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. Author summary: Millions of people worldwide are infected with intestinal worms known as soil-transmitted helminths (STHs). These include Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus) and Trichuris trichiura. Globally, the current main strategy to control these parasites is the periodical distribution of treatment to populations which are at particular risk of infection. However, the two drugs exclusively used in these mass treatment campaigns (albendazole and mebendazole) do not perform well against some of the STH species. Adding another drug, such as ivermectin, to albendazole holds promise for improved performance. This combination is already being widely used for the treatment of lymphatic filariasis. However, policy makers need evidence that this co-administration is efficacious and safe when taken together for STH infections. To fill this knowledge gap, we systematically reviewed the scientific literature for studies on the efficacy and safety of the co-administration of ivermectin and albendazole. We identified four studies reporting on the efficacy of the co-treated and five studies assessing their tolerability. Our results suggest that the co-administration performs significantly better than albendazole alone against T. trichiura–the STH species which is most difficult to treat–and is generally well-tolerated. Yet, we conclude that definitive evidence to support the use of ivermectin together with albendazole for STH will require more high-quality studies.