人类免疫缺陷病毒(HIV)与妊娠

 

Seble G. Kassaye, M.D, David A. Katzenstein, M.D

      

译者：张旭喆 博士

         中国协和医科大学

            Email：neuron-power@hotmail.com

 

审阅者：孙永涛  教授

                西安唐都医院

 

               Globally, more than 20 million women of childbearing age are estimated to be HIV positive with the epidemic rapidly expanding in young women, of whom 95% are unaware of their infection. Thus millions of children are at risk of acquiring HIV infection during pregnancy, parturition and through breast-feeding. Rapid-testing in antenatal clinics, short-course and single dose antiretroviral treatments to mothers and infants and exclusive breast-feeding with early weaning are evolving interventions.   

        HIV正在年轻女性中迅速蔓延，据估计全球范围内已有2千万以上的育龄期妇女为HIV阳性者，而她们当中95%对于自己的感染状态并不知晓。因此，成千上万的儿童面临着在妊娠、分娩及母乳喂养的过程中感染HIV的风险。目前正在开展的干预措施包括产前门诊的快速检测、对母亲及婴儿的短程和单剂抗逆转录病毒治疗以及尽早断奶和避免母乳喂养。

               In industrialized countries, treatment of pregnant women with potent antiretroviral therapies has resulted in a greater than 10-fold reduction in the vertical transmission of infection and pediatric AIDS. Highly active antiretroviral therapies (HAART) are effective in pregnancy and with certain exceptions, recommendations for treatment of adult and adolescent women are suitable during pregnancy. Additional strategies to reduce mother-to-child-transmission include active promotion of voluntary testing and counseling to identify HIV infection, antiretroviral therapy, elective caesarean section, prophylactic antiretrovirals to newborns and avoidance of breast-feeding. Rapid testing for detection of HIV-1 infection is now possible, and is recommended by Centers for Disease Control for pregnant women who go into labor without having had an HIV test (11, 42). Detection of disease, even at this late stage, would allow for interventions such as antiretroviral prophylaxis, minimization of invasive procedures intrapartum, and avoidance of breast feeding allowing further decreases in the incidence of mother to child transmission (MTCT) of HIV-1.

        在工业化国家，对孕妇进行的有效抗逆转录病毒治疗已使HIV的垂直传播及儿童艾滋病患者减少了10倍。高效抗逆转录病毒治疗(HAART)在妊娠中是有效的，除某些特殊情况外，应将该疗法推荐给所有成年及青少年孕妇。其它减少母婴传播的策略包括积极促进自愿检测与咨询以发现HIV感染，抗逆转录病毒治疗，择期剖宫产术，新生儿预防性抗逆转录病毒治疗，以及避免母乳喂养。目前已能实现对HIV-1进行快速检测，该检测已被疾病控制中心推荐用于那些已开始分娩但尚未进行过HIV检测的孕妇(11, 42)。即使是在这样晚期的阶段，对于疾病的发现仍然能够使得诸如预防性抗逆转录病毒治疗、减少分娩过程中的有创操作及避免母乳喂养等干预措施得以实施，并进一步降低HIV-1母婴传播(MTCT)的发生率。

Epidemiology of HIV in Women and Children

HIV在妇女和儿童中的流行病学

               Over 130,000 women had been diagnosed with AIDS in the U.S. by the end of June 2001, most of who were of reproductive age. In the absence of antiretroviral treatment about 30% of infected women will transmit infection to their babies during pregnancy, labor and delivery, or breastfeeding. Estimated fractions of intrauterine, intrapartum and post partum breast feeding transmission are approximately 5-10%, 10-15% and 10-12%, respectively. Although over 8,900 children in the U.S. were diagnosed with AIDS by the end of June 2001 (22), increased surveillance and antiretroviral treatment of pregnant women has led to a 10 year decline in the number of new pediatric AIDS cases in this country. In contrast, adolescent and adult women comprise 50% of estimated HIV infections worldwide and >500,000 infants are estimated to acquire HIV infection from their mothers each year (21). More women than males are infected with HIV in sub-Saharan Africa, with even higher proportions in females in the 15-24 year age category (28).

        截至2001年6月底，在美国已有超过130,000名妇女被诊断为艾滋病患者，而其中大部分处于育龄期。在没有抗逆转录病毒治疗的情况下，大约30%已感染妇女会在妊娠、分娩及母乳喂养的过程中将HIV传播给她们的婴儿。据估计，宫内、分娩过程中及产后母乳喂养过程中的传播率分别为5-10%，10-15%及10-12%。尽管截至2001年6月底，已有超过8,900名美国儿童被诊断为艾滋病患者(22)，不断增加的对于孕妇的监测和抗逆转录病毒治疗已经使美国的新发儿童艾滋病病例数连续10年持续减少。与此相反，在世界范围内，估计HIV感染者的50%为青少年及成年女性，而每年有超过500,000名婴儿被他们的母亲感染(21)。在撒哈拉以南的非洲，女性HIV感染者比男性更多，在15-24岁人群组女性感染的比例更高(28)。

