Randomized non-inferiority and safety trial of dihydroartemisin-piperaquine and artesunate-amodiaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Cameroonian children.

BACKGROUND: Artemether-lumefantrine and artesunate-amodiaquine are first-line treatment for uncomplicated malaria in Cameroon. No study has yet compared the efficacy of these drugs following the WHO recommended 42-day follow-up period. The goal of this study was to compare the clinical efficacy, tolerability and safety of artesunate-amodiaquine (ASAQ), artemether-lumefantrine (AL) and dihydroartemisinin piperaquine (DHAP) among children aged less than ten years in two malaria-endemic ecological regions of Cameroon. METHODS: A three-arm, randomized, controlled, non-inferiority trial was conducted among children of either gender aged six months (>5 kg) to ten years (n = 720) with acute uncomplicated Plasmodium falciparum infection. Parents/guardians of children provided consent prior to randomization to receive ASAQ, DHAP or AL in the ratio of 2:2:1, respectively. Treatment outcome was assessed based on standard WHO 2003 classification after 42 days of follow-up. The primary outcome was PCR-corrected day-42 cure rates. The non-inferiority, one-sided, lower limit asymptotic 97.5% confidence interval (CI) on the difference in PCR-corrected cure rates of ASAQ and DHAP when compared to AL was accepted if the lower limit of the CI was greater than -10%. Secondary outcomes were parasite and fever clearances and day 7 haemoglobin changes. RESULTS: PCR-corrected PP cure rates of 96.7, 98.1 and 96.3, respectively, for AL, ASAQ and DHAP was observed. The lower bound of the one-sided 97.5% CI calculated around the difference between day-42 cure rate point estimates in AL and ASAQ groups, AL and DHAP groups were, -6% and -4% respectively. There were no statistical significant differences in parasite or fever clearance times between treatments, although fever clearance pattern was different between ASAQ and DHAP. No statistical significant differences were observed in the occurrence of adverse events among treatment groups. CONCLUSION: ASAQ and DHAP are considered safe and tolerable and are not inferior to AL in the treatment of uncomplicated P. falciparum malaria in Cameroonian children. TRIAL REGISTRATION: NCT01845701.

Neglected tropical disease (NTD) diagnostics: current development and operations to advance control.

Neglected tropical diseases (NTDs) have become important public health threats that require multi-faceted control interventions. As late treatment and management of NTDs contribute significantly to the associated burdens, early diagnosis becomes an important component for surveillance and planning effective interventions. This review identifies common NTDs and highlights the progress in the development of diagnostics for these NTDs. Leveraging existing technologies to improve NTD diagnosis and improving current operational approaches for deployment of developed diagnostics are crucial to achieving the 2030 NTD elimination target. Point-of-care NTD (POC-NTD) diagnostic tools are recommended preferred diagnostic options in resource-constrained areas for mapping risk zones and monitoring treatment efficacy. However, few are currently available commercially. Technical training of remote health care workers on the use of POC-NTD diagnostics, and training of health workers on the psychosocial consequences of these diagnostics are critical in harnessing POC-NTD diagnostic potential. While the COVID-19 pandemic has challenged the possibility of achieving NTD elimination in 2030 due to the disruption of healthcare services and dwindling financial support for NTDs, the possible contribution of NTDs in exacerbating COVID-19 pandemic should motivate NTD health system strengthening.

A new online toolkit to support implementation research to enhance the use of digital innovations to End TB.

