Restarting Neglected Tropical Diseases Programs in West Africa during the COVID-19 Pandemic: Lessons Learned and Best Practices.

Countries across West Africa began reporting COVID-19 cases in February 2020. By March, the pandemic began disrupting activities to control and eliminate neglected tropical diseases (NTDs) as health ministries ramped up COVID-19-related policies and prevention measures. This was followed by interim guidance from the WHO in April 2020 to temporarily pause mass drug administration (MDA) and community-based surveys for NTDs. While the pandemic was quickly evolving worldwide, in most of West Africa, governments and health ministries took quick action to implement mitigation measures to slow the spread. The U.S. Agency for International Development's (USAID) Act to End NTDs | West program (Act | West) began liaising with national NTD programs in April 2020 to pave a path toward the eventual resumption of activities. This process consisted of first collecting and analyzing COVID-19 epidemiological data, policies, and standard operating procedures across the program's 11 countries. The program then developed an NTD activity restart matrix that compiled essential considerations to restart activities. By December 2020, all 11 countries in Act | West safely restarted MDA and certain surveys to monitor NTD prevalence or intervention impact. Preliminary results show satisfactory MDA program coverage, meaning that enough people are taking the medicine to keep countries on track toward achieving their NTD disease control and elimination goals, and community perceptions have remained positive. The purpose of this article is to share the lessons and best practices that have emerged from the adoption of strategies to limit the spread of the novel coronavirus during MDA and other program activities.

Towards a comprehensive research and development plan to support the control, elimination and eradication of neglected tropical diseases.

To maximise the likelihood of success, global health programmes need repeated, honest appraisal of their own weaknesses, with research undertaken to address any identified gaps. There is still much to be learned to optimise work against neglected tropical diseases. To facilitate that learning, a comprehensive research and development plan is required. Here, we discuss how such a plan might be developed.

Risk factors associated with failing pre-transmission assessment surveys (pre-TAS) in lymphatic filariasis elimination programs: Results of a multi-country analysis.

Achieving elimination of lymphatic filariasis (LF) as a public health problem requires a minimum of five effective rounds of mass drug administration (MDA) and demonstrating low prevalence in subsequent assessments. The first assessments recommended by the World Health Organization (WHO) are sentinel and spot-check sites-referred to as pre-transmission assessment surveys (pre-TAS)-in each implementation unit after MDA. If pre-TAS shows that prevalence in each site has been lowered to less than 1% microfilaremia or less than 2% antigenemia, the implementation unit conducts a TAS to determine whether MDA can be stopped. Failure to pass pre-TAS means that further rounds of MDA are required. This study aims to understand factors influencing pre-TAS results using existing programmatic data from 554 implementation units, of which 74 (13%) failed, in 13 countries. Secondary data analysis was completed using existing data from Bangladesh, Benin, Burkina Faso, Cameroon, Ghana, Haiti, Indonesia, Mali, Nepal, Niger, Sierra Leone, Tanzania, and Uganda. Additional covariate data were obtained from spatial raster data sets. Bivariate analysis and multilinear regression were performed to establish potential relationships between variables and the pre-TAS result. Higher baseline prevalence and lower elevation were significant in the regression model. Variables statistically significantly associated with failure (p-value ≤0.05) in the bivariate analyses included baseline prevalence at or above 5% or 10%, use of Filariasis Test Strips (FTS), primary vector of Culex, treatment with diethylcarbamazine-albendazole, higher elevation, higher population density, higher enhanced vegetation index (EVI), higher annual rainfall, and 6 or more rounds of MDA. This paper reports for the first time factors associated with pre-TAS results from a multi-country analysis. This information can help countries more effectively forecast program activities, such as the potential need for more rounds of MDA, and prioritize resources to ensure adequate coverage of all persons in areas at highest risk of failing pre-TAS.

The design and development of a multicentric protocol to investigate the impact of adjunctive doxycycline on the management of peripheral lymphoedema caused by lymphatic filariasis and podoconiosis.

BACKGROUND: As new lymphatic filariasis infections are eliminated through mass chemotherapy, previously affected individuals are left with the sequellae, especially chronic progressive lymphoedema. Currently this is managed by careful attention to limb hygiene to prevent infection. Studies over the past 15 years have suggested that the incorporation of doxycycline treatment may arrest or even reverse progression of lymphoedema. Most of this work has been observational or based on small studies, and if this intervention is effective, studies need to be conducted on a larger scale and under diverse geographical and social conditions before it can be incorporated into treatment policy. METHODS/DESIGN: The double-blind, placebo-controlled study was designed to investigate the impact of six weeks treatment with doxycycline added to standard limb hygiene on early stage filarial lymphoedema in five sites in Africa and the Indian subcontinent. One site in Cameroon is selected for studying lymphoedema in podoconiosis. Each site was individually powered with the potential to undertake a meta-analysis on completion. Evaluation methods followed those used in Ghana in 2012 with additions resulting from advances in technology. The details of the core protocol and how it was varied to take account of differing situations at each of the sites are provided. The study will enrol up to 1800 patients and will complete in mid-2021. CONCLUSIONS: This paper provides details of what challenges were faced during its development and discusses the issues and how they were resolved. In particular, the reasons for inclusion of new technology and the problems encountered with the supply of drugs for the studies are described in detail. By making these details available, it is hoped that the study protocol will help others interested in improving treatment for filarial lymphoedema in the design of future studies. Trial registration India: Clintrials.gov. NCT02929121 registered 10 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT02929121 Mali: Clintrials.gov. NCT02927496 registered 7 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT0292749 Sri Lanka: Clintrials.gov. NCT02929134 registered 10 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT02929134 Ghana: ISRCTN. 14042737 registered 10 July 2017: https://doi.org/10.1186/ISRCTN14042737 Tanzania: ISRCTN. 65756724 registered 21 July 2017: https://doi.org/10.1186/ISRCTN65756724 Cameroon: ISRCTN. 1181662 registered 25 July 2017: https://doi.org/10.1186/ISRCTN11881662.

