Livestock, pathogens, vectors, and their environment: A causal inference-based approach to estimating the pathway-specific effect of livestock on human African trypanosomiasis risk.

Livestock are important reservoirs for many zoonotic diseases, however the effects of livestock on human and environmental health extend well beyond direct disease transmission. In this retrospective ecological cohort study we use pre-existing data and the parametric g-formula, which imputes potential outcomes to quantify mediation, to estimate three hypothesized mechanisms by which livestock can influence human African trypanosomiasis (HAT) risk: the reservoir effect, where infected cattle and pigs are a source of infection to humans; the zooprophylactic effect, where preference for livestock hosts exhibited by the tsetse fly vector of HAT means that their presence protects humans from infection; and the environmental change effect, where livestock keeping activities modify the environment in such a way that habitat suitability for tsetse flies, and in turn human infection risk, is reduced. We conducted this study in four high burden countries: at the point level in Uganda, Malawi, and Democratic Republic of Congo (DRC), and at the county level in South Sudan. Our results indicate cattle and pigs play a reservoir role for the rhodesiense form (rHAT) in Uganda (rate ratio (RR) 1.68, 95% CI 0.84, 2.82 for cattle; RR 2.16, 95% CI 1.18, 3.05 for pigs), however zooprophylaxis outweighs this effect for rHAT in Malawi (RR 0.85, 95% CI 0.68, 1.00 for cattle, RR 0.38, 95% CI 0.21, 0.69 for pigs). For the gambiense form (gHAT) we found evidence that pigs may be a competent reservoir (RR 1.15, 95% CI 0.92, 1.72 in Uganda; RR 1.25, 95% CI 1.11, 1.42 in DRC). Statistical significance was reached for rHAT in Malawi (pigs and cattle) and Uganda (pigs only) and for gHAT in DRC (pigs and cattle). We did not find compelling evidence of an environmental change effect (all effect sizes close to 1).

A modelling assessment of short- and medium-term risks of programme interruptions for gambiense human African trypanosomiasis in the DRC.

Gambiense human African trypanosomiasis (gHAT) is a deadly vector-borne, neglected tropical disease found in West and Central Africa targeted for elimination of transmission (EoT) by 2030. The recent pandemic has illustrated how it can be important to quantify the impact that unplanned disruption to programme activities may have in achieving EoT. We used a previously developed model of gHAT fitted to data from the Democratic Republic of the Congo, the country with the highest global case burden, to explore how interruptions to intervention activities, due to e.g. COVID-19, Ebola or political instability, could impact progress towards EoT and gHAT burden. We simulated transmission and reporting dynamics in 38 regions within Kwilu, Mai Ndombe and Kwango provinces under six interruption scenarios lasting for nine or twenty-one months. Included in the interruption scenarios are the cessation of active screening in all scenarios and a reduction in passive detection rates and a delay or suspension of vector control deployments in some scenarios. Our results indicate that, even under the most extreme 21-month interruption scenario, EoT is not predicted to be delayed by more than one additional year compared to the length of the interruption. If existing vector control deployments continue, we predict no delay in achieving EoT even when both active and passive screening activities are interrupted. If passive screening remains as functional as in 2019, we expect a marginal negative impact on transmission, however this depends on the strength of passive screening in each health zone. We predict a pronounced increase in additional gHAT disease burden (morbidity and mortality) in many health zones if both active and passive screening were interrupted compared to the interruption of active screening alone. The ability to continue existing vector control during medical activity interruption is also predicted to avert a moderate proportion of disease burden.

Efficacy and safety of acoziborole in patients with human African trypanosomiasis caused by Trypanosoma brucei gambiense: a multicentre, open-label, single-arm, phase 2/3 trial.

BACKGROUND: Human African trypanosomiasis caused by Trypanosoma brucei gambiense (gambiense HAT) in patients with late-stage disease requires hospital admission to receive nifurtimox-eflornithine combination therapy (NECT). Fexinidazole, the latest treatment that has been recommended by WHO, also requires systematic admission to hospital, which is problematic in areas with few health-care resources. We aim to assess the safety and efficacy of acoziborole in adult and adolescent patients with gambiense HAT. METHODS: This multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score greater than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955. FINDINGS: Between Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2-97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1-99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%. INTERPRETATION: Given the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030. FUNDING: Bill & Melinda Gates Foundation, UK Aid, Federal Ministry of Education and Research, Swiss Agency for Development and Cooperation, Médecins Sans Frontières, Dutch Ministry of Foreign Affairs, Norwegian Agency for Development Cooperation, Norwegian Ministry of Foreign Affairs, the Stavros Niarchos Foundation, Spanish Agency for International Development Cooperation, and the Banco Bilbao Vizcaya Argentaria Foundation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Trypanosome spliced leader RNA for diagnosis of acoziborole treatment outcome in gambiense human African trypanosomiasis: A longitudinal follow-up study.

