Trypanosoma brucei gambiense

冈比亚锥虫
  • 文章类型: Journal Article
    背景:血清学筛查试验在诊断冈比亚人非洲锥虫病(gHAT)中起着至关重要的作用。目前,他们预选个人进行微观确认,但在未来的“筛选和治疗”策略中,他们将确定需要治疗的个体。报告的特异性的可变性,新的快速诊断试验(RDT)的发展以及疟疾感染可能降低RDT特异性的假设,促使我们评估5gHAT筛查试验的特异性.
    方法:在主动筛查期间,来自科特迪瓦和几内亚的1095名个体的静脉血样本进行了连续商业测试(CATT,HATSero-K-SeT,雅培BiolineHAT2.0)和原型(DCNHATRDT,HATSero-K-SeT2.0)gHAT筛查测试和疟疾RDT。gHAT筛查试验≥1阳性的个体接受了显微镜检查和进一步的免疫学检查(用T.b.gambienseLiTat1.3、1.5和1.6进行胰蛋白酶分解;间接ELISA/T.b.gambiense;用T.b.gambienseLiTat1.3和1.5VSG进行T.b.7SL佐恩,和TgsGP;锥虫虫S2-RT-qPCR18S2,177T,GPI-PLC和TgsGP多重;RT-qPCRDT8、DT9和TgsGP多重)。显微镜锥虫检测证实gHAT,而其他人则被认为是无gHAT。通过卡方评估组间分数的差异,并通过McNemar对同一个体进行2次测试之间的特异性差异。
    结果:诊断为一例gHAT病例。总体测试特异性(n=1094)为:CATT98.9%(95%CI:98.1-99.4%);HATSero-K-SeT86.7%(95%CI:84.5-88.5%);BiolineHAT2.082.1%(95%CI:79.7-84.2%);在疟疾阳性中,gHAT筛查测试似乎不太具体,但仅在几内亚,雅培BiolineHAT2.0(P=0.03)和HATSero-K-Set2.0(P=0.0006)的差异显着。gHAT血清阳性的免疫学和分子实验室检测的特异性为98.7-100%(n=399)和93.0-100%(n=302),分别。在44个参考实验室测试阳性中,只有确诊的gHAT患者和1个筛查试验血清阳性的结合免疫学和分子参考实验室检测阳性。
    结论:虽然不能排除疟疾的轻微影响,gHATRDT特异性远低于WHO目标产品概况规定的95%最低特异性,这是一种简单的诊断工具,用于识别符合治疗条件的个体。除非特异性得到改善,基于RDT的“筛查和治疗”策略将导致大规模的过度治疗。鉴于其结果不一致,参考实验室测试的诊断性能的额外比较评估是为了更好地识别,在筛查测试阳性中,那些对gHAT越来越怀疑的人。
    背景:该试验于2022年7月15日在clinicaltrials.gov中根据NCT05466630进行回顾性注册。
    BACKGROUND: Serological screening tests play a crucial role to diagnose gambiense human African trypanosomiasis (gHAT). Presently, they preselect individuals for microscopic confirmation, but in future \"screen and treat\" strategies they will identify individuals for treatment. Variability in reported specificities, the development of new rapid diagnostic tests (RDT) and the hypothesis that malaria infection may decrease RDT specificity led us to evaluate the specificity of 5 gHAT screening tests.
    METHODS: During active screening, venous blood samples from 1095 individuals from Côte d\'Ivoire and Guinea were tested consecutively with commercial (CATT, HAT Sero-K-SeT, Abbott Bioline HAT 2.0) and prototype (DCN HAT RDT, HAT Sero-K-SeT 2.0) gHAT screening tests and with a malaria RDT. Individuals with ≥ 1 positive gHAT screening test underwent microscopy and further immunological (trypanolysis with T.b. gambiense LiTat 1.3, 1.5 and 1.6; indirect ELISA/T.b. gambiense; T.b. gambiense inhibition ELISA with T.b. gambiense LiTat 1.3 and 1.5 VSG) and molecular reference laboratory tests (PCR TBRN3, 18S and TgsGP; SHERLOCK 18S Tids, 7SL Zoon, and TgsGP; Trypanozoon S2-RT-qPCR 18S2, 177T, GPI-PLC and TgsGP in multiplex; RT-qPCR DT8, DT9 and TgsGP in multiplex). Microscopic trypanosome detection confirmed gHAT, while other individuals were considered gHAT free. Differences in fractions between groups were assessed by Chi square and differences in specificity between 2 tests on the same individuals by McNemar.
