Safety and efficacy of paromomycin/miltefosine/liposomal amphotericin B combinations for the treatment of post-kala-azar dermal leishmaniasis in Sudan: A phase II, open label, randomized, parallel arm study.

BACKGROUND: Treatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the limitations of current therapies, namely toxicity and long hospitalization. We assessed the safety and efficacy of miltefosine combined with paromomycin and liposomal amphotericin B (LAmB) for the treatment of PKDL in Sudan. METHODOLOGY/PRINCIPAL FINDINGS: An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with persistent (stable or progressive disease for ≥ 6 months) or grade 3 PKDL, aged 6 to ≤ 60 years in Sudan. The median age was 9.0 years (IQR 7.0-10.0y) and 87% of patients were ≤12 years old. Patients were randomly assigned to either daily intra-muscular paromomycin (20mg/kg, 14 days) plus oral miltefosine (allometric dose, 42 days)-PM/MF-or LAmB (total dose of 20mg/kg, administered in four injections in week one) and oral miltefosine (allometric dose, 28 days)-LAmB/MF. The primary endpoint was a definitive cure at 12 months after treatment onset, defined as clinical cure (100% lesion resolution) and no additional PKDL treatment between end of therapy and 12-month follow-up assessment. 104/110 patients completed the trial. Definitive cure at 12 months was achieved in 54/55 (98.2%, 95% CI 90.3-100) and 44/55 (80.0%, 95% CI 70.2-91.9) of patients in the PM/MF and AmB/MF arms, respectively, in the mITT set (all randomized patients receiving at least one dose of treatment; in case of error of treatment allocation, the actual treatment received was used in the analysis). No SAEs or deaths were reported, and most AEs were mild or moderate. At least one adverse drug reaction (ADR) was reported in 13/55 (23.6%) patients in PM/MF arm and 28/55 (50.9%) in LAmB/MF arm, the most frequent being miltefosine-related vomiting and nausea, and LAmB-related hypokalaemia; no ocular or auditory ADRs were reported. CONCLUSIONS/SIGNIFICANCE: The PM/MF regimen requires shorter hospitalization than the currently recommended 60-90-day treatment, and is safe and highly efficacious, even for patients with moderate and severe PKDL. It can be administered at primary health care facilities, with LAmB/MF as a good alternative. For future VL elimination, we need new, safe oral therapies for all patients with PKDL. TRIAL REGISTRATION: ClinicalTrials.gov NCT03399955, https://clinicaltrials.gov/study/NCT03399955 ClinicalTrials.gov ClinicalTrials.gov.

Host preference and human blood index of Phlebotomus orientalis, an exophilic sand fly vector of visceral leishmaniasis in eastern Sudan.

Visceral leishmaniasis (VL, kala azar), caused by Leishmania donovani, transmitted by Phlebotomus orientalis, is a serious systemic disease that causes high morbidity and mortality rates in Sudan and other parts of East Africa and the world. Despite progress in understanding the epidemiology of the disease in East Africa, little is known about the host preference of P. orientalis in kala azar endemic villages of Sudan, which have some of the highest VL incidence rates in the world. The present study used host choice experiments and blood-meal identification approaches to determine the host preference of P. orientalis in kala azar endemic villages in Gedarif state, eastern Sudan. In the host choice experiment, tent traps were used to compare the attractiveness of cows, donkeys, sheep and goats for host-seeking P. orientalis. In the blood-meal identification study, blood-fed P. orientalis females, captured inside houses and peri-domestic habitats, were subjected to molecular typing using cytochrome b gene (cyt b) amplification and sequence analysis. Cows and donkeys were the most attractive to blood-seeking P. orientalis, followed by goats. Similarly, the blood-meal analysis of P. orientalis showed that the vector preferentially feeds on cows, followed by donkeys, humans and goats. The human blood index of P. orientalis was 19.4% (42/216), indicating a high zoophilic habit of the vector, both inside and outside the houses. Although the order of host preference varied by location, it was clear that cows are the most preferred host of P. orientalis in the area. Results are discussed in relation to the role of domestic/livestock animals in VL zoopotentiation and zooprophylaxis. Inference is made on the potential impact of insecticide treatment of cows in control of the vector and the transmission of VL in Sudan and other parts of East Africa.

