Key Contributions by the Swiss Tropical and Public Health Institute Towards New and Better Drugs for Tropical Diseases.

Thanks to its expertise in clinical research, epidemiology, infectious diseases, microbiology, parasitology, public health, translational research and tropical medicine, coupled with deeply rooted partnerships with institutions in low- and middle-income countries (LMICs), the Swiss Tropical and Public Health Institute (Swiss TPH) has been a key contributor in many drug research and development consortia involving academia, pharma and product development partnerships. Our know-how of the maintenance of parasites and their life-cycles in the laboratory, plus our strong ties to research centres and disease control programme managers in LMICs with access to field sites and laboratories, have enabled systems for drug efficacy testing in vitro and in vivo, clinical research, and modelling to support the experimental approaches. Thus, Swiss TPH has made fundamental contributions towards the development of new drugs - and the better use of old drugs - for neglected tropical diseases and infectious diseases of poverty, such as Buruli ulcer, Chagas disease, food-borne trematodiasis (e.g. clonorchiasis, fascioliasis and opisthorchiasis), human African trypanosomiasis, leishmaniasis, malaria, schistosomiasis, soil-transmitted helminthiasis and tuberculosis. In this article, we show case the success stories of molecules to which Swiss TPH has made a substantial contribution regarding their use as anti-infective compounds with the ultimate aim to improve people's health and well-being.

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study.

BACKGROUND: To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, accessing facilities offering parenteral antimalarials may be difficult. A randomised controlled trial found pre-referral treatment with rectal artesunate (RAS) to reduce deaths and disability in children who arrived at a referral facility with delay. This study examined the effectiveness of pre-referral RAS treatment implemented through routine procedures of established community-based health care systems. METHODS: An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children <5 years of age presenting to a community-based health provider with a positive malaria test and signs of severe malaria were enrolled and followed up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment. RESULTS: Post-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 13.8% (865/6286) of patients were sick on day 28. The CFR was higher after RAS roll-out in Nigeria (16.1 vs. 4.2%) and stable in DRC (6.7 vs. 6.6%) and Uganda (0.7 vs. 0.3%). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR=3.06, 95% CI 1.35-6.92 and aOR=2.16, 95% CI 1.11-4.21, respectively). Only in Uganda, RAS users were less likely to be dead or sick at follow-up (aOR=0.60, 95% CI 0.45-0.79). Post-referral parenteral antimalarials plus oral artemisinin-based combination therapy (ACT), a proxy for appropriate post-referral treatment, was protective. However, in referral health facilities, ACT was not consistently administered after parenteral treatment (DRC 68.4%, Nigeria 0%, Uganda 70.9%). CONCLUSIONS: Implemented at scale to the recommended target group, pre-referral RAS had no beneficial effect on child survival in three highly malaria-endemic settings. RAS is unlikely to reduce malaria deaths unless health system issues such as referral and quality of care at all levels are addressed. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov : NCT03568344.

Vector composition, abundance, biting patterns and malaria transmission intensity in Madang, Papua New Guinea: assessment after 7 years of an LLIN-based malaria control programme.