    RESULTS: One gHAT case was diagnosed. Overall test specificities (n = 1094) were: CATT 98.9% (95% CI: 98.1-99.4%); HAT Sero-K-SeT 86.7% (95% CI: 84.5-88.5%); Bioline HAT 2.0 82.1% (95% CI: 79.7-84.2%); DCN HAT RDT 78.2% (95% CI: 75.7-80.6%); and HAT Sero-K-SeT 2.0 78.4% (95% CI: 75.9-80.8%). In malaria positives, gHAT screening tests appeared less specific, but the difference was significant only in Guinea for Abbott Bioline HAT 2.0 (P = 0.03) and HAT Sero-K-Set 2.0 (P = 0.0006). The specificities of immunological and molecular laboratory tests in gHAT seropositives were 98.7-100% (n = 399) and 93.0-100% (n = 302), respectively. Among 44 reference laboratory test positives, only the confirmed gHAT patient and one screening test seropositive combined immunological and molecular reference laboratory test positivity.
    CONCLUSIONS: Although a minor effect of malaria cannot be excluded, gHAT RDT specificities are far below the 95% minimal specificity stipulated by the WHO target product profile for a simple diagnostic tool to identify individuals eligible for treatment. Unless specificity is improved, an RDT-based \"screen and treat\" strategy would result in massive overtreatment. In view of their inconsistent results, additional comparative evaluations of the diagnostic performance of reference laboratory tests are indicated for better identifying, among screening test positives, those at increased suspicion for gHAT.
    BACKGROUND: The trial was retrospectively registered under NCT05466630 in clinicaltrials.gov on July 15 2022.
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  • 文章类型: Clinical Trial
    背景:在医疗机构一级被动诊断人类非洲锥虫病(HAT)是几内亚HAT控制的主要组成部分。我们检查了哪些临床体征和症状与HAT相关,并评估选定临床表现的表现,快速诊断测试(RDT),以及用于诊断几内亚HAT的干血点(DBS)的参考实验室测试。
    方法:这项研究在几内亚的14个医疗机构进行,2345名临床嫌疑人接受了RDT测试(HATSero-K-Set,rHATSero-Strip,和SDBioline帽子)。血清阳性接受了寄生虫学检查(参考测试),以确认HAT及其DBS已在间接酶联免疫测定(ELISA)/布氏锥虫中进行了测试。胰蛋白酶,loopamp布氏锥虫检测试剂盒(LAMP)和m18S定量PCR(qPCR)。多变量回归分析评估了临床表现与HAT的关联。灵敏度,特异性,关键临床表现的阳性和阴性预测值,确定了用于HAT诊断的RDT和DBS测试。
    结果:HAT患病率,正如寄生虫学证实的那样,为2.0%(48/2345,95%CI:1.5-2.7%)。对于淋巴结肿大的参与者,HAT的赔率(OR)增加(OR=96.7,95%CI:20.7-452.0),重要的体重减轻(OR=20.4,95%CI:7.05-58.9),严重瘙痒(OR=45.9,95%CI:7.3-288.7)或运动障碍(OR=4.5,95%CI:0.89-22.5)。这些临床表现中的至少一种的存在是75.6%(95%CI:73.8-77.4%)特异性和97.9%(95%CI:88.9-99.9%)对HAT敏感。HATSero-K-Set,rHATSero-Strip,和SDBiolineHAT分别为97.5%(95%CI:96.8-98.1%),99.4%(95%CI:99.0-99.7%)和97.9%(95%CI:97.2-98.4%)和100%(95%CI:92.5-100.0%),59.6%(95%CI:44.3-73.3%)和93.8%(95%CI:82.8-98.7%)对HAT敏感。RDT的阳性和阴性预测值分别为45.2-66.7%和99.2-100%。所有DBS测试的特异性≥92.9%。虽然LAMP和m18SqPCR敏感性低于50%,胰蛋白酶和ELISA/T.b.冈比亚的敏感性分别为85.3%(95%CI:68.9-95.0%)和67.6%(95%CI:49.5-82.6%)。
    结论:淋巴结肿大,重要的减肥,严重瘙痒或运动障碍是几内亚HAT流行地区HAT转诊的简单但准确的临床标准.HATSero-K-Set和SDBiolineHAT的诊断性能足以将阳性标记为显微镜。DBS上的锥虫溶解可能会将HAT患者与假RDT阳性区分开。试验注册该试验在clinicaltrials.gov(2017年11月29日,回顾性注册https://clinicaltrials.gov/ct2/show/NCT03356665)中根据NCT03356665注册。
    BACKGROUND: Passive diagnosis of human African trypanosomiasis (HAT) at the health facility level is a major component of HAT control in Guinea. We examined which clinical signs and symptoms are associated with HAT, and assessed the performance of selected clinical presentations, of rapid diagnostic tests (RDT), and of reference laboratory tests on dried blood spots (DBS) for diagnosing HAT in Guinea.