Social determinants of visceral leishmaniasis elimination in Eastern Africa.

Visceral leishmaniasis is a vector-borne, protozoan disease with severe public health implications. Following the successful implementation of an elimination programme in South Asia, there is now a concerted endeavour to replicate these efforts in Eastern Africa based on the five essential elimination pillars of case management, integrated vector management, effective surveillance, social mobilisation and operational research. This article highlights how key social determinants (SD) of health (poverty, sociocultural factors and gender, housing and clustering, migration and the healthcare system) operate at five different levels (socioeconomic context and position, differential exposure, differential vulnerability, differential outcomes and differential consequences). These SD should be considered within the context of increasing the success of the five-pillar elimination programme and reducing inequity in health.

Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial.

BACKGROUND: This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa. METHODS: An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months. RESULTS: Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, -7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug-related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults. CONCLUSIONS: PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa. CLINICAL TRIALS REGISTRATION: NCT03129646.

Assessment of pan-Leishmania detection by recombinase polymerase amplification assay.

The spread of vector habitats along with increasing human mobility can introduce atypical Leishmania species and hence can challenge existing diagnostic practices for rapid detection of active infection with species outside the narrow target range. Here we assessed the pan-Leishmania detection ability of isothermal recombinase polymerase amplification (RPA) assays targeting 18S rRNA gene, cathepsin L-like cysteine proteinase B (Cpb) gene, and kinetoplast minicircle DNA (kDNA) regions. While the lowest limit of detection of the 18S rRNA-RPA and Cpb-RPA assays were estimated as 12 and 17 standard DNA molecules, respectively, both assays could amplify genomic DNA of 7 pathogenic Leishmania species. Evaluation of 18S rRNA-RPA and our previously developed kDNA-RPA assays on 70 real-time PCR-positive leishmaniasis samples of varying pathologies resulted in sensitivity rates of 35.71% and 88.57%, respectively, while the combined sensitivity was 98.57%. Combinatorial application of 18S rRNA-RPA and kDNA-RPA assays can be recommended for further diagnostic assessments.

Towards the elimination of visceral leishmaniasis as a public health problem in east Africa: reflections on an enhanced control strategy and a call for action.

East Africa is the world region most affected by visceral leishmaniasis, accounting for 45% of cases globally that were reported to WHO in 2018, with an annual incidence that is only slightly decreasing. Unlike southeast Asia, east Africa does not have a regional approach to achieving elimination of visceral leishmaniasis as a public health problem. The goal of the WHO 2021-30 Neglected Tropical Diseases road map is to reduce mortality caused by the disease to less than 1%. To achieve this goal in east Africa, it will be necessary to roll out diagnosis and treatment at the primary health-care level and implement evidence-based personal protection methods and measures to reduce human-vector contact. Investment and collaboration to develop the necessary tools are scarce. In this Health Policy paper, we propose a strategic framework for a coordinated regional approach in east Africa for the elimination of visceral leishmaniasis as a public health problem.

Elevated Anti-SARS-CoV-2 Antibodies and IL-6, IL-8, MIP-1ß, Early Predictors of Severe COVID-19.