Vertical HIV Transmission   

HIV垂直传播途径

               Although infants may acquire HIV throughout pregnancy, most in utero transmission occurs after the first trimester. Intrapartum transmission during labor and delivery accounts for the majority of vertical transmission with additional risk from breastfeeding in up to 15% of cases of vertical transmission (4, 30, 52). The risk of vertical transmission is influenced by viral load, antiretroviral treatment, mode of delivery, duration of ruptured membranes, breastfeeding, chorioamnionitis and fetal maturity, as well as illicit drug use (32, 49). Plasma HIV RNA levels are probably the single best predictor of the risk of transmission, however, there is no threshold below which lack of transmission can be assured (32, 13, 17, 50, 51). Transmission may also differ based on HIV-1 subtype, with subtype D HIV-1 infection being associated with a higher rate of transmission compared to subtype-A HIV-1 infection (70). Additionally, timing of transmission can vary by subtype, with subtype C HIV-1 vertical transmission more likely to occur in utero, than subtype A or D HIV-1 transmission (58).

        尽管在整个妊娠期间婴儿都有可能感染HIV，但大部分的宫内感染发生在孕初三个月。垂直传播大部分发生于分娩过程中，而母乳喂养可使多达15%的病例中垂直传播的风险进一步增加(4, 30, 52)。病毒载量、抗逆转录病毒治疗、分娩方式、破膜至分娩的时间、母乳喂养、慢性羊膜炎、胎儿的成熟度以及非法药品的应用均可影响垂直传播风险(32, 49)。血浆HIV RNA水平可能是对垂直传播风险的最佳单一预测因素，但是目前尚不清楚低于怎样的阈值水平才能能够保证不发生垂直传播(32, 13, 17, 50, 51)。不同HIV-1亚型的传播程度也有所不同，如D亚型HIV-1的传播率就高于A亚型HIV-1(70)。此外，不同亚型的传播时间也有所区别，如相较于A亚型或D亚型HIV-1，C亚型的垂直传播更容易发生在宫内(58)。

Effects of Pregnancy on HIV Disease

妊娠对HIV感染的影响

               Controlled studies in the United States and Europe have not demonstrated an effect of pregnancy on HIV disease progression (3, 12, 59, 63, 68). Some data do suggest, however, that pregnancy may accelerate HIV disease progression in resource-poor settings (23, 31, 54). Although a direct effect of pregnancy on HIV disease is uncertain, there is no doubt that physiologic changes associated with pregnancy can indirectly affect the kinetics of drug absorption, distribution, biotransformation, and elimination (57). These physiological changes may in some cases increase (prolonged gastrointestinal transit time and decreased plasma protein concentrations) or decrease (increased volume of distribution and increased blood flow to the liver and kidney) effective drug concentrations. However, specific recommendations on adjustments to antiretroviral drug dosing in pregnant women are not available.

        在美国及欧洲开展的对照研究并未证明妊娠会影响HIV感染的进展(3, 12, 59, 63, 68)。但是，一些数据确实提示，在健康资源有限的情况下，妊娠确有可能加速HIV感染的进展(23, 31, 54)。尽管妊娠对于HIV感染的直接影响尚不明确，妊娠相关的生理改变可以间接影响药物的吸收、分布、生物转化以及清楚却是毫无疑问的 (57)。这些生理改变在某些病例中可能增加(延长胃肠道通过时间及降低血浆蛋白浓度)或减少(增加分布容积以及增加肝肾血流量)药物的有效浓度。但是，目前尚无针对妊娠期妇女的抗逆转录病毒药物调整推荐方案。

Effects of HIV on Outcome of Pregnancy       

HIV对妊娠结局的影响        

               HIV-infected women receiving antiretroviral therapy have a higher risk of pre-term delivery than uninfected women (8, 43, 45, 47, 15). Whether this risk is due to HIV disease, antiretroviral therapy, other correlated maternal risk factors (e.g. nutritional deficiencies, concomitant infections), or a combination of the above is not known. One large population-based survey in Uganda found that HIV-infected women had lower rates of conception and increased rates of spontaneous abortion (33).

        与未感染HIV的妇女相比，正在接受抗逆转录病毒治疗的妇女早产的风险更高(8, 43, 45, 47, 15)。但目前尚不明确这些风险应归因于HIV感染、抗逆转录病毒治疗、其它相关的母源性风险因素(如营养缺乏、合并感染)或是上述因素的联合作用。在乌干达进行的一项基于种族的大型调查发现感染HIV的妇女受孕率降低而自然流产率升高。