    METHODS: The study took place in 14 health facilities in Guinea, where 2345 clinical suspects were tested with RDTs (HAT Sero-K-Set, rHAT Sero-Strip, and SD Bioline HAT). Seropositives underwent parasitological examination (reference test) to confirm HAT and their DBS were tested in indirect enzyme-linked immunoassay (ELISA)/Trypanosoma brucei gambiense, trypanolysis, Loopamp Trypanosoma brucei Detection kit (LAMP) and m18S quantitative PCR (qPCR). Multivariable regression analysis assessed association of clinical presentation with HAT. Sensitivity, specificity, positive and negative predictive values of key clinical presentations, of the RDTs and of the DBS tests for HAT diagnosis were determined.
    RESULTS: The HAT prevalence, as confirmed parasitologically, was 2.0% (48/2345, 95% CI: 1.5-2.7%). Odds ratios (OR) for HAT were increased for participants with swollen lymph nodes (OR = 96.7, 95% CI: 20.7-452.0), important weight loss (OR = 20.4, 95% CI: 7.05-58.9), severe itching (OR = 45.9, 95% CI: 7.3-288.7) or motor disorders (OR = 4.5, 95% CI: 0.89-22.5). Presence of at least one of these clinical presentations was 75.6% (95% CI: 73.8-77.4%) specific and 97.9% (95% CI: 88.9-99.9%) sensitive for HAT. HAT Sero-K-Set, rHAT Sero-Strip, and SD Bioline HAT were respectively 97.5% (95% CI: 96.8-98.1%), 99.4% (95% CI: 99.0-99.7%) and 97.9% (95% CI: 97.2-98.4%) specific, and 100% (95% CI: 92.5-100.0%), 59.6% (95% CI: 44.3-73.3%) and 93.8% (95% CI: 82.8-98.7%) sensitive for HAT. The RDT\'s positive and negative predictive values ranged from 45.2-66.7% and 99.2-100% respectively. All DBS tests had specificities ≥ 92.9%. While LAMP and m18S qPCR sensitivities were below 50%, trypanolysis and ELISA/T.b. gambiense had sensitivities of 85.3% (95% CI: 68.9-95.0%) and 67.6% (95% CI: 49.5-82.6%).
    CONCLUSIONS: Presence of swollen lymph nodes, important weight loss, severe itching or motor disorders are simple but accurate clinical criteria for HAT referral in HAT endemic areas in Guinea. Diagnostic performances of HAT Sero-K-Set and SD Bioline HAT are sufficient for referring positives to microscopy. Trypanolysis on DBS may discriminate HAT patients from false RDT positives. Trial registration The trial was registered under NCT03356665 in clinicaltrials.gov (November 29, 2017, retrospectively registered https://clinicaltrials.gov/ct2/show/NCT03356665 ).
