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Cutaneous leishmaniasis (CL) is a parasitic vector-borne disease affecting mostly low- and middle-income countries. CL is endemic in Guatemala, where an increase in the number of cases and incidence and a changing disease distribution in the past decade have been reported. Important research was conducted in Guatemala in the 1980s and 1990s to understand the epidemiology of CL and two Leishmania species were identified as the aetiologic agents. Several species of sand flies have been reported, five of which are naturally infected with Leishmania. Clinical trials conducted in the country evaluated different treatments against the disease and provided solid evidence for CL control strategies that are applicable worldwide. More recently, in the 2000s and 2010s, qualitative surveys were conducted to understand community perceptions of the disease and to highlight the challenges and enablers for disease control. However, limited recent data have been generated regarding the current CL situation in Guatemala, and key information necessary for effective disease control, such as incrimination of vectors and reservoirs, is still lacking. This review describes the current state of knowledge of CL in Guatemala, including the main parasite and sand fly species, disease reservoirs, diagnosis and control, as well as the perceptions of communities in endemic regions.

Background Systemic pentavalent antimonials, mainly meglumine antimoniate, continue to be the first-choice drugs for treatment of cutaneous leishmaniasis (CL) despite their toxicity, difficulty of administration and high cost. In the search for therapeutic alternatives, combining two treatment interventions has emerged as a potential alternative to either reduce the use of antimonials with the associated toxicities, or to increase efficacy. Here, we report the results of a recently completed trial assessing the efficacy and safety of a combination of thermotherapy (TT) plus a short course of miltefosine (MLT) for the treatment of uncomplicated CL in Colombia and Peru. Methods A multicenter, randomized, evaluator-blinded, phase II, controled clinical trial was conducted. Adult volunteers with a parasitologically confirmed diagnosis of uncomplicated CL were randomly allocated to receive either a single session of TT or a combination of TT plus a short course of MLT (3 weeks). Therapeutic response outcomes and safety were assessed. Results 130 subjects were included in the study, of whom 64 were randomly assigned to the TT arm and 66 to the TT + MLT arm. Cure at 3 months’ follow-up was achieved in 57.8% (n = 37) and 80.3% (n = 53) in the TT and TT + MLT groups, respectively, in the intention to treat analysis. The TT + MLT regimen was better that TT alone (p = 0.0055). The presence of vesicles at the site of heat application was the most common adverse event reported associated with the use of TT; while vomiting (31.8%) and elevation of liver enzymes (28.8%) were the most frequent adverse events reported associated with the use of MLT. Conclusion The combination of TT plus a short course of MLT was shown to be significantly better than TT alone for the treatment of uncomplicated CL in the New World. Trial registration Registered in clinicaltrials.gov NCT02687971.

Background Treatment guidance for children and older adult patients affected by cutaneous leishmaniasis (CL) is unclear due to limited representation of these groups in clinical trials. Methods We conducted a collaborative retrospective study to describe the effectiveness and safety of antileishmanial treatments in children ≤ 10 and adults ≥ 60 years of age, treated between 2014 and 2018 in ten CL referral centers in Latin America. Results 2,037 clinical records were assessed for eligibility. Of them, the main reason for non-inclusion was lack of data on treatment follow-up and therapeutic response (182/242, 75% of children and 179/468, 38% of adults). Data on 1,325 eligible CL patients (736 children and 589 older adults) were analyzed. In both age groups, disease presentation was mild, with a median number of lesions of one (IQR: 1–2) and median lesion diameter of less than 3 cm. Less than 50% of the patients had data for two or more follow-up visits post-treatment (being only 28% in pediatric patients). Systemic antimonials were the most common monotherapy regimen in both age groups (590/736, 80.2% of children and 308/589, 52.3% of older adults) with overall cure rates of 54.6% (95% CI: 50.5–58.6%) and 68.2% (95% CI: 62.6–73.4%), respectively. Other treatments used include miltefosine, amphotericin B, intralesional antimonials, and pentamidine. Adverse reactions related to the main treatment were experienced in 11.9% (86/722) of children versus 38.4% (206/537) of older adults. Most adverse reactions were of mild intensity. Conclusion Our findings support the need for greater availability and use of alternatives to systemic antimonials, particularly local therapies, and development of strategies to improve patient follow-up across the region, with special attention to pediatric populations.