Viral and host immune kinetics during acute COVID-19 and after remission of acute symptoms need better characterization. SARS-CoV-2 RNA, anti-SARS-CoV-2 IgA, IgM, and IgG antibodies, and proinflammatory cytokines were measured in sequential samples from hospitalized COVID-19 patients during acute infection and six months following diagnosis. Twenty four laboratory confirmed COVID-19 patients with mild/moderate and severe COVID-19 were included. Most were males (83%) with a median age of 61 years. Twenty one percent were admitted to the intensive care unit (ICU) and eight of them (33.3%) met the criteria for severe COVID-19 disease. A delay in SARS-CoV-2 levels' decline during the first six days of follow up, and viral load persistence until month 3 were related to severe COVID-19, but not viral load levels at the diagnosis. Higher levels of anti-SARS-CoV-2 IgA, IgM, IgG and the cytokines IL-6, IL-8 and MIP-1ß at the diagnosis time were related to the severe COVID-19 outcome. Higher levels of MIP-1ß, IL-1ß, MIP-1α and IFN-γ were observed at month 1 and 3 during mild/moderate disease, compared to severe COVID-19. IgG persisted at low levels after six months of diagnosis. In conclusion, higher concentrations of IgA, IgM, and IgG, and IL-6, IL-8 and MIP-1ß are identified as early predictors of COVID-19 severity, whereas no significant association is found between baseline SARS-COV-2 viral load and COVID-19 severity.

In Vitro Susceptibility to Miltefosine of Leishmania infantum (syn. L. chagasi) Isolates from Different Geographical Areas in Brazil.

Treatment of visceral leishmaniasis in Brazil still relies on meglumine antimoniate, with less than ideal efficacy and safety, making new therapeutic tools an urgent need. The oral drug miltefosine was assayed in a phase II clinical trial in Brazil with cure rates lower than previously demonstrated in India. The present study investigated the susceptibility to miltefosine in 73 Brazilian strains of Leishmania infantum from different geographic regions, using intracellular amastigote and promastigote assays. The EC50 for miltefosine of 13 of these strains evaluated in intracellular amastigotes varied between 1.41 and 4.57 µM. The EC50 of the 73 strains determined in promastigotes varied between 5.89 and 23.7 µM. No correlation between in vitro miltefosine susceptibility and the presence of the miltefosine sensitive locus was detected among the tested strains. The relatively low heterogeneity in miltefosine susceptibility observed for the 73 strains tested in this study suggests the absence of decreased susceptibility to miltefosine in Brazilian L. infantum and does not exclude future clinical evaluation of miltefosine for VL treatment in Brazil.

Outdoor Residual Insecticide Spraying (ODRS), a New Approach for the Control of the Exophilic Vectors of Human Visceral Leishmaniasis: Phlebotomus orientalis in East Africa.

Visceral Leishmaniasis (VL) due to Leishmania donovani is a neglected protozoan parasitic disease in humans, which is usually fatal if untreated. Phlebotomus orientalis, the predominant VL vector in East Africa, is a highly exophilic/exophagic species that poses a major challenge to current Integrated Vector Management (IVM). Here we report results of pilot studies conducted in rural villages in Gedarif state, Sudan, to evaluate outdoor residual spraying of 20mg active ingredient (a.i.) /m2 deltamethrin insecticide applied to the characteristic household compound boundary reed fence and to the outside of household buildings (Outdoor Residual Insecticide Spraying, ODRS), and as an alternative, spraying restricted to the boundary fence only (Restricted Outdoor Residual Insecticide Spraying, RODRS). Four to six clusters of 20 households were assigned to insecticide treatments or control in three experiments. Changes in sand fly numbers were monitored over 2,033 trap-nights over 43-76 days follow-up in four sentinel houses per cluster relative to unsprayed control clusters. Sand fly numbers were monitored by sticky traps placed on the ground on the inside ("outdoor") and the outside ("peridomestic") of the boundary fence, and by CDC light traps suspended outdoors in the household compound. The effects of ODRS on sand fly numbers inside sleeping huts were monitored by insecticide knockdown. After a single application, ODRS reduced P. orientalis abundance by 83%-99% in outdoor and peridomestic trap locations. ODRS also reduced numbers of P. orientalis found resting inside sleeping huts. RODRS reduced outdoor and peridomestic P. orientalis by 60%-88%. By direct comparison, RODRS was 58%-100% as effective as ODRS depending on the trapping method. These impacts were immediate on intervention and persisted during follow-up, representing a large fraction of the P. orientalis activity season. Relative costs of ODRS and RODRS delivery were $5.76 and $3.48 per household, respectively. The study demonstrates the feasibility and high entomological efficacy of ODRS and RODRS, and the expected low costs relative to current IVM practises. These methods represent novel sand fly vector control tools against predominantly exophilic/exophagic sand fly vectors, aimed to lower VL burdens in Sudan, with potential application in other endemic regions in East Africa.