Digital technologies are playing an increasing role in the global response to tuberculosis (TB), however their effectiveness and impact are often shaped in the context in which they are implemented. Implementation research can help facilitate the effective introduction of digital health technologies in TB programmes. In 2020, the Implementation Research for Digital Technologies and TB online toolkit (IR4DTB) was developed and launched by the Special Programme for Research and Training in Tropical Diseases, and the Global TB Programme at the World Health Organization (WHO), to build local capacity for IR and promote the effective use of digital technologies within TB programmes. This paper describes the development and piloting of the IR4DTB toolkit, a self-learning tool designed for TB programme implementers. The toolkit comprises six modules reflecting key steps of the IR process, practical instructions and guidance on how to complete these steps, and real-word case studies to illustrate key learning points. This paper also describes the launch of the IR4DTB during a five-day training workshop with TB staff from China, Uzbekistan, Pakistan, Malaysia. The workshop included facilitated sessions on the IR4DTB modules, and provided an opportunity for participants to work with facilitators to develop a comprehensive IR proposal addressing an identified challenge related to the implementation and/or scale-up of digital health technologies for TB care in their home country. Post-workshop evaluation revealed high level of satisfaction among participants with the workshop content and format. The IR4DTB toolkit is a replicable model which can be used to strengthen the TB staff capacity to innovate within a culture of continuous collection of evidence. Through continued trainings and adaptation of the toolkit alongside the integration of digital technologies within TB prevention and care, this model has the potential to contribute directly to all components of the End TB Strategy.

Febrile illness experience among Nigerian nomads.

BACKGROUND: An understanding of the febrile illness experience of Nigerian nomadic Fulani is necessary for developing an appropriate strategy for extending malaria intervention services to them. An exploratory study of their malaria illness experience was carried out in Northern Nigeria preparatory to promoting malaria intervention among them. METHODS: Ethnographic tools including interviews, group discussions, informal conversations and living-in-camp observations were used for collecting information on local knowledge, perceived cause, severity and health seeking behaviour of nomadic Fulani in their dry season camps at the Gongola-Benue valley in Northeastern Nigeria. RESULTS: Nomadic Fulani regarded pabboje (a type of "fever" that is distinct from other fevers because it "comes today, goes tomorrow, returns the next") as their commonest health problem. Pabboje is associated with early rains, ripening corn and brightly coloured flora. Pabboje is inherent in all nomadic Fulani for which treatment is therefore unnecessary despite its interference with performance of duty such as herding. Traditional medicines are used to reduce the severity, and rituals carried out to make it permanently inactive or to divert its recurrence. Although modern antimalaria may make the severity of subsequent pabboje episodes worse, nomads seek treatment in private health facilities against fevers that are persistent using antimalarial medicines. The consent of the household head was essential for a sick child to be treated outside the camp. The most important issues in health service utilization among nomads are the belief that fever is a Fulani illness that needs no cure until a particular period, preference for private medicine vendors and the avoidance of health facilities. CONCLUSIONS: Understanding nomadic Fulani beliefs about pabboje is useful for planning an acceptable community participatory fever management among them.

Exposure to anti-malarial drugs and monitoring of adverse drug reactions using toll-free mobile phone calls in private retail sector in Sagamu, Nigeria: implications for pharmacovigilance.

BACKGROUND: Adverse drug reactions (ADRs) contribute to ill-health or life-threatening outcomes of therapy during management of infectious diseases. The exposure to anti-malarial and use of mobile phone technology to report ADRs following drug exposures were investigated in Sagamu--a peri-urban community in Southwest Nigeria. METHODS: Purchase of medicines was actively monitored for 28 days in three Community Pharmacies (CP) and four Patent and Proprietary Medicine Stores (PPMS) in the community. Information on experience of ADRs was obtained by telephone from 100 volunteers who purchased anti-malarials during the 28-day period. RESULTS AND DISCUSSION: A total of 12,093 purchases were recorded during the period. Antibiotics, analgesics, vitamins and anti-malarials were the most frequently purchased medicines. A total of 1,500 complete courses of anti-malarials were purchased (12.4% of total purchases); of this number, purchases of sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) were highest (39.3 and 25.2% respectively). Other anti-malarials purchased were artesunate monotherapy (AS)--16.1%, artemether-lumefantrine (AL) 10.0%, amodiaquine (AQ)--6.6%, quinine (QNN)--1.9%, halofantrine (HF)--0.2% and proguanil (PR)--0.2%. CQ was the cheapest (USD 0.3) and halofantrine the most expensive (USD 7.7). AL was 15.6 times ($4.68) more expensive than CQ. The response to mobile phone monitoring of ADRs was 57% in the first 24 hours (day 1) after purchase and decreased to 33% by day 4. Participants in this monitoring exercise were mostly with low level of education (54%). CONCLUSION: The findings from this study indicate that ineffective anti-malaria medicines including monotherapies remain widely available and are frequently purchased in the study area. Cost may be a factor in the continued use of ineffective monotherapies. Availability of a toll-free telephone line may facilitate pharmacovigilance and follow up of response to medicines in a resource-poor setting.