Background Cutaneous leishmaniasis (CL) is a disease that often affects exposed skin areas and may heal leaving lifelong scars. Patients’ expectations from treatment are rarely considered in drug development for CL. An initiative aiming to address shortcomings in clinical trial design and conduct for CL treatments involving the researchers’ community is on-going. This manuscript presents patient-preferred outcomes for CL and an assessment on how to consider these in the conduct of future trials. Methodology/Principal findings We report preferred treatment outcomes by 74 patients with confirmed CL in endemic regions of Brazil, Burkina Faso, Colombia, Iran, Morocco, Peru and Tunisia during individual in-depth interviews. Beyond outcomes customarily considered in trials (such as lesion appearance and adverse events), patients talked about a large number of outcomes related to quality of life, such as pain, scar formation, and others affecting their work and daily activities. They also reported fears around getting rid of the parasite, disease recurrence, and possible sequelae. Conclusions/Significance The study results provide a rich insight into important outcomes for CL treatments, as well as related topics, from the perspective of a diverse patient population. Among the outcomes identified, we argue that those related to quality of life as well as recurrence should be included to a greater extent for assessment in clinical trials, and discuss the suitability of measurement instruments such as the Dermatology Quality of Life Index (DLQI). Interviews also point out the potential need to address concerns related to parasitological cure or scar formation, such as social stigmatization and disability. In addition, patients should be given information in order to clarify reported misconceptions. This study therefore suggests a methodology for consulting CL patients on outcomes as elements of clinical trial design, and how to incorporate these outcomes in trials. It also discusses how reported outcomes could be addressed in clinical care., Author summary Cutaneous Leishmaniasis (CL) is a parasitic disease transmitted by sand fly vectors causing lesions and potentially life-long scars. Trials for CL treatments so far have not included patients’ input, such as their preferences on outcomes. This study reports treatment outcomes seen as important by patients that were explored through semi-structured interviews conducted in CL-endemic regions in Brazil, Burkina Faso, Colombia, Iran, Morocco, Peru and Tunisia. In addition to outcomes mostly considered in trials centered on lesion evolution and adverse events, patients reported a wide range of further outcomes and concerns. These are related to their quality of life, but also parasitological cure, potential for recurrence and sequelae of the disease. We suggest possibilities on how to include and measure a number of these patient-preferred outcomes into trials, and discuss ways of considering others in the context of treatment and clinical trials, e.g. via information provided to patients.

Although there have been significant advances in the treatment of visceral leishmaniasis (VL) and several novel compounds are currently in pre-clinical and clinical development for this manifestation of leishmaniasis, there have been limited advances in drug research and development (R & D) for cutaneous leishmaniasis (CL). Here we review the need for new treatments for CL, describe in vitro and in vivo assays, models and approaches taken over the past decade to establish a pathway for the discovery, and pre-clinical development of new drugs for CL. These recent advances include novel mouse models of infection using bioluminescent Leishmania, the introduction of PK/PD approaches to skin infection, and defined pre-clinical candidate profiles., Graphical abstract Image 1

Objectives: Localized cutaneous leishmaniasis and its evolving forms diffuse cutaneous leishmaniasis, mucosal leishmaniasis and cutaneous leishmaniasis recidivans, together with the visceral leishmaniasis sequelae post-kala azar dermal leishmaniasis account for about one million dermal leishmaniases cases per year worldwide. Although not lethal, the dermal leishmaniases cause chronic and disfiguring skin lesions, which are an important cause of morbidity and stigma.Microscopy remains the reference test for diagnosis of dermal leishmaniasis; however, it has low and variable sensitivity and requires well trained personnel. The technical complexity and cost of the more sensitive molecular techniques (e.g. PCR) limits their application in routine diagnosis in endemic areas. Point-of-care (POC) tests for early diagnosis are much needed in order to benefit both patients and communities, by reducing the risk of both sequelae and Leishmania transmission. To this end we developed a Target Product Profile (TPP) for a POC test for dermal leishmaniases. Methods: The TPP was defined through several rounds of discussions and by consensus with stakeholders and experts in dermal leishmaniases from different type of organizations and endemic regions. Results and conclusions: A rapid, simple and robust test that can be implemented in resource-limited settings, enabling decentralized diagnosis and treatment of dermal leishmaniasis should be developed. Ideally it should enable the diagnosis of all forms of dermal leishmaniasis, but the minimally accepted target would be localized cutaneous leishmaniasis. A minimum sensitivity of 95% and specificity of 90% would be required. The consensus was that the POC test should target Leishmania antigens. We would like to thank all experts and colleagues involved in the consultations, the animated discussions during the meetings of experts and online reviews, the useful comments and contributions to the different features of the TPP. UK aid from the UK Government, and the Government of Switzerland contributed to FIND's participation in this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Sí