BACKGROUND: Detection of spliced leader (SL)-RNA allows sensitive diagnosis of gambiense human African trypanosomiasis (HAT). We investigated its diagnostic performance for treatment outcome assessment. METHODS: Blood and cerebrospinal fluid (CSF) from a consecutive series of 97 HAT patients, originating from the Democratic Republic of the Congo, were prospectively collected before treatment with acoziborole, and during 18 months of longitudinal follow-up after treatment. For treatment outcome assessment, SL-RNA detection was compared with microscopic trypanosome detection and CSF white blood cell count. The trial was registered under NCT03112655 in clinicaltrials.gov. FINDINGS: Before treatment, respectively 94.9% (92/97; CI 88.5-97.8%) and 67.7% (65/96; CI 57.8-76.2%) HAT patients were SL-RNA positive in blood or CSF. During follow-up, one patient relapsed with trypanosomes observed at 18 months, and was SL-RNA positive in blood and CSF at 12 months, and CSF positive at 18 months. Among cured patients, one individual tested SL-RNA positive in blood at month 12 (Specificity 98.9%; 90/91; CI 94.0-99.8%) and 18 (Specificity 98.9%; 88/89; CI 93.9-99.8%). INTERPRETATION: SL-RNA detection for HAT treatment outcome assessment shows ≥98.9% specificity in blood and 100% in CSF, and may detect relapses without lumbar puncture. FUNDING: The DiTECT-HAT project is part of the EDCTP2 programme, supported by Horizon 2020, the European Union Funding for Research and Innovation (grant number DRIA-2014-306-DiTECT-HAT).

The effect of livestock density on Trypanosoma brucei gambiense and T. b. rhodesiense: A causal inference-based approach.

Domestic and wild animals are important reservoirs of the rhodesiense form of human African trypanosomiasis (rHAT), however quantification of this effect offers utility for deploying non-medical control activities, and anticipating their success when wildlife are excluded. Further, the uncertain role of animal reservoirs-particularly pigs-threatens elimination of transmission (EOT) targets set for the gambiense form (gHAT). Using a new time series of high-resolution cattle and pig density maps, HAT surveillance data collated by the WHO Atlas of HAT, and methods drawn from causal inference and spatial epidemiology, we conducted a retrospective ecological cohort study in Uganda, Malawi, Democratic Republic of the Congo (DRC) and South Sudan to estimate the effect of cattle and pig density on HAT risk. For rHAT, we found a positive effect for cattle (RR 1.61, 95% CI 0.90, 2.99) and pigs (RR 2.07, 95% CI 1.15, 2.75) in Uganda, and a negative effect for cattle (RR 0.88, 95% CI 0.71, 1.10) and pigs (RR 0.42, 95% CI 0.23, 0.67) in Malawi. For gHAT we found a negative effect for cattle in Uganda (RR 0.88, 95% CI 0.50, 1.77) and South Sudan (RR 0.63, 95% CI 0.54, 0.77) but a positive effect in DRC (1.17, 95% CI 1.04, 1.32). For pigs, we found a positive gHAT effect in both Uganda (RR 2.02, 95% CI 0.87, 3.94) and DRC (RR 1.23, 95% CI 1.10, 1.37), and a negative association in South Sudan (RR 0.66, 95% CI 0.50, 0.98). These effects did not reach significance for the cattle-rHAT effect in Uganda or Malawi, or the cattle-gHAT and pig-gHAT effects in Uganda. While ecological bias may drive the findings in South Sudan, estimated E-values and simulation studies suggest unmeasured confounding and underreporting are unlikely to explain our findings in Malawi, Uganda, and DRC. Our results suggest cattle and pigs may be important reservoirs of rHAT in Uganda but not Malawi, and that pigs-and possibly cattle-may be gHAT reservoirs.

Modelling to infer the role of animals in gambiense human African trypanosomiasis transmission and elimination in the DRC.