Keeping communities at the centre of efforts to eliminate lymphatic filariasis: learning from the past to reach a future free of lymphatic filariasis.

Since the launch of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) in 2000, more than 910 million people have received preventive chemotherapy for lymphatic filariasis (LF) and many thousands have received care for chronic manifestations of the disease. To achieve this, millions of community drug distributors (CDDs), community members and health personnel have worked together each year to ensure that at-risk communities receive preventive chemotherapy through mass drug administration (MDA). The successes of 20 y of partnership with communities is celebrated, including the application of community-directed treatment, the use of CDDs and integration with other platforms to improve community access to healthcare. Important challenges facing the GPELF moving forward towards 2030 relate to global demographic, financing and programmatic changes. New innovations in research and practice present opportunities to encourage further community partnership to achieve the elimination of LF as a public health problem. We stress the critical need for community ownership in the current Covid-19 pandemic, to counter concerns in relaunching MDA programmes for LF.

Potential contribution of prescription practices to the emergence and spread of chloroquine resistance in south-west Nigeria: caution in the use of artemisinin combination therapy.

BACKGROUND: Prescription practices have been shown to influence the emergence of anti-malarial drug resistance. Thus efforts in this study were devoted to evaluating the prescribing practices prior to introduction of the artemisinin based combination therapy (ACT) in Nigeria and its potential contribution to emergence of chloroquine resistant malaria in south-west Nigeria, in order to forestall a similar situation with the ACT. METHODS: A retrospective quantitative study was designed to examine case records of patients treated for malaria in either a government or a private hospital in Ibadan, south-west Nigeria, over a 20-year period, cutting across three phases of resistance to chloroquine in Nigeria: pre-resistance, emerging resistance and dissemination of resistance. Patient prescriptions were examined for use of anti-malarial drugs, sub-therapeutic doses of chloroquine, co-administration of anti-histamines with chloroquine. Descriptive statistics of frequency and percentage were used to describe trends in the parameters assessed using EPI-info. RESULTS: Case record files of 2,529 patients were examined. Chloroquine was the main drug used in treatment of malaria throughout the periods studied, with frequency of prescription at both sites ranging from 91.4% to 98.3% during the pre-resistance years. It was administered as standard doses during the pre resistance years. Anti-histamines, especially promethazine, were routinely co-administered with chloroquine at this period too. However, the practice of prescribing sub-therapeutic doses of chloroquine at the private health care facility coincided with the latter phase of emerging resistance and phase of dissemination of resistance. Frequency of prescription of sub-therapeutic doses increased from 6.7% in 1983 (pre-resistance years) to 43.6% in 1997 (dissemination of resistance phase) at the private health care facility. Frequency of co-administration of anti-histamines with chloroquine also reduced during the period of dissemination of resistance. CONCLUSION: The results from this study describe a lack of adherence to national treatment guidelines, especially in the private sector, and a relationship between prescription practices and dissemination of drug resistant falciparum malaria. As Nigeria adopts the use of ACT, there is an urgent need to improve malaria treatment practices in Nigeria in order to prolong the clinical shelf-life of the combination.

Addressing the under-reporting of adverse drug reactions in public health programs controlling HIV/AIDS, Tuberculosis and Malaria: A prospective cohort study.

