童服用依非韦伦的治疗效果结果与成年人类似（49，70）。奈韦拉平则仅被建议作为这一年龄组的一种替代治疗药物，主要是因为成人临床试验中观察到的较高毒性。两种药物都可能会出现罕见而严重的皮疹（包括斯-约二氏综合征）以及肝脏毒性，但奈韦拉平更容易出现以上副作用（4，79，82）。

               Results of studies comparing nevirapine with efavirenz in adults are conflicting, and no head-to-head comparative studies have been done in children. A recent study in Uganda recently revealed that children on nevirapine-based regimens (D4T/3TC/NVP) were almost 2.5 times more likely to have viral failure than those on efavirenz (ZDV/3TC/EFV) (odds ratio 2.46, 95% confidence interval: 1.23 to 4.90) (41). Efavirenz is not recommended for children < 3 years as it is available only in capsule form, and the appropriate dose has yet to be determined.

　　奈韦拉平和依非韦伦对于成年人的研究结果是不一致的，对于儿童而言，尚没有直接的比较研究。最近有一项在乌干达的研究发现，以采用奈韦拉平的治疗方案（D4T/3TC/NVP）的儿童出现病毒治疗失败的可能性几乎是依非韦伦治疗方案（ZDV/3TC/EFV）儿童的2.5倍（比值比为2.46，95％可信区间：1.23-4.90）（41）。3岁以下的儿童不建议使用依非韦伦方案，因为它只有胶囊剂型，而且尚未确定适当的治疗剂量。

               The major limitations of efavirenz are the central nervous system side effects. Mostly transient, these effects include fatigue, poor sleeping patterns, vivid dreams, poor concentration, agitation, and depression. These may appear less frequently in children than in adults (22). Efavirenz is contraindicated in adolescent females who are sexually active unless adequate contraception can be assured due to the drug’s teratogenicity and potential for fetal CNS malformations.

　　依非韦伦最主要的缺点是对中枢神经系统的副作用。大部分副作用是一过性的，包括疲倦、睡眠模式不良、多梦、注意力难集中、易怒和抑郁症。儿童出现以上症状的频率可能会低于成人（22）。性活跃的青春期女性除非有足够的避孕保证，否则禁忌使用依非韦伦，因为该药物具有致畸性且可能导致胎儿中枢神经系统畸形。

               Nevirapine is recommended for children < 3 years, or those unable to take pills as it comes in liquid formulations. In a large adult trial, while virological efficacy was comparable between nevirapine and efavirenz, serious hepatic toxicity was more frequent in the nevirapine arm than the efavirenz arm, particularly in women with CD4 cells > 250 cells/mm3 (34). This may be less of an issue in pre-pubertal children as hepatotoxicity appears to be less frequent than in adults (84); however, nevirapine should not be used in post-pubertal adolescent girls with CD4 counts > 250 cells/mm3 (92).

　　3岁以下的儿童推荐使用奈韦拉平，无法服用药丸的患者也建议使用奈韦拉平，因为它有液体配方。在一项大规模的成人临床试验中，奈韦拉平和依非韦伦的病毒学疗效相当，奈韦拉平比依非韦伦更容易频繁出现严重的肝脏毒性，特别是对于CD4细胞计数>250个/mm3 的妇女（34）。由于青春前期儿童肝脏毒性的发生频率低于成人使该问题不再那么严重（84），然而，青春后期少女CD4细胞计数>250个/mm3不应使用奈韦拉平（92）。

PI-Based Regimens

基于PI的方案

               Nine PIs are currently approved for treatment of HIV infection; 7 of which are approved for use in children (treatment-naïve and treatment-experienced) and have pediatric drug formulations. Advantages of PI-based regimens include excellent virologic potency, high barrier for development of drug resistance (requiring multiple mutations) and sparing of the NNRTI drug class. However, the drugs have potential for multiple drug-drug interactions due to their metabolism via hepatic enzymes and may be associated with metabolic complications such as dyslipidemia, fat redistribution and insulin resistance (80).

