Target product profile for a diagnostic test to confirm leprosy in individuals with clinical signs and symptoms

Leprosy, is a chronic infectious disease caused by Mycobacterium leprae or, in some cases, by Mycobacterium lepromatosis. The bacteria is likely transmitted via tiny droplets (aerosols) from the nose and mouth during close and frequent contact with untreated cases. In some circumstances, skin-to-skin contact has also been implicated. Close and frequent contact increase the risk of contacts developing leprosy. Stigmatization and discrimination impede the life of an individual suffering from leprosy; overcoming them is an essential part of leprosy control. As with other neglected tropical diseases (NTDs), the occurrence of leprosy is often related to socioeconomic determinants of health. Despite the available treatment, more than 200 000 new leprosy patients were diagnosed globally in 2019, Early case detection is important to help contain the spread of infection and prevent disabilities.1. Epidemiology. 2. Public health response. 3. Available diagnostic tools. 4. WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases. 5. WHO Technical Advisory Group on Leprosy. 6. Purpose of the Target product profile (TPP). 7. Audiences engaged and external consultations to develop the diagnostic TPP.S

Target product profile for a diagnostic test to detect Mycobacterium leprae infection among asymptomatic household and familial contacts of leprosy patients

Leprosy remains a significant health problem in endemic tropical countries where about 200,000 new cases are reported annually from more than 155 WHO Member States and territories. The stable incidence rates during the past 15 years and the occurrence of about 10% of paediatric cases among newly detected leprosy cases annually indicate ongoing transmission of the disease in endemic countries. Leprosy is caused by an obligate intracellular bacilli, Mycobacterium leprae and, in some cases, by Mycobacterium lepromatosis. Transmission of leprosy bacilli is poorly understood, and existing evidence suggests that inhalation of aerosols containing M. leprae is the main route of transmission. In some circumstances, skin-to-skin contact has also been implicated in transmission. To date, there is no conclusive evidence that the shedding of bacteria into the environment by an active case can lead to subsequent infection of individuals. Owing to the chronicity of M. leprae infection, individuals in close contact with leprosy cases may harbour infection before clinical signs appear. During this latent period, infection without any clinical signs can eventually progress towards manifesting overt clinical signs and symptoms of leprosy. Limited evidence suggests that subclinically infected individuals may transmit M. leprae to other individuals in close physical contact. Those at highest risk are household and family contacts. Hence it is vital to detect M. leprae infection primarily in the household and among familial contacts of leprosy cases in order to determine individuals who require an enhanced regimen of post-exposure prophylaxis (PEP) and to prevent M. leprae transmission. In the new WHO road map for neglected tropical diseases 2021−2030 (“the road map”), leprosy is targeted for elimination (interruption of M. leprae transmission). Guidelines for contact tracing and interrupting transmission with appropriate prophylactic interventions have also been developed. However, the precise mechanisms of action of these interventions have not yet been studied, and the long-term consequences of the interventions are not known.1. Epidemiology. 2. Public health response. 3. Available diagnostic tools. 4. WHO Diagnostic Technical Advisory Group for Neglected Tropical Diseases. 5. WHO Technical Advisory Group on Leprosy. 6. Purpose of the Target product profile (TPP). 7. Audiences engaged and external consultations to develop the TPPS

WHO fungal priority pathogens list to guide research, development and public health action

Infectious diseases are among the top causes of mortality and a leading cause of disability worldwide. Drug-resistant bacterial infections are estimated to directly cause 1.27 million deaths and to contribute to approximately 4.95 million deaths every year, with the greatest burden in resource- limited settings. Against the backdrop of this major global health threat, invasive fungal diseases (IFDs) are rising overall and particularly among immunocompromised populations. The diagnosis and treatment of IFDs are challenged by limited access to quality diagnostics and treatment as well as emergence of antifungal resistance in many settings. Despite the growing concern, fungal infections receive very little attention and resources, leading to a paucity of quality data on fungal disease distribution and antifungal resistance patterns. Consequently, it is impossible to estimate their exact burden. In 2017, WHO developed its first bacterial priority pathogens list (WHO BPPL) in the context of increasing antibacterial resistance to help galvanize global action, including the research and development (R&D) of new treatments. Inspired by the BPPL, WHO has now developed the first fungal priority pathogens list (WHO FPPL). The WHO FPPL is the first global effort to systematically prioritize fungal pathogens, considering their unmet R&D needs and perceived public health importance. The WHO FPPL aims to focus and drive further research and policy interventions to strengthen the global response to fungal infections and antifungal resistance. The development of the list followed a multicriteria decision analysis (MCDA) approach. The prioritization process focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections for which drug resistance or other treatment and management challenges exist. The pathogens included were ranked, then categorized into three priority groups (critical, high, and medium). The critical group includes Cryptococcus neoformans, Candida auris, Aspergillus fumigatus and Candida albicans. The high group includes Nakaseomyces glabrata (Candida glabrata), Histoplasma spp., eumycetoma causative agents, Mucorales, Fusarium spp., Candida tropicalis and Candida parapsilosis. Finally, pathogens in the medium group are Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii and Paracoccidioides spp. This document proposes actions and strategies for policymakers, public health professionals and other stakeholders, targeted at improving the overall response to these priority fungal pathogens, including preventing the development of antifungal drug resistance. Three primary areas for action are proposed, focusing on: (1) strengthening laboratory capacity and surveillance; (2) sustainable investments in research, development, and innovation; and (3) public health interventions. Countries are encouraged to improve their mycology diagnostic capacity to manage fungal infections and to perform surveillance. In most contexts, this might require a stepwise approach. There is a need for sustainable investments in research, development, and innovation. More investments are needed in basic mycology research, R&D of antifungal medicines and diagnostics. Innovative approaches are needed to optimize and standardize the use of current diagnostic modalities globally. In addition, public health interventions are needed to highlight the importance of fungal infections, including through incorporating fungal diseases and priority pathogens in medical (clinical) and public health training programmes and curricula at all levels of training. Similarly, collaboration across sectors is required to address the impact of antifungal use on resistance across the One Health spectrum. Finally, regional variations and national contexts need to be taken into consideration while implementing the WHO FPPL to inform priority actions.S