Safety of Antiretroviral Therapy During Pregnancy

妊娠期间抗逆转录病毒治疗的安全性

               Data on the safety of antiretroviral drugs in pregnancy come from four sources: animal studies, anecdotal reports, patient clinical trials, and the Antiretroviral Pregnancy Registry (66). Antiretroviral drugs may be directly toxic to a fetus or may indirectly harm a fetus by through maternal toxicity. Nucleoside analog associated mitochondrial toxicity (including lactic acidosis and hepatic steatosis), anemia, and leukopenia can occur. Pharmacokinetics of antiretrovirals can be different during pregnancy. For example, saquinavir/ ritonavir (800mg/100mg BID) levels are higher during pregnancy than during the postpartum period (1), while nelfinavir levels are lower in the antepartum period (9) (14/17 meeting the targeted AUCO-12), than postpartum (10/11 met targeted AUCO-12). There is not an absolute correlation between drug levels and transmission, as despite detectable HIV-1 RNA > 400 copies/ ml in 3/14 women, there was only 1 documented case of vertical transmission in a small study of nelfinavir (1/23) in a woman treated for less than 3 weeks. Pregnancy may be complicated by protease inhibitor-induced gestational diabetes as found in PACTG 316, with an increased risk seen in pregnant women on a protease inhibitor containing regimen before or during the first trimester, less so in those initiated on such treatment during later time points (67). The possibility of unrecognized drug-related teratogenic effects as well as nausea and anorexia in the first trimester suggest that antiretroviral therapy may be interrupted or withheld, in pregnancy until the second trimester (24 weeks), unless there are maternal indications for treatment (e.g. symptomatic HIV disease, fewer than 200-300 CD4 cells, or plasma HIV-1 RNA levels > 55,000 copies/ml).

        妊娠期抗逆转录病毒药物的安全性数据主要来自以下四个来源：动物研究，个案报告，临床试验以及妊娠期间应用抗逆转录病毒药物登记(66)。抗逆转录病毒药物可能对胎儿有直接毒性，也可能通过对母体的毒性间接伤害胎儿。核苷类似物有可能引起线粒体毒性(包括乳酸酸中毒和肝脏纤维化 )、贫血以及白细胞减少。妊娠期间抗逆转录病毒药物的药代动力学也可能发生变化。例如沙奎那韦/利托那韦(800mg/100mg 每天2次)在妊娠期间的水平较分娩后高(1)，而奈非那韦水平在分娩前(14/17达到目标曲线下面积)较分娩后(10/11达到目标曲线下面积)会降低。目前药物水平与垂直传播之间的绝对关系尚无明确定论，除了在3/14名妇女中检测到HIV-1 RNA〉400拷贝/ml，仅在1项关于奈非那韦的小规模研究中记载1例(1/23)治疗不足3周的妇女发生了垂直传播。蛋白酶抑制剂可能引发妊娠合并症，在儿科艾滋病临床试验联盟316研究中发现蛋白酶抑制剂可引起妊娠糖尿病，且在孕初三个月之前及期间应用含蛋白酶抑制剂的方案将使风险进一步升高，而同样的治疗若在较晚时间开始则风险较小(67)。在孕初三个月存在尚未被认识到的药物相关致畸作用的可能以及恶心和食欲减退均提示抗逆转病毒治疗可能应中断直至孕中期(24周)，除非存在母亲方面的治疗指征(例如症状性HIV感染，CD4细胞少于200-300，或血浆HIV-1 RNA>55,000拷贝/ml)。

               It is generally recommended that women who become pregnant while receiving combination antiretroviral therapy continue treatment with close monitoring for pregnancy-related complications and drug toxicities (10, 17, 57). However, hydroxyurea, efavirenz, and delavirdine are contraindicated in pregnant women or in women planning to become pregnant. Hydroxyurea has carcinogenic and teratogenic potential. Efavirenz has been shown to cause anencephaly, anopthalmia, and micropthalmia in primates. Of 188 women with exposure to efavirenz in the first trimester, reported prospectively to the Pregnancy antiretroviral registry, birth defects were reported in 5. Independently, 4 cases of neural tube defects associated with first trimester exposure have also been reported (package insert Efavirenz 12/2004). Thus pregnancy testing, before the initiation of efavirenz is advised as well as strict adherence to both barrier and hormonal contraception by women with reproductive potential who are prescribed efavirenz. Delavirdine has demonstrated embryotoxicity in other animal models.). PACTG 1022 compared the safety of nelfinavir to nevirapine initiated between 10 and 30 weeks gestation, and showed evidence of increased hepatotoxicity, including one death, in the nevirapine arm in women with CD4+ lymphocyte counts greater than 250 cells per cu mm (5/14 subjects, p=0.04) (35).