BACKGROUND: A malaria control programme based on distribution of long-lasting insecticidal bed nets (LLINs) and artemisinin combination therapy began in Papua New Guinea in 2009. After implementation of the programme, substantial reductions in vector abundance and malaria transmission intensity occurred. The research reported here investigated whether these reductions remained after seven years of sustained effort. METHODS: All-night (18:00 to 06:00) mosquito collections were conducted using human landing catches and barrier screen methods in four villages of Madang Province between September 2016 and March 2017. Anopheles species identification and sporozoite infection with Plasmodium vivax and Plasmodium falciparum were determined with molecular methods. Vector composition was expressed as the relative proportion of different species in villages, and vector abundance was quantified as the number of mosquitoes per barrier screen-night and per person-night. Transmission intensity was quantified as the number of sporozoite-infective vector bites per person-night. RESULTS: Five Anopheles species were present, but vector composition varied greatly among villages. Anopheles koliensis, a strongly anthropophilic species was the most prevalent in Bulal, Matukar and Wasab villages, constituting 63.7-73.8% of all Anopheles, but in Megiar Anopheles farauti was the most prevalent species (97.6%). Vector abundance varied among villages (ranging from 2.8 to 72.3 Anopheles per screen-night and 2.2-31.1 Anopheles per person-night), and spatially within villages. Malaria transmission intensity varied among the villages, with values ranging from 0.03 to 0.5 infective Anopheles bites per person-night. Most (54.1-75.1%) of the Anopheles bites occurred outdoors, with a substantial proportion (25.5-50.8%) occurring before 22:00. CONCLUSION: The estimates of vector abundance and transmission intensity in the current study were comparable to or higher than estimates in the same villages in 2010-2012, indicating impeded programme effectiveness. Outdoor and early biting behaviours of vectors are some of the likely explanatory factors. Heterogeneity in vector composition, abundance and distribution among and within villages challenge malaria control programmes and must be considered when planning them.

Acceptability of pre-referral rectal artesunate for severe malaria in children under 5 years by health workers and caregivers in the Democratic Republic of the Congo, Nigeria and Uganda.

BACKGROUND: For children below 6 years with suspected severe malaria attending a health care provider unable to provide parenteral malaria treatment, pre-referral rectal artesunate (RAS) is recommended by the World Health Organization to prevent death and disability. A number of African countries are in the process of rolling out quality-assured RAS for pre-referral treatment of severe malaria at community-level. The success of RAS depends, among other factors, on the acceptability of RAS in the communities where it is being rolled-out. Yet to date, there is limited literature on RAS acceptability. This study aimed to determine the acceptability of RAS by health care providers and child caregivers in communities where quality assured RAS was rolled out. This study was nested within the comprehensive multi-country observational research project Community Access to Rectal Artesunate for Malaria (CARAMAL), implemented in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Data from three different sources were analysed to understand RAS acceptability: interviews with health workers during three health care provider surveys (N = 341 community health workers and 467 primary health facility workers), with caregivers of children < 5 years of age during three household surveys (N = 9332 caregivers), and with caregivers of children < 5 years of age who were treated with RAS and enrolled in the CARAMAL Patient Surveillance System (N = 3645 caregivers). RESULTS: RAS acceptability was high among all interviewed stakeholders in the three countries. After the roll-out of RAS, 97-100% heath care providers in DRC, 98-100% in Nigeria and 93-100% in Uganda considered RAS as very good or good. Majority of caregivers whose children had received RAS for pre-referral management of severe malaria indicated that they would want to get the medication again, if their child had the same illness (99.8% of caregivers in DRC, 100% in Nigeria and 99.9% in Uganda). In three household surveys, 67-80% of caregivers whose children had not previously received RAS considered the medication as useful. CONCLUSION: RAS was well accepted by health workers and child caregivers in DRC, Nigeria and Uganda. Acceptability is unlikely to be an obstacle to the large-scale roll-out of RAS in the studied settings.

Diagnostic capacity and antimalarial availability in Papua New Guinea before the introduction of a revised national malaria treatment protocol.

