Onchocerciasis drug development: from preclinical models to humans

Twenty diseases are recognized as neglected tropical diseases (NTDs) by World Health Assembly resolutions, including human filarial diseases. The end of NTDs is embedded within the Sustainable Development Goals for 2030, under target 3.3. Onchocerciasis afflicts approximately 20.9 million people worldwide with > 90% of those infected residing in Africa. Control programs have made tremendous efforts in the management of onchocerciasis by mass drug administration and aerial larviciding; however, disease elimination is not yet achieved. In the new WHO roadmap, it is recognized that new drugs or drug regimens that kill or permanently sterilize adult filarial worms would significantly improve elimination timelines and accelerate the achievement of the program goal of disease elimination. Drug development is, however, handicapped by high attrition rates, and many promising molecules fail in preclinical development or in subsequent toxicological, safety and efficacy testing; thus, research and development (R&D) costs are, in aggregate, very high. Drug discovery and development for NTDs is largely driven by unmet medical needs put forward by the global health community; the area is underfunded and since no high return on investment is possible, there is no dedicated drug development pipeline for human filariasis. Repurposing existing drugs is one approach to filling the drug development pipeline for human filariasis. The high cost and slow pace of discovery and development of new drugs has led to the repurposing of “old” drugs, as this is more cost-effective and allows development timelines to be shortened. However, even if a drug is marketed for a human or veterinary indication, the safety margin and dosing regimen will need to be re-evaluated to determine the risk in humans. Drug repurposing is a promising approach to enlarging the pool of active molecules in the drug development pipeline. Another consideration when providing new treatment options is the use of combinations, which is not addressed in this review. We here summarize recent advances in the late preclinical or early clinical stage in the search for a potent macrofilaricide, including drugs against the nematode and against its endosymbiont, Wolbachia pipientis.

Gene editing in Farm Animals: A Step Change for Eliminating Epidemics on our Doorstep?

Recent breakthroughs in gene-editing technologies that can render individuals fully resistant to infections may offer unprecedented opportunities for controlling future epidemics. Yet, their potential for reducing disease spread are poorly understood as the necessary theoretical framework for estimating epidemiological effects arising from gene editing applications is currently lacking. Here, we develop semi-stochastic modelling approaches to investigate how the adoption of gene editing may affect infectious disease prevalence in farmed animal populations and the prospects and time-scale for disease elimination. We apply our models to the Porcine Reproductive and Respiratory Syndrome PRRS, one of the most persistent global livestock diseases to date. Whereas extensive control efforts have shown limited success, recent production of gene-edited pigs that are fully resistant to the PRRS virus have raised expectations for eliminating this deadly disease. Our models predict that disease elimination on a national scale would be difficult to achieve if gene editing was used as the only disease control. However, when complemented with vaccination, the introduction of 10% of genetically resistant animals in a fraction of herds could be sufficient for eliminating the disease within 3-6 years. Besides strategic distribution of genetically resistant animals, several other key determinants underpinning the epidemiological impact of gene-editing were identified.

Understanding the concept of Purgation (Ishal) in Unani Medicine: A Review

The theory of humours (akhlat) is one of the fundamental pillars of the Unani System of Medicine (USM). The concept of health and disease depends on the quality (kaifiyat) and quantity (kammiyat) of humour (khilt). Health (sehat) lasts when humours remain in equilibrium and the main determinant of health is the balance in six essential factors (asbab-e-sittah zarooriya). These factors are highly modifiable and deviation in any of them leads to disequilibrium in humours either qualitatively or quantitatively which ultimately manifests in the form of the disease. Elimination (istifragh) of these morbid humours from the body becomes mandatory to treat the diseases or to restore health. One of the effective methods of elimination is purgation (ishal). It is a method by which morbid humours from the body are eliminated through the anal route. Before the elimination of any pathological humour especially in chronic diseases, it is mandatory to make the humour easily eliminable. This process of making the pathological humour eliminable is known as concoction (nuzj). The process of concoction is a regular and continuous process of the tabiyat (mediatrix naturae) of the body. In case of a minor deviation in humour, tabiyat itself eliminates it from the body after concoction. When the causative pathological humours are in abundance or grossly deviated from normalcy, tabiyat needs help from outside the body. This help of tabiyat can be done with some humour specific drugs which are known as concoctive medicines (munzij advia). Once, the humours become eliminable, the process of evacuation can be started. Classical Unani literature and published papers were explored to find the rationale of purgation therapy. Purgation is found to be advisable in the treatment of many chronic diseases. Tabiyat is the ultimate healer in the body and purgation helps it to overcome the diseases. Keywords: Istifragh; Munzij; Nuzj; Akhlat; Humours; Concoction

Economic evaluation of disease elimination: an extension to the net benefits framework and application to human African trypanosomiasis

The net benefits framework has become a mainstay of the cost-effectiveness literature, guiding decision-makers to select among strategies in the presence of budget constraints and imperfect information. However, disease elimination programs are socially desirable but not always cost-effective. Therefore, analytical frameworks are necessary to consider the additional premium for reaching global goals that are beyond the cost-effective use of country resources. We propose a modification to the net benefits framework to consider the implications of switching from an optimal strategy (in terms of cost-per-burden-averted) to a strategy with a higher likelihood of meeting the global target (i.e. elimination of transmission by a specified date). Our expanded framework informs decisions under uncertainty, determines the share of funding necessary to align local and global priorities, enabling local partners to use their resources efficiently while cooperating to meet global health targets. We illustrate the advantages of our framework by considering the economic case of efforts to eliminate transmission by 2030 of gambiense human African trypanosomiasis (gHAT), a vector-borne parasitic disease in West and Central Africa. Significance Statement Various diseases have now been earmarked for elimination by the global health community. While the health economic implications of elimination have been discussed before, one important topic remains unexplored: uncertainty and its consideration within extant cost-effectiveness frameworks. Here we extend the ubiquitous net benefits framework to consider the comparative efficiency of alternative elimination strategies when these strategies have different probabilities of reaching elimination. We evaluate the premium of elimination, and we apply our method to efforts against human African trypanosomiasis in three settings. This method could be directly applied to simulation-based studies of the cost-effectiveness of other disease elimination efforts, therefore giving the global health community a common metric by which to budget for such initiatives.

Seventy years’ achievements of international cooperation by the National Institute of Parasitic Diseases at the Chinese Center for Disease Control and Prevention

Background With the promotion of national control programs on parasitic and tropical diseases in China, the National Institute of Parasitic Diseases (NIPD), Chinese Center for Disease Control and Prevention has gained significant experience in the global health arena through international cooperation over the last seven decades allowing a multilateral impact in the elimination of major endemic diseases. Methods The achievements of NIPD since 1950 has been analyzed with emphasis on the various stages that started with research and control of the endemic parasitic and other tropical diseases at the national level and progressed via international cooperation into a global presence. Results The major achievements contributed by NIPD consist of (i) improving technical capability; (ii) promoting control and elimination of parasitic and tropical diseases; (iii) participating in global health governance and cooperation; and (iv) developing a cooperation model for technical assistance and global public health development. It is expected that NIPD’s experience of international cooperation will be essential for the dissemination of China's successful experience in global health governance, emergency response and development, with focus on malaria and neglected tropical diseases such as schistosomiasis, soil-borne and food-borne helminthiases and echinococcosis. Conclusions NIPD’s new tasks will not only continue to promote national control of endemic parasitic infections and disease elimination programs in China, but also play a leading role in global health and disease elimination programs in the future.