Gambiense human African trypanosomiasis (gHAT) has been targeted for elimination of transmission (EoT) to humans by 2030. Whilst this ambitious goal is rapidly approaching, there remain fundamental questions about the presence of non-human animal transmission cycles and their potential role in slowing progress towards, or even preventing, EoT. In this study we focus on the country with the most gHAT disease burden, the Democratic Republic of Congo (DRC), and use mathematical modelling to assess whether animals may contribute to transmission in specific regions, and if so, how their presence could impact the likelihood and timing of EoT. By fitting two model variants-one with, and one without animal transmission-to the human case data from 2000-2016 we estimate model parameters for 158 endemic health zones of the DRC. We evaluate the statistical support for each model variant in each health zone and infer the contribution of animals to overall transmission and how this could impact predicted time to EoT. We conclude that there are 24/158 health zones where there is substantial to decisive statistical support for some animal transmission. However-even in these regions-we estimate that animals would be extremely unlikely to maintain transmission on their own. Animal transmission could hamper progress towards EoT in some settings, with projections under continuing interventions indicating that the number of health zones expected to achieve EoT by 2030 reduces from 68/158 to 61/158 if animal transmission is included in the model. With supplementary vector control (at a modest 60% tsetse reduction) added to medical screening and treatment interventions, the predicted number of health zones meeting the goal increases to 147/158 for the model including animal transmission. This is due to the impact of vector reduction on transmission to and from all hosts.

Health work and skills in the last mile of disease elimination. Experiences from sleeping sickness health workers in South Sudan and DR Congo.

Human African trypanosomiasis (HAT) is considered a highly promising candidate for elimination within the next decade. This paper argues that the experiential knowledge of frontline health workers will be critical to achieve this goal. Interviews are used to explore the ways in which HAT workers understand, maintain, and adjust their skills amidst global and national challenges. We contrast two cases: South Sudan where HAT expertise is scattered and has been repeatedly rebuilt, and the Democratic Republic of Congo (DRC) where specialised mobile detection teams have pro-actively tested people at risk for almost a century. We describe HAT careers where skills are built through participation in HAT technology trials and screening programmes; in the DRC expertise is also supported through formal rotations in screening teams and HAT referral centres for new health workers. As cases fade, de-skilling is a real threat as awareness of populations and authorities diminishes and previously vertical programmes evolve, re-configuring professional development and career paths and associated opportunities for HAT practice. To avoid repeating the mistakes of the 1960s, when elimination also seemed close at hand, we need to recognise that the 'last mile' of elimination hinges on protecting the fragile expertise of frontline health workers.

Quantifying epidemiological drivers of gambiense human African Trypanosomiasis across the Democratic Republic of Congo.

Gambiense human African trypanosomiasis (gHAT) is a virulent disease declining in burden but still endemic in West and Central Africa. Although it is targeted for elimination of transmission by 2030, there remain numerous questions about the drivers of infection and how these vary geographically. In this study we focus on the Democratic Republic of Congo (DRC), which accounted for 84% of the global case burden in 2016, to explore changes in transmission across the country and elucidate factors which may have contributed to the persistence of disease or success of interventions in different regions. We present a Bayesian fitting methodology, applied to 168 endemic health zones (∼100,000 population size), which allows for calibration of a mechanistic gHAT model to case data (from the World Health Organization HAT Atlas) in an adaptive and automated framework. It was found that the model needed to capture improvements in passive detection to match observed trends in the data within former Bandundu and Bas Congo provinces indicating these regions have substantially reduced time to detection. Health zones in these provinces generally had longer burn-in periods during fitting due to additional model parameters. Posterior probability distributions were found for a range of fitted parameters in each health zone; these included the basic reproduction number estimates for pre-1998 (R0) which was inferred to be between 1 and 1.14, in line with previous gHAT estimates, with higher median values typically in health zones with more case reporting in the 2000s. Previously, it was not clear whether a fall in active case finding in the period contributed to the declining case numbers. The modelling here accounts for variable screening and suggests that underlying transmission has also reduced greatly-on average 96% in former Equateur, 93% in former Bas Congo and 89% in former Bandundu-Equateur and Bandundu having had the highest case burdens in 2000. This analysis also sets out a framework to enable future predictions for the country.

Assessing the impact of aggregating disease stage data in model predictions of human African trypanosomiasis transmission and control activities in Bandundu province (DRC).

Since the turn of the century, the global community has made great progress towards the elimination of gambiense human African trypanosomiasis (HAT). Elimination programs, primarily relying on screening and treatment campaigns, have also created a rich database of HAT epidemiology. Mathematical models calibrated with these data can help to fill remaining gaps in our understanding of HAT transmission dynamics, including key operational research questions such as whether integrating vector control with current intervention strategies is needed to achieve HAT elimination. Here we explore, via an ensemble of models and simulation studies, how including or not disease stage data, or using more updated data sets affect model predictions of future control strategies.