　　目前有9种蛋白酶抑制剂( PIs)已通过审批用于HIV感染的治疗，其中7种已获准可用于儿童（从未接受治疗和接受过治疗的儿童）和儿童药物制剂。基于PI的方案的优点包括：突出的病毒学效力，耐药性形成的高阻断（需要多个基因突变）和可以避免使用NNRTI类药物。然而，该类药物具有潜在的多重相互作用，由于其代谢经肝脏一种酶，可能与一些代谢性并发症有关，如血脂异常，脂肪再分布和胰岛素抵抗（80）。

               Currently, the preferred PI for the treatment-naïve child is co-formulated lopinavir/ritonavir based on virologic potency in both adult and pediatric studies (57). Studies have shown that lopinavir/ritonavir has a high barrier for the development of drug resistance with an excellent toxicity profile and the availability of appropriate dosing for children. In both ARV-naïve and -experienced children, lopinavir/ritonavir has demonstrated durable virologic activity and low toxicity (57). In a study of 44 treatment-naïve children, 84% had plasma HIV RNA < 400 copies/mL and 71% < 50 copies/mL after 48 weeks of therapy (67). Dosing and efficacy data is also available in infants under age 6 months.

　　目前，在成人和儿童的研究中，从未接受抗病毒治疗儿童的首选PI治疗方案是基于病毒学效力的洛匹那韦/利托那韦联合治疗方案（57）。研究结果表明，洛匹那韦/利托那韦有很好的耐受性，并不易出现耐药，还能够为儿童提供适当的剂量。无论是从未使用过抗病毒治疗药物的儿童还是有治疗经历的儿童，洛匹那韦/利托那韦已经被证实有持久病毒学活性和低毒性的特点（57）。在一项有关44名从未接受抗病毒治疗儿童的研究中，经过48周的治疗后，84%的血浆HIV RNA<400份/mL，71%的血浆HIV RNA<50拷贝/毫升（67）。目前已经有6个月龄以下婴幼儿抗病毒治疗的剂量和疗效数据。

               Alternative PIs for children > 6 years old include atazanavir with low-dose ritonavir and fosamprenavir with low-dose ritonavir. Nelfinavir can also be used in children age > 2 years old. Since March 31, 2008, all nelfinavir manufactured and released by Pfizer meets the ethyl methane sulfonate (EMS) limits, which was a problem in the prior product (92).

　　6岁以上儿童的另一种备选方案包括低剂量利托那韦+阿扎那韦和低剂量利托那韦+福沙那韦。奈非那韦还可以用于2岁以上年龄的儿童。自2008年3月31日起，所有由辉瑞制造并销售的奈非那韦符合甲基磺酸乙酯（EMS）的限制标准，解决了一个早期产品的问题（92）。

               Three other PI-based regimens are recommended for children only in special circumstances, such as when the patient can not tolerate ritonavir. Atazanavir without ritonavir may be used in children age > 13 years and >39 kilograms. Higher doses may be required to achieve adequate concentrations, and tenofovir and didanosine should not be used in the backbone NRTI regimen. Fosamprenavir without ritonavir can be used in children age > 2 years old. Lastly, older adolescents have the option to use saquinavir with low-dose ritonavir.

　　其他三种基于PI的方案建议只有在特殊情况下，比如当患者不能耐受利托那韦，儿童才可以使用。阿扎那韦不加利托那韦可以用于13岁以上，并且体重在39公斤以上的儿童。高剂量可能用于达到足够的浓度，而且替诺福韦和去羟肌苷不能合用。福沙那韦（不加利托那韦）可用于2岁以上的儿童。最后，年龄较大的青少年可以选择使用沙奎那韦加小剂量利托那韦。

               Several new PI’s, including darunavir and tipranavir, have been approved in the last few years with the target population being highly-experienced patients with pre-existing viral resistance to other PI’s. In December 2008, the U.S. Food and Drug Administration approved the use of darunavir with low-dose ritonavir in children age > 6 years old (19). Until there is more data to evaluate its safety and efficacy, darunavir is not currently recommended for initial therapy. Likewise, tipranavir should only be used in treatment-experienced children.