BACKGROUND: Papua New Guinea (PNG) introduced a revised national malaria treatment protocol (NMTP) in late 2011. Successful implementation of the revised protocol requires all health facilities in PNG to have reliable access to microscopy or malaria rapid diagnostic kits as well as a reliable supply of all recommended first-line medications. This paper presents findings from a study that sought to assess the availability of microscopy, malaria rapid diagnostic kits and recommended first-line antimalarial medication in Papua New Guinean health facilities across the country before the introduction of the revised treatment protocol. METHODS: A country-wide cross-sectional survey of 79 randomly selected health centres, health subcentres and aid posts. Data were collected via an interviewer-administered questionnaire completed with the officer in charge of participating health facilities. RESULTS: Overall, 15% of surveyed health facilities had unexpired rapid diagnostic test (RDT) in stock or working microscopy available. A recommended first-line antimalarial for uncomplicated malaria was available in 85% of health facilities. The preferred first-line antimalarial combination for treating severe malaria was present in 42% of health facilities, although 68% had the capacity to provide either the preferred or recommended substitute first-line medication for severe malaria. The total number of health workers employed in the 79 surveyed health facilities was 443, only 3 of whom were medical doctors. CONCLUSIONS: Our findings indicate that diagnostic capacity was low in Papua New Guinean health facilities before the introduction of the new NMTP and that access to recommended first-line antimalarial medication was variable. Substantial improvements in diagnostic capacity and antimalarial procurement and distribution will need to be made if the revised protocol is to be adhered to.

Long-lasting insecticidal nets remain efficacious after five years of use in Papua New Guinea.

Long-lasting insecticide-treated nets (LLINs) have been distributed throughout Papua New Guinea since 2004 as part of the country's malaria control program. This study aimed to evaluate the efficacy of these used bednets over time and with respect to the various household factors related to their use in order to enable the National Department of Health to maximize on the benefits of LLINs. In 2008 and early 2009, used LLINs (0-9 years old) were collected in various villages in Papua New Guinea as part of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)-supported National Malaria Control Program and data were collected on net usage. A subset of the nets were tested for residual insecticide content. Net efficacy was measured by the rate of knockdown of Anopheles farauti s.s. following exposure to LLINs using the World Health Organization cone bioassay. Optimal effectiveness (> 95% knockdown 1 hour post exposure) was observed in 92% of the LLINs. A slight reduction in efficacy was observed after two years of household use and there was a significant relationship between the number of years in use and percent knockdown (p < 0.001) as well as deltamethrin concentration (p < 0.001). Washing of nets was not associated with a reduction in deltamethrin concentration, but drying them in the sun was (p = 0.008). The physical conditions of these nets also degraded over time with a significant increase in the number of large holes after 5 years (p = 0.02). These findings are in support of the current recommendation to replace LLINs after five years of use, and demonstrate that proper net care can extend the length of efficacy.

Starting at the community: Treatment-seeking pathways of children with suspected severe malaria in Uganda.

Community health workers (CHW) usually refer children with suspected severe malaria to the nearest public health facility or a designated public referral health facility (RHF). Caregivers do not always follow this recommendation. This study aimed at identifying post-referral treatment-seeking pathways that lead to appropriate antimalarial treatment for children less than five years with suspected severe malaria. An observational study in Uganda enrolled children below five years presenting to CHWs with signs of severe malaria. Children were followed up 28 days after enrolment to assess their condition and treatment-seeking history, including referral advice and provision of antimalarial treatment from visited providers. Of 2211 children included in the analysis, 96% visited a second provider after attending a CHW. The majority of CHWs recommended caregivers to take their child to a designated RHF (65%); however, only 59% followed this recommendation. Many children were brought to a private clinic (33%), even though CHWs rarely recommended this type of provider (3%). Children who were brought to a private clinic were more likely to receive an injection than children brought to a RHF (78% vs 51%, p<0.001) and more likely to receive the second or third-line injectable antimalarial (artemether: 22% vs. 2%, p<0.001, quinine: 12% vs. 3%, p<0.001). Children who only went to non-RHF providers were less likely to receive an artemisinin-based combination therapy (ACT) than children who attended a RHF (odds ratio [OR] = 0.64, 95% CI 0.51-0.79, p<0.001). Children who did not go to any provider after seeing a CHW were the least likely to receive an ACT (OR = 0.21, 95% CI 0.14-0.34, p<0.001). Health policies should recognise local treatment-seeking practices and ensure adequate quality of care at the various public and private sector providers where caregivers of children with suspected severe malaria actually seek care.