Inferring transmission trees to guide targeting of interventions against visceral leishmaniasis and post-kala-azar dermal leishmaniasis.

Understanding of spatiotemporal transmission of infectious diseases has improved significantly in recent years. Advances in Bayesian inference methods for individual-level geo-located epidemiological data have enabled reconstruction of transmission trees and quantification of disease spread in space and time, while accounting for uncertainty in missing data. However, these methods have rarely been applied to endemic diseases or ones in which asymptomatic infection plays a role, for which additional estimation methods are required. Here, we develop such methods to analyze longitudinal incidence data on visceral leishmaniasis (VL) and its sequela, post-kala-azar dermal leishmaniasis (PKDL), in a highly endemic community in Bangladesh. Incorporating recent data on VL and PKDL infectiousness, we show that while VL cases drive transmission when incidence is high, the contribution of PKDL increases significantly as VL incidence declines (reaching 55% in this setting). Transmission is highly focal: 85% of mean distances from inferred infectors to their secondary VL cases were <300 m, and estimated average times from infector onset to secondary case infection were <4 mo for 88% of VL infectors, but up to 2.9 y for PKDL infectors. Estimated numbers of secondary cases per VL and PKDL case varied from 0 to 6 and were strongly correlated with the infector's duration of symptoms. Counterfactual simulations suggest that prevention of PKDL could have reduced overall VL incidence by up to 25%. These results highlight the need for prompt detection and treatment of PKDL to achieve VL elimination in the Indian subcontinent and provide quantitative estimates to guide spatiotemporally targeted interventions against VL.

Understanding sand fly sampling methods: sticky traps are attraction-based and not interceptive sampling tools of Phlebotomus orientalis.

BACKGROUND: Sticky traps are generally viewed as interceptive sand fly sampling methods; although no previous experimental evidence has supported this assumption. In this study, we tested this assumption experimentally for Phlebotomus orientalis, the principal vector of visceral leishmaniasis in East Africa, and propose an explanation for the highly male-biased collection of sticky traps. METHODS: A number of field experiments were carried out in March-June 2016-2019, in Gedarif state, eastern Sudan. In the first experiment, we compared numbers of P. orientalis caught on sticky traps made of black, red, transparent, white, yellow, green and blue A4 size papers set simultaneously at different lunar light conditions. In the second and third experiments, we compared numbers of P. orientalis captured on sticky traps placed side-by-side horizontally or vertically on the ground, or horizontally on a 15 cm height stool. We also witnessed mating behaviour of sand flies following their landing on un-sticky papers placed on the ground. RESULTS: Phlebotomus orientalis showed significant attraction to white, yellow and transparent traps, with negligible numbers caught on the black and the red traps. Similarly, significantly higher numbers of P. orientalis were attracted to the horizontal traps, resulting in an 8-fold increase in sand fly trapping efficacy as compared to the vertical traps. Placing the traps on the stools resulted in significant reduction in this attraction. In contrast to the sticky traps that captured only very few females; we found that when male sand flies land on un-sticky white paper they successfully lure females and copulate with them. CONCLUSIONS: We demonstrate that, for P. orientalis, sticky traps are more attractant-based than interception-based sampling tools. Further, our findings support the notion that males of this sand fly species likely utilize the bright surface of the trap papers to perform mating rituals that attract the females for copulation. However, pre-mature death in the sticky oil hampers the completion of these rituals, and thus results in failure to attract the females. These findings inform our understanding of P. orientalis behaviour and have important implications for optimization of sticky trap design for vector surveillance purposes.