BACKGROUND: Adverse Drug Reactions (ADRs) are a major clinical and public health problem world-wide. The prompt reporting of suspected ADRs to regulatory authorities to activate drug safety surveillance and regulation appears to be the most pragmatic measure for addressing the problem. This paper evaluated a pharmacovigilance (PV) training model that was designed to improve the reporting of ADRs in public health programs treating the Human Immunodeficiency Virus (HIV), Tuberculosis (TB) and Malaria. METHODS: A Structured Pharmacovigilance and Training Initiative (SPHAR-TI) model based on the World Health Organization accredited Structured Operational Research and Training Initiative (SOR-IT) model was designed and implemented over a period of 12 months. A prospective cohort design was deployed to evaluate the outcomes of the model. The primary outcomes were knowledge gained and Individual Case Safety Reports (ICSR) (completed adverse drug reactions monitoring forms) submitted, while the secondary outcomes were facility based Pharmacovigilance Committees activated and health facility healthcare workers trained by the participants. RESULTS: Fifty-five (98%) participants were trained and followed up for 12 months. More than three quarter of the participants have never received training on pharmacovigilance prior to the course. Yet, a significant gain in knowledge was observed after the participants completed a comprehensive training for six days. In only seven months, 3000 ICSRs (with 100% completeness) were submitted, 2,937 facility based healthcare workers trained and 46 Pharmacovigilance Committees activated by the participants. Overall, a 273% increase in ICSRs submission to the National Agency for Food and Drug Administration and Control (NAFDAC) was observed. CONCLUSION: Participants gained knowledge, which tended to increase the reporting of ADRs. The SPHAR-TI model could be an option for strengthening the continuous reporting of ADRs in public health programs in resource limited settings.

Multilateral initiative on malaria: justification, evolution, achievements, challenges, opportunities, and future plans.

Malaria is a major public health problem; about half of the world's populations live under exposure. The problem is increasing in magnitude and complexity because it is entwined with low socio-economic status, which makes African women and children particularly vulnerable. Combating malaria therefore requires concerted international efforts with an emphasis on Africa. The Multilateral Initiative on Malaria (MIM) was founded in 1997 to meet that need through strengthening research capacity in Africa, increasing international cooperation and communication, and utilization of research findings to inform malaria prevention, treatment, and control. The review undertaken in 2002 showed that through improved communication and science-focused institutional networks, MIM had brought African scientists together, opened up communication among malaria stakeholders, and provided Internet access to literature. The achievements were made through four autonomous constituents including the coordinating Secretariat being hosted for the first time in Africa by the African Malaria Network Trust (AMANET) for the period 2006-2010. The other constituents are the MIM TDR providing funding for peer-reviewed research; MIMCom facilitating Internet connectivity, access to medical literature, and communication between scientists inside and outside of Africa; and MR4 providing scientists access to research tools, standardized reagents, and protocols. Future plans will mostly consolidate the gains made under the MIM Strategic Plan for the period 2003-2005.

Research themes and advances in malaria research capacity made by the Multilateral Initiative on Malaria.

The Multilateral Initiative on Malaria was created after an international conference on malaria in Africa held in Dakar, Senegal, in early 1997. The main goal of the conference was to "strengthen and sustain, through collaborative research and training, the capability of malaria endemic countries in Africa to carry out research required to develop or improve tools for malaria control." This conference marked the beginning of a new global focus on malaria research and capacity building three decades after a partially successful global malaria eradication program. In addition to promoting research on and institutional strengthening for malaria, the initiative was created to develop mechanisms and systems to facilitate timely communication of information to scientists working in Africa, enhance the capacity to conduct malaria collaborative/multi center research in Africa, and promote application of research results to address malaria control needs. This report summarizes the increased malaria research capacity and empowerment of African researchers facilitated by the Multilateral Initiative on Malaria through the Special Program for Research and Training in Tropical Disease Research at the World Health Organization.

World Antimalarial Resistance Network (WARN) IV: clinical pharmacology.

A World Antimalarial Resistance Network (WARN) database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any) studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics). By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered) individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject) characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD) studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component of the WARN database can play a pivotal role in monitoring accurately for true antimalarial drug resistance and promptly correcting sub-optimal dosage regimens to prevent these contributing to the emergence and spread of antimalarial resistance.

Brief Report: Decentralizing ART Supply for Stable HIV Patients to Community-Based Distribution Centers: Program Outcomes From an Urban Context in Kinshasa, DRC.

