耐多药结核病的治疗现状

耐多药结核病（MDR-TB）是指至少对抗结核药物中H、R产生耐药的结核病。据报道全球有2／3的结核患处于发生MDR-TB的危险之中。我国2000年结核病流调结果显示总耐药率为27．8％,初始耐药率为18．6％,获得性耐药率为46．5％,属高耐药国家,耐多药率为10．7％。MDR-TB是治疗费用高,治愈率最低,死亡率最高,影响结核病控制的特殊类型结核病。因此加速攻克MDR—TB的治疗难关是结核病控制领域亟待解决的问题,现将这方面的资料做一简要的介绍：[第一段]     

耐多药结核病的治疗现状

自上世纪中叶以来 ,随着化学治疗的不断完善 ,90 %以上的肺结核病人获得了治愈。然而 ,由于化学药物的广泛应用、HIV感染及治疗的不规范等 ,耐药结核病 ,尤其是耐多药结核病 (MDR TB)的出现 ,对全球结核病控制构成了严重的威胁。据WHO统计 ,目前 ,全球已有 5 0 0 0万人感染了耐     

耐多药结核病的预防

耐多药结核病（MDR—TB）是指至少同时对异烟肼和利福平产生耐药的结核分枝杆菌引起的结核病。由于这类患者同时耐至少两种最有效的抗结核病药物，不仅治疗困难，还有可能不可治愈而持续传播耐多药结核菌，增加原发性MDR—TB发病的可能性，造成严重的流行病学和公共卫生隐患。WHO估计全球每年有30万MDR—TB新病例，而我国2000年耐多药率已达10．7％，其中初始耐多药率为7．6％，获得性耐多药率为17．1％。近年来一些省市报道的耐多药率还远远超过该水平，辽宁省和河南省已分别居于西太区9个耐药监测国家和地区的第1和第2位，被WHO称为两个MDR—TB的“热点省”，我国的耐多药结核病问题已经引起了我国和世界范围的关注。紧抓“初治”这个根本环节，采取多种积极措施，预防耐多药结核病的产生，已经成为控制结核病及耐药结核病在我国流行的迫切任务之一。     

耐多药结核病临床研究的回顾与展望

近年来全球结核病发病率呈现居高不下之势,据世界卫生组织（World Health Organization,WHO）2009年全球结核病控制报告显示,全球每年约有800万新发结核病例,约有200万因结核死亡,其中我国每年新发结核病150万例,每年约有13万人死于结核病。     

1例儿童耐多药结核病的治疗

目的 总结儿童耐多药结核病的有效治疗方法。方法 对1例耐多药肺结核患儿的治疗过程作回顾性分析。结果 患儿女,13岁,因咳嗽1月余,发热4天住院,影像学检查可见肺组织高密度结节、结核菌纯蛋白衍生物皮内注射试验强阳性、痰结核Xpert检测阳性明确诊断为利福平（R）耐药的肺结核,予口服异烟肼（H）300 mg、吡嗪酰胺（Z）750 mg、乙胺丁醇（E）750 mg、利奈唑胺（Lzd）300 mg(8小时1次)治疗,治疗后患儿病情平稳。治疗第14天时患儿痰结核菌耐药基因提示结核分枝杆菌R、H耐药,考虑MDR-TB,调整为口服大剂量H 600 mg、Lzd 300 mg(8小时1次)、环丝氨酸（Cs） 500 mg、左氧氟沙星（Lfx）500 mg、E 750 mg。治疗第51天时Lzd不良反应导致患儿重度贫血,调整为口服Cs 500 mg、Lfx 500 mg、氯法齐明（Cfz）100 mg、丙硫异烟肼（Pto）500 mg。治疗第3个月时患儿痰标本结核分枝杆菌培养结果显示R、H、Lfx、Mfx及Ofx均耐药,明确诊断为准泛耐药结核病,调整为口服Lzd 10 mg/（kg·d）(12小时1次)...     