Long-term incidence of relapse and post-kala-azar dermal leishmaniasis after three different visceral leishmaniasis treatment regimens in Bihar, India.

BACKGROUND: Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: A Phase IV trial included 1761 VL patients treated between 2012-2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models. Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse. CONCLUSIONS/SIGNIFICANCE: Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent.

Role of asymptomatic and symptomatic humans as reservoirs of visceral leishmaniasis in a Mediterranean context.

BACKGROUND: In the Mediterranean basin, Leishmania infantum is the causative agent of visceral leishmaniasis (VL), a zoonosis in which the dog is the primary domestic reservoir, although wildlife may have a leading role in the sylvatic cycle of the disease in some areas. Infections without disease are very frequent. There is limited information regarding the role that VL patients and asymptomatic infected individuals could be playing in the transmission of L. infantum. Xenodiagnosis of leishmaniasis has been used in this descriptive study to explore the role of symptomatic and asymptomatic infected individuals as reservoirs in a recent focus of leishmaniasis in southwestern Madrid, Spain. METHODOLOGY AND MAIN FINDINGS: Asymptomatic blood donors (n = 24), immunocompetent patients who were untreated (n = 12) or treated (n = 11) for visceral leishmaniasis (VL), and immunocompromised patients with VL (n = 3) were enrolled in the study. Their infectivity to Phlebotomus perniciosus was studied by indirect xenodiagnosis on peripheral blood samples. Quantitative polymerase chain reaction of blood samples from immunocompetent patients untreated for VL and immunocompromised untreated, treated and under secondary prophylaxis for VL was performed. Antibodies against Leishmania were studied by indirect fluorescent antibody and rK39-immunochromatographic tests. A lymphoproliferative assay with a soluble Leishmania antigen was used to screen for leishmaniasis infection in the healthy population. Sixty-two xenodiagnostic tests were carried out and 5,080 sand flies were dissected. Positive xenodiagnosis was recorded in four patients, with different sand fly infection rates: 1 immunosuppressed HIV / L. infantum coinfected asymptomatic patient, 1 immunosuppressed patient with multiple myeloma and symptomatic active VL, and 2 immunocompetent patients with untreated active VL. All blood donors were negative for both xenodiagnosis and conventional PCR. CONCLUSIONS / SIGNIFICANCE: There is no consensus amongst authors on the definition of an 'asymptomatic case' nor on the tools for screening; we, therefore, have adopted one for the sake of clarity. Immunocompetent subjects, both infected asymptomatics and those treated for VL, are limited in number and appear to have no epidemiological relevance. The impact is limited for immunocompetent patients with untreated active VL, whilst immunosuppressed individuals undergoing immunosuppressive therapy and immunosuppressed individuals HIV / L. infantum coinfected were the most infectious towards sand flies. It is noteworthy that the HIV / L. infantum coinfected patient with asymptomatic leishmaniasis was easily infectious to sand flies for a long time, despite being under continuous prophylaxis for leishmaniasis. Accordingly, screening for latent Leishmania infection in HIV-infected patients is recommended in scenarios where transmission occurs. In addition, screening for VL in HIV-infected patients who have spent time in VL-endemic areas should also be implemented in non-endemic areas. More research is needed to better understand if some asymptomatic coinfected individuals contribute to transmission as 'super-spreaders'.

Implications of asymptomatic infection for the natural history of selected parasitic tropical diseases.