Facility-based antiretroviral therapy (ART) provision for stable patients with HIV congests health services in resource-limited countries. We assessed outcomes and risk factors for attrition after decentralization to community-based ART refill centers among 2603 patients with HIV in Kinshasa, Democratic Republic of Congo, using a multilevel Poisson regression model. Death, loss to follow-up, and transfer out were 0.3%, 9.0%, and 0.7%, respectively, at 24 months. Overall attrition was 5.66/100 person-years. Patients with >3 years on ART, >500 cluster of differentiation type-4 count, body mass index >18.5, and receiving nevirapine but not stavudine showed reduced attrition. ART refill centers are a promising task-shifting model in low-prevalence urban settings with high levels of stigma and poor ART coverage.

Procurement and Supply Management System for MDR-TB in Nigeria: Are the Early Warning Targets for Drug Stock Outs and Over Stock of Drugs Being Achieved?

BACKGROUND: The World Health Organisation (WHO) introduced the twelve early warning indicators for monitoring and evaluating drug Procurement and Supply management (PSM) systems, intended to prevent drug stock-outs and overstocking. Nigeria--one of the high Multi Drug Resistant Tuberculosis (MDR-TB) burden countries, scaled-up treatment in 2012 with the concurrent implementation of a PSM system. METHOD: We evaluated how well this system functioned using the WHO indicators, including all seven MDR-TB treatment centres in the country that were functional throughout 2013. RESULTS: The quantity of MDR-TB drugs ordered for 2013 matched the annual forecast and all central orders placed during the year were delivered in full and on time. Drug consumption was 81%-106% of the quantity allocated for routine consumption. Timely submission of complete inventory reports ranged from 86-100%, late submissions being 5-15 days late. Forty to 71% of treatment centres placed a drug order when stock was below the minimum level of three months. The proportion of drug orders received at the treatment centres in full and on time ranged from 29-80%, late orders being 1-19 days late. CONCLUSION: The PSM was found to be performing well in terms of forecasting and procurement of MDR-TB drugs, but there were shortcomings in drug distribution, reporting at treatment centre level and in drug order placements. Despite these gaps, there were no stock outs. These findings indicate that where it matters most, namely ensuring that no drug stock outs affect patient management, the PSM system is effective. Addressing the observed shortcomings will help to strengthen the existing PSM system in anticipation of a growing MDR-TB case burden in the country.

Impact of health research capacity strengthening in low- and middle-income countries: the case of WHO/TDR programmes.

BACKGROUND: Measuring the impact of capacity strengthening support is a priority for the international development community. Several frameworks exist for monitoring and evaluating funding results and modalities. Based on its long history of support, we report on the impact of individual and institutional capacity strengthening programmes conducted by the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) and on the factors that influenced the outcome of its Research Capacity Strengthening (RCS) activities. METHODOLOGY AND PRINCIPAL FINDINGS: A mix of qualitative and quantitative methods (questionnaires and in-depth interviews) was applied to a selected group of 128 individual and 20 institutional capacity development grant recipients that completed their training/projects between 2000 and 2008. A semi-structured interview was also conducted on site with scientists from four institutions. Most of the grantees, both individual and institutional, reported beneficial results from the grant. However, glaring inequities stemming from gender imbalances and a language bias towards English were identified. The study showed that skills improvement through training contributed to better formulation of research proposals, but not necessarily to improved project implementation or communication of results. Appreciation of the institutional grants' impact varied among recipient countries. The least developed countries saw the programmes as essential for supporting basic infrastructure and activities. Advanced developing countries perceived the research grants as complementary to available resources, and particularly suitable for junior researchers who were not yet able to compete for major international grants. CONCLUSION: The study highlights the need for a more equitable process to improve the effectiveness of health research capacity strengthening activities. Support should be tailored to the existing research capacity in disease endemic countries and should focus on strengthening national health research systems, particularly in the least developing countries. The engagement of stakeholders at country level would facilitate the design of more specific and comprehensive strategies based on local needs.