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  • 文章类型: Clinical Trial, Phase II
    背景:晚期疾病患者中由布氏冈比亚锥虫(gambienseHAT)引起的人类非洲锥虫病需要入院接受硝呋替莫-依氟鸟氨酸联合治疗(NECT)。Fexinidazole,世卫组织推荐的最新治疗方法,还需要系统的入院,这在医疗保健资源很少的地区是有问题的。我们的目的是评估成人和青少年冈比亚HAT患者使用acoziborole的安全性和有效性。
    方法:这个多中心,prospective,开放标签,单臂,2/3期研究从刚果民主共和国和几内亚的10家医院招募了15岁或以上确诊冈比亚HAT感染的患者.纳入标准包括Karnofsky得分小于50,吞咽片剂的能力,永久地址或可追溯性,遵守后续访问和学习要求的能力,并同意在治疗期间入院。口服acoziborole以单次960mg剂量(3×320mg片剂)给予禁食的患者。在医院中观察患者直到治疗给药后15天,然后作为门诊患者在3、6、12和18个月时就诊18个月。主要疗效终点是晚期冈比亚HAT(改良意向治疗[mITT]人群)患者在18个月时的acoziborole治疗成功率,根据修改后的世卫组织标准。进行了补充事后分析,比较了acoziborole和NECT的18个月成功率(使用历史数据)。这项研究在ClinicalTrials.gov注册,NCT03087955。
    结果:在2016年10月11日至2019年3月25日之间,对260名患者进行了筛查,其中52人不合格,208人纳入(167人晚期,41人早期或中期冈比亚HAT;主要疗效分析集).所有41名(100%)早期或中期患者和167名晚期疾病患者中的160名(96%)完成了最后18个月的随访。参与者的平均年龄为34·0岁(SD12·4),其中男性117人(56%),女性91人(44%)。在167例晚期冈比亚HAT患者(mITT人群)中,有159例达到18个月的治疗成功率为95·2%(95%CI91·2-97·7),在162例患者(可评估人群)中,有159例达到98·1%(95·1-99·5)。总的来说,208例患者中有155例(75%)出现600例治疗引起的不良事件。29例(14%)患者发生了38例与药物相关的治疗引起的不良事件;所有患者均为轻度或中度,最常见的是发热和虚弱。研究期间发生4例死亡;没有人被认为与治疗相关。事后分析显示,与NECT的估计历史成功率94%相似。
    结论:鉴于高疗效和良好的安全性,acoziborole有望实现世卫组织到2030年阻断HAT传播的目标。
    背景:比尔和梅琳达·盖茨基金会,英国援助,联邦教育和研究部,瑞士发展与合作署,无国界医生,荷兰外交部,挪威发展合作署,挪威外交部,StavrosNiarchos基金会,西班牙国际发展合作署,和毕尔巴鄂比斯卡亚银行阿根廷基金会。
    UNASSIGNED:有关摘要的法语翻译,请参见补充材料部分。
    Human African trypanosomiasis caused by Trypanosoma brucei gambiense (gambiense HAT) in patients with late-stage disease requires hospital admission to receive nifurtimox-eflornithine combination therapy (NECT). Fexinidazole, the latest treatment that has been recommended by WHO, also requires systematic admission to hospital, which is problematic in areas with few health-care resources. We aim to assess the safety and efficacy of acoziborole in adult and adolescent patients with gambiense HAT.
    This multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score greater than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955.
    Between Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2-97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1-99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%.
    Given the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030.
    Bill & Melinda Gates Foundation, UK Aid, Federal Ministry of Education and Research, Swiss Agency for Development and Cooperation, Médecins Sans Frontières, Dutch Ministry of Foreign Affairs, Norwegian Agency for Development Cooperation, Norwegian Ministry of Foreign Affairs, the Stavros Niarchos Foundation, Spanish Agency for International Development Cooperation, and the Banco Bilbao Vizcaya Argentaria Foundation.
    For the French translation of the abstract see Supplementary Materials section.
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  • 文章类型: Clinical Trial
    背景:剪接前导序列(SL)-RNA的检测可以灵敏地诊断冈比亚人非洲锥虫病(HAT)。我们调查了其用于治疗结果评估的诊断性能。
    方法:连续97例HAT患者的血液和脑脊液(CSF),源自刚果民主共和国,在用acoziborole治疗前前瞻性收集,以及治疗后18个月的纵向随访。对于治疗结果评估,将SL-RNA检测与显微镜锥虫检测和CSF白细胞计数进行比较。该试验已在clinicaltrials.gov上根据NCT03112655注册。
    结果:治疗前,分别有94.9%(92/97;CI88.5-97.8%)和67.7%(65/96;CI57.8-76.2%)的HAT患者在血液或CSF中SL-RNA阳性。随访期间,一名患者在18个月时观察到锥虫复发,在12个月时血液和脑脊液中SL-RNA呈阳性,18个月时脑脊液呈阳性。在治愈的患者中,1例患者在第12个月(特异性98.9%;90/91;CI94.0-99.8%)和18个月(特异性98.9%;88/89;CI93.9-99.8%)时在血液中检测到SL-RNA阳性。
    结论:用于HAT治疗结果评估的SL-RNA检测显示血液中的特异性≥98.9%,CSF中的特异性≥100%,并且可以在没有腰椎穿刺的情况下发现复发。
    背景:DiTECT-HAT项目是EDCTP2计划的一部分,由Horizon2020支持,欧盟研究与创新资助(资助编号DRIA-2014-306-DiTECT-HAT)。
    BACKGROUND: Detection of spliced leader (SL)-RNA allows sensitive diagnosis of gambiense human African trypanosomiasis (HAT). We investigated its diagnostic performance for treatment outcome assessment.