Cutaneous leishmaniasis (CL) affects the lives of 0.7–1 million people every year causing lesions that take months to heal. These lesions can result in disfiguring scars with psychological, social and economic consequences. Antimonials are the first line of therapy for CL, however the treatment is lengthy and linked to significant toxicities; further, its efficacy is variable and resistant parasites are emerging. Shorter or lower dose antimonial treatment regimens, which would decrease the risk of adverse events and improve patient compliance, have shown reduced efficacy and further increase the risk emergence of antimonial-resistant strains. The progression of lesions in CL is partly determined by the immune response it elicits, and previous studies showed that administration of immunomodulatory type D CpG ODNs, magnifies the immune response to Leishmania and reduces lesion severity in nonhuman primates (NHP) challenged with Leishmania major or Leishmania amazonensis. Here we explored whether the addition of a single dose of immunomodulating CpG ODN D35 augments the efficacy of a short-course, low-dose pentavalent antimonial treatment regimen. Results show that macaques treated with D35 plus 5mg/kg sodium stibogluconate (SbV) for 10 days had smaller lesions and reduced time to re-epithelization after infection with Leishmania major. No toxicities were evident during the studies, even at doses of D35 10 times higher than those used in treatment. Critically, pentavalent antimonial treatment did not modify the ability of D35 to induce type I IFNs. The findings support the efficacy of D35 as adjuvant therapy for shorter, low dose pentavalent antimonial treatment., Author summary Cutaneous leishmaniasis is a devastating disease that affects close to a million people every year. Its clinical presentation ranges from small uncomplicated lesions that heal over a few months to debilitating large chronic or recurring lesions that result in disfigurement, stigma, and economic loss. Antimonials are the first line treatment for cutaneous leishmaniasis in most countries, but the lengthy treatment schedules, significant associated toxicities, and the emergence of resistant strains, require the development of alternative strategies. As the immune response is a key determinant of disease course, immunomodulatory therapies could be harnessed to act in concert with antimonials to improve the safety and efficacy of CL treatment. Synthetic oligonucleotide D35 selectively activates plasmacytoid dendritic cells and was previously shown to reduce the severity of L. major and L. amazonensis lesions in rhesus macaques, but its activity in combination with antimonials was unknown. Our studies show that a single subcutaneous dose of innate immune modulator D35 improved the response to a low-dose abbreviated antimonial course, reducing the severity of the lesions and accelerating healing in primates. No toxicities were evident with D35 at doses ten-fold higher than the effective dose. The studies suggest that the combined therapy strategy shows clinical promise.

SUMMARY Research in visceral leishmaniasis in the last decade has been focused on how better to use the existing medicines as monotherapy or in combination. Systematic research by geographical regions has shown that a universal treatment is far from today9s reality. Substantial progress has been made in the elimination of kala-azar in South Asia, with a clear strategy on first- and second-line therapy options of single-dose liposomal amphotericin B and a combination of paromomycin and miltefosine, respectively, among other interventions. In Eastern Africa, sodium stibogluconate (SSG) and paromomycin in combination offer an advantage compared to the previous SSG monotherapy, although not exempted of limitations, as this therapy requires 17 days of painful double injections and bears the risk of SSG-related cardiotoxicity. In this region, attempts to improve the combination therapy have been unsuccessful. However, pharmacokinetic studies have led to a better understanding of underlying mechanisms, like the underexposure of children to miltefosine treatment, and an improved regimen using an allometric dosage. Given this global scenario of progress and pitfalls, we here review what steps need to be taken with existing medicines and highlight the urgent need for oral drugs. Furthermore, it should be noted that six candidates belonging to five new chemical classes are reaching phase I, ensuring an optimistic near future.

