如果不进行治疗,该病通常致命,但是也曾有一些自发性恢复的罕见病例报告。[133]Checchi F, Filipe JA, Barrett MP, et al. The natural progression of gambiense sleeping sickness: what is the evidence? PLoS Negl Trop Dis. 2008;2(12):e303.http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0000303http://www.ncbi.nlm.nih.gov/pubmed/19104656?tool=bestpractice.com[134]Jamonneau V, Ilboudo H, Kaboré J, et al. Untreated human infections by Trypanosoma brucei gambiense are not 100% fatal. PLoS Negl Trop Dis. 2012;6(6):e1691.http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001691http://www.ncbi.nlm.nih.gov/pubmed/22720107?tool=bestpractice.com[135]Bucheton B, MacLeod A, Jamonneau V. Human host determinants influencing the outcome of Trypanosoma brucei gambiense infections. Parasite Immunol. 2011 Aug;33(8):438-47.http://www.ncbi.nlm.nih.gov/pubmed/21385185?tool=bestpractice.com
用于治疗非洲人类锥虫病(HAT)的所有药物都对人体产生潜在明显毒性作用。 疾病的治疗与疾病类型和分期有关。 因此,在开始治疗之前,要求必须对患者进行疾病分期。 鉴于治疗用的药物都会产生毒性副作用,必须严格监护治疗过程。[136]Pepin J, Milord F. The treatment of human African trypanosomiasis. Adv Parasitol. 1994;33:1-47.http://www.ncbi.nlm.nih.gov/pubmed/8122565?tool=bestpractice.com[137]Barrett MP, Boykin DW, Brun R, et al. Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. Br J Pharmacol. 2007 Dec;152(8):1155-71.http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0707354/fullhttp://www.ncbi.nlm.nih.gov/pubmed/17618313?tool=bestpractice.com[138]Delespaux V, de Koning HP. Drugs and drug resistance in African trypanosomiasis. Drug Resist Updat. 2007 Feb-Apr;10(1-2):30-50.http://www.ncbi.nlm.nih.gov/pubmed/17409013?tool=bestpractice.com 应对患者提供支持性疗法,以治疗与本病相关疾病或伴发疾病。
采取治疗措施的目的是治愈本病,但是实际疗效因人而异(治愈率为 70%~95%)。 以往会在人类非洲锥虫病治疗结束后对患者进行系统性的随访,但是现在不再建议进行随访。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1 仅推荐对有症状的患者进行治疗结局评估,包括脑脊液检查,并且发现锥虫是判定复发的确切证据。
可以从世界卫生组织的疾病创新和强化管理 (World Health Organization's Innovative and Intensified Disease Management) 项目中免费获取所有推荐药物。[139]Simarro PP, Franco J, Diarra A, et al. Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology. 2012 Jun;139(7):842-6.http://www.ncbi.nlm.nih.gov/pubmed/22309684?tool=bestpractice.com
早期冈比亚锥虫病的治疗
推荐将喷他脒用作一线治疗药物。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1[140]Centers for Disease Control and Prevention. Parasites - African trypanosomiasis (also known as sleeping sickness): resources for health professionals. August 2016 [internet publication].https://www.cdc.gov/parasites/sleepingsickness/health_professionals/index.html 注射喷他脒时较痛。患者应在注射前摄入适量糖分,以减少患者出现低血糖的风险。接受喷他脒治疗之后,患者应仰卧 1-2 小时,同时切监测患者的血压和心律。推荐在治疗期间监测患者的血糖、血钙、肾功能和胰腺功能、钾和血清肌酐水平。应定期对患者进行心电图监测。[68]Blum JA, Schmid C, Burri C, et al. Cardiac alterations in human African trypanosomiasis (T b gambiense) with respect to the disease stage and antiparasitic treatment. PLoS Negl Trop Dis. 2009;3(2):e383.http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0000383http://www.ncbi.nlm.nih.gov/pubmed/19221604?tool=bestpractice.com目前使用此药物进行治疗的有效率为 95%-98%。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1[141]Balasegaram M, Harris S, Checchi F, et al. Treatment outcomes and risk factors for relapse in patients with early-stage human African trypanosomiasis (HAT) in the Republic of the Congo. Bull World Health Organ. 2006 Oct;84(10):777-82.http://www.ncbi.nlm.nih.gov/pubmed/17128357?tool=bestpractice.com