        总体上推荐正在接受联合抗逆转录病毒治疗的妇女在怀孕后继续治疗，同时应密切监测妊娠相关合并症及药物毒性(10, 17, 57)。然而羟基脲、依法韦仑和地拉夫定在妊娠妇女及准备妊娠的妇女中是禁用的。羟基脲有致癌和致畸的可能。依法韦仑已被证明可以在灵长类中引起无脑畸形、无眼及小眼畸形。妊娠期间应用抗逆转录病毒药物登记前瞻性地报告了188名在孕初三个月暴露于依法韦仑的妇女，其中有5人报告了出生缺陷。在另外1项独立研究中也报告了4例与孕初三个月暴露于依法韦仑相关的神经管缺陷(依法韦仑的药品说明书12/2004)。因此建议有生殖能力的妇女在开始应用依法韦仑之前检测妊娠试验，并在用药期间严格进行药物及工具避孕。儿科艾滋病临床试验联盟1022试验比较了于孕10周至孕30周开始应用奈非那韦和奈韦拉平的安全性，结果显示在CD4+淋巴细胞计数高于250/mm3组中，奈非那韦的肝脏毒性更高(5/14 受试者, p=0.04，含一例死亡病例) (35)。

               Recent case reports of fatal maternal lactic acidosis (accompanied by pancreatitis in 2 of 3 women) have led to recommendations to avoid the use of d4T-ddI-containing regimens in pregnancy (6, 46, 71). Pregnant women receiving NRTIs should have their hepatic enzymes, blood counts, and electrolytes monitored during the third trimester and those receiving protease inhibitors should be monitored for the development of hyperglycemia. Although the British HIV Association treatment guidelines state that physicians should consider monitoring lactate in women receiving NRTIs during pregnancy (7), this is likely to be impractical because the normal range for lactate levels in pregnant women is not known and it is difficult to obtain accurate, reproducible venous lactate results (66). Initial reports of a possible increased risk of ventricular septal defects due to Zidovudine (ZDV, AZT, Retrovir®, GlaxoSmithKline) were not confirmed in a large prospective study (44).

        近期关于母亲发生致命性乳酸酸中毒(3位妇女中有2位合并有胰腺炎)的病例报告，导致建议避免给孕妇应用含有司坦夫定+去羟肌苷的制剂(6, 46, 71)。正在应用核苷类逆转录酶抑制剂的孕妇应在孕晚期监测肝酶、电解质和血细胞计数，应用蛋白酶抑制剂者应检测 高血糖的发生。尽管英国HIV协会治疗指南规定医生应考虑在服用核苷类逆转录酶抑制剂的孕妇中监测乳酸水平(7)，但由于目前尚不明确孕妇的正常乳酸范围，且很难获得准确并具有重复性的静脉乳酸值(66)，该监测可能难于实现。最初的关于齐多夫定(ZDV, AZT,立妥威®, 制造商：葛兰素史克)增加室间隔缺损风险的报道并未在大规模的前瞻性试验中得到证实(44)。

               NRTI exposure has been associated with mitochondrial dysfunction in the first few months of life even in uninfected infants (5, 45). However, the benefits of the reduced risk of transmission due to antiretroviral therapy far outweigh the extremely low risk of clinically apparent fetal mitochondrial toxicity (55, 66). Health care providers are requested to report infants with prenatal exposure to antiretroviral drugs to the Antiretroviral Pregnancy Registry, a project to collect observational data on exposure during pregnancy to assess the potential teratogenicity of these drugs (2).    

        暴露于核苷类逆转录酶抑制剂与婴儿(即使是未被感染的婴儿)最初几个月的线粒体功能障碍有关。但是，使用抗逆转录病毒治疗可减少垂直传播的风险，其所带来的收益远超过出现明显临床表现的胎儿线粒体毒性的极低风险(55, 66)。妊娠期间应用抗逆转录病毒药物登记项目旨在收集在孕期暴露于抗逆转录病毒药物的观察性数据，以评估这些药物    的致畸性(2)，健康服务提供者被要求向该项目报告在出生前暴露于这些药物的婴儿病例。

Efficacy of Antiretroviral Therapy During Pregnancy

妊娠期间抗逆转录病毒治疗的有效性           

               Data on 419 mother-infant pairs enrolled in PACTG 076 revealed a 66% reduction in perinatal HIV transmission, from 23% in the placebo group to 8% in the ZDV group, when ZDV was administered during the 2nd and 3rd trimesters of pregnancy, intrapartum, and to the neonate (three-part prophylaxis) (16, 61). Although most of the women enrolled in this particular trial had low viral loads, ZDV can also benefit women with advanced disease, low CD4+ count, and even prior ZDV therapy (29, 62). The potential mechanism of protection by ZDV includes but is not limited to its ability to reduce maternal levels of HIV RNA. Unlike Didanosine (ddI, Videx®, Bristol Myers Squibb), Zalcitabine (ddC, Hivid®, Roche) and Stavudine (d4T, Zerit®, Bristol Myers Squibb), ZDV is metabolized into the active triphosphate compound within the placenta, providing a theoretical advantage for its use to interrupt mother-to-child transmission (19, 56, 60).