Progress has been made in the control or elimination of tropical diseases, with a significant reduction of incidence. However, there is a risk of re-emergence if the factors fueling transmission are not dealt with. Although it is essential to understand these underlying factors for each disease, asymptomatic carriers are a common element that may promote resurgence; their impact in terms of proportion in the population and role in transmission needs to be determined. In this paper, we review the current evidence on whether or not to treat asymptomatic carriers given the relevance of their role in the transmission of a specific disease, the efficacy and toxicity of existing drugs, the Public Health interest, and the benefit at an individual level, for example, in Chagas disease, to prevent irreversible organ damage. In the absence of other control tools such as vaccines, there is a need for safer drugs with good risk/benefit profiles in order to change the paradigm so that it addresses the complete infectious process beyond manifest disease to include treatment of non-symptomatic infected persons.

Field effectiveness of new visceral leishmaniasis regimens after 1 year following treatment within public health facilities in Bihar, India.

BACKGROUND: An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. METHODS: The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. RESULTS: Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. CONCLUSION: Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL.

Effect of insecticide-treated bed nets on visceral leishmaniasis incidence in Bangladesh. A retrospective cohort analysis.

BACKGROUND: Visceral leishmaniasis (VL) is a parasitic disease, transmitted by the sand fly species Phlebotomus argentipes in the Indian sub-continent. Effective vector control is highly desirable to reduce vector density and human and vector contact in the endemic communities with the aim to curtail disease transmission. We evaluated the effect of long lasting insecticide treated bed nets (LLIN) and bed nets impregnated with slow-release insecticide tablet K-O TAB 1-2-3 (jointly insecticide-treated nets or ITN) on VL incidence in a highly endemic sub-district (upazila) in Bangladesh. METHODS: Several distributions of LLIN or K-O TAB 1-2-3 for self-impregnation of bed nets at home took place in Fulbaria upazila, Mymensigh district from 2004 to 2008 under three research projects, respectively funded by CDC, Atlanta, USA (2004) and WHO-TDR, Geneva, Switzerland (2006 & 2008). We included all households (n = 8142) in the 20 villages that had benefited in the past from one of these interventions (1295 donated LLIN and 11,918 local bed nets impregnated with K-O TAB 1-2-3) in the "exposed cohort". We recruited a "non-exposed cohort" in villages with contemporaneously similar incidence rates who had not received such vector control interventions (7729 HHs from nine villages). In both cohorts, we visited all families house to house and ascertained any VL cases for the 3 year period before and after the intervention. We evaluated the incidence rate (IR) of VL in both cohorts as primary endpoint, applying the difference-in-differences method. RESULTS: The study identified 1011 VL cases (IR 140.47/10,000 per year [py]) before the intervention, of which 534 and 477 cases in the intervention and control areas respectively. The IR was 144.13/10,000 py (534/37050) and 136.59/10,000 py (477/34923) in the intervention and control areas respectively, with no significant difference (p = 0.3901) before the intervention. After the intervention, a total of 555 cases (IR 77.11/10,000 py) were identified of which 178 (IR 48.04/10,000 py) in the intervention and 377 (107.95/10,000 py) in the control area. The intervention area had a significant lower IR than the control area during follow up, rate difference = -59.91, p<0.0001. The IR during follow up was significantly reduced by 96.09/10,000 py in the intervention area (p<0.0001) and 28.63/10,000 py in control area (p<0.0001) compared to baseline. There was a strong and significant overall effect of the ITN intervention, δ = -67.45, p <0.0001. Sex (OR = 1.36, p<0.0001) and age (OR = 0.99, p<0.0001) also had a significant effect on VL incidence. Male had a higher risk of VL than female and one year increase in age decreased the likelihood of VL by about 0.92%. Two third of the VL incidence occurred in the age range 2 to 30 years (median age of VL patients was 17 years). CONCLUSION: VL incidence rate was significantly lower in the ITN intervention cohort compared to control in Bangladesh. Some bias due to more intense screen-and-treat activities or other interventions in the intervention area cannot be ruled out. Nonetheless, given their feasibility and sustainability, ITNs should be considered for integrated vector control during the maintenance phase of the VL elimination programme.