　　还有许多新的PI治疗方案，包括已批准的达芦纳韦和替拉那韦，在过去几年中其主要目标人群是那些多种抗病毒治疗后的患者，且对先前几种PI治疗方案耐药。2008年12月，美国食品和药物管理局批准6岁以上的儿童可以使用低剂量利托那韦加达芦纳韦（19）。目前达芦纳韦并不建议用于初治方案，除非出现更多评估其安全性和有效性的数据。同样，替拉那韦只应该用于接受过抗病毒治疗的儿童。

NRTIs In Pediatrics

儿童NRTIs方案

               Currently 6 NRTIs (zidovudine, didanosine, stavudine, abacavir, lamivudine and emtricitabine) are FDA-approved for use in children less than 13 years old. All of these medications come in pediatric formulations. A combination of these drugs typically makes up the “backbone” of the pediatric ART regimen, combined with either a NNRTI or PI.

　　目前有6 种NRTIs（齐多夫定，去羟肌苷，司他夫定，阿巴卡韦，拉米夫定和恩曲他滨）被FDA批准用于13岁以下儿童。所有这些药物均可作为儿童配方。将这些药物与NNRTI或PI进行组合。

               The NIH is currently recommending abacavir plus either lamivudine or emtricitabine as one of 3 preferred NRTI backbone combinations (92). When available, HLA B*5701 genetic testing should be performed for HIV-infected children prior to initiating abacavir-based therapy due to the increased risk for the rare but life-threatening hypersensitivity reaction among HLA B*5701+ patients. Abacavir-containing regimens have been shown to be equally or possible more potent than zidovudine-containing regimens (29). Recently, PENTA 13, an open-label pharmacokinetic study, demonstrated that once daily abacavir/lamivudine obtained concentration levels that were non-inferior to those achieved with twice daily (5). This simplified dosing regimen would greatly improve adherence.

　　目前美国国立卫生研究院正在推荐将阿巴卡韦与加拉米夫定或恩曲他滨组合起来，作为3种NRTI核心组合方案中的一种（92）。如果可以，应当在开始基于阿巴卡韦的治疗方案之前，为感染艾滋病病毒的儿童提供人类白细胞抗原B*5701基因检测，因为这种治疗会增加人类白细胞抗原B*5701阳性患者出现罕见且危及生命的过敏反应出现的风险。阿巴卡韦治疗方案已被证明与齐多夫定具有疗效相同或更有效（29）。PENTA 13，近来一项开放性药代动力学研究，表明每天一次阿巴卡韦/拉米夫定的药物浓度水平并不低于每天两次给药的药物浓度水平（5）。这种简化用药剂量的方案将会极大地改善抗病毒治疗的依从性。

               Another preferred NRTI combination consists of didanosine plus emtricitabine, although didanosine is complicated by the recommendation it should be given when fasting which is difficult when feeding infants. A comparison of didanosine given with or without food in children found that systemic exposure was similar, but that the fraction absorbed was lower and slower with food (77).

　　另一个首选NRTI组合方案包括去羟肌苷加恩曲他滨。去羟肌苷建议空腹服用，给婴幼儿服用带来了一定的困难。比较在进食和禁食情况下服用去羟肌苷的研究发现，虽然总体暴露相似，但进食后部分吸收率较低、速度较慢（77）。 

               The preferred combination with the most experience in children is zidovudine plus lamivudine. While there is less experience with emtricitabine, it is relatively interchangeable with lamivudine and has been shown to have the same plasma area under the concentration-time curve (AUC) in pediatrics as in adults (87). Emtricitabine’s advantages include once daily-dosing and availability as an oral solution.

