Forecasting Human African Trypanosomiasis Prevalences from Population Screening Data Using Continuous Time Models

To eliminate and eradicate gambiense human African trypanosomiasis (HAT), maximizing the effectiveness of active case finding is of key importance. The progression of the epidemic is largely influenced by the planning of these operations. This paper introduces and analyzes five models for predicting HAT prevalence in a given village based on past observed prevalence levels and past screening activities in that village. Based on the quality of prevalence level predictions in 143 villages in Kwamouth (DRC), and based on the theoretical foundation underlying the models, we consider variants of the Logistic Model—a model inspired by the SIS epidemic model—to be most suitable for predicting HAT prevalence levels. Furthe

Feasibility of eliminating visceral leishmaniasis from the Indian subcontinent: explorations with a set of deterministic age-structured transmission models

textabstractBackground: Visceral leishmaniasis (VL) is a neglected tropical disease transmitted by sandflies. On the Indian subcontinent (ISC), VL is targeted for elimination as a public health problem by 2017. In the context of VL, the elimination target is defined as an annual VL incidence of <1 per 10,000 capita at (sub-)district level. Interventions focus on vector control, surveillance and on diagnosing and treating VL cases. Many endemic areas have not yet achieved optimal control due to logistical, biological as well as technical challenges. We used mathematical modelling to quantify VL transmission dynamics and predict the feasibility of achieving the VL elimination target with current control strategies under varying assumptions about the reservoir of infection in humans. Methods: We developed three deterministic age-structured transmission models with different main reservoirs of infection in humans: asymptomatic infections (model 1), reactivation of infection after initial infection (model 2), and post kala-azar dermal leishmaniasis (PKDL; model 3). For each model, we defined four sub-variants based on different assumptions about the duration of immunity and age-patterns in exposure to sandflies. All 12 model sub-variants were fitted to data from the KalaNet study in Bihar (India) and Nepal, and the best sub-variant was selected per model. Predictions were made for optimal and sub-optimal indoor residual spraying (IRS) effectiveness for three different levels of VL endemicity. Results: Structurally different models explained the KalaNet data equally well. However, the predicted impact of IRS varied substantially between models, such that a conclusion about reaching the VL elimination targets for the ISC heavily depends on assumptions about the main reservoir of infection in humans: asymptomatic cases, recovered (immune) individuals that reactivate, or PKDL cases. Conclusions: Available data on the impact of IRS so far suggest one model is probably closest to reality (model 1). According to this model, elimination of VL (incidence of <1 per 10,000) by 2017 is only feasible in low and medium endemic settings with optimal IRS. In highly endemic settings and settings with sub-optimal IRS, additional interventions will be required

Visceral leishmaniasis: Spatiotemporal heterogeneity and drivers underlying the hotspots in Muzaffarpur, Bihar, India

Background: Despite the overall decrease in visceral leishmaniasis (VL) incidence on the Indian subcontinent, there remain spatiotemporal clusters or ‘hotspots’ of new cases. The characteristics of these hotspots, underlying transmission dynamics, and their importance for shaping control strategies are not yet fully understood and are investigated in this study for a VL endemic area of ~100,000 inhabitants in Bihar, India between 2007–2015. Methodology/Principal findings VL incidence (cases/10,000/year) dropped from 12.3 in 2007 to 0.9 in 2015, which is just below the World Health Organizations’ threshold for elimination as a public health problem. Clustering of VL was assessed between subvillages (hamlets), using multiple geospatial and (spatio)temporal autocorrelation and hotspot analyses. One to three hotspots were identified each year, often persisting for 1–5 successive years with a modal radius of ~500m. The relative risk of having VL was 5–86 times higher for inhabitants of hotspots, compared to those living outside hotspots. Hotspots harbour significantly more households from the two lowest asset quintiles (as proxy for socio-economic status). Overall, children and young adelescents (5–14 years) have the highest risk for VL, but within hotspots and at the start of outbreaks, older age groups (35+ years) show a comparable high risk. Conclusions/Significance: This study demonstrates significant spatiotemporal heterogeneity in VL incidence at subdistrict level. The association between poverty and hotspots confirms that VL is a disease of ‘the poorest of the poor’ and age patterns suggest a potential role of waning immunity as underlying driver of hotspots. The recommended insecticide spraying radius of 500m around detected VL cases corresponds to the modal hotspot radius found in this study. Additional data on immunity and asymptomatic infection, and the development of spatiotemporally explicit transmission models that simulate hotspot dynamics and predict the impact of interventions at the smaller geographical scale will be crucial tools in sustaining elimination

Policy Recommendations From Transmission Modeling for the Elimination of Visceral Leishmaniasis in the Indian Subcontinent.