Introduction Lack of investments in drug development, lack of standardisation of clinical trials and the complexity of disease presentations contribute to the current lack of effective, safe and adapted treatments for cutaneous leishmaniasis (CL). One aspect concerns outcomes affecting patients’ quality of life (QoL): these are hardly assessed in trials, despite potential functional and/or aesthetic impairment caused by CL, which typically affects disadvantaged and vulnerable people living in rural areas. Here, we describe the approach used to bring perspectives of patients with CL into designing and assessing treatments. Methods and analysis This international qualitative study uses interviews with patients to explore their experiences with CL to (1) elicit outcomes and eligibility criteria for clinical trials important to them and (2) to better understand their needs and views about the disease and their requirements and expectations from treatment. Here, we describe the set-up of this collaborative study and the protocol. Data collection is ongoing. The protocol includes study design, preparation, conduct and analysis of individual interviews with approximately 80 patients in seven countries (Burkina Faso, Brazil, two sites in Colombia, Iran, Morocco, Peru and Tunisia) where CL is prevalent. Principal investigators and sites were selected through an open call, and two workshops were organised for protocol development and training in conduct and analysis of qualitative health research. Patient recruitment aims at covering a maximum variation of experiences. Transcripts will be analysed to identify outcomes and eligibility criteria as well as further topics that are expected to emerge from the interviews, such as direct and indirect costs related to CL, its psychological impact, preferred modes of drug administration and traditional treatments. Ethics and dissemination The study received ethical approval by the responsible committees of each of the participating institutions. Findings will be disseminated through publication in peer-reviewed journals, scientific meetings and to participants and their communities. 0015099

Background Pentavalent antimonials (Sb5) are the first-line drugs for treating cutaneous leishmaniasis in Colombia; however, given problems with toxicity, compliance, availability, and cost, it is imperative to look for better therapeutic options. Intravenous amphotericin B (AmB) has been used extensively to treat visceral leishmaniasis; however, evidence on its topical use for cutaneous leishmaniasis is limited. Anfoleish is a topical formulation based on 3% AmB, which was developed following GMP standards by HUMAX and PECET. Anfoleish was shown to be safe and efficacious in animal model and in an open label study in CL patients. Hereafter we show the results of the first controlled and randomized study assessing the safety and efficacy of Anfoleish administered topically, two or three times per day for 28 days, for the treatment of non-complicated cutaneous leishmaniasis in Colombia. Methods An open-label, randomized, non-comparative phase Ib/II clinical trial was performed. Adult volunteers with a parasitologically confirmed diagnosis of cutaneous leishmaniasis were randomly allocated to receive Anfoleish cream either 3 (TID group) or 2 (BID group) times per day for 4 weeks. Results 80 out of 105 subjects screened were included in the study. In intention to treat analysis, final cure was observed in 13 (32.5%) out of 40 subjects (IC 95% = 20.1–48) and in 12 (30%) out of 40 subjects (IC 95% = 18.1–45.5) in the BID and TID group respectively. In the per protocol analysis, cure rates were 39.4% (n = 13) (IC 95% = 24.7–56.3) and 35.3% (n = 12) (IC 95% = 21.5–52.1) in the BID and TID groups respectively. Anfoleish proved to be safe, and the few adverse events reported were local, around the area of application of the cream, and of mild intensity. Conclusion Anfoleish showed to be a safe and well-tolerated intervention. Its efficacy results however do not support at this time continuing with its clinical development or recommending it for the treatment of CL. Additional, studies to improve its current formulation are needed before thinking in conducting additional studies in patients. Trial registration Registered in clinicaltrials.gov NCT01845727., Author summary Cutaneous leishmaniasis is a disease caused by Leishmania parasites and transmitted by sand flies. It is a complex disease and is underresearched disease, that depending on the parasite species, can take multiple forms, which can be less or more aggressive. It manifests as ulcers, nodules or other lesions mostly on the face and extremities. Cutaneous leishmaniasis is found across South and Central America, Africa, Europe, the Middle-East and Asia, and generally it is classified into forms of the Old World and New World. Colombia now ranks second after Brazil, with around 15,000 reported cases per year. Most cases are caused by L. panamensis, L. braziliensis, and L. guyanensis. Since the 1940’s, Pentavalent antimonials (Sb5) parenteral treatment have been the first-line of drugs for treating cutaneous leishmaniasis, however, the cost, the variable efficacy and the toxicity associated with its use, make it necessary to search for new treatments. Although there are other approved treatments for the disease, They also show issues of adverse reactions, and are used is mainly as a second option of treatment depending on the availability of these in health programs. Topical therapy of cutaneous leishmaniasis is a promising approach. Anfoleish is a cream than developed in Colombia. In this paper, we report the results of phase Ib/II, randomized trial in Colombia to assess the safety and therapeutic response of topical Anfoleish for the treatment of Cutaneous leishmaniasis.