        来自入选儿科艾滋病临床试验联盟076试验的419对母婴的数据显示干预组出生前的HIV传播较对照组减少了66%：安慰剂组的垂直传播率为23%；而当于孕中期、孕晚期、分娩期应用齐多夫定并予新生儿预防治疗(三部分药物预防)时，垂直传播率为8%(16, 61)。尽管入选该项试验的大部分妇女病毒载量较低，齐多夫定仍可使疾病更为进展、CD4+计数降低甚至之前接受过齐多夫定治疗的妇女受益(29, 62)。齐多夫定的可能保护机制包括(但不仅限于)降低母体HIV RNA水平。与去羟肌苷(ddI,惠妥滋®, 制造商：百时美施贵宝),扎西他滨(ddC, Hivid®, 制造商：罗氏) 及司坦夫定(d4T, 赛瑞特，制造商：百时美施贵宝)不同，齐多夫定可在胎盘内代谢为具有活性的三磷酸盐形式，为其用于阻断母婴传播提供了理论优势。

               In the United States and Europe, ZDV prophylaxis has been superseded by highly active antiretroviral therapy (HAART). Treatment with a combination of ZDV and lamivudine (3TC, Epivir®, GlaxoSmithKline) further reduced the risk of transmission to 1.6% (7/437 exposed infants) (45). It is likely that the more commonly used triple-drug regimens may reduce transmission even further while also slowing maternal HIV disease progression. The Public Health Service Task Force recommends including ZDV in the maternal treatment regimen because of the data showing that it is metabolized to the active triphosphate within the placenta and because its demonstrated efficacy as a single agent in clinical studies (57).

        在美国和欧洲，预防治疗已被HAART所取代。联合应用齐多夫定和拉米夫定(3TC, 贺普丁®, 制造商：葛兰素史克)的治疗进一步将垂直传播率减少至1.6%(7/437 暴露于HIV母亲的婴儿) (45)。更常应用的三药组方可能在减缓母亲HIV疾病进展的同时进一步减少垂直传播。由于数据显示齐多夫定在胎盘中可代谢为具有活性的三磷酸盐形式且临床研究已证明其单独应用的有效性(57)，公共健康服务特别工作组推荐将齐多夫定包含于母亲的治疗组方中。

Prophylaxis Regimens in Resource-Limited Settings    

医疗资源短缺情况下的预防性用药

               In resource-limited settings, less expensive, shorter prophylaxis regimens have been studied providing guidance for the management of pregnant women in regions where HAART regimens are not available, as well as insight into the dynamics of maternal-to-child transmission that are particularly relevant when HIV infection is identified late in pregnancy or at parturition. In a Thailand study initiating treatment with ZDV of the mother at 28 weeks and extending the treatment in the neonate for 6 weeks was associated with a significantly lower rate of vertical transmission of 4.1% (40). Similarly, the Petra study in Africa showed that earlier initiation of ZDV-3TC at 36 weeks with continued treatment of the infant post-partum for 7 days decreased transmission by more than 60% compared to placebo, but sustained efficacy in prevention of transmission was more likely in infants who were not breastfed (25). More recent data from studies in Thailand show transmission rates of 4.6% when ZDV treatment was initiated in the mother between 34-36 weeks gestation and continued through delivery, with the addition a single dose of nevirapine to the mother, and prophylaxis in the infant using a single dose of nevirapine between 48 and 72 hours of life in addition to ZDV for 4 weeks (14). Earlier administration of ZDV starting close to 28 weeks of gestation with an intrapartum single dose of nevirapine to the mother, followed by a single dose of nevirapine and a week of ZDV to the infant resulted in a further decrease in vertical transmission to less than 2% (41).

        在医疗资源短缺的情况下，已对更廉价、更短期的预防方案进行了研究，以提供对无法获得HAART地区的孕妇进行干预的指导原则，并深入了解与孕晚期或分娩时才被发现的HIV感染显著相关的母婴传播的动力学。在一项泰国的研究中，从孕28周开始给予母亲齐多夫定治疗并对新生儿持续治疗至6周大，其垂直传播率显著降低至4.1%(40)。与此相似，非洲的Petra研究显示更早地于孕36周开始齐多夫定+拉米夫定治疗并持续治疗新生儿到产后7天，相较于安慰剂组，可使垂直传播减少60%以上，但是对于垂直传播的持续保护效应更可能出现在非母乳喂养的婴儿中(25)。来自泰国的更新近的研究数据显示，当于孕34-36周开始给予母亲齐多夫定治疗并于分娩过程中给予单剂的奈韦拉平，之后给予新生儿齐多夫定1周及单剂的那韦拉平，可使垂直传播进一步降低至2%以下。

               Another study in Uganda showed that a single oral dose of nevirapine given at the onset of labor combined with a single oral dose given to the neonate reduced transmission by 50% in treatment naïve women when compared to an equivalent dosing schedule of ZDV (34), with the greatest difference between the two interventions seen in women with HIV-1 RNA levels (>50,000 copies/ ml) and lower CD4+ t-lymphocyte counts (<200 per cu mm). However, approximately 20%-44% of the women receiving nevirapine were found to have genotypic resistance to each of the NNRTIs eight to ten weeks following their dose of nevirapine (37, 48). This observation was confirmed in a PACTG 316 in which about 15% of pregnant women who added a single dose of nevirapine at the time of delivery also developed NNRTI resistance virus despite already being on at least one or two additional antiretroviral medications (18). Even with co-administration of ZDV, as in the Thai study described above, development of HIV-1 mutations conferring resistance to NNRTI’s were seen in up to 32% of women at 10 days post-partum (38). Viral subtype is also thought to play a role in the development of resistance after single dose nevirapine administration, with higher NNRTI resistant mutation rates in subtypes C, and D, compared to A (36, 39). Ideally, efforts to decrease vertical transmission of HIV-1 likely need to be more sophisticated, with consideration given to subtype, stage of maternal disease as well as to the implications of prevention efforts to possible future treatment options for the mother.  