早期罗得西亚锥虫病感染的治疗
推荐将苏拉明 (Suramin) 用作一线治疗药物。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1[140]Centers for Disease Control and Prevention. Parasites - African trypanosomiasis (also known as sleeping sickness): resources for health professionals. August 2016 [internet publication].https://www.cdc.gov/parasites/sleepingsickness/health_professionals/index.html 建议密切监测患者血液参数和肾功能。
晚期冈比亚锥虫病感染的治疗
可以将静脉输注依氟鸟氨酸用作一线治疗药物,单药治疗或联合硝呋莫司使用皆可。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1[140]Centers for Disease Control and Prevention. Parasites - African trypanosomiasis (also known as sleeping sickness): resources for health professionals. August 2016 [internet publication].https://www.cdc.gov/parasites/sleepingsickness/health_professionals/index.html
依氟鸟氨酸作为单药治疗时需要以静脉输注方式连续治疗 14 天。[124]Priotto G, Pinoges L, Fursa IB, et al. Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study. BMJ. 2008 Mar 29;336(7646):705-8.http://www.bmj.com/content/336/7646/705.fullhttp://www.ncbi.nlm.nih.gov/pubmed/18321960?tool=bestpractice.com[142]Balasegaram M, Harris S, Checchi F, et al. Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bull World Health Organ. 2006 Oct;84(10):783-91.http://www.ncbi.nlm.nih.gov/pubmed/17128358?tool=bestpractice.com[143]Chappuis F. Melarsoprol-free drug combinations for second-stage Gambian sleeping sickness: the way to go. Clin Infect Dis. 2007 Dec 1;45(11):1443-5.http://www.ncbi.nlm.nih.gov/pubmed/17990226?tool=bestpractice.com[144]Balasegaram M, Young H, Chappuis F, et al. Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Medecins Sans Frontieres programmes. Trans R Soc Trop Med Hyg. 2009 Mar;103(3):280-90.http://www.ncbi.nlm.nih.gov/pubmed/18947846?tool=bestpractice.com[145]Lutje V, Seixas J, Kennedy A. Chemotherapy for second-stage human African trypanosomiasis. Cochrane Database Syst Rev. 2013 Jun 28;(6):CD006201.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006201.pub3/fullhttp://www.ncbi.nlm.nih.gov/pubmed/23807762?tool=bestpractice.com[146]Priotto G, Kasparian S, Mutombo W, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009 Jul 4;374(9683):56-64.http://www.ncbi.nlm.nih.gov/pubmed/19559476?tool=bestpractice.com 医源性死亡率报告为 0.7%-2%。[147]Chappuis F, Udayraj N, Stietenroth K, et al. Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clin Infect Dis. 2005 Sep 1;41(5):748-51.http://www.ncbi.nlm.nih.gov/pubmed/16080099?tool=bestpractice.com 应密切监测患者的血细胞计数,检查是否存在感染。治疗结束后,还应继续密切监测 2-4 周。鉴于药物的骨髓抑制效应,需要密切监测血细胞计数,确定并治疗可能的早期感染(静脉炎、蜂窝织炎、传染性皮炎、多发性肌炎)。[124]Priotto G, Pinoges L, Fursa IB, et al. Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study. BMJ. 2008 Mar 29;336(7646):705-8.http://www.bmj.com/content/336/7646/705.fullhttp://www.ncbi.nlm.nih.gov/pubmed/18321960?tool=bestpractice.com[147]Chappuis F, Udayraj N, Stietenroth K, et al. Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clin Infect Dis. 2005 Sep 1;41(5):748-51.http://www.ncbi.nlm.nih.gov/pubmed/16080099?tool=bestpractice.com