This chapter provides an overview of the different in vitro and in vivo strategies to progress a new compound for visceral leishmaniasis from early screening, through in vivo testing and potential translation, to clinical development, including the value of novel pharmacokinetic–pharmacodynamic modelling and simulation tools to support this transition. The case of miltefosine, the only oral drug currently available for leishmaniasis, is presented to demonstrate how pharmacokinetic–pharmacodynamic modelling and simulation can provide new insights into how to optimize currently available drugs, such as the use of allometric dosing of miltefosine to overcome the lower drug exposure in children and the practical example of the clinically recommended minimal duration of contraception for female patients of child-bearing age.

This chapter provides a general overview of the current situation of leishmaniasis, including the biology of the parasite, description of the main clinical forms and its geographical distribution and transmission factors. Special emphasis is placed on the recent outbreaks of leishmaniasis, as well as the role of human migration and invasiveness of the environment in influencing the distribution of the disease and its transmission. In this regard, the relevance of HIV–Leishmania coinfection and of asymptomatic carriers is pinpointed. A description of control strategies, including diagnostic methods, biomarkers and, of utmost relevance, treatment options, including drug combinations, are analysed from a geographical and pathological perspective. The importance of and efforts aimed at increasing drug accessibility for the population in highly endemic areas in order to curtail the incidence of leishmaniasis are described. Finally, the foreseeable evolution of the disease and the ways to tackle unfulfilled challenges are examined.

Background The South-East Asia Region Kala-azar Elimination Programme (KAEP) is expected to enter the consolidation phase in 2017, which focuses on case detection, vector control, and identifying potential sources of infection. Post-kala-azar dermal leishmaniasis (PKDL) is thought to play a role in the recurrence of visceral leishmaniasis (VL)/kala-azar outbreaks, and control of PKDL is among the priorities of the KAEP. Methodology and principal finding We reviewed the literature with regard to PKDL in Asia and interpreted the findings in relation to current intervention methods in the KAEP in order to make recommendations. There is a considerable knowledge gap regarding the pathophysiology of VL and PKDL, especially the underlying immune responses. Risk factors (of which previous VL treatments may be most important) are poorly understood and need to be better defined. The role of PKDL patients in transmission is largely unknown, and there is insufficient information about the importance of duration, distribution and severity of the rash, time of onset, and self-healing. Current intervention methods focus on active case detection and treatment of all PKDL cases with miltefosine while there is increasing drug resistance. The prevention of PKDL by improved VL treatment currently receives insufficient attention. Conclusion and significance PKDL is a heterogeneous and dynamic condition, and patients differ with regard to time of onset after VL, chronicity, and distribution and appearance of the rash, as well as immune responses (including tendency to self-heal), all of which may vary over time. It is essential to fully describe the pathophysiology in order to make informed decisions on the most cost-effective approach. Emphasis should be on early detection of those who contribute to transmission and those who are in need of treatment, for whom short-course, effective, and safe drug regimens should be available. The prevention of PKDL should be emphasised by innovative and improved treatment for VL, which may include immunomodulation.