Eliminating Neglected Tropical Diseases in Urban Areas: A Review of Challenges, Strategies and Research Directions for Successful Mass Drug Administration.

Since 1950, the global urban population grew from 746 million to almost 4 billion and is expected to reach 6.4 billion by mid-century. Almost 90% of this increase will take place in Asia and Africa and disproportionately in urban slums. In this context, concerns about the amplification of several neglected tropical diseases (NTDs) are warranted and efforts towards achieving effective mass drug administration (MDA) coverage become even more important. This narrative review considers the published literature on MDA implementation for specific NTDs and in-country experiences under the ENVISION and END in Africa projects to surface features of urban settings that challenge delivery strategies known to work in rural areas. Discussed under the thematics of governance, population heterogeneity, mobility and community trust in MDA, these features include weak public health infrastructure and programs, challenges related to engaging diverse and dynamic populations and the limited accessibility of certain urban settings such as slums. Although the core components of MDA programs for NTDs in urban settings are similar to those in rural areas, their delivery may need adjustment. Effective coverage of MDA in diverse urban populations can be supported by tailored approaches informed by mapping studies, research that identifies context-specific methods to increase MDA coverage and rigorous monitoring and evaluation.

Establishing quality assured (QA) laboratory support for onchocerciasis elimination in Africa.

An essential component in achieving accepted successful elimination of a disease or a pathogen involves the acquisition of quality-assured (QA) data that ultimately define the absence of infection or transmission in previously endemic areas. The acquisition of these essential data, in the case of onchocerciasis elimination, requires strong laboratory support for both testing and continuing evaluation/validation of the tools used for the required diagnostic and epidemiology procedures. There is also a need for standardization of the laboratory-based and field-based assays used across the onchocerciasis-endemic countries as well as continuing technical, fiscal and logistical support for laboratory activities. To achieve these needs, it is proposed to build on the existing onchocerciasis programme laboratory activities in the endemic areas by expanding these to include additional laboratories as referral services organized on a regional basis to support the needs of endemic countries. Included in these plans are the development of quality assurance mechanisms, supply chain procedures and standardization of protocols for the basic assays needed for both national onchocerciasis elimination programme surveys and supporting research activities. Such an entity could then include quality-assured testing for other neglected tropical diseases.

Malaria diagnostics in clinical trials.

Malaria diagnostics are widely used in epidemiologic studies to investigate natural history of disease and in drug and vaccine clinical trials to exclude participants or evaluate efficacy. The Malaria Laboratory Network (MLN), managed by the Office of HIV/AIDS Network Coordination, is an international working group with mutual interests in malaria disease and diagnosis and in human immunodeficiency virus/acquired immunodeficiency syndrome clinical trials. The MLN considered and studied the wide array of available malaria diagnostic tests for their suitability for screening trial participants and/or obtaining study endpoints for malaria clinical trials, including studies of HIV/malaria co-infection and other malaria natural history studies. The MLN provides recommendations on microscopy, rapid diagnostic tests, serologic tests, and molecular assays to guide selection of the most appropriate test(s) for specific research objectives. In addition, this report provides recommendations regarding quality management to ensure reproducibility across sites in clinical trials. Performance evaluation, quality control, and external quality assessment are critical processes that must be implemented in all clinical trials using malaria tests.

Promoting good clinical laboratory practices and laboratory accreditation to support clinical trials in sub-Saharan Africa.

Laboratory capacity in the developing world frequently lacks quality management systems (QMS) such as good clinical laboratory practices, proper safety precautions, and adequate facilities; impacting the ability to conduct biomedical research where it is needed most. As the regulatory climate changes globally, higher quality laboratory support is needed to protect study volunteers and to accurately assess biological parameters. The University of Bamako and its partners have undertaken a comprehensive QMS plan to improve quality and productivity using the Clinical and Laboratory Standards Institute standards and guidelines. The clinical laboratory passed the College of American Pathologists inspection in April 2010, and received full accreditation in June 2010. Our efforts to implement high-quality standards have been valuable for evaluating safety and immunogenicity of malaria vaccine candidates in Mali. Other disease-specific research groups in resource-limited settings may benefit by incorporating similar training initiatives, QMS methods, and continual improvement practices to ensure best practices.