耐多药和广泛耐药结核病

最近的估计提示全球2006年新发耐多药结核病（MDR—TB）大约50万,耐多药结核病感染的结核分枝杆菌至少对异烟肼和利福平耐药。在信息完整的MDR—TB报告中,7％为致死的广泛耐药结核病（XDR—TB）,其定义是对氟喹诺酮类以及3种二线注射剂（卷曲霉素（CM）,卡那霉素（Km）和丁胺卡那霉素（Am））中至少一种耐药的MDR—TB。MDR—TB和XDR—TB治疗困难,给全球结核病控制带来巨大挑战。     

耐多药结核30例耐药原因及治疗观察

耐多药结核病 (MDR- TB)是目前结核病防治工作中最为困难的问题 ,是造成难治结核病的根源。 1995年～ 2 0 0 0年我们收治耐多药结核 30例 ,现就其原因及防治措施 ,分析如下。材料与方法1.病例来源本组男 2 0例 ,女 10例 ;年龄 2 0～ 6 5岁。病程 1～ 2 0年。 型肺结核 19例 , 型肺结核 11例 ;肺结核并有空洞 2 5例。2 .治疗前痰菌耐药情况30例经菌型鉴定皆为人型结核分支杆菌 ,耐 HR4型 ,耐HRS 15例 ,耐 HRE 4例 ,耐 SHRE 7例 (本文未作 PZA耐药性测定 )。3.治疗方案耐 HR者 3THOEZAK (S/ KM/ CPM) / 18THO;耐 HRS者 THO…     

耐多药结核病的综合治疗

耐药结核病是对一种或多种抗结核药物耐药的结核病,至少对异烟肼和利福平同时耐药的结核病称为耐多药结核病。耐药结核病的确定,是通过患者留取痰标本,在实验室进行结核菌的培养以及药物敏感试验测定,从而确定是否为耐药结核病。这种结核病的治疗极为困难。在治疗方案的设计等方面不够合理,极易引发更多、     

多重耐药HBV感染特点及挽救治疗策略

多重耐药HBV感染的治疗是临床面临的一个难题。多重耐药的发生主要与病毒因素、宿主因素和药物因素等相关。严格评估抗病毒治疗指征,初治选择高耐药基因屏障的抗病毒药物,避免以低耐药基因屏障药物起始的单药序贯治疗等措施能够降低多重耐药HBV株产生的风险。对于已发生耐药与多重耐药HBV感染的患者,应尽早开始挽救性治疗。有多项研究提示恩替卡韦与替诺福韦酯联合是针对难治性多重耐药HBV感染的更加有效、安全的挽救性治疗方案。研究开发多靶点作用的新型抗病毒药物是治疗多重耐药HBV感染的新途径。     

Pentameric complex of viral glycoprotein H is the primary target for potent neutralization by a human cytomegalovirus vaccine