依氟鸟氨酸联合使用硝呋莫司治疗已被用于临床实践,以减少依氟鸟氨酸单药治疗的持续时间和负荷,延缓耐药性的出现。[145]Lutje V, Seixas J, Kennedy A. Chemotherapy for second-stage human African trypanosomiasis. Cochrane Database Syst Rev. 2013 Jun 28;(6):CD006201.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006201.pub3/fullhttp://www.ncbi.nlm.nih.gov/pubmed/23807762?tool=bestpractice.com[146]Priotto G, Kasparian S, Mutombo W, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009 Jul 4;374(9683):56-64.http://www.ncbi.nlm.nih.gov/pubmed/19559476?tool=bestpractice.com[148]Alirol E, Schrumpf D, Amici Heradi J, et al. Nifurtimox-eflornithine combination therapy for second-stage Gambiense human African trypanosomiasis: Médecins sans Frontières experience in the Democratic Republic of the Congo. Clin Infect Dis. 2013 Jan;56(2):195-203.https://academic.oup.com/cid/article/56/2/195/318180/Nifurtimox-Eflornithine-Combination-Therapy-forhttp://www.ncbi.nlm.nih.gov/pubmed/23074318?tool=bestpractice.com 联合药物治疗也可用于治疗疾病复发的患者。[146]Priotto G, Kasparian S, Mutombo W, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009 Jul 4;374(9683):56-64.http://www.ncbi.nlm.nih.gov/pubmed/19559476?tool=bestpractice.com 硝呋莫司是一种治疗美洲锥虫病的药物,但其作为单药治疗人类非洲锥虫病的疗效有限。 在无法获得硝呋莫司的地区,可以给予依氟鸟氨酸单药治疗。
可以将美拉胂醇与泼尼松龙联合用于(以预防美拉胂醇相关性脑病)疾病复发的患者。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1[142]Balasegaram M, Harris S, Checchi F, et al. Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bull World Health Organ. 2006 Oct;84(10):783-91.http://www.ncbi.nlm.nih.gov/pubmed/17128358?tool=bestpractice.com[145]Lutje V, Seixas J, Kennedy A. Chemotherapy for second-stage human African trypanosomiasis. Cochrane Database Syst Rev. 2013 Jun 28;(6):CD006201.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006201.pub3/fullhttp://www.ncbi.nlm.nih.gov/pubmed/23807762?tool=bestpractice.com[149]Schmid C, Richer M, Bilenge CM, et al. Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (Impamel II). J Infect Dis. 2005 Jun 1;191(11):1922-31.https://academic.oup.com/jid/article/191/11/1922/2191985/Effectiveness-of-a-10-Day-Melarsoprol-Schedule-forhttp://www.ncbi.nlm.nih.gov/pubmed/15871127?tool=bestpractice.com 它是一种高毒性药物,医源性死亡率为 5%-10%。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1 使用此药物进行治疗时,应密切监测患者情况,一旦出现明显的副作用,立即停止治疗。[147]Chappuis F, Udayraj N, Stietenroth K, et al. Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clin Infect Dis. 2005 Sep 1;41(5):748-51.http://www.ncbi.nlm.nih.gov/pubmed/16080099?tool=bestpractice.com[149]Schmid C, Richer M, Bilenge CM, et al. Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (Impamel II). J Infect Dis. 2005 Jun 1;191(11):1922-31.https://academic.oup.com/jid/article/191/11/1922/2191985/Effectiveness-of-a-10-Day-Melarsoprol-Schedule-forhttp://www.ncbi.nlm.nih.gov/pubmed/15871127?tool=bestpractice.com推荐在使用过程中密切监测血液参数、肾功能和肝功能。治疗期间禁止饮酒。
晚期罗得西亚锥虫病感染的治疗
美拉胂醇与泼尼松龙联合使用(以预防美拉胂醇相关性脑病),是治疗晚期罗得西亚型人类非洲锥虫病的唯一可用药物。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1[140]Centers for Disease Control and Prevention. Parasites - African trypanosomiasis (also known as sleeping sickness): resources for health professionals. August 2016 [internet publication].https://www.cdc.gov/parasites/sleepingsickness/health_professionals/index.html 药物治疗期间应密切监测患者情况,一旦出现显著副作用,立即停止用药。 通常须每日静脉注射此药,疗程为 10 天。