Relationship between treatment regimens for visceral leishmaniasis and development of post-kala-azar dermal leishmaniasis and visceral leishmaniasis relapse: A cohort study from Bangladesh.

BACKGROUND: We investigated the relationship of treatment regimens for visceral leishmaniasis (VL) with post-kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis relapse (VLR) development. METHODS: Study subjects included cohorts of patients cured of VL since treatment with monotherapy by sodium stibogluconate (SSG), miltefosine (MF), paromomycin intramuscular injection (PMIM), liposomal amphotericin B [AmBisome (AMB)] in a single dose (SDAMB) and in multidose (MDAMB), and combination therapies by AMB+PMIM, AMB+MF, and PMIM+MF. Follow up period was 4 years after treatment. Cohorts were prospective except SSG (retrospective) and MF (partially retrospective). We compared incidence proportion and rate in 100-person-4year of PKDL and VLR by treatment regimens using univariate and multivariate analysis. FINDINGS: 974 of 984 enrolled participants completed the study. Overall incidence proportion for PKDL and VLR was 12.3% (95% CI, 10.4%-14.5%) and 7.0% (95% CI, 5.6%-8.8%) respectively. The incidence rate (95% CI) of PKDL and VLR was 14.0 (8.6-22.7) and 7.6 (4.1-14.7) accordingly. SSG cohort had the lowest incidence rate of PKDL at 3.0 (1.3-7.3) and VLR at 1.8 (0.6-5.6), followed by MDAMB at 8.2 (4.3-15.7) for PKDL and at 2.7 (0.9-8.4) for VLR. INTERPRETATION: Development of PKDL and VLR is related with treatment regimens for VL. SSG and MDAMB resulted in less incidence of PKDL and VLR compared to other treatment regimens. MDAMB should be considered for VL as a first step for prevention of PKDL and VLR since SSG is highly toxic and not recommended for VL.

Cutaneous leishmaniasis and co-morbid major depressive disorder: A systematic review with burden estimates.

BACKGROUND: Major depressive disorder (MDD) associated with chronic neglected tropical diseases (NTDs) has been identified as a significant and overlooked contributor to overall disease burden. Cutaneous leishmaniasis (CL) is one of the most prevalent and stigmatising NTDs, with an incidence of around 1 million new cases of active CL infection annually. However, the characteristic residual scarring (inactive CL) following almost all cases of active CL has only recently been recognised as part of the CL disease spectrum due to its lasting psychosocial impact. METHODS AND FINDINGS: We performed a multi-language systematic review of the psychosocial impact of active and inactive CL. We estimated inactive CL (iCL) prevalence for the first time using reported WHO active CL (aCL) incidence data that were adjusted for life expectancy and underreporting. We then quantified the disability (YLD) burden of co-morbid MDD in CL using MDD disability weights at three severity levels. Overall, we identified 29 studies of CL psychological impact from 5 WHO regions, representing 11 of the 50 highest burden countries for CL. We conservatively calculated the disability burden of co-morbid MDD in CL to be 1.9 million YLDs, which equalled the overall (DALY) disease burden (assuming no excess mortality in depressed CL patients). Thus, upon inclusion of co-morbid MDD alone in both active and inactive CL, the DALY burden was seven times higher than the latest 2016 Global Burden of Disease study estimates, which notably omitted both psychological impact and inactive CL. CONCLUSIONS: Failure to include co-morbid MDD and the lasting sequelae of chronic NTDs, as exemplified by CL, leads to large underestimates of overall disease burden.

Long term outcomes and prognostics of visceral leishmaniasis in HIV infected patients with use of pentamidine as secondary prophylaxis based on CD4 level: a prospective cohort study in Ethiopia.

BACKGROUND: The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited. METHODS: A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/µL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/µL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed. RESULTS: Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/µL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/µL who started pentamidine. Three patients with CD4 <200 cells/µL did not start pentamidine. Amongst those with CD4 ≥200 cells/µL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns. CONCLUSION: The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/µL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/µL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count.