A Quality Management Approach to Implementing Point-of-Care Technologies for HIV Diagnosis and Monitoring in Sub-Saharan Africa.

Technology advances in rapid diagnosis and clinical monitoring of human immunodeficiency virus (HIV) infection have been made in recent years, greatly benefiting those at risk of HIV infection, those needing care and treatment, and those on antiretroviral (ART) therapy in sub-Saharan Africa. However, resource-limited, geographically remote, and harsh climate regions lack uniform access to these technologies. HIV rapid diagnostic tests (RDTs) and monitoring tools, such as those for CD4 counts, as well as tests for coinfections, are being developed and have great promise in these settings to aid in patient care. Here we explore the advances in point-of-care (POC) technology in the era where portable devices are bringing the laboratory to the patient. Quality management approaches will be imperative for the successful implementation of POC testing in endemic settings to improve patient care.

Utility of a point-of-care malaria rapid diagnostic test for excluding malaria as the cause of fever among HIV-positive adults in rural Rakai, Uganda.

We compared results of a malaria rapid diagnostic test (Binax Now Malaria, Binax-M, Inverness Medical Innovations, Inc., Waltham, MA) performed at rural mobile clinics in Uganda by clinicians evaluating febrile adult HIV patients to thick smear evaluated at a central laboratory by trained microscopists. Two hundred forty-six samples were analyzed, including 14 (5.7%) which were thick-smear positive for falciparum malaria. Sensitivity of Binax-M compared with thick smear was 85.7% (95% CI: 57.2-98.2), specificity 97.8% (95% CI: 94.9-99.3), positive and negative predictive values were 70.6% (95% CI: 44.0-89.7) and 99.1% (95% CI: 96.8-99.9), respectively. The rapid diagnostic test accurately ruled malaria "in or out" at the point-of-care, facilitating appropriate clinical management and averting unnecessary anti-malarial therapy.

Performance of a prototype malaria rapid diagnostic test versus thick film microscopy among HIV-positive subjects in rural Rakai, Uganda.

In this study, we report the performance of a prototype malaria rapid diagnostic test, Malaria F-test (MFT), compared with thick blood films from HIV-positive Ugandans undergoing malaria testing. In total, 21/154 samples (13.6%) were concordantly positive by both thick film and MFT and 129/154 samples (83.8%) were concordantly negative; 1 sample (0.6%) was thick film-positive but MFT-negative and 3 samples (1.9%) were thick film-negative but MFT-positive. The sensitivity of MFT was 95.5% (95% CI 77.2-99.9%) compared with thick film microscopy and the specificity was 97.7% (95% CI 93.5-99.5%). MFT was simple, rapid and effective for detection of Plasmodium falciparum among HIV-positive subjects in a rural, malaria-endemic African setting.

CD4 stabilization tubes provide improved accuracy of absolute CD4 T-cell counts compared to standard k3 EDTA tubes in human immunodeficiency virus immunologic monitoring in resource-poor settings.

CD4 stabilization tubes have the ability to ensure internal quality control in the human immunodeficiency virus (HIV) monitoring laboratory by maintaining accurate absolute CD4 T-cell counts for up to 6 days. Here, we assessed this technology for its use in an HIV clinical monitoring laboratory in a resource-poor setting in rural Uganda.

Adenovirus 5 and 35 vectors expressing Plasmodium falciparum circumsporozoite surface protein elicit potent antigen-specific cellular IFN-gamma and antibody responses in mice.

Falciparum malaria vaccine candidates have been developed using recombinant, replication-deficient serotype 5 and 35 adenoviruses (Ad5, Ad35) encoding the Plasmodium falciparum circumsporozoite surface protein (CSP) (Ad5.CS, Ad35.CS) (Crucell Holland BV, Leiden, The Netherlands). To evaluate the immunogenicity of these constructs, BALB/cJ mice were immunized twice with either Ad5.CS, Ad35.CS, empty Ad5-vector (eAd5), empty Ad35 vector (eAd35), or saline. Another group received the CSP-based RTS,S malaria vaccine formulated in the proprietary Adjuvant System AS01B (GlaxoSmithKline Biologicals, Rixensart, Belgium). Here we report that Ad5.CS, Ad35.CS, and RTS,S/AS01B, elicited both cellular and serologic CSP antigen-specific responses in mice. These adenoviral vectors induce strong malaria-specific immunity and warrant further evaluation.

Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone.

The RTS,S/AS02A protein-based vaccine consistently demonstrates significant protection against infection with Plasmodium falciparum malaria and also against clinical malaria and severe disease in children in areas of endemicity. Here we demonstrate with rhesus macaques that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding circumsporozoite protein (CS) (Ad35.CS), followed by boosting with RTS,S in an improved MPL- and QS21-based adjuvant formulation, AS01B, maintains antibody responses and dramatically increases levels of T cells producing gamma interferon and other Th1 cytokines in response to CS peptides. The increased T-cell responses induced by the combination of Ad35.CS and RTS,S/AS01B are sustained for at least 6 months postvaccination and may translate to improved and more durable protection against P. falciparum infection in humans.