　　对于已接受多种抗病毒治疗的儿童，其首选组合是齐多夫定加拉米夫定。当不经常使用恩曲他滨时，相对来说，可以用拉米夫定加以替代，而且拉米夫定在儿童和成人血液中已被证明具有相同的浓度-时间曲线（AUC）（87）。恩曲他滨的优点包括每日一次用药和可以口服。

               Alternative dual NRTI combinations include zidovudine in combination with either abacavir or didanosine. In adolescents who are post-pubertal or Tanner stage 4, tenofovir plus either lamivudine or emtricitabine can be used. Only in special circumstances should stavudine plus either lamivudine or emtricitabine be used given the higher risk of lipoatrophy and hyperlactemia with stavudine versus other NRTI drugs (38). Stavudine plus didanosine should only be used for salvage therapy in treatment-experienced children given the greater rates of neurotoxicity, lactic acidosis, and lipodystrophy seen more frequently with this combination than with other therapies (33).

　　其他的NRTI替代组合包括齐多夫定加阿巴卡韦或者加去羟肌苷。青春期末的青少年或唐纳症四期，使用替诺福韦加拉米夫定或者加恩曲他滨都可以。由于皮下脂肪萎缩和高血脂的风险要高于其他NRTI类药物，因此，司他夫定只有在特殊情况下才会考虑与拉米夫定或者加恩曲他滨合用（38）。司他夫定加去羟肌苷只应当用于接受过抗病毒治疗的儿童的挽救性治疗，由于这种组合比其他疗法的神经毒性更大，乳酸性酸中毒和脂肪营养障碍也更容易出现（33）。

              Tenofovir has now been used off-label in children as part of salvage therapy regimens. Small studies suggest that tenofovir is well-tolerated and effective (32, 63) in pediatric patients, and it is being studied in combination with other NRTIs as an investigational oral suspension and in a “sprinkle” formulation. One of the benefits would be its activity against hepatitis B. At this time, however, there is insufficient safety data to recommend it. Due to its potential bone and renal toxicity, the drug is only recommended in children when there are no other options available. Decreased bone mineral density has been seen in pre-pubescent treatment-experienced children when taking tenofovir for 48 weeks (23). Renal toxicity has been seen as well, most often with concurrent didanosine and lopinavir/ritonavir use (63). For adolescents in Tanner Stage 4 or who are post-puberty, tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI combination.

　　泰诺福韦已经被作为儿童抢救治疗方案的一部分。有研究表明，儿童患者使用泰诺福韦其耐受性良好且有效（32，63），并且与其他NRTIs组合成口服混悬液，目前正在研究喷雾剂型。其中一个好处就是泰诺福韦的活性可以抑制乙型肝炎病毒，然而，这时由于没有足够的安全性数据，不能被推荐使用。由于其存在潜在的骨和肾毒性，该药物仅仅适用于儿童在没有其他选择建议时的用药。当接受泰诺福韦治疗48周后，经常观察到青春期前接受过抗病毒治疗的儿童出现骨密度下降（23）。与去羟肌苷和洛匹那韦/利托那韦联合使用时，往往会出现肾毒性（63）。泰诺福韦加拉米夫定或恩曲他滨是青少年或青春末期唐纳症四期患者的首选双重NRTI组合。

               In addition, a triple NRTI regimen such as zidovudine, lamivudine, and abacavir is only recommended in special circumstances such as when a preferred or alternative NNRTI-based or PI-based regimen cannot be used as first-line therapy in treatment-naïve children. This situation may occur when the patient is on anti-tuberculosis medications due to the drug-drug interactions (e.g. nevirapine or lopinavir/ritonavir with rifampin). One advantage of this regimen is its simplicity and lower pill burden particularly when using the single pill combination. Data on the efficacy of triple NRTI regimens for treatment-naïve children is limited. In adult trials, these regimens have shown less potent virological efficacy when compared to NNRTI- or PI-based regimens (31, 60), although a recent trial from Uganda suggested this regimen is still a valid option (75).