        另一项乌干达的研究显示，在未接受过治疗的妇女中，于分娩开始时给予单剂奈韦拉平口服并予新生儿单剂口服，相较于等价剂量的齐多夫定方案可使传播减少50%(34)，两种干预方案结果的差异在HIV-1 RNA水平高(>50,000拷贝/ml)而CD4+ T淋巴细胞计数低(<200/mm3)的妇女中最为明显。然而在应用奈韦拉平8到10周后对每种非核苷类逆转录酶抑制剂耐药的病毒基因型可在大约20%-40%的妇女中被发现(37, 48)。这一观察结果在儿科艾滋病临床试验联盟316研究中得到了证实，在这项研究中，尽管已经至少附加应用了1到2种抗逆转录病毒药物，大约15%在分娩时加用了单剂奈韦拉平的孕妇产生了非核苷类逆转录酶抑制剂 耐药的病毒 (18)。即使如之前所述的泰国研究那样同时应用了齐多夫定，32%的妇女在分娩后10天产生了非核苷类逆转录酶抑制剂耐药的HIV-1突变(38)。病毒亚型也被认为与单剂应用奈韦拉平后耐药性的产生有关，与A亚型相比，C和D亚型产生非核苷类逆转录酶抑制剂耐药突变的比率更高(36, 39)。理想情况下，减少HIV-1垂直传播的方案可能应更为精细，应将病毒亚型、母亲疾病阶段以及预防手段对未来可供母亲可选择接受的治疗的影响纳入考虑范围。   

Treatment Recommendations   

推荐治疗方案  

               The Public Health Service Task Force has a series of recommendations for treating pregnant women that take into account the time of presentation with respect to conception and delivery (Table 1) (57). Women whose immunologic or virologic status requires treatment, or who have plasma HIV RNA levels >1,000 copies/ml should receive HAART including ZDV.

        公共健康服务特别工作组为如何治疗感染HIV的孕妇提供了一系列同时考虑到就诊距受孕和分娩时间的推荐方案 (表 1) (57)。那些免疫或病毒状态需要治疗或血浆HIV RNA水平>1,000拷贝/ml的妇女应接受含有齐多夫定的HARRT。

               In pregnant women with plasma HIV RNA levels <1,000 copies/ml, perinatal transmission is reduced from about 10% without treatment to 1% in women receiving ZDV prophylaxis (36). Therefore, even women whose virologic and immunologic status does not require treatment should be offered therapy, such as ZDV monotherapy or a standard HAART regimen, to prevent perinatal transmission. Dual nucleoside regimens have also been used in this setting, but may lead to the development of NRTI resistance, and should be viewed with caution Antiretroviral treatment can be discontinued postnatally in women for whom treatment was used only to prevent perinatal transmission.

        在HIV RNA水平<1,000拷贝/ml的孕妇中，接受齐多夫定预防性治疗可使围产期传播由未接受治疗时的10%降至1%(36)。因此，即使对于那些病毒或免疫状态并不需要治疗的母亲，也应向其提供诸如齐多夫定单药治疗或标准HARRT等治疗，以避免围产期传播。联用两个核苷类药物的疗法也曾被用于这种情况，但有可能导致对核苷类逆转录酶抑制剂耐药性的产生，因此应被谨慎考虑。对于那些只是为了避免围产期传播而接受抗逆转录病毒治疗的妇女，产后可以停止治疗。

               Because most perinatal transmission occurs during late pregnancy and delivery, HIV-infected women may consider withholding therapy during the first 10 weeks of gestation when nausea and vomiting may interfere with adherence, tolerance, and bioavailability and increase the risk of drug resistance. In addition, definitive safety data are for most antiretroviral drugs during the first trimester are still pending.

        因为大部分的围产期传播发生于孕晚期及分娩中，在妊娠最初的10周内，当恶心、呕吐可能影响药物依从性、耐受性、药物的生物利用度并增加产生耐药性的风险时，可考虑停止药物治疗。此外，目前大部分抗逆转录病毒药物仍缺乏关于其在孕初三个月应用的安全性的确定性数据。

               Treatment-naïve women presenting during labor should be offered one of the following four regimens: (i) a single dose of nevirapine at the onset of labor followed by a single dose of 4 mg/kg of nevirapine to the newborn 48 hours after birth; (ii) oral ZDV and 3TC during labor followed by one week of the same combination for the newborn; (iii) intravenously administered ZDV intrapartum followed by six weeks of therapy for the newborn; or (iv) combination of the two dose nevirapine regimen, intrapartum ZDV and six weeks of ZDV therapy for the newborn (Table 1) (57).