Background The decade following the Regional Strategic Framework for Visceral Leishmaniasis (VL) elimination in 2005 has shown compelling progress in the reduction of VL burden in the Indian subcontinent. The Special Programme for Research and Training in Tropical Diseases (TDR), hosted by the World Health Organization (WHO) and other stakeholders, has coordinated and financed research for the development of new innovative tools and strategies to support the regional VL elimination initiative. This paper describes the process of the TDR’s engagement and contribution to this initiative. Methodology/principal findings Multiple databases were searched to identify 152 scientific papers and reports with WHO funding or authorship affiliation around the following 3 framework strategies: detection of new cases, morbidity reduction, and prevention of infection. TDR has played a critical role in the evaluation and subsequent use of the 39-aminoacid–recombinant kinesin antigen (rK39) rapid diagnostic test (RDT) as a confirmatory test for VL in the national program. TDR has supported the clinical research and development of miltefosine and single-dose liposomal amphotericin B as a first-line treatment against VL. TDR has engaged with in-country researchers, national programme managers, and partners to generate evidence-based interventions for early detection and treatment of VL patients. TDR evaluated the quality, community acceptance, and cost effectiveness of indoor residual spraying, insecticide-treated bed nets, insecticide-impregnated durable wall linings, insecticidal paint, and environmental management as tools for integrated vector management in reducing sandfly density. Conclusions/significance TDR’s engagement with country policy makers, scientists, and clinicians in the development of effective diagnosis, treatment, case detection, and vector control represents an important example of TDR’s stewardship toward the elimination of VL in the Indian subcontinent., Author summary Since the early days of the kala-azar elimination programme in the Indian subcontinent, TDR has engaged with national control and research institutions to conduct research aimed at informing country policy and practice to identify and treat cases and to prevent transmission of the infection. This includes the evaluation of the rK39 rapid diagnostic test for the diagnosis of VL, the clinical development and evaluation of first-line treatments (miltefosine and liposomal amphotericin B), the generation of evidence-based tools for early detection and complete clinical management of VL, the evaluation of the cost effectiveness of indoor residual spraying, insecticide-treated bed nets, insecticide-impregnated durable wall linings, and environmental vector management as tools for integrated vector management. The interaction and interdependence between implementation research, technical advice, partnership, and policy is yet another example of TDR’s stewardship contribution and empowerment toward VL elimination in the Indian subcontinent. Continuing investment in translational research from the bench to the bedside to public health, established jointly by national control programmes, academics, and TDR coordinators, is imperative to block transmission and prevent a resurgence of VL in the future.

Background As Bangladesh, India and Nepal progress towards visceral leishmaniasis (VL) elimination, it is important to understand the role of asymptomatic Leishmania infection (ALI), VL treatment relapse and post kala-azar dermal leishmaniasis (PKDL) in transmission. Methodology/ Principal Finding We reviewed evidence systematically on ALI, relapse and PKDL. We searched multiple databases to include studies on burden, risk factors, biomarkers, natural history, and infectiveness of ALI, PKDL and relapse. After screening 292 papers, 98 were included covering the years 1942 through 2016. ALI, PKDL and relapse studies lacked a reference standard and appropriate biomarker. The prevalence of ALI was 4–17-fold that of VL. The risk of ALI was higher in VL case contacts. Most infections remained asymptomatic or resolved spontaneously. The proportion of ALI that progressed to VL disease within a year was 1.5–23%, and was higher amongst those with high antibody titres. The natural history of PKDL showed variability; 3.8–28.6% had no past history of VL treatment. The infectiveness of PKDL was 32–53%. The risk of VL relapse was higher with HIV co-infection. Modelling studies predicted a range of scenarios. One model predicted VL elimination was unlikely in the long term with early diagnosis. Another model estimated that ALI contributed to 82% of the overall transmission, VL to 10% and PKDL to 8%. Another model predicted that VL cases were the main driver for transmission. Different models predicted VL elimination if the sandfly density was reduced by 67% by killing the sandfly or by 79% by reducing their breeding sites, or with 4–6y of optimal IRS or 10y of sub-optimal IRS and only in low endemic setting. Conclusion/ Significance There is a need for xenodiagnostic and longitudinal studies to understand the potential of ALI and PKDL as reservoirs of infection., Author Summary The role of asymptomatic Leishmania infection (ALI), PKDL and VL relapse in transmission is unclear as VL elimination is achieved in the Indian subcontinent. ALI, PKDL and relapse studies lacked a reference standard and appropriate biomarker. ALI was 4–17-fold more prevalent than VL. The risk of ALI was higher in VL case contacts. Most infections remained asymptomatic or resolved spontaneously. The natural history of PKDL showed variability. Twenty nine percent had no past history of VL treatment. The risk of VL relapse was higher with HIV co-infection. Modelling studies predicted different effects. Early diagnosis was unlikely to eliminate VL in the long term. ALI was predicted to contribute to 82% of the overall transmission, VL to 10% and PKDL to 8%. Another model predicted that VL cases were the main driver for transmission. VL elimination was predicted if the sandfly density was reduced by 67% by killing the sandfly or by 79% by reducing their breeding sites, or with 4–6y of optimal IRS or 10y of sub-optimal IRS and only in low endemic setting. There is a need for more studies to fully understand the potential of ALI and PKDL as reservoirs of infection.