　　此外，三重NRTI方案，如齐多夫定，拉米夫定和阿巴卡韦，不能作为一线用药，只是建议在特殊情况下可以使用，例如当首选方案、或基于NNRTI或PI的方案不能使用时。例如，当患者用药与抗结核药物发生拮抗时，由于药物的相互作用（奈维拉平，或洛匹那韦/利托那韦与利福平等），这种情况可能会出现。这种方案的一个优点是比较简单和药物负担较轻。三重NRTI方案初治儿童中的效资料还很有限。成人研究表明与基于NNRTI或PI的方案相比，三重NRTI方案的病毒学疗效偏低（31，60），但最近乌干达的一项试验则认为三重NRTI方案仍然是一个有效的选择（75）。

New Classes of Drugs

新型药物

               Enfuvirtide, or T-20, is the only entry inhibitor approved for use in both adults and children currently. It works by blocking the fusion of the virus to the target cell. Dosage recommendations exist for children aged 6 years or older. A recent multicenter, open-label, non-randomized study showed the safety and efficacy in the pediatric population (90). Of importance in this study was that efficacy in adolescents (>11 years old) was inferior, most likely due to adherence. Toxicities are primarily local site reactions.

　　恩夫韦地，或T-20，是目前唯一被批准用于成人和儿童的整合抑制剂。其工作原理是通过拦截融合的病毒进入靶细胞。建议用于6岁或以上儿童的抗病毒治疗。最近一项多中心开放非随机研究表明，恩夫韦地用于儿童人群是安全和有效的（90）。值得注意的是，本研究中11岁以上青少年的疗效稍低，可能是受依从性的影响。毒性主要是用药部位的局部反应。

               Maraviroc, another entry inhibitor that works by blocking the CCR5 receptor, was approved for use in adults in 2007. However, its safety and efficacy has not yet been established in pediatric patients (50).

　　Maraviroc是另外一个病毒进入细胞过程的抑制剂，它的工作原理是通过阻断CCR5受体，在2007年被批准用于成人的抗病毒治疗。但是，它在儿童患者中的安全性和有效性尚未得到确定（50）。

               Also in 2007, the integrase inhibitor raltegravir was approved for use in adults (62). Interim findings from the ongoing IMPAACT study (ACTG P1066), a prospective, non-randomized, open label study for treatment-experienced children and adolescents, were presented at the 2009 Conference on Retroviruses and Opportunistic Infections in Montreal, Canada. After 12 weeks, 88% had less than 400 copies/mL. Raltegravir was found to be well tolerated. Researchers are currently developing a chewable formulation (91).

　　同样在2007年，整合酶抑制剂拉替拉韦也被批准用于成人（62）的抗病毒治疗。正在进行的IMPAACT研究（ACTG P1066）是一项前瞻性、非随机、开放性研究，研究有关曾经接受治疗儿童和青少年的拉替拉韦治疗效果，其中期结果报告于加拿大蒙特利尔2009年逆转录病毒和机会性感染会议上。12周后，88%的儿童和青少年病毒载量低于400拷贝/毫升。拉替拉韦的耐受性良好，研究人员目前正在开发一种可以咀嚼的药物形式（91）。

               In 2008, etravirine, considered to be a second-generation NNRTI, was approved by the FDA in treatment-experienced adults. Again, its safety and efficacy in children < 16 years has not been established (81).

　　2008年，依曲韦林被认为是第二代非核苷类逆转录酶抑制剂，经美国FDA批准用于曾经接受抗病毒治疗的成年人。此外，对于16岁以下的儿童，其安全性和有效性尚未确定（81）。

Drug Resistance

耐药性

               HIV drug resistance due to mutations now poses the newest challenge. In a recent study performed in the United States, 24% of children were found to have resistance to NRTIs prior to starting ART, and 19% had resistance to NNRTIs (61). Furthermore, maternal history did not always provide a clear explanation for the drug resistance patterns encountered. Two of the 4 infants with virus containing NNRTI resistance mutations had not been exposed to nevirapine during pregnancy (61).

　　由于突变产生的HIV耐药构成了目前最新的挑战。美国最近的一份研究报告，在开始抗逆转录病毒药物治疗之前，24%的儿童出现耐核苷类逆转录酶抑制剂，19%出现耐非核苷类逆转录酶抑制剂（61）。而且，母亲的病史并不总是能够对遇到的耐药模式提供一个明确的解释。4名婴幼儿中，有2例在怀孕期间尚未使用奈韦拉平，但他们的病毒却包含耐非核苷类逆转录酶抑制剂的突变（61）。

               For antiretroviral dug resistance testing, several genotypic (GT) and phenotypic (PT) assays are available. GT assays detect specific HIV genetic mutations contributing to resistance. PT assays directly measure the ability of a viral isolate to grow in the presence of a drug. Virtual phenotyping is a method of predicting phenotype based on the genotype of a viral isolate. Using GT, PT or virtual phenotype can be helpful to the clinician when changing ART due to virologic failure. Resistance testing is now recommended prior to the initiation of therapy due to the possibility of perinatal HIV infection by a drug-resistant virus from the mother.