    METHODS: Blood and cerebrospinal fluid (CSF) from a consecutive series of 97 HAT patients, originating from the Democratic Republic of the Congo, were prospectively collected before treatment with acoziborole, and during 18 months of longitudinal follow-up after treatment. For treatment outcome assessment, SL-RNA detection was compared with microscopic trypanosome detection and CSF white blood cell count. The trial was registered under NCT03112655 in clinicaltrials.gov.
    RESULTS: Before treatment, respectively 94.9% (92/97; CI 88.5-97.8%) and 67.7% (65/96; CI 57.8-76.2%) HAT patients were SL-RNA positive in blood or CSF. During follow-up, one patient relapsed with trypanosomes observed at 18 months, and was SL-RNA positive in blood and CSF at 12 months, and CSF positive at 18 months. Among cured patients, one individual tested SL-RNA positive in blood at month 12 (Specificity 98.9%; 90/91; CI 94.0-99.8%) and 18 (Specificity 98.9%; 88/89; CI 93.9-99.8%).
    CONCLUSIONS: SL-RNA detection for HAT treatment outcome assessment shows ≥98.9% specificity in blood and 100% in CSF, and may detect relapses without lumbar puncture.
    BACKGROUND: The DiTECT-HAT project is part of the EDCTP2 programme, supported by Horizon 2020, the European Union Funding for Research and Innovation (grant number DRIA-2014-306-DiTECT-HAT).
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  • 文章类型: Journal Article
    OBJECTIVE: To investigate the prognosis of two rare imported patients with human African trypanosomias (HAT) after treatment in a follow-up study, and to evaluate the therapeutic efficacy, so as to provide insights into the treatment of imported HAT patients.
    METHODS: The white blood cells in cerebrospinal fluid samples and the trypomastigotes in cerebrospinal fluid and blood samples were monitored in an imported case with Trypanosoma brucei rhodesiense infection 1, 3, 11 and 25 months post-treatment and in an imported case with T. brucei gambiense infection 1, 3, 8 and 12 months post-treatment to evaluate the therapeutic efficacy and prognosis.
    RESULTS: There were 1, 1, 4 and 2 white blood cells in per μL of cerebrospinal fluid in the case with T. brucei rhodesiense infection 1, 3, 11 and 25 months post-treatment, and there were 3, 6, 4 and 3 white blood cells in per μL of cerebrospinal fluid in the case with T. brucei gambiense infection 1, 3, 8 and 12 months post-treatment. In addition, no trypomastigotes were identified in the cerebrospinal fluid or blood samples of either case with T. brucei rhodesiense or T. brucei gambiense infection.
    CONCLUSIONS: Following standardized treatment, two imported cases with human African trypanosomiasis cases recover satisfactorily, without any signs of relapse.
    [摘要] 目的 对2例罕见的输入性非洲锥虫病 (human african trypanosomiasis, HAT) 病例治疗后进行随访研究, 评判治 疗效果, 从而为输入性锥虫病临床治疗提供参考依据。方法 1例输入性罗德西锥虫病病例在治疗完成后第1、3、11、25 个月以及1例输入性冈比亚锥虫病病例在治疗完成后第1、3、8、12个月, 分别检测患者脑脊液中白细胞计数及脑脊液和 血液中锥鞭毛体, 比较治疗时、治疗后生理生化指标变化, 根据其检测结果进行治疗效果和预后评判。结果 罗德西亚 锥虫病病例在治疗后第1、3、11、25个月, 脑脊液中白细胞计数分别为1、1、4、2个/μL; 冈比亚锥虫病病例在治疗后第1、 3、8、12个月, 脑脊液中白细胞计数分别为3、6、4、3个/μL。2例病例在随访中均未在脑脊液和血液中查见锥鞭毛体。结论 经过规范治疗, 2例输入性锥虫病病例恢复良好, 没有复发迹象。.