[2]World Health Organization. Control and surveillance of human African trypanosomiasis. Technical Report Series 984. Geneva, Switzerland: WHO; 2013.http://apps.who.int/iris/bitstream/10665/95732/1/9789241209847_eng.pdf?ua=1[150]Kuepfer I, Schmid C, Allan M, et al. Safety and efficacy of the 10-day melarsoprol schedule for the treatment of second stage Rhodesiense sleeping sickness. PLoS Negl Trop Dis. 2012 Aug;6(8):e1695.http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001695http://www.ncbi.nlm.nih.gov/pubmed/22970329?tool=bestpractice.com 过去,采用的治疗计划是按 3 个疗程用药,10 天为一疗程,前 3 天每日注射药物,然后停药 7 天;然而,美国疾病预防控制中心仍然推荐这种时间更长、更复杂的治疗方案。[140]Centers for Disease Control and Prevention. Parasites - African trypanosomiasis (also known as sleeping sickness): resources for health professionals. August 2016 [internet publication].https://www.cdc.gov/parasites/sleepingsickness/health_professionals/index.html使用过程中建议密切监测血液参数、肾功能和肝功能。
对儿童患者的治疗
有关人类非洲锥虫病儿童患者的治疗数据有限,但是儿童的治疗通常遵循与成人相同的治疗方案。[151]Eperon G, Schmid C, Loutan L, et al. Clinical presentation and treatment outcome of sleeping sickness in Sudanese pre-school children. Acta Trop. 2007 Jan;101(1):31-9.http://www.ncbi.nlm.nih.gov/pubmed/17207760?tool=bestpractice.com 曾有报告称对未满 12 岁儿童采用依氟鸟氨酸治疗,其生物利用度较低。 因此,给予儿童患者依氟鸟氨酸单药治疗时,须增加给药剂量。[152]Milord F, Pepin J, Loko L, et al. Efficacy and toxicity of eflornithine for treatment of Trypanosoma brucei gambiense sleeping sickness. Lancet. 1992 Sep 12;340(8820):652-5.http://www.ncbi.nlm.nih.gov/pubmed/1355219?tool=bestpractice.com
孕妇的治疗
妊娠期间使用治疗人类非洲锥虫病药物的安全性尚未得到明确证实。 妊娠期间使用抗锥虫药物治疗应考虑药物对孕妇和胎儿的潜在获益和危害,慎重作出决定。[153]World Health Organization. WHO model prescribing information: drugs used in parasitic diseases, 2nd edition. Geneva: World Health Organization, 1995.http://apps.who.int/medicinedocs/collect/medicinedocs/pdf/h2922e/h2922e.pdf
如果是孕妇处于人类非洲锥虫病感染第一阶段,建议使用喷他脒进行治疗。
如果处于人类非洲锥虫病第二阶段:
如果患有重度冈比亚锥虫病,且是高危孕产妇,建议依洛尼塞与硝呋莫司联合用药进行治疗。 在无法获得硝呋莫司的地区,可以给予依氟鸟氨酸单药治疗。 美拉胂醇和泼尼松龙联合使用可用来治疗复发患者。
如果为罗得西亚锥虫病重症患者,且产妇处于高风险状态,建议美拉胂醇与泼尼松龙联合用药进行治疗。
如果疾病并不严重,建议在妊娠和分娩期间给予喷他脒治疗,并进行密切随访,但在产后给予针对二阶段的药物进行治疗。
重症患者是指患者一般情况恶化(无法进行日常活动,或卡氏指数<50%),且在中期时,该疾病危及生命。 非重症患者是指疾病在中期不会危及生命,且患者可以进行日常活动。 它还取决于医学标准(考虑到孕妇的妊娠月份)。
喷他脒已被认为无致突变性、无遗传毒性,可在妊娠期间给予常规剂量治疗。[154]Stauffert I, Paulini H, Steinmann U, et al. Investigations on mutagenicity and genotoxicity of pentamidine and some related trypanocidal diamidines. Mutation Research. 1990 Oct;245(2):93-8.http://www.ncbi.nlm.nih.gov/pubmed/2215556?tool=bestpractice.com 苏拉明已被证实具有致畸毒性,并且是导致动物胎儿生长迟缓的病因,但是苏拉明的疗效优于美拉胂醇。[153]World Health Organization. WHO model prescribing information: drugs used in parasitic diseases, 2nd edition. Geneva: World Health Organization, 1995.http://apps.who.int/medicinedocs/collect/medicinedocs/pdf/h2922e/h2922e.pdf[155]Freeman SJ, Lloyd JB. Evidence that suramin and aurothiomalate are teratogenic in rat by disturbing yolk sac-mediated embryonic protein nutrition. Chem Biol Interact. 1986 May;58(2):149-60.http://www.ncbi.nlm.nih.gov/pubmed/3087638?tool=bestpractice.com 有报告称美拉胂醇是导致婴儿低出生体重、自然流产和畸形的原因。[156]Reinhardt MC, MacLeod CL. African trypanosomiasis (African sleeping sickness). In: MacLeod CL, ed. Parasitic infections in pregnancy and the newborn. Oxford: Oxford University Press; 1988:1-308. 依氟鸟氨酸已被认为可导致大鼠流产、胎儿较小和发育迟缓。[157]Kirchner DL, Mercieca MD, Crowell JA, et al. Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits. Toxicol Sci. 1999 Jul;50(1):127-35.http://toxsci.oxfordjournals.org/content/50/1/127.full.pdf+htmlhttp://www.ncbi.nlm.nih.gov/pubmed/10445761?tool=bestpractice.com 在妊娠期使用硝呋莫司的相关数据有限。
确诊患病产妇所生的新生儿需要检查是否患病,并进行随访。