Health system readiness and the implementation of rectal artesunate for severe malaria in sub-Saharan Africa: an analysis of real-world costs and constraints.

BACKGROUND: Rectal artesunate, an efficacious pre-referral treatment for severe malaria in children, was deployed at scale in Uganda, Nigeria, and DR Congo. In addition to distributing rectal artesunate, implementation required additional investments in crucial but neglected components in the care for severe malaria. We examined the real-world costs and constraints to rectal artesunate implementation. METHODS: We collected primary data on baseline health system constraints and subsequent rectal artesunate implementation expenditures. We calculated the equivalent annual cost of rectal artesunate implementation per child younger than 5 years at risk of severe malaria, from a health system perspective, separating neglected routine health system components from incremental costs of rectal artesunate introduction. FINDINGS: The largest baseline constraints were irregular health worker supervisions, inadequate referral facility worker training, and inadequate malaria commodity supplies. Health worker training and behaviour change campaigns were the largest startup costs, while supervision and supply chain management accounted for most annual routine costs. The equivalent annual costs of preparing the health system for managing severe malaria with rectal artesunate were US$2·63, $2·20, and $4·19 per child at risk and $322, $219, and $464 per child treated in Uganda, Nigeria, and DR Congo, respectively. Strengthening the neglected, routine health system components accounted for the majority of these costs at 71·5%, 65·4%, and 76·4% of per-child costs, respectively. Incremental rectal artesunate costs accounted for the minority remainder. INTERPRETATION: Although rectal artesunate has been touted as a cost-effective pre-referral treatment for severe malaria in children, its real-world potential is limited by weak and under-financed health system components. Scaling up rectal artesunate or other interventions relying on community health-care providers only makes sense alongside additional, essential health system investments sustained over the long term. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Care Seeking and Treatment of Febrile Children with and without Danger Signs of Severe Disease in Northern Uganda: Results from Three Household Surveys (2018-2020).

Identification, stabilization, and prompt referral of children with signs of severe febrile disease (danger signs) in rural communities are crucial for preventing complications and death from severe malaria, pneumonia, and diarrhea. We set out to determine the treatment-seeking practices and treatment patterns for children < 5 years of age with an acute febrile illness, with or without danger signs of severe disease, in a highly malaria-endemic area of northern Uganda. Three household surveys were conducted from November through December each year in 2018, 2019, and 2020. Overall, 30% of the children in the study were reported to have had a WHO-classified danger sign including convulsions, unconsciousness/unusually sleepy, inability to feed or drink, and vomiting everything. Only half of the children in this study sought care from a health provider. However, significantly more children with danger signs of severe disease sought and received treatment and diagnostics from a health provider, compared with those without danger signs (adjusted odds ratio: 1.6, 95% confidence interval: 1.2-2.0; P < 0.01). In the total population studied, care seeking in the public sector was 26% and similar to care seeking in the private sector (24%). Community health workers were used as the first source of care by 12% of the children. Approximately 38% of the children who were reported to have danger signs of severe disease requiring prompt referral and treatment did not seek care from a health provider. Understanding and addressing barriers to accessing healthcare could contribute to better treatment seeking practices.

Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda.

INTRODUCTION: Children who receive prereferral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child's condition after RAS administration may influence a caregiver's decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited. METHODS: An observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under 5 years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment-seeking pathways. RESULTS: Referral completion was 67% (1408/2104) in DRC, 48% (287/600) in Nigeria and 58% (2170/3745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted OR (aOR)=0.48, 95% CI 0.30 to 0.77 and aOR=0.72, 95% CI 0.58 to 0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared with RAS non-users in the post-roll-out phase (aOR=0.18, 95% CI 0.05 to 0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR=1.81, 95% CI 1.17 to 2.79). CONCLUSIONS: The findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered prereferral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral. TRIAL REGISTRSTION NUMBER: NCT03568344; ClinicalTrials.gov.