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  • 文章类型: Journal Article
    由布氏冈比亚锥虫(g-HAT)引起的人类非洲锥虫病的分期和治疗需要腰椎穿刺以评估脑脊液(CSF)和静脉内穿过血脑屏障的药物以进行晚期感染。这些程序在疾病流行国家的农村卫生系统中不方便。一项关键研究确立了非西硝唑作为第一个有效对抗非重度2g-HAT的口服单一疗法。我们旨在评估非西硝唑在早期g-HAT中的安全性和有效性。
    在这个前景中,多中心,开放标签,单臂队列研究,我们从刚果民主共和国的8个治疗中心招募了1期或2期早期g-HAT患者.主要纳入标准包括年龄超过15岁,能够每天摄取至少一餐(或至少一袋Plumpy\'Nut®),Karnofsky评分高于50,血液或淋巴中有锥虫的证据,但CSF中没有锥虫的证据,愿意入院接受治疗,有一个永久地址,并能够遵守后续访问时间表。排除标准包括严重营养不良,无法口服药物,孕妇或哺乳期妇女,任何可能危及患者安全或参与研究的临床重要医疗状况,总体状况严重恶化,任何咪唑药物的禁忌症,在过去的两年中,HAT治疗,以前参加研究或以前摄入非西硝唑,在治疗前重复评估中未恢复正常或被认为具有临床重要性的心电图异常,使用至少450ms的Fridericia公式校正的QT间隔,以及未接受疟疾测试或未接受疟疾或土壤传播蠕虫病适当治疗的患者。根据血液中锥虫的证据,将患者分为1期或2期早期g-HAT组,淋巴,和脑脊液缺失,并使用脑脊液中的白细胞计数。患者在第1-4天每天一次接受1800mg非西硝唑,然后在第5-10天接受1200mg非西硝唑。总共观察患者约19个月。研究参与者在治疗期间的第5天和第8天进行随访,在第11天治疗结束时,在第11-18天住院结束时,在第9周,六个月后,12个月,还有18个月.主要终点是12个月时的治疗成功。通过常规监测评估安全性。在意向治疗人群中进行了分析。可接受的成功率定义为超过80%的患者的治疗效果。本研究已完成并在ClinicalTrials.gov(NCT02169557)注册。
    患者的入组时间为2014年4月30日至2017年4月25日。招募了238名患者:195名(82%)患有1g-HAT的患者和43名(18%)患有早期2g-HAT的患者。最终纳入了195例1g-HAT期患者中的189例(97%)和43例早期2g-HAT患者中的41例(95%),并完成了10天的治疗期。3例1g-HAT期患者在10天治疗期后和12个月初次随访前死亡,被认为是治疗失败,并从研究中退出。在12个月时,230名患者中的227名(99%)(95%CI96·2-99·7)治疗有效:189名患者(95·4-99·7)中的186名(98%)为1期,41名患者(91·4-100·0)为2期早期患者中的41名(100%),表明达到了主要研究终点。没有观察到新的安全问题。最常见的不良事件是头痛和呕吐。总的来说,230例患者中有214例(93%)出现因治疗引起的不良事件,主要是1至3级不良事件的常用术语标准。没有导致治疗中断。
    Fexinidazole是g-HAT早期有价值的一线治疗选择。
    通过“被忽视疾病药物”倡议:比尔和梅林达·盖茨基金会,日内瓦共和国和州(瑞士),荷兰外交部(也称为DGIS;荷兰),挪威发展合作署(又称挪威),联邦教育和研究部(也称为BMBF)通过KfW(德国),BrianMercer慈善信托基金(英国),以及HAT运动中的其他私人基金会和个人。
    有关摘要的法语翻译,请参见补充材料部分。
    Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood-brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT.
    In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy\'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia\'s formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1-4 then 1200 mg fexinidazole on days 5-10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11-18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557).
    Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2-99·7): 186 (98%) of 189 patients (95·4-99·7) with stage 1 and 41 (100%) of 41 patients (91·4-100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation.
    Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT.
    Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign.
    For the French translation of the abstract see Supplementary Materials section.