Functional and structural analysis of AT-specific minor groove binders that disrupt DNA–protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast

Trypanosoma brucei, the causative agent of sleeping sickness (Human African Trypanosomiasis, HAT), contains a kinetoplast with the mitochondrial DNA (kDNA), comprising of >70% AT base pairs. This has prompted studies of drugs interacting with AT-rich DNA, such as the N-phenylbenzamide bis(2-aminoimidazoline) derivatives 1 [4-((4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide dihydrochloride] and 2 [N-(3-chloro-4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-imidazol-2-yl)amino)benzamide] as potential drugs for HAT. Both compounds show in vitro effects against T. brucei and in vivo curative activity in a mouse model of HAT. The main objective was to identify their cellular target inside the parasite. We were able to demonstrate that the compounds have a clear effect on the S-phase of T. brucei cell cycle by inflicting specific damage on the kinetoplast. Surface plasmon resonance (SPR)–biosensor experiments show that the drug can displace HMG box-containing proteins essential for kDNA function from their kDNA binding sites. The crystal structure of the complex of the oligonucleotide d[AAATTT]2 with compound 1 solved at 1.25 Å (PDB-ID: 5LIT) shows that the drug covers the minor groove of DNA, displaces bound water and interacts with neighbouring DNA molecules as a cross-linking agent. We conclude that 1 and 2 are powerful trypanocides that act directly on the kinetoplast, a structure unique to the order Kinetoplastida

Efficacy of anthelminthic drugs and drug combinations against soil-transmitted helminths: a systematic review and network meta-analysis.

Background: Periodic mass distribution of benzimidazole anthelminthic drugs is the key strategy to control soil-transmitted helminths (STH) globally. However, benzimidazoles have low efficacy against Trichuris trichiura, and there are concerns about benzimidazole resistance potentially emerging in humans. Therefore, identifying alternative drug regimens is a pressing priority. We present a systematic review and network meta-analysis, comparing the efficacy of 21 different anthelminthic drug regimens, including standard, novel, and combination treatments. Methods: We searched PubMed, MEDLINE, Embase, Web of Science, and Cochrane databases and identified studies comparing anthelminthic treatments to each other or placebo. The outcomes calculated were relative risk (RR) of cure and difference in egg reduction rates (dERR). We used an automated generalized pair-wise modelling framework to generate mixed treatment effects against a common comparator, the current standard treatment (single-dose albendazole). This study is registered with PROSPERO (CRD42016050739). Findings: Our search identified 4876 studies, of which 114 were included in meta-analysis. Results identified several drug combinations with higher efficacy than single-dose albendazole for T. trichiura, including albendazole-ivermectin (RR of cure 3.22, 95%CI 1.84-5.63; dERR 0.97, 95%CI 0.21-1.74), albendazole-oxantel pamoate (RR 5.07, 95%CI 1.65-15.59; dERR 0.51, 95%CI 0.450-0.52), mebendazole-ivermectin (RR 3.37, 95%CI 2.20-5.16), and tribendimidine-oxantel pamoate (RR 4.06, 95%CI 1.30-12.64). Interpretation: There are several promising drug combinations that may enhance the impact of STH control programs on T. trichiura, without compromising efficacy against A. lumbricoides and hookworm. We suggest further, large-scale trials of these drug combinations and consideration of their use in STH control programs where T. trichiura is present