　　许多基因型（GT）和表型（PT）试验是目前可用的抗逆转录病毒耐药检测。基因型试验是通过测定产生耐药的HIV特定的基因突变，表型试验是在出现一种药物时，通过直接测定病毒分离的能力。虚拟表型是一种预测病毒分离基因型基础上的表型的方法。用基因型，表型或虚拟表型可以帮助临床医师在病毒学治疗失败时，更换抗逆转录病毒疗法。由于围产期从母亲获得HIV耐药株可能性的存在，目前，在儿童开始初次治疗前，建议先做耐药性检测。

Adherence

依从性

               Adherence to ART is particularly critical in the treatment of pediatric HIV infection. Data on ART suggests that medication adherence is a strong predictor of therapeutic impact (21). Lack of adherence to prescribed regimens can lead to sub-therapeutic levels of antiretroviral medications, which enhances the risk of the development of drug resistance and likelihood of virologic failure.

　　在治疗儿童HIV感染时，抗逆转录病毒治疗的依从性是特别关键的。有数据表明，服药依从性对预测治疗效果有非常大的影响（21）。缺少对规定方案的依从性可能会导致抗逆转录病毒药物的水平低于治疗水平，这也就增加了耐药进一步发展的危险性以及病毒学失败的可能性。

               Despite the benefits of treatment and adverse consequences of disease progression, adherence is reportedly suboptimal among children, and perhaps worse among adolescents. Factors for poor adherence include pill burden, frequency of medications, and patients’ lack of awareness of their own diagnosis, social stressors, and poor support systems.

　　无论如何强调治疗的益处和对疾病进展的不利后果，研究发现儿童的依从性通常不最理想，而青少年可能更差一些。导致依从性差的因素包括药物负担，用药的频率，病人缺乏自我诊断的意识，社会压力和支持系统缺乏。

               Adherence varies widely in studies, ranging from 20-100% depending on how adherence was assessed (e.g. whether via pill count or by self-reporting measures), how ‘optimal adherence’ was defined, and how findings were reported (74).

　　有关依从性的研究结果波动于20-100%之间，这取决于依从性是如何评估的（如是否通过药丸计数或采取自我报告的措施等），理想依从性是如何定义的，以及调查结果是如何报告的（74）。

               Participation by the caregivers and child in the decision-making process is crucial. Issues related to adherence to therapy should be fully assessed, discussed and addressed with the child’s caregiver and the child (when age-appropriate) before the decision to initiate therapy is made. Potential problems should be identified and resolved prior to starting therapy, even if this delays initiation of therapy.

　　看护者和儿童参与决策过程是至关重要的。在决定开始治疗之前，与治疗有关的依从性问题应同看护者和儿童（当与年龄相适应时）进行充分评估，讨论和处理。即使会延迟开始治疗的时间，一些潜在问题应当在开始治疗前找出并解决。

CONCLUSION

结论

               The use of PMTCT has significantly dropped the number of children born with HIV in Western countries, but yet pediatric HIV/AIDS remains a medical challenge in the developed world – in part due to the migration of HIV-infected children from higher prevalence countries, the fact that more children are living longer with the disease, and that the numbers of sexually-acquired infection among young adolescents are increasing. In resource-limited countries, pediatric HIV infection poses more than just a medical challenge – but rather a devastating health crisis. Antiretroviral medications are becoming more widely available in these settings which will certainly save lives. With increasing exposure to antiretrovirals, however, there will be growing resistance, making antiretroviral management increasingly complex. This is coupled with the fact that adherence is already difficult in children, particularly when there are many pills which are often unpalatable. Genotype testing, currently cost-prohibitive in many parts of the world, will become more critical including at baseline in the treatment-naïve patient. As HIV management becomes more technical, many of these patients will certainly require assistance by pediatric HIV sub-specialists. This is another problem in resource-limited settings where health care workers are in dire shortage.