Background: Visceral leishmaniasis (VL) has been targeted by the World Health Organization (WHO) and 5 countries in the Indian subcontinent for elimination as a public health problem. To achieve this target, the WHO has developed guidelines consisting of 4 phases of different levels of interventions, based on vector control through indoor residual spraying of insecticide (IRS) and active case detection (ACD). Mathematical transmission models of VL are increasingly used for planning and assessing the efficacy of interventions and evaluating the intensity and timescale required to achieve the elimination target. Methods: This paper draws together the key policy-relevant conclusions from recent transmission modeling of VL, and presents new predictions for VL incidence under the interventions recommended by the WHO using the latest transmission models. Results: The model predictions suggest that the current WHO guidelines should be sufficient to reach the elimination target in areas that had medium VL endemicities (up to 5 VL cases per 10000 population per year) prior to the start of interventions. However, additional interventions, such as extending the WHO attack phase (intensive IRS and ACD), may be required to bring forward elimination in regions with high precontrol endemicities, depending on the relative infectiousness of different disease stages. Conclusions: The potential hurdle that asymptomatic and, in particular, post-kala-azar dermal leishmaniasis cases may pose to reaching and sustaining the target needs to be addressed. As VL incidence decreases, the pool of immunologically naive individuals will grow, creating the potential for new outbreaks

Policy Recommendations From Transmission Modeling for the Elimination of Visceral Leishmaniasis in the Indian Subcontinent.

Background: Visceral leishmaniasis (VL) has been targeted by the World Health Organization (WHO) and 5 countries in the Indian subcontinent for elimination as a public health problem. To achieve this target, the WHO has developed guidelines consisting of 4 phases of different levels of interventions, based on vector control through indoor residual spraying of insecticide (IRS) and active case detection (ACD). Mathematical transmission models of VL are increasingly used for planning and assessing the efficacy of interventions and evaluating the intensity and timescale required to achieve the elimination target. Methods: This paper draws together the key policy-relevant conclusions from recent transmission modeling of VL, and presents new predictions for VL incidence under the interventions recommended by the WHO using the latest transmission models. Results: The model predictions suggest that the current WHO guidelines should be sufficient to reach the elimination target in areas that had medium VL endemicities (up to 5 VL cases per 10000 population per year) prior to the start of interventions. However, additional interventions, such as extending the WHO attack phase (intensive IRS and ACD), may be required to bring forward elimination in regions with high precontrol endemicities, depending on the relative infectiousness of different disease stages. Conclusions: The potential hurdle that asymptomatic and, in particular, post-kala-azar dermal leishmaniasis cases may pose to reaching and sustaining the target needs to be addressed. As VL incidence decreases, the pool of immunologically naive individuals will grow, creating the potential for new outbreaks

Long-lasting Insecticidal Nets to Prevent Visceral Leishmaniasis in the Indian Subcontinent; Methodological Lessons Learned from a Cluster Randomised Controlled Trial