Reported reasons for not using a mosquito net when one is available: a review of the published literature.

BACKGROUND: A review of the barriers to mosquito net use in malaria-endemic countries has yet to be presented in the published literature despite considerable research interest in this area. This paper partly addresses this gap by reviewing one component of the evidence base; namely, published research pertaining to self-reported reasons for not using a mosquito net among net 'owning' individuals. It was anticipated that the review findings would potentially inform an intervention or range of interventions best suited to promoting greater net use amongst this group. METHOD: Studies were sought via a search of the Medline database. The key inclusion criteria were: that study participants could be identified as owning a mosquito net or having a mosquito net available for use; that these participants on one or more occasions were identified or self-reported as not using the mosquito net; and that reasons for not using the mosquito net were reported. Studies meeting these criteria were included irrespective of mosquito net type. RESULTS: A total of 22 studies met the inclusion criteria. Discomfort, primarily due to heat, and perceived (low) mosquito density were the most widely identified reason for non-use. Social factors, such as sleeping elsewhere, or not sleeping at all, were also reported across studies as were technical factors related to mosquito net use (i.e. not being able to hang a mosquito net or finding it inconvenient to hang) and the temporary unavailability of a normally available mosquito net (primarily due to someone else using it). However, confidence in the reported findings was substantially undermined by a range of methodological limitations and a dearth of dedicated research investigation. CONCLUSIONS: The findings of this review should be considered highly tentative until such time as greater quantities of dedicated, well-designed and reported studies are available in the published literature. The current evidence-base is not sufficient in scope or quality to reliably inform mosquito net promoting interventions or campaigns targeted at individuals who own, but do not (reliably) use, mosquito nets.

Does test-based prescription of evidence-based treatment for malaria improve treatment seeking and satisfaction? Findings of repeated cross-sectional surveys in Papua New Guinea.

INTRODUCTION: The presumptive treatment of febrile illness with antimalarial medication is becoming less common in low-income and middle-income countries as access to reliable diagnostic tests improves. We explore whether the shift towards test-based antimalarial prescription, and the introduction of highly efficacious artemisinin combination therapies (ACTs), reduces critical delays in seeking treatment for febrile illness or increases patient satisfaction. METHODS: We conducted countrywide repeat, cross-sectional surveys in 118 randomly selected primary healthcare services in Papua New Guinea. The clinical case management of 1765 consecutively presenting febrile patients was observed and exit interviews were completed at discharge. This was done prior to implementation of test-based ACT prescription (2011) and at 12 (2012) and 60 months (2016) postimplementation. We conducted multiple logistic regressions. Treatment response time was dichotomised as <24 hours from symptom onset vs 24+ hours. Satisfaction was dichotomised as a 'high' vs 'low' rating based on participant response to a visual, 7-point Likert-type scale. RESULTS: 62% (322/517) of febrile patients reported seeking treatment within 24 hours of symptom onset in 2011 compared with 53% (230/434) in 2012 and 42% (339/814) in 2016. Adjusted ORs for reporting a treatment response time <24 hours in the postimplementation surveys were 0.77 (95% CI 0.48 to 1.26) and 0.45 (95% CI 0.31 to 0.65), respectively when compared with the preimplementation period. 53% (230/533) of febrile patients reported 'high' satisfaction with the service received in 2011 compared with 32% (143/449) in 2012 and 35% (278/803) in 2016. Adjusted ORs for reporting high satisfaction in the postimplementation surveys were 0.52 (95% CI 0.32 to 0.85) and 0.65 (95% CI 0.39 to 1.10), respectively when compared with the preimplementation period. CONCLUSION: Nationwide implementation of test-based ACT prescription in Papua New Guinea has increased the likelihood of critical treatment seeking delays and decreased patient satisfaction with the service received.

Understanding and improving access to prompt and effective malaria treatment and care in rural Tanzania: the ACCESS Programme.