        应向在分娩过程中就诊的未接受过治疗的妇女提供以下四种药物用法中的一种：(i)在分娩开始时的单剂奈韦拉平继以新生儿生后第 48小时4 mg/kg的奈韦拉平单剂治疗；(ii)在分娩过程中口服齐多夫定+拉米夫定继以新生儿口服同样药物组合1周；(iii)分娩中静脉应用齐多夫定继以新生儿应用齐多夫定6周；或(iv)联合应用2剂奈韦拉平及静脉齐多夫定继以新生儿应用齐多夫定6周(表 1) (57).

               Infants born to mothers who have received no antiretroviral treatment at any time during pregnancy or intrapartum are candidates for treatment for six weeks of ZDV after birth. ZDV should be started within 6 to 12 hours after birth and may be used in combination with other antiretroviral drugs if the mother is suspected to have ZDV-resistant virus. As in other post-exposure prophylaxis situations, some physicians would institute HAART both to treatment-naive women presenting during labor and to infants born to mothers who may or may not have received intrapartum antiretroviral drugs.

        那些在怀孕及分娩过程中的任何时候均未接受过抗逆转录病毒治疗的母亲的婴儿都应考虑接受6周齐多夫定治疗。齐多夫定应在生后6到12小时内开始应用，如果怀疑母亲有齐多夫定耐药病毒可以联合应用其他抗逆转录病毒药物。同其它暴露后预防的情况一样，一些医生选择将HARRT给予在分娩过程中就诊的未接受过治疗的妇女和那些在分娩过程中接受或未接受抗逆转录病毒药物的母亲所生的婴儿。

Guideline: Guidelines for diagnosis and treatment of HIV/AIDS. Taiwan CDC, Jan 2008.

Guideline:  Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIG-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. July 8, 2008.  http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf

Vertical Transmission of Drug-Resistant HIV

耐药HIV的垂直传播

               Antiretroviral drug resistance testing should be obtained in all pregnant women with detectable viremia who are receiving antiretroviral therapy or in pregnant women residing in areas with significant rates of primary HIV resistance who are about to start antiretroviral therapy (65, 71). Limited data suggest that ZDV-resistant isolates are more likely to be transmitted than ZDV-susceptible isolates (69) and a recent study of ARV naïve pregnant women in St Louis found evidence of NNRTI resistant virus in 2 of 17 pregnant women, consistent with an increasing rate of acquisition of and transmission of NNRTI resistance.

        所有正在接受抗逆转录病毒治疗但仍可检测到病毒血症的孕妇或居住在原发HIV耐药率明显升高的地区并且将要开始抗逆转录病毒治疗的孕妇，都应进行抗逆转录病毒药物耐药性测试(65, 71)。仅有有限的数据显示齐多夫定耐药的分离株较齐多夫定敏感的分离株更易传播(69)，而一项新近在圣路易斯进行的研究在未接受过抗逆转录病毒治疗的17名孕妇中发现2人有非核苷类逆转录酶抑制剂耐药病毒，与增长的非核苷类逆转录酶抑制剂耐药病毒感染率及传播率相符。

               In heavily treated women with persistent viremia, it is important to consider drugs received in the past, the current drug regimen, and the available options for post-partum prophylaxis of the infant. For example, if a woman previously developed virologic failure while receiving an NNRTI or 3TC, then it is unlikely that an NNRTI or 3TC will be effective at suppressing maternal viremia. However, these drugs may be useful for post-partum prophylaxis if resistance to these drugs is not evident in maternal virus near delivery. Although efavirenz is contraindicated during the first trimester, it may be used later in pregnancy, particularly if it is needed to treat a drug-resistant maternal strain (66).

        对于那些虽经过积极治疗仍有持续性病毒血症的妇女，考虑其既往用药、当前用药以及可供产后选择用于新生儿预防治疗的药物是很重要的。举例来说，如果一个妇女在之前接受非核苷类逆转录酶抑制剂或拉米夫定时，在病毒学方面治疗失败，那么在抑制母体病毒血症方面非核苷类逆转录酶抑制剂或拉米夫定不太可能是有效的。但是，如果在接近分娩时母体内的病毒对这些药物的耐药性并不明显，那么这些药物有可能在产后预防方面是有效的。尽管依法韦仑被禁止在孕初三个月应用，但在妊娠的稍晚阶段可以应用，特别是需要用其治疗母体的耐药性菌株时(66)。

               Optimal antiretroviral prophylaxis of the infant born to a woman with drug-resistant HIV should be determined in consultation with pediatric infectious diseases specialists and should be based on the levels of maternal viremia and resistance tests done during pregnancy.