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  • 文章类型: Journal Article
    人类非洲锥虫病(HAT)是由锥虫亚种布氏锥虫和T.b引起的潜在致命的寄生虫感染。目前,在许多疾病病灶中,全球HAT病例数达到每10,000人中不到1例。因此,需要简单的筛选工具和策略来代替对GambianHAT和RhodesianHAT的长期消除后可以维持的人群的主动筛选。这里,我们描述了一种新颖的高分辨率熔解测定法在采采录中的异种监测中的原理应用证明。将靶向物种特异性单拷贝基因的新的和先前描述的引物用作多重qPCR的一部分。在多重中包括另外的引物组以确定样品是否具有足够的基因组材料用于检测以低拷贝数存在的基因。对先前鉴定为T.bruceis.l阳性的96个野生捕获的采采采进行评估。已知其中两个对T.b.Rhodesiense呈阳性。发现该测定是高度特异性的,没有与非靶锥虫物种的交叉反应性,并且测定检测极限为104胰蛋白酶/mL。qPCR成功鉴定出三只罗得西亚氏杆菌阳性果蝇,与参考物种特异性PCR一致。该测定提供了在筛选T.bruceis.l的致病性亚种时运行多个PCR的替代方案,并在不到2小时内产生结果,避免凝胶电泳和主观分析。该方法可以提供一种简单有效的方法的组成部分,该方法可以在已知的HAT病灶中或在有复发风险或受到两种形式的HAT分布变化威胁的区域中筛选大量的采采蝇。
    Human African Trypanosomiasis (HAT) is a potentially fatal parasitic infection caused by the trypanosome sub-species Trypanosoma brucei gambiense and T. b. rhodesiense transmitted by tsetse flies. Currently, global HAT case numbers are reaching less than 1 case per 10,000 people in many disease foci. As such, there is a need for simple screening tools and strategies to replace active screening of the human population which can be maintained post-elimination for Gambian HAT and long-term for Rhodesian HAT. Here, we describe the proof of principle application of a novel high-resolution melt assay for the xenomonitoring of Trypanosoma brucei gambiense and T. b. rhodesiense in tsetse. Both novel and previously described primers which target species-specific single copy genes were used as part of a multiplex qPCR. An additional primer set was included in the multiplex to determine if samples had sufficient genomic material for detecting genes present in low copy number. The assay was evaluated on 96 wild-caught tsetse previously identified to be positive for T. brucei s. l. of which two were known to be positive for T. b. rhodesiense. The assay was found to be highly specific with no cross-reactivity with non-target trypanosome species and the assay limit of detection was 104 tryps/mL. The qPCR successfully identified three T. b. rhodesiense positive flies, in agreement with the reference species-specific PCRs. This assay provides an alternative to running multiple PCRs when screening for pathogenic sub-species of T. brucei s. l. and produces results in less than 2 hours, avoiding gel electrophoresis and subjective analysis. This method could provide a component of a simple and efficient method of screening large numbers of tsetse flies in known HAT foci or in areas at risk of recrudescence or threatened by the changing distribution of both forms of HAT.
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  • 文章类型: Clinical Trial
    While the combination of nifurtimox and eflornithine (NECT) is currently recommended for the treatment of the late stage human African trypansomiasis (HAT), single-agent eflornithine was still the treatment of choice when this trial commenced. This study intended to provide supportive evidence to complement previous trials.
    A multi-centre randomised, open-label, non-inferiority trial was carried out in the Trypanosoma brucei gambiense endemic districts of North-Western Uganda to compare the efficacy and safety of NECT (200 mg/kg eflornithine infusions every 12 h for 7 days and 8 hourly oral nifurtimox at 5 mg/kg for 10 days) to the standard eflornithine regimen (6 hourly at 100 mg/kg for 14 days). The primary endpoint was the cure rate, determined as the proportion of patients alive and without laboratory signs of infection at 18 months post-treatment, with no demonstrated trypanosomes in the cerebrospinal fluid (CSF), blood or lymph node aspirates, and CSF white blood cell count < 20 /μl. The non-inferiority margin was set at 10%.
    One hundred and nine patients were enrolled; all contributed to the intent-to-treat (ITT), modified intent-to-treat (mITT) and safety populations, while 105 constituted the per-protocol population (PP). The cure rate was 90.9% for NECT and 88.9% for eflornithine in the ITT and mITT populations; the same was 90.6 and 88.5%, respectively in the PP population. Non-inferiority was demonstrated for NECT in all populations: differences in cure rates were 0.02 (95% CI: -0.07-0.11) and 0.02 (95% CI: -0.08-0.12) respectively. Two patients died while on treatment (1 in each arm), and 3 more during follow-up in the NECT arm. No difference was found between the two arms for the secondary efficacy and safety parameters. A meta-analysis involving several studies demonstrated non-inferiority of NECT to eflornithine monotherapy.
    These results confirm findings of earlier trials and support implementation of NECT as first-line treatment for late stage T. b. gambiense HAT. The overall risk difference for cure between NECT and eflornithine between this and two previous randomised controlled trials is 0.03 (95% CI: -0.02-0.08). The NECT regimen is simpler, safer, shorter and less expensive than single-agent DFMO.
    ISRCTN ISRCTN03148609 (registered 18 April 2008).
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  • 文章类型: Clinical Trial, Phase III
    OBJECTIVE: To estimate the diagnostic accuracy of HAT Sero K-SeT for the field diagnosis of second-stage human African trypanosomiasis (HAT).