In a recent paper, Nagpal et al. voiced concerns about the limited or biased use of scientific evidence to support public health interventions to control neglected tropical diseases (NTDs). Visceral leishmaniasis (VL), also known as kala-azar, is one of the major NTDs and does not escape this problem. Transmission is vector-borne and the Indian subcontinent is the region reporting most of the VL cases worldwide. In this region, the main causative species is Leishmania donovani and Phlebotomus argentipes is the vector. Transmission is considered anthroponotic and peridomestic—occurring at night when female sand flies bite people sleeping inside their house. The World Health Organization and the governments of India, Nepal, and Bangladesh set out in 2005 to eliminate VL from the region by 2015 through a combination of early treatment of cases and vector control. However, while recent advances in diagnostic tools and drugs have significantly improved case management strategies, the available vector control tools against P. argentipes remain limited. The elimination initiative promotes the use of indoor residual spraying (IRS) of households and cattle sheds to reduce vector density, but the evidence underpinning the effectiveness of IRS in this region is scanty. Historical observations show that L. donovani transmission declined concomitantly with dichlorodiphenyltrichloroethane (DDT) spraying during the 1950s–60s to eradicate malaria. In the aftermath of this malaria eradication campaign, very few VL cases were observed in endemic regions until the mid-seventies, when there was resurgence of a VL epidemic in India. To date, there are no randomized trials showing the effect of IRS on the incidence of clinical VL, though some studies showed a reduction in vector density. When the VL elimination initiative was launched in 2005, there were no clear alternatives for IRS as a vector control strategy. Insecticide treated nets (ITNs) were proposed as an alternative or complement to IRS on the basis of analogy arguments regarding their given efficacy against malaria or on data from observational studies suggesting ITNs reduce the risk of VL; but as for IRS, there were no randomized trials evaluating the effect of ITNs on L. donovani transmission. In this context, a number of field studies were conducted in the Indian subcontinent in the past decade to evaluate the effectiveness and impact of ITNs and other vector control tools on VL. Most of these studies have been reviewed in detail in two recent papers. The only two studies evaluating the impact of vector control interventions on clinical outcomes found conflicting results. First, the KALANET project, a cluster randomised controlled trial (CRT) in India and Nepal, showed that mass-distribution of ITNs did not reduce the risk of L. donovani infection or clinical VL. Then, an intervention trial in Bangladesh suggested that widespread bed net impregnation with slow-release insecticide may reduce the frequency of VL. Technical (e.g., type of nets and insecticides, lack of replicas and randomisation in Bangladesh) and biological factors (e.g., insecticide susceptibility and sand fly behaviour) may explain the different results observed. This apparent contradiction raises the question about the role that ITN may play in controlling VL in the Indian subcontinent but has also triggered a lot of discussion on methodology and evidence levels required when evaluating vector control tools for VL. In this paper, we would like to summarise the lessons learned from the KALANET CRT in terms of methodology to inform the generation of future evidence and discuss interpretation of findings against this background

Elimination of visceral leishmaniasis in the Indian subcontinent: a comparison of predictions from three transmission models.

We present three transmission models of visceral leishmaniasis (VL) in the Indian subcontinent (ISC) with structural differences regarding the disease stage that provides the main contribution to transmission, including models with a prominent role of asymptomatic infection, and fit them to recent case data from 8 endemic districts in Bihar, India. Following a geographical cross-validation of the models, we compare their predictions for achieving the WHO VL elimination targets with ongoing treatment and vector control strategies. All the transmission models suggest that the WHO elimination target (<1 new VL case per 10,000 capita per year at sub-district level) is likely to be met in Bihar, India, before or close to 2020 in sub-districts with a pre-control incidence of 10 VL cases per 10,000 people per year or less, when current intervention levels (60% coverage of indoor residual spraying (IRS) of insecticide and a delay of 40days from onset of symptoms to treatment (OT)) are maintained, given the accuracy and generalizability of the existing data regarding incidence and IRS coverage. In settings with a pre-control endemicity level of 5/10,000, increasing the effective IRS coverage from 60 to 80% is predicted to lead to elimination of VL 1-3 years earlier (depending on the particular model), and decreasing OT from 40 to 20days to bring elimination forward by approximately 1year. However, in all instances the models suggest that L. donovani transmission will continue after 2020 and thus that surveillance and control measures need to remain in place until the longer-term aim of breaking transmission is achieved

Protocol, rationale and design of PEOPLE (Post ExpOsure Prophylaxis for LEprosy in the Comoros and Madagascar): A cluster randomized trial on effectiveness of different modalities of implementation of post-exposure prophylaxis of leprosy contacts