　　在西方国家，PMTCT的使用已大大减少了儿童出生时感染HIV的人数，但是儿童HIV/AIDS依然是发达国家面临的一个医学挑战，部分原因是儿童发病率较高的国家HIV的转移，事实上有更多的儿童携带这种疾病生活，而且青少年通过性行为感染HIV的人数正在不断增加。在一些资源匮乏的国家，儿童HIV感染不仅仅是一个医学挑战，而是一种毁灭性的健康危机。抗逆转录病毒药物在这些地区正在被广泛应用，并且必将挽救生命。但是，随着接受抗逆转录病毒治疗的人数越多，耐药性也将出现，抗逆转录病毒治疗的管理也日益复杂。另外，加上儿童依从性问题已经很困难，尤其许多药片口味往往不好。对于从未接受过治疗的患者来说，基因型检测在基线治疗时将变得更加重要，在世界许多地方目前成本还过高。随着HIV感染者管理的专业化，其中有许多患者必然需要儿童HIV感染方面的专家提供支持。另外一个问题是，在资源有限的地方卫生服务工作人员严重短缺。

               At the same time, there is hope. The last 2 years has been very beneficial to the world of antiretrovirals as several new classes of medications have been approved including the integrase inhibitor raltegravir, the CCR5 inhibitor maraviroc, and the new NNRTI etravirine. As of yet, none of these drugs have been officially approved for use in children. Pediatric clinical trials and pharmacokinetic research continue to lag behind adults. For many currently available antiretrovirals there still are no proper dosing recommendations nor are there solutions readily available for children who can not swallow pills. This, too, appears to be changing slowly as fixed drug combination pills, designed specifically for children and infants, become more widely used.

　　与此同时，还有希望存在。过去2年中多种新型药物被批准使用，包括整合酶抑制拉替拉韦，CCR5抑制剂Maraviroc和非核苷类逆转录酶抑制剂新药依曲韦林。截至目前，这些药物都没有被正式批准用于儿童。儿童临床试验和药代动力学研究依然落后于成年人的研究。对于许多现有的抗逆转录病毒药物仍然没有适当的用药建议，对于不能吞咽药片的儿童也没有目前可行的解决方案。这也似乎正在慢慢地改变，固定的药物组合方式和专为儿童和婴幼儿设计的药物也得到更广泛的应用。

KEY ISSUES

关键问题

* Management of HIV infection in the pediatric population is rapidly evolving and increasingly complex. Treatment of these patients typically should include assistance from a pediatric HIV specialist.

*近年来，儿童人群HIV感染者的诊治不断变化，而且日益复杂。对这些患者的治疗通常应需要从儿童艾滋病专家那里获得支持。

* The overall consensus is that treatment in children should be more aggressive in children than in adults, given that the risk of life-threatening complications of HIV is greatest in infants.

*考虑到婴幼儿感染HIV后的并发症对其生存的巨大影响，儿童HIV的治疗应比成年人的治疗更加积极。

* Antiretroviral therapy is now recommended for all infants < 12 months, regardless of CD4 lymphocyte parameters and HIV viral load.

*不论CD4淋巴细胞计数和HIV病毒载量如何，抗逆转录病毒疗法是目前推荐的用于12个月龄以下所有婴幼儿的治疗方法。

* When feasible and/or accessible, drug resistance testing should be performed before initiation of therapy. This applies not only to those exposed perinatally to nevirapine, but in all infants.

*在可行和/或可及的情况下，开始接受治疗之前应进行耐药性检测。这不仅仅适用于那些围产期有奈韦拉平暴露的婴幼儿，而是适用于所有的婴幼儿。

* There is a need to expand the number of pediatric formulations of current antiretrovirals as well as develop new agents for pediatric use, including against highly-resistant variants.