    METHODS: A phase III diagnostic accuracy design. Consecutive patients with symptoms clinically suggestive of HAT were prospectively enrolled. We compared results of the index test HAT Sero K-SeT with those of a composite reference standard: demonstration of trypanosomes in cerebrospinal fluid (CSF), or trypanosomes detected in any other body fluid AND white blood cell count in CSF >5/μl.
    METHODS: Rural hospital in the Democratic Republic of the Congo.
    METHODS: All patients above five years old presenting at Mosango hospital with a neurological problem of recent onset at the exclusion of trauma.
    METHODS: n.a.
    METHODS: Sensitivity and specificity of HAT Sero K-SeT test.
    RESULTS: The sensitivity of the HAT Sero K-SeT was 8/8 or 100.0% (95% confidence interval: 67.6 to 100.0%) and the specificity was 258/266 or 97.0% (94.2% to 98.5%).
    CONCLUSIONS: The high sensitivity of the HAT Sero K-SeT is in line with previously published estimates, though the sample of HAT cases in this study was small. The specificity estimate was very high and precise. This test, when negative, allows the clinician to rule out HAT in a clinical suspect in a hospital setting in this endemic region.
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  • 文章类型: Clinical Trial, Phase II
    Few therapeutic options are available to treat the late-stage of human African trypanosomiasis, a neglected tropical disease, caused by Trypanosoma brucei gambiense (g-HAT). The firstline treatment is a combination therapy of oral nifurtimox and intravenous eflornithine that needs to be administered in a hospital setting by trained personnel, which is not optimal given that patients often live in remote areas with few health resources. Therefore, we aimed to assess the safety and efficacy of an oral regimen of fexinidazole (a 2-substituted 5-nitroimidazole with proven trypanocidal activity) versus nifurtimox eflornithine combination therapy in patients with late-stage g-HAT.
    In this randomised, phase 2/3, open-label, non-inferiority trial, we recruited patients aged 15 years and older with late-stage g-HAT from g-HAT treatment centres in the Democratic Republic of the Congo (n=9) and the Central African Republic (n=1). Patients were randomly assigned (2:1) to receive either fexinidazole or nifurtimox eflornithine combination therapy according to a predefined randomisation list (block size six). The funder, data management personnel, and study statisticians were masked to treatment. Oral fexinidazole was given once a day (days 1-4: 1800 mg, days 5-10: 1200 mg). Oral nifurtimox was given three times a day (days 1-10: 15 mg/kg per day) with eflornithine twice a day as 2 h infusions (days 1-7: 400 mg/kg per day). The primary endpoint was success at 18 months (ie, deemed as patients being alive, having no evidence of trypanosomes in any body fluid, not requiring rescue medication, and having a cerebrospinal fluid white blood cell count ≤20 cells per μL). Safety was assessed through routine monitoring. Primary efficacy analysis was done in the modified intention-to-treat population and safety analyses in the intention-to-treat population. The acceptable margin for the difference in success rates was defined as 13%. This study has been completed and is registered with ClinicalTrials.gov, number NCT01685827.
    Between October, 2012, and November, 2016, 419 patients were pre-screened. Of the 409 eligible patients, 14 were not included because they did not meet all inclusion criteria (n=12) or for another reason (n=2). Therefore, 394 patients were randomly assigned, 264 to receive fexinidazole and 130 to receive nifurtimox eflornithine combination therapy. Success at 18 months was recorded in 239 (91%) patients given fexinidazole and 124 (98%) patients given nifurtimox eflornithine combination therapy, within the margin of acceptable difference of -6·4% (97·06% CI -11·2 to -1·6; p=0·0029). We noted no difference in the proportion of patients who experienced treatment-related adverse events (215 [81%] in the fexinidazole group vs 102 [79%] in the nifurtimox eflornithine combination therapy group). Treatment discontinuations were unrelated to treatment (n=2 [1%] in the fexinidazole group). Temporary nifurtimox eflornithine combination therapy interruption occurred in three (2%) patients. 11 patients died during the study (nine [3%] in the fexinidazole group vs two [2%] in the nifurtimox eflornithine combination therapy group).
    Our findings show that oral fexinidazole is effective and safe for the treatment of T b gambiense infection compared with nifurtimox eflornithine combination therapy in late-stage HAT patients. Fexinidazole could be a key asset in the elimination of this fatal neglected disease.
    Drugs for Neglected Diseases initiative.
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