Background: Leprosy is an ancient infectious disease with a global annual incidence that has plateaued above 200,000 new cases since over a decade. New strategies are required to overcome this stalemate. Post-exposure prophylaxis (PEP) with a single dose of Rifampicin (SDR) has conditionally been recommended by the World Health Organization (WHO), based on a randomized-controlled-Trial in Bangladesh. More evidence is required. The Post ExpOsure Prophylaxis for Leprosy (PEOPLE) trial will assess effectiveness of different modalities of PEP on the Comoros and Madagascar. Methods: PEOPLE is a cluster-randomized trial with villages selected on previous leprosy-incidence and randomly allocated to four arms. Four annual door-To-door surveys will be performed in all arms. All consenting permanent residents will be screened for leprosy. Leprosy patients will be treated according to international guidelines and eligible contacts will be provided with SDR-PEP. Arm-1 is the comparator in which no PEP will be provided. In arms 2, 3 and 4, SDR-PEP will be provided at double the regular dose (20 mg/kg) to eligible contacts aged two years and above. In arm 2 all household-members of incident leprosy patients are eligible. In arm 3 not only household-members but also neighbourhood contacts living within 100-m of an incident case are eligible. In arm 4 such neighbourhood contacts are only eligible if they test positive to anti-PGL-I, a serological marker. Incidence rate ratios calculated between the comparator arm 1 and each of the intervention arms will constitute the primary outcome. Discussion: Different trials on PEP have yielded varying results. The pivotal COLEP trial in Bangladesh showed a 57% reduction in incidence over a two-year period post-intervention without any rebound in the following years. A study in a high-incidence setting in Indonesia showed no effect of PEP provided to close contacts but a major effect of PEP provided as a blanket measure to an entire island population. High background incidence could be the reason of the lack of effect of PEP provided to individual contacts. The PEOPLE trial will assess effectiveness of PEP in a high incidence setting and will compare three different approaches, to identify who benefits most from PEP. Trial registration: Clinicaltrials.Gov. NCT03662022. Initial Protocol Version 1.2, 27-Aug-2018

Visceral leishmaniasis: Spatiotemporal heterogeneity and drivers underlying the hotspots in Muzaffarpur, Bihar, India

BACKGROUND: Despite the overall decrease in visceral leishmaniasis (VL) incidence on the Indian subcontinent, there remain spatiotemporal clusters or 'hotspots' of new cases. The characteristics of these hotspots, underlying transmission dynamics, and their importance for shaping control strategies are not yet fully understood and are investigated in this study for a VL endemic area of ~100,000 inhabitants in Bihar, India between 2007-2015. METHODOLOGY/PRINCIPAL FINDINGS: VL incidence (cases/10,000/year) dropped from 12.3 in 2007 to 0.9 in 2015, which is just below the World Health Organizations' threshold for elimination as a public health problem. Clustering of VL was assessed between subvillages (hamlets), using multiple geospatial and (spatio)temporal autocorrelation and hotspot analyses. One to three hotspots were identified each year, often persisting for 1-5 successive years with a modal radius of ~500m. The relative risk of having VL was 5-86 times higher for inhabitants of hotspots, compared to those living outside hotspots. Hotspots harbour significantly more households from the two lowest asset quintiles (as proxy for socio-economic status). Overall, children and young adelescents (5-14 years) have the highest risk for VL, but within hotspots and at the start of outbreaks, older age groups (35+ years) show a comparable high risk. CONCLUSIONS/SIGNIFICANCE: This study demonstrates significant spatiotemporal heterogeneity in VL incidence at subdistrict level. The association between poverty and hotspots confirms that VL is a disease of 'the poorest of the poor' and age patterns suggest a potential role of waning immunity as underlying driver of hotspots. The recommended insecticide spraying radius of 500m around detected VL cases corresponds to the modal hotspot radius found in this study. Additional data on immunity and asymptomatic infection, and the development of spatiotemporally explicit transmission models that simulate hotspot dynamics and predict the impact of interventions at the smaller geographical scale will be crucial tools in sustaining elimination

Adherence to miltefosine treatment for visceral leishmaniasis under routine conditions in Nepal

To assess patient adherence to unsupervised single-drug miltefosine treatment for visceral leishmaniasis and to identify the factors influencing adherence. This is a prospective cohort study of 171 patients with Visceral leishmaniasis (VL) in three healthcare settings in Nepal. Adherence was assessed through pill count, checking of treatment cards and adherence questionnaires, as well as miltefosine concentration measurements at the end of treatment. Poor adherence was defined as less than 90% of required capsules taken. Patient adherence to miltefosine was 83%. Predictors of adherence were being the male sex (OR = 2.60, 95% CI 1.02-6.67) and knowing the duration of treatment (OR = 3.05, 95% CI 1.16-8.04). Adherence was also better for patients who were literate and knew the side effects of treatment. Gastrointestinal side effects and negligence after the resolution of clinical symptoms of VL were the main reasons for poor adherence. Poor adherence was associated (though not statistically significant) with future relapse. Effective counselling during the treatment, a short take-home message on VL and on side effects and action of miltefosine, and follow-up visits are the best way to prevent poor adherence. Single end-of-treatment measurements of miltefosine concentrations as objective assessment of adherence would only be useful in addition to the subjective assessments when substantial doses of miltefosine have been misse