Whose Elimination? Frontline Workers' Perspectives on the Elimination of the Human African Trypanosomiasis and Its Anticipated Consequences.

While academic literature has paid careful attention to the technological efforts-drugs, tests, and tools for vector control-deployed to eliminate Gambiense Human African Trypanosomiasis (HAT), the human resources and health systems dimensions of elimination are less documented. This paper analyses the perspectives and experiences of frontline nurses, technicians, and coordinators who work for the HAT programme in the former province of Bandundu in the Democratic Republic of the Congo, at the epidemic's very heart. The research is based on 21 semi-structured interviews conducted with frontline workers in February 2018. The results highlight distinctive HAT careers as well as social elevation through specialised work. Frontline workers are concerned about changes in active screening strategies and the continued existence of the vector, which lead them to question the possibility of imminent elimination. Managers seem to anticipate a post-HAT situation and prepare for the employment of their staff; most workers see their future relatively confidently, as re-allocated to non-vertical units. The findings suggest concrete pathways for improving the effectiveness of elimination efforts: improving active screening through renewed engagements with local leaders, conceptualising horizontal integration in terms of human resources mobility, and investing more in detection and treatment activities (besides innovation).

Screening Strategies for a Sustainable Endpoint for Gambiense Sleeping Sickness.

BACKGROUND: Gambiense human African trypanosomiasis ([gHAT] sleeping sickness) is a vector-borne disease that is typically fatal without treatment. Intensified, mainly medical-based, interventions in endemic areas have reduced the occurrence of gHAT to historically low levels. However, persistent regions, primarily in the Democratic Republic of Congo (DRC), remain a challenge to achieving the World Health Organization's goal of global elimination of transmission (EOT). METHODS: We used stochastic models of gHAT transmission fitted to DRC case data and explored patterns of regional reporting and extinction. The time to EOT at a health zone scale (~100 000 people) and how an absence of reported cases informs about EOT was quantified. RESULTS: Regional epidemiology and level of active screening (AS) both influenced the predicted time to EOT. Different AS cessation criteria had similar expected infection dynamics, and recrudescence of infection was unlikely. However, whether EOT has been achieved when AS ends is critically dependent on the stopping criteria. Two or three consecutive years of no detected cases provided greater confidence of EOT compared with a single year (~66%-75% and ~82%-84% probability of EOT, respectively, compared with 31%-51%). CONCLUSIONS: Multiple years of AS without case detections is a valuable measure to assess the likelihood that the EOT target has been met locally.

The Flipside of Eradicating a Disease; Human African Trypanosomiasis in a Woman in Rural Democratic Republic of Congo: A Case Report.

Human African Trypanosomiasis (HAT) is a neglected disease caused by the protozoan parasites Trypanosoma brucei and transmitted by tsetse flies that progresses in two phases. Symptoms in the first phase include fever, headaches, pruritus, lymphadenopathy, and in certain cases, hepato- and splenomegaly. Neurological disorders such as sleep disorder, aggressive behavior, logorrhea, psychotic reactions, and mood changes are signs of the second stage of the disease. Diagnosis follows complex algorithms, including serological testing and microscopy. Our case report illustrates the course of events of a 41-year old woman with sleep disorder, among other neurological symptoms, whose diagnosis was made seven months after the onset of symptoms. The patient had consulted two different hospitals in Kinshasa and was on the verge of being discharged from a third due to negative laboratory test results. This case report highlights the challenges that may arise when a disease is on the verge of eradication.

Village-scale persistence and elimination of gambiense human African trypanosomiasis.

Gambiense human African trypanosomiasis (gHAT) is one of several neglected tropical diseases that is targeted for elimination by the World Health Organization. Recent years have seen a substantial decline in the number of globally reported cases, largely driven by an intensive process of screening and treatment. However, this infection is highly focal, continuing to persist at low prevalence even in small populations. Regional elimination, and ultimately global eradication, rests on understanding the dynamics and persistence of this infection at the local population scale. Here we develop a stochastic model of gHAT dynamics, which is underpinned by screening and reporting data from one of the highest gHAT incidence regions, Kwilu Province, in the Democratic Republic of Congo. We use this model to explore the persistence of gHAT in villages of different population sizes and subject to different patterns of screening. Our models demonstrate that infection is expected to persist for long periods even in relatively small isolated populations. We further use the model to assess the risk of recrudescence following local elimination and consider how failing to detect cases during active screening events informs the probability of elimination. These quantitative results provide insights for public health policy in the region, particularly highlighting the difficulties in achieving and measuring the 2030 elimination goal.