        为耐药HIV母亲的婴儿确定最适抗逆转录病毒预防治疗方案，应咨询儿科感染性疾病专科医生，并应基于母亲病毒血症的水平及妊娠期间进行的耐药性测试作出决定。

Cesarean Delivery  

剖宫产 

               Studies from the United States and Europe have shown that in the absence of antiretroviral therapy, elective cesarean section reduces the risk of perinatal HIV transmission from about 20% to 10% or lower (26, 64). In the presence of ZDV chemoprophylaxis, perinatal HIV transmission is reduced from 4-7% with regular delivery to 1-2% with cesarean delivery (26, 64). Whether elective cesarean delivery offers any benefit to the infants of women receiving HAART who have low or undetectable plasma HIV RNA levels is not known.

        美国及欧洲的研究显示在没有抗逆转录病毒治疗的情况下择期剖宫产术可使围产期的HIV传染由大约20%下降至10%甚至更低(26, 64)。在应用了齐多夫定预防性治疗的情况下，剖宫产可使围产期HIV传播由常规分娩的4-7%降至1-2%(26, 64)。尚不明确择期剖宫产是否会给正在接受HARRT并且血浆HIV RNA水平很低或测不出的妇女的婴儿带来收益。

               Plasma HIV RNA levels should be checked at 34-36 weeks gestation and options for mode of delivery should be discussed at that time. Based on the low risk associated with low plasma HIV RNA levels, the American College of Obstetrics and Gynecology has chosen 1,000 copies/ml as the threshold above which to recommend scheduled cesarean delivery as an adjunct for preventing perinatal HIV transmission (57). Elective cesarean delivery should be performed at 38-39 weeks gestation or at the onset of labor. The benefit of a slightly reduced risk of HIV transmission should be balanced against the increased risk of post-operative complications associated with cesarean delivery. Cesarean delivery should be accompanied by intravenous ZDV administered three hours prior to the surgery followed by six weeks of ZDV therapy for the neonate.

        应在孕34-36周检测血清HIV RNA水平并讨论分娩方式。由于血浆HIV RNA水平较低的妇女其垂直传播风险亦较低，美国妇产科学院选择以1,000拷贝/ml为界线，向高于这一界限的妇女推荐择期剖宫产作为避免围产期HIV传播的辅助手段(57)。择期剖宫产应在孕38-39周或分娩开始时进行。剖宫产可少量减少HIV传播，但也有其相关的产后并发症，应注意权衡利弊。在剖宫产手术开始前3小时应开始静脉应用齐多夫定，并应给予新生儿6周的齐多夫定治疗。

               There are not enough data to evaluate the role of cesarean delivery in women in labor or after membrane rupture. This situation should be evaluated on a case-by-case basis, taking into account the duration of membrane rupture, progress of labor, plasma HIV RNA levels, the woman's current antiretroviral therapy regimen and other clinical factors. The public health service guidelines have been recently updated with respect to four scenarios: (A) HIV-infected women presenting late in pregnancy not receiving antiretroviral therapy and in whom virus load data are not expected to be available before delivery, (B) HIV-infected women who initiated prenatal care early in 3rd trimester, are receiving HAART, and have had an initial virologic response, but have RNA levels that are >1,000 copies/ml at 36 weeks gestation, (C) HIV-infected women on HAART with undetectable plasma HIV RNA levels at 36 weeks gestation, (D) HIV-infected women who have elected scheduled cesarean section but present in early labor or shortly after rupture of membranes (57).

        目前尚没有足够的数据来评估剖宫产在已经进入分娩阶段或已经破膜的妇女中的作用。这一情况应该以每一个病例为基础逐一进行评估，并同时考虑到破膜距分娩时间、产程进展阶段、血浆HIV RNA水平、这位妇女目前的抗逆转录病毒治疗方案以及其它临床因素。公共健康服务指南最近根据以下四种情况进行了更新：(A)感染HIV且没有接受过抗逆转录病毒治疗的孕妇在晚孕期就诊，而预计在分娩前不可能获得其病毒载量数据，(B)在晚孕期早期开始围产保健、正在接受HARRT且最初有病毒学改善的妇女，在孕36周其HIV RNA水平仍>1,000拷贝/ml，(C)正在接受HARRT且在孕36周血浆不能检测到HIV RNA的妇女，(D)已经计划行择期剖宫产术，但在就诊时发生早产或刚刚破膜的感染HIV的妇女(57)。

Breastfeeding

母乳喂养

               Breastfeeding appears to confer an additional risk above and beyond the risk of pregnancy and parturition proportional to the duration of breastfeeding (20, 24, 53, 54). In settings in which alternatives to breastfeeding are available, safe, and affordable, formula feeding is recommended.

目前认为母乳喂养会在妊娠及分娩的风险以外，带来与母乳喂养持续时间成比例的附加风险(20, 24, 53, 54)。 在能够提供安全并且可负担的母乳以外喂养方式的地区，推荐使用配方奶喂养。

 

Tables and Figures

Table 1.Clinical Scenarios and Recommendations for the Use of Antiretroviral Drugs to Reduce Perinatal HIV Transmission  [Download PDF]

表 1. 临床情况和推荐用于减少围产期HIV传播的抗逆转录病毒药物 [下载 PDF文件]

临床情况和减少围产期HIV传播的抗逆转录病毒药物的用药推荐

 

 

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