*目前抗逆转录病毒的药物有必要扩大儿童配方的数量，还要开发新的儿科用药代理商，其中就包括对高度耐药病毒株的药物。

* There is likewise a need for more pharmacokinetic data in the highly variable population of HIV-infected children.

*同样，对于异质性很高的儿童人群，还需要获得更多的药代动力学数据。

* More work needs to be done on improving adherence in children and adolescents, as poor adherence leads to increased resistance and virologic failure.

*在改善儿童和青少年的依从性方面还有很多的工作需要做，因为依从性较差会导致耐药和抗病毒治疗失败。

TABLES

圖表

Table 1: Indications for initiation of antiretroviral therapy in children infected with HIV (12)

表1 ：儿童HIV感染者启动抗逆转录病毒治疗的适应证（12）

¹ CDC 临床分类为C类和B类 (B类有以下情况除外：单一重度细菌性感染或淋巴性间质性肺炎) 

² CD4% <20%的患者比CD4%介于20-24%之间的患者明显有更多的数据支持

³ CDC 临床分类为A 类或N类或者 B类有以下情况：单一重度细菌性感染或淋巴样间质性肺炎

⁴每3-4个月，临床及实验室数据应该进行重新评估。

⁵ CD4细胞计数<200个/mm³的患者比CD4细胞计数介于200-350个/mm³之间的患者明显有更多的数据支持

Table 2:  Recommended Antiretroviral Regimens for Initial Therapy for HIV Infection in Children (12)

表 2:  推荐儿童初治方案 （12）

儿童方案通常包含1个 NNRTI或1 个PI 加2个NRTI. 3个 NRTI 的组合（齐多夫定, 阿巴卡韦, 拉米夫定）只在上述方案不能使用时考虑。

含NNRTI的方案

首选:             儿童 ≥ 3岁: 2 NRTIs + 依非韦伦¹

                      儿童 < 3岁或不能使用胶囊: 2 NRTIs + 奈韦拉平¹

替代方案:                 2 NRTIs + 奈韦拉平 (儿童 ≥ 3岁)

含PI的方案

首选方案:           2 NRTIs + 洛匹那韦/利托那韦

替代方案:                 2 NRTI + 阿扎那韦 + 低剂量 利托那韦 (儿童 > 6岁)

                                  2 NRTI + 福沙那韦 + 低剂量 利托那韦 (儿童 > 6岁)

                                  2 NRTI + 奈非那韦 (儿童 > 2岁)

特殊情况下

                                  2 NRTI +无增强的阿扎那韦 (初治青少年>13岁、体重>39 kg)

                                  2 NRTIs +无增强的福沙那韦 (儿童 > 2岁)

                                  齐多夫定 + 拉米夫定 + 阿巴卡韦

2 NRTI 组合方案

首选:                        阿巴卡韦 + (拉米夫定或恩曲他滨)

                                    去羟肌苷 + 恩曲他滨

                                    齐多夫定 + (拉米夫定或恩曲他滨)

                                    泰诺福韦 + (拉米夫定或恩曲他滨) (用于特纳症4级或青春期后少年)

替代方案:                   阿巴卡韦 + 齐多夫定

                                    齐多夫定 + 去羟肌苷

特殊情况:  司他夫定 + (拉米夫定或恩曲他滨)

作为一线方案证据不充分

• 低剂量利托那韦增强PI 方案, 但洛匹那韦/利托那韦 (所有年龄), 阿扎那韦/利托那韦在儿童 > 6 岁 和 沙那韦/利托那韦用于 > 6岁儿童除外

• 双PI方案

• 含无增强的阿扎那韦方案用于 <13岁，体重<39公斤的儿童

• NRTI + NNRTI + PI

• 含泰诺福韦方案用于特纳症1-3级儿童

• 含替拉那韦或达芦那韦方案

• 含Maraviroc方案

• 含拉替拉韦方案

• 含依曲韦林方案

• 含恩夫韦地方案

¹ 依非韦伦目前只有胶囊剂型; 奈韦拉平在< 3岁儿童或需要液体剂型时为首选。

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