BACKGROUND: Prompt access to effective treatment is central in the fight against malaria. However, a variety of interlinked factors at household and health system level influence access to timely and appropriate treatment and care. Furthermore, access may be influenced by global and national health policies. As a consequence, many malaria episodes in highly endemic countries are not treated appropriately. PROJECT: The ACCESS Programme aims at understanding and improving access to prompt and effective malaria treatment and care in a rural Tanzanian setting. The programme's strategy is based on a set of integrated interventions, including social marketing for improved care seeking at community level as well as strengthening of quality of care at health facilities. This is complemented by a project that aims to improve the performance of drug stores. The interventions are accompanied by a comprehensive set of monitoring and evaluation activities measuring the programme's performance and (health) impact. Baseline data demonstrated heterogeneity in the availability of malaria treatment, unavailability of medicines and treatment providers in certain areas as well as quality problems with regard to drugs and services. CONCLUSION: The ACCESS Programme is a combination of multiple complementary interventions with a strong evaluation component. With this approach, ACCESS aims to contribute to the development of a more comprehensive access framework and to inform and support public health professionals and policy-makers in the delivery of improved health services.

Decreased availability of antimalarials in the private sector following the policy change from chloroquine to sulphadoxine-pyrimethamine in the Kilombero Valley, Tanzania.

BACKGROUND: Malaria control strategies emphasize the need for prompt and effective treatment of malaria episodes. To increase treatment efficacy, Tanzania changed its first-line treatment from chloroquine to sulphadoxine-pyrimethamine (SP) in 2001. The effect of this policy change on the availability of antimalarials was studied in rural south-eastern Tanzania. METHODS: In 2001 and 2004, the study area was searched for commercial outlets selling drugs and their stocks were recorded. Household information was obtained from the local Demographic Surveillance System. RESULTS: From 2001 to 2004, the number of general shops stocking drugs increased by 15% and the number of drug stores nearly doubled. However, the proportion of general shops stocking antimalarials dropped markedly, resulting in an almost 50% decrease of antimalarial selling outlets. This led to more households being located farther from a treatment source. In 2004, five out of 25 studied villages with a total population of 13,506 (18%) had neither a health facility, nor a shop as source of malaria treatment. CONCLUSION: While the change to SP resulted in a higher treatment efficacy, it also led to a decreased antimalarial availability in the study area. Although there was no apparent impact on overall antimalarial use, the decline in access may have disproportionately affected the poorest and most remote groups. In view of the imminent policy change to artemisinin-based combination therapy these issues need to be addressed urgently if the benefits of this new class of antimalarials are to be extended to the whole population.

Indifferent to disease: a qualitative investigation of the reasons why some Papua New Guineans who own mosquito nets choose not to use them.

This paper presents findings from a qualitative study designed to explore the reasons why some Papua New Guineans who own mosquito nets choose not to use them, whether on a regular or episodic basis. In-depth interviews (IDIs) were conducted with a sub-sample (n = 44) of participants in a country wide household survey who reported owning or having access to a mosquito net, but not having slept under a mosquito net the night prior to survey. All IDIs were completed between December 2010 and June 2011. Analysis was informed by a general inductive methodology. Multiple impediments to regular mosquito net use were identified by study participants, although all were broadly grouped into the inter-related categories of net-, environmental- or human-factors. Indifference emerged as the most influential impediment towards regular net use presenting as a general attitudinal context in which a majority of participant responses were grounded. A lack of knowledge regarding malaria transmission pathways or the utility of mosquito nets did not appear to underlie this indifference. Rather, the indifference appeared to be rooted in a lack of fear of malaria infection cultivated through lived experience. A wide range of interventions could potentially promote greater mosquito net use amongst this population. However, the basis of any intervention strategy, given the pervasive indifferent attitude towards regular mosquito net use, should be to render individual mosquito net use as easy and as convenient as possible and to promote complementary malaria control strategies where appropriate.