Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-transmitted helminths: A systematic review, meta-analysis and individual patient data analysis

Background
The soil-transmitted helminths (STH), Ascaris lumbricoides, Trichuris trichiura and hookworms, infect 1.5 billion people worldwide and cause an estimated burden of 3.3 million disability-adjusted life years (DALYs). Current control strategies focus on morbidity reduction through preventive chemotherapy (PC) but the most commonly used recommended drugs (albendazole and mebendazole) are particularly inefficacious against T. trichiura. This, together with the threat of emerging drug resistance, calls for new control strategies, including co-administration with other anthelminthics. Ivermectin plus albendazole is widely used against lymphatic filariasis, but its efficacy and safety against STH infections has not yet been fully understood.
Methods and findings
We conducted a systematic literature review and meta-analysis on the efficacy and safety of ivermectin-albendazole co-administration in five different databases (i.e. PubMed, ISI Web of Science, ScienceDirect, CENTRAL and clinicaltrials.gov) from 1960 to January 2018. Four studies reporting efficacy of ivermectin-albendazole against STH infections and five studies on its safety met the selection criteria and were included for quantitative analysis. Ivermectin-albendazole was significantly associated with lower risk (risk ratio (RR) = 0.44, 95% confidence interval (CI) = 0.31–0.62) for T. trichiura infection after treatment compared to albendazole alone. The co-administration revealed no or only a marginal benefit on cure and egg reduction rates over albendazole alone for A. lumbricoides and hookworm infections. Adverse events (AEs) occurring after ivermectin-albendazole co-administration were mostly mild and transient. Overall, the number of individuals reporting any AE was not different (RR = 1.09, 95% CI = 0.87–1.36) in co-treated and albendazole-treated patients. However, although not statistically significant, sub-group analysis showed a tendency for slightly more AEs in patients with filariasis treated with ivermectin-albendazole compared to those treated with albendazole alone (RR = 1.29, 95% CI = 0.81–2.05).
Conclusions
Our findings suggest a good tolerability and higher efficacy of ivermectin-albendazole against T. trichiura compared to the current standard single-dose albendazole treatment, which supports the use of this co-administration in PC programs. Large-scale definitive randomized controlled trials are required to confirm our results.

Background
土壤传播的蠕虫（soil-transmitted helminths, STH），包括似蚓蛔线虫（Ascaris lumbricoides）、毛首鞭形线虫（Trichuris trichiura）和钩虫，全球感染人数达15亿，造成约330万伤残调整生命年（disability-adjusted life years, DALYs）的疾病负担。当前的防控策略以预防性化学治疗（preventive chemotherapy, PC）降低发病负担为主，但临床常用推荐药物阿苯达唑（albendazole）和甲苯达唑（mebendazole）对毛首鞭形线虫的疗效尤为不佳。加之出现的药物耐药性威胁，亟需包括与其他抗蠕虫药物联合给药在内的新型防控策略。伊维菌素联合阿苯达唑已广泛用于淋巴丝虫病的治疗，但其针对土壤传播蠕虫感染的疗效与安全性尚未完全明确。
Methods and findings
本研究于1960年至2018年1月期间，在PubMed、ISI Web of Science、ScienceDirect、Cochrane对照试验中心注册库（CENTRAL）以及clinicaltrials.gov这5个数据库中开展了伊维菌素-阿苯达唑联合给药疗效与安全性的系统综述与荟萃分析。经筛选，共有4项评估伊维菌素-阿苯达唑针对土壤传播蠕虫感染疗效的研究、5项评估其安全性的研究纳入定量分析。相较于单用阿苯达唑，伊维菌素-阿苯达唑联合给药可显著降低毛首鞭形线虫感染的发病风险（风险比（risk ratio, RR）=0.44，95%置信区间（confidence interval, CI）=0.31–0.62）。对于似蚓蛔线虫与钩虫感染，联合给药在治愈率与虫卵减少率方面未体现显著优势，或仅较单用阿苯达唑存在边际效益。伊维菌素-阿苯达唑联合给药后的不良反应（adverse events, AEs）多为轻度且具有自限性。总体而言，联合给药组与单用阿苯达唑组报告任意不良反应的人数无显著差异（RR=1.09，95%CI=0.87–1.36）。不过，亚组分析显示，尽管无统计学显著性，接受伊维菌素-阿苯达唑治疗的丝虫病患者出现不良反应的数量略高于单用阿苯达唑组（RR=1.29，95%CI=0.81–2.05）。
Conclusions
本研究结果表明，相较于当前标准的单剂量阿苯达唑治疗方案，伊维菌素-阿苯达唑联合给药具有良好的耐受性，且对毛首鞭形线虫感染的疗效更优，支持将该联合给药方案纳入预防性化学治疗项目。未来仍需开展大规模的权威随机对照试验以验证本研究结果。