Human cytomegalovirus (HCMV) can cause serious morbidity/mortality in transplant patients, and congenital HCMV infection can lead to birth defects. Developing an effective HCMV vaccine is a high medical priority. One of the challenges to the efforts has been our limited understanding of the viral antigens important for protective antibodies. Receptor-mediated viral entry to endothelial/epithelial cells requires a glycoprotein H (gH) complex comprising five viral proteins (gH, gL, UL128, UL130, and UL131). This gH complex is notably missing from HCMV laboratory strains as well as HCMV vaccines previously evaluated in the clinic. To support a unique vaccine concept based on the pentameric gH complex, we established a panel of 45 monoclonal antibodies (mAbs) from a rabbit immunized with an experimental vaccine virus in which the expression of the pentameric gH complex was restored. Over one-half (25 of 45) of the mAbs have neutralizing activity. Interestingly, affinity for an antibody to bind virions was not correlated with its ability to neutralize the virus. Genetic analysis of the 45 mAbs based on their heavy- and light-chain sequences identified at least 26 B-cell linage groups characterized by distinct binding or neutralizing properties. Moreover, neutralizing antibodies possessed longer complementarity-determining region 3 for both heavy and light chains than those with no neutralizing activity. Importantly, potent neutralizing mAbs reacted to the pentameric gH complex but not to gB. Thus, the pentameric gH complex is the primary target for antiviral antibodies by vaccination.Human cytomegalovirus (HCMV) is an important pathogen in transplant patients (1–5), and its infection can lead to invasive end-organ diseases, such as pneumonitis and hepatitis, as well as vascular pathology contributing to graft failure (4, 6, 7). HCMV is also the most common cause of in utero viral infections in North America and Europe, affecting 0.5–2% of newborns annually (8–10). Congenital HCMV infection can lead to symptomatic diseases at birth and also cause developmental disabilities in children (10, 11). Maternal seropositivity before conception protects against congenital transmission (12, 13), and both maternal humoral and cellular immunity are likely to contribute to the protection (14–16). Antibodies in particular are important for preventing congenital infection, serving as the first line of defense against maternal infection. It may also play a role in preventing transmission to the fetus, supported by the results of a small, nonrandomized study in pregnant women with primary HCMV infection, in which the passive immunity of monthly infusions of HCMV hyperimmune human IgG (HCMV-HIG) (200 mg/kg maternal weight) was ∼60% effective in protecting against congenital HCMV infection (17, 18). These studies suggest that it is feasible to develop a vaccine for preventing congenital HCMV infection and its sequelae. However, despite the fact that the Institute of Medicine has identified development of an effective vaccine for prevention of congenital HCMV as a top priority since 1999 (19), progress toward this goal has only been incremental (8, 20, 21). One of the hurdles to the efforts is our limited understanding of component of natural immunity associated with protection against HCMV infection.HCMV is a large, complex virus, with a genome capable of encoding >150 proteins (22–26). Because of the strict species specificity, options of animal models for HCMV research are limited (27). Thus, the functions of most HCMV antigens in viral infection in vivo and their roles as targets for host immunity are poorly understood. Furthermore, culture systems of single cell types have limitations for studying HCMV pathogenesis. Immunohistochemistry studies showed that HCMV can infect varieties of cells in vivo, including endothelial, epithelial cells, fibroblasts, and leukocytes (28–36). Many HCMV end-organ diseases, such as pneumonitis and gastroenteritis, are due to infection of the epithelial/endothelial cells in the affected organ (35–39). However, common laboratory strains, such as AD169 and Towne, were culture-adapted in fibroblast cells, with genomic mutations (22, 24, 40) and, more importantly, have lost their tropism to endothelial and epithelial cells, in contrast to pathogenic clinical isolates (32, 33, 41, 42).Loss of viral tropism to endothelial and epithelial cells was mapped to various mutations in the viral UL131-128 locus, and these mutations abrogated the expression of the pentameric glycoprotein H (gH) complex, composed of gH, gL, UL128, UL130, and UL131 proteins, a determinant for viral tropism to endothelial and epithelial cells (42–44). Because the pentameric gH complex is missing in common laboratory strains (42, 43), its importance in viral tropism, viral pathogenesis, and vaccine design was not fully appreciated until recently (42, 45). With this understanding, it is not surprising that Towne virus and recombinant glycoprotein B (gB) vaccines, although with ∼50% efficacy against primary infection in the clinic (46–49), induced poor neutralizing titers against viral infection of epithelial cells, in contrast to immune sera from HCMV-seropositive donors (50, 51). Thus, missing the pentameric gH complex is likely a deficiency in antigen composition for both vaccines (50). Studies of monoclonal antibodies (mAbs) isolated from HCMV-seropositive donors or polyclonal IgG enriched for antigen specificity supported the hypothesis that the pentameric gH complex, not gB, appears to be important for neutralizing activity in human subjects with natural infection (52).We recently described an experimental vaccine virus in which expression of the pentameric gH complex was restored (53). Unlike the parental AD169 virus and the recombinant gB vaccine, this virus can elicit high levels of neutralizing antibodies in rabbits and rhesus macaques (53). To support clinical development of this vaccine centered its concept on the pentameric gH complex, we established a comprehensive panel of 45 mAbs from a single rabbit that received vaccination. Of the 45 mAbs, 25 had neutralizing activity against viral entry in epithelial cells, including 11 elite neutralizers with ≥10-fold greater potency than HCMV-HIG. Biochemical analysis demonstrated that all elite neutralizers preferentially bound to the virus expressing the pentameric gH complex, and the majority of elite neutralizers (8 of 11) specifically recognized a recombinant form of the pentameric gH complex. Interestingly, binding affinity for intact virions was not correlated with neutralizing activity. Moreover, genetic analysis of the 45 mAbs based on their heavy- and light-chain sequences identified at least 26 B-cell linage groups characterized by distinct binding or neutralizing properties. In addition, neutralizing antibodies had longer complementarity-determining region 3 (CDR3) for both heavy and light chains than those of antibodies with no neutralizing activity. These data establish the importance of the pentameric gH complex as the primary target for potent neutralizing antibodies by vaccination, and support development of an experimental HCMV vaccine featuring the pentameric gH complex.     