Objectives To investigate the changes of bacteriological index and leprosy reactions among Multi-bacillary (MB) patients treated with uniform multi-drug therapy (UMDT). Methods Newly diagnosed leprosy patients were recruited after taking informed consent in three districts in Guizhou Province and one district in Yunnan Province China during November 2003 to June 2005 and were treated with Uniform Multidrug Therapy. All patients were followed up once a year for 3 years after completion of treatment. All data on bacteriological index (BI) and the frequencies of leprosy reaction were collected and analysed. Results A total of 166 patients were recruited for UMDT trial. Among them 114 patients had positive BI smear, and 83 patients had been followed up for 42 months. The mean BI of 83 patients decreased from 2.84 before treatment to 0.33 at the end of 42 months follow-up. At the end of this period, 61 patients (73.5%) had become BI negative. There were 13 (14.6%) patients who had a Type I reaction during 24 months of follow-up. One patient in the study group relapsed 13 months after stopping treatment of the UMDT. Conclusion There was a significant decrease in the mean BI and 73.5% of patients treated with UMDT became BI negative during 3 years' follow-up. The frequency of Type I reaction seemed a little higher among patients treated with UMDT, but the numbers of patients enrolled were too few to determine statistical significance. Future studies on U-MDT should also study Type I reactions in these patients.

Summary Background Pneumonia causes more child deaths than does any other disease. Observational studies have indicated that smoke from household solid fuel is a significant risk factor that affects about half the world's children. We investigated whether an intervention to lower indoor wood smoke emissions would reduce pneumonia in children. Methods We undertook a parallel randomised controlled trial in highland Guatemala, in a population using open indoor wood fires for cooking. We randomly assigned 534 households with a pregnant woman or young infant to receive a woodstove with chimney (n=269) or to remain as controls using open woodfires (n=265), by concealed permuted blocks of ten homes. Fieldworkers visited homes every week until children were aged 18 months to record the child's health status. Sick children with cough and fast breathing, or signs of severe illness were referred to study physicians, masked to intervention status, for clinical examination. The primary outcome was physician-diagnosed pneumonia, without use of a chest radiograph. Analysis was by intention to treat (ITT). Infant 48-h carbon monoxide measurements were used for exposure-response analysis after adjustment for covariates. This trial is registered, number ISRCTN29007941. Findings During 29 125 child-weeks of surveillance of 265 intervention and 253 control children, there were 124 physician-diagnosed pneumonia cases in intervention households and 139 in control households (rate ratio [RR] 0·84, 95% CI 0·63–1·13; p=0·257). After multiple imputation, there were 149 cases in intervention households and 180 in controls (0·78, 0·59–1·06, p=0·095; reduction 22%, 95% CI −6% to 41%). ITT analysis was undertaken for secondary outcomes: all and severe fieldworker-assessed pneumonia; severe (hypoxaemic) physician-diagnosed pneumonia; and radiologically confirmed, RSV-negative, and RSV-positive pneumonia, both total and severe. We recorded significant reductions in the intervention group for three severe outcomes—fieldworker-assessed, physician-diagnosed, and RSV-negative pneumonia—but not for others. We identified no adverse effects from the intervention. The chimney stove reduced exposure by 50% on average (from 2·2 to 1·1 ppm carbon monoxide), but exposure distributions for the two groups overlapped substantially. In exposure-response analysis, a 50% exposure reduction was significantly associated with physician-diagnosed pneumonia (RR 0·82, 0·70–0·98), the greater precision resulting from less exposure misclassification compared with use of stove type alone in ITT analysis. Interpretation In a population heavily exposed to wood smoke from cooking, a reduction in exposure achieved with chimney stoves did not significantly reduce physician-diagnosed pneumonia for children younger than 18 months. The significant reduction of a third in severe pneumonia, however, if confirmed, could have important implications for reduction of child mortality. The significant exposure-response associations contribute to causal inference and suggest that stove or fuel interventions producing lower average exposures than these chimney stoves might be needed to substantially reduce pneumonia in populations heavily exposed to biomass fuel air pollution. Funding US National Institute of Environmental Health Sciences and WHO.

