National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), Shanghai, China; NHC Key Laboratory of Parasite and Vector Biology, Shanghai, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China; National Center for International Research on Tropical Diseases, Shanghai, China; School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland.
Lancet Microbe. 2022 Aug;3(8):e616-e624. doi: 10.1016/S2666-5247(22)00026-X. Epub 2022 Jun 10.
Clonorchis sinensis, Opisthorchis viverrini, and Opisthorchis felineus are the three most important human liver fluke species in the Opisthorchiidae family, infecting approximately 25 million people worldwide. Drug treatment is needed to control morbidity and is also useful in lowering transmission. Several drugs used in various regimens are available to treat these infections, but their comparative efficacy is uncertain. We aimed to compare the efficacy in terms of cure rate and egg reduction rate of currently registered drugs against human liver fluke infection.
We conducted a systematic review using readily available electronic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, KoreaMed, China National Knowledge Infrastructure, and Wanfang Data) without language restrictions from inception until June 29, 2021. Clinical trials with pairwise comparison of drugs (praziquantel, albendazole, mebendazole, tribendimidine, or combinations of these drugs) against C sinensis, O viverrini, and O felineus were eligible, including trials comparing these drugs or their combinations with placebo. We compared efficacy in terms of cure rate by network meta-analysis. We conducted mixed binomial regression analyses for each species to derive predicted median cure rates for each drug regimen. The models included treatment and infection intensity as fixed factors, year of publication as covariate, and random effects of the different studies assumed to be normally distributed. We also assessed the quality of the included studies. This study was registered with PROSPERO (CRD42018109232).
Overall, 26 trials from 25 studies were included, of which 18 involved C sinensis, seven studied O viverrini, and one focused on O felineus. These trials included a total of 3340 participants. The two long-term treatment courses against C sinensis infection using 400 mg of albendazole (400 mg twice a day for 5 days and 400 mg twice a day for 7 days) resulted in cure rates of 100%, while two other multiple-dose regimens of albendazole resulted in high predicted cure rates: 300 mg twice a day for 5 days (93·9% [95% CI 49·6-99·6]) and 400 mg twice a day for 3 days (91·0% [50·9-99·0]). The WHO-recommended praziquantel regimen (25 mg/kg three times a day for 2 days) also showed a high predicted cure rate (98·5% [85·4-99·9]) in C sinensis infection, and predicted cure rates were above 90% for several other multiple-dose praziquantel regimens, including 20 mg/kg three times a day for 3 days (97·6% [74·7-99·8]), 14 mg/kg three times a day for 5 days (93·9% [44·8-99·7]), and 20 mg/kg twice a day for 3 days (91·0% [50·9-99·0]). In O viverrini infection, the regimen of 50 mg/kg and 25 mg/kg of praziquantel given in a single day showed the highest predicted cure rate (93·8% [85·7-97·5]), while a single dose of 50 mg/kg praziquantel also resulted in a high predicted cure rate (92·1% [64·9-98·6]). The single dose of 400 mg tribendimidine showed a high predicted cure rate of 89·8% (77·5-95·8). A low quality of evidence was demonstrated in most studies, especially those published before 2000. Selection bias due to poor random sequence generation and allocation concealment was high, and performance and detection biases were frequently unreported.
Praziquantel shows high efficacy against clonorchiasis and opisthorchiasis. Tribendimidine might serve as a treatment alternative and warrants further investigation. Although albendazole is efficacious when long treatment schedules (5 days or 7 days) are applied, limited size of studies and high risk of bias affect the interpretation of results. More high-quality studies are needed to promote the establishment of treatment guidelines for human liver fluke infection.
Fourth Round of Three-Year Public Health Action Plan (2015-2017; Shanghai, China) and Swiss National Science Foundation.
华支睾吸虫、肝片形吸虫和猫后睾吸虫是片形科中最重要的三种人体肝吸虫，全世界约有 2500 万人感染。需要药物治疗来控制发病率，也有助于降低传播。有几种药物可用于各种方案来治疗这些感染，但它们的疗效比较不确定。我们旨在比较目前注册的抗人体肝吸虫感染药物的治愈率和虫卵减少率。
我们使用 MEDLINE、Embase、Cochrane 对照试验中心注册库、韩国医学数据库、中国国家知识基础设施和万方数据等现有电子数据库进行了系统评价，无语言限制，检索时间从建库至 2021 年 6 月 29 日。有对照药物（吡喹酮、阿苯达唑、甲苯咪唑、三苯双脒或这些药物的组合）治疗华支睾吸虫、肝片形吸虫和猫后睾吸虫的临床试验，包括比较这些药物或其组合与安慰剂的试验，均符合纳入标准。我们通过网络荟萃分析比较了治愈率。我们对每个物种进行了混合二项式回归分析，得出每个药物方案的预测中位治愈率。该模型包括治疗和感染强度作为固定因素、出版年份作为协变量，并假设不同研究的随机效应呈正态分布。我们还评估了纳入研究的质量。本研究在 PROSPERO（CRD42018109232）注册。
共有 25 项研究的 26 项试验被纳入，其中 18 项涉及华支睾吸虫，7 项研究肝片形吸虫，1 项研究猫后睾吸虫。这些试验共纳入 3340 名参与者。针对华支睾吸虫感染的两种长期治疗方案（400mg 阿苯达唑，每日 2 次，连续 5 天和每日 2 次，连续 7 天）的治愈率为 100%，而另外两种阿苯达唑多剂量方案的预测治愈率较高：每日 2 次，每次 300mg，连续 5 天（93.9%[95%CI 49.6-99.6]）和每日 2 次，每次 400mg，连续 3 天（91.0%[50.9-99.0]）。世界卫生组织推荐的吡喹酮方案（25mg/kg，每日 3 次，连续 2 天）在华支睾吸虫感染中也显示出高预测治愈率（98.5%[85.4-99.9]），其他几种吡喹酮多剂量方案的预测治愈率也高于 90%，包括每日 3 次，每次 20mg/kg，连续 3 天（97.6%[74.7-99.8]）、每日 3 次，每次 14mg/kg，连续 5 天（93.9%[44.8-99.7]）和每日 2 次，每次 20mg/kg，连续 3 天（91.0%[50.9-99.0]）。在肝片形吸虫感染中，每日 50mg/kg 和 25mg/kg 的吡喹酮单剂量方案显示出最高的预测治愈率（93.8%[85.7-97.5]），而每日 50mg/kg 的吡喹酮单剂量方案也显示出高预测治愈率（92.1%[64.9-98.6]）。三苯双脒单剂量 400mg 显示出 89.8%（77.5-95.8）的高预测治愈率。大多数研究的证据质量较低，特别是那些发表于 2000 年之前的研究。由于随机序列生成和分配隐藏的选择偏差较高，存在高度偏倚风险，并且经常未报告性能和检测偏倚。需要更多高质量的研究来促进人体肝吸虫感染治疗指南的建立。
吡喹酮对华支睾吸虫和肝片形吸虫感染显示出高疗效。三苯双脒可能是一种治疗选择，值得进一步研究。虽然当应用长治疗方案（5 天或 7 天）时，阿苯达唑是有效的，但研究规模小和高偏倚风险影响了结果的解释。需要更多高质量的研究来促进人体肝吸虫感染治疗指南的建立。
第四轮三年公共卫生行动计划（2015-2017；上海，中国）和瑞士国家科学基金会。