Discordant memory B cell and circulating anti-Env antibody responses in HIV-1 infection

Long-lived memory B cells (B_Mem) provide an archive of historic Ab responses. By contrast, circulating Abs typically decline once the immunogen is cleared. Consequently, circulating Abs can underestimate the nature of cognate humoral immunity. On the other hand, the B_Mem pool should provide a comprehensive picture of Ab specificities that arise over the entire course of infection. To test this hypothesis, we compared circulating Ab and B_Mem from natural virus suppressors who control HIV-1 without therapy and maintain a relatively intact immune system. We found high frequencies of B_Mem specific for the conserved neutralizing CD4 induced or CD4 binding site epitopes of gp120, whereas low Ab titers to these determinants were detected in contemporaneous plasma. These data suggest that plasma Ab repertoires can underestimate the breadth of humoral immunity, and analyses of B_Mem should be included in studies correlating Ab specificity with protective immunity to HIV-1.     

血小板在HIV-1慢性感染中作用的研究进展

血小板不仅介导机体止血和凝血过程,而且作为炎症细胞参与机体感染免疫。在1型艾滋病病毒(HIV-1)感染中,血小板内化吞噬HIV-1,充当病毒感染CD4+T淋巴细胞的中介,并且保护HIV-1不被机体免疫系统识别,促进HIV-1在体内的系统传播与持续存在。同时,活化的血小板可以通过释放促炎因子,维持系统的免疫活化和持续炎症反应。而且,血小板通过与免疫细胞的结合精准调节免疫细胞功能,进而影响机体对HIV-1感染的免疫应答。本文旨在了解血小板在促进HIV-1感染与免疫致病中的研究进展。     

A human anti-D monoclonal antibody selected for enhanced FcgammaRIII engagement clears RhD+ autologous red cells in human volunteers as efficiently as polyclonal anti-D antibodies

A human anti-RhD immunoglobulin G1 monoclonal antibody (mAb), R297, was tested in a phase I study to assess its ability to induce the clearance of antibody-coated autologous RhD⁺ red blood cells (RBCs) in healthy male volunteers. The clearance potency of R297 was compared with that of a marketed human polyclonal anti-D product (Rhophylac^®). This mAb has been selected for its ability to strongly engage Fc-gamma receptor IIIA and to mediate a potent antibody-dependent cell cytotoxicity (ADCC) against RhD⁺ RBCs. Autologous RhD⁺ RBCs were sensitized with either Rhophylac^® or R297 at three different coating percentages (25, 12·5 and 6·25%), before re-infusion. This phase I study showed that the human R297 mAb promoted rapid and complete clearance of RBCs, and showed activity that was at least as potent as the human polyclonal anti-D antibody preparation. Clearance of RBCs could still be observed when the percentage of R297 used to coat the RBCs was reduced to 6·25%. Finally, none of the adverse events was severe or considered to be related to R297. Thus, R297 is a promising candidate for the prevention of allo-immunization and represents a new generation of Fc-modified monoclonal antibodies with increased FcγRIII binding and increased ADCC.     

索非布韦治疗慢性丙型肝炎的研究进展

近几年慢性丙型肝炎的治疗发生了新的变化,直接抗病毒药物治疗活动性丙型肝炎显示出强大的作用,即使是难治性丙型肝炎也能出现较高的持续病毒学应答。其中索非布韦(SOF)以其抗病毒疗程短,应答率高,甚至对于某些丙型肝炎基因型患者可免干扰素治疗的优势脱颖而出。介绍了SOF的作用机制、临床应用现状以及主要不良反应,指出了其在难治性丙型肝炎患者中的应用前景。     

抗病毒治疗患者HIV耐药发生的研究进展

由于HIV的高度变异性,患者在服用抗病毒药物时易产生耐药,耐药的产生是影响治疗效果和患者预后的重要原因。本文对抗病毒治疗人群HIV耐药流行及其影响因素相关文献进行回顾。