Background: A large body of evidence suggests that fine particulate matter (PM) air pollution is a cause of cardiovascular disease, but little is known in particular about the cardiovascular effects of indoor air pollution from household use of solid fuels in developing countries. RESPIRE (Randomized Exposure Study of Pollution Indoors and Respiratory Effects) was a randomized trial of a chimney woodstove that reduces wood smoke exposure. Objectives: We tested the hypotheses that the stove intervention, compared with open fire use, would reduce ST-segment depression and increase heart rate variability (HRV). Methods: We used two complementary study designs: a) between-groups comparisons based on randomized stove assignment, and b) before-and-after comparisons within control subjects who used open fires during the trial and received chimney stoves after the trial. Electrocardiogram sessions that lasted 20 hr were repeated up to three times among 49 intervention and 70 control women 38–84 years of age, and 55 control subjects were also assessed after receiving stoves. HRV and ST-segment values were assessed for each 30-min period. ST-segment depression was defined as an average value below –1.00 mm. Personal fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] exposures were measured for 24 hr before each electrocardiogram. Results: PM2.5 exposure means were 266 and 102 μg/m3 during the trial period in the control and intervention groups, respectively. During the trial, the stove intervention was associated with an odds ratio of 0.26 (95% confidence interval, 0.08–0.90) for ST-segment depression. We found similar associations with the before-and-after comparison. The intervention was not significantly associated with HRV. Conclusions: The stove intervention was associated with reduced occurrence of nonspecific ST-segment depression, suggesting that household wood smoke exposures affect ventricular repolarization and potentially cardiovascular health.

The world's burden of infectious diseases can be substantially reduced by more-effective use of existing interventions. Advances in case detection, diagnosis, and treatment strategies have made it possible to consider the elimination of visceral leishmaniasis in the Indian subcontinent. The priority must now be to effectively implement existing interventions at the community level by actively finding cases in endemic villages and treating them with single-dose liposomal amphotericin B at primary-health-care centres. Once the elimination target of one case per 10,000 population has been reached, combination therapies involving miltefosine and paromomycin can be introduced to ensure long-term availability of several drugs for visceral leishmaniasis and to protect against resistance.

WOS: 000424022700022, PubMed ID: 29329311, Introduction Progress with the treatment of cutaneous leishmaniasis (CL) has been hampered by inconsistent methodologies used to assess treatment effects. A sizable number of trials conducted over the years has generated only weak evidence backing current treatment recommendations, as shown by systematic reviews on old-world and new-world CL (OWCL and NWCL). Materials and methods Using a previously published guidance paper on CL treatment trial methodology as the reference, consensus was sought on key parameters including core eligibility and outcome measures, among OWCL (7 countries, 10 trial sites) and NWCL (7 countries, 11 trial sites) during two separate meetings. Results Findings and level of consensus within and between OWCL and NWCL sites are presented and discussed. In addition, CL trial site characteristics and capacities are summarized. Conclusions The consensus reached allows standardization of future clinical research across OWCL and NWCL sites. We encourage CL researchers to adopt and adapt as required the proposed parameters and outcomes in their future trials and provide feedback on their experience. The expertise afforded between the two sets of clinical sites provides the basis for a powerful consortium with potential for extensive, standardized assessment of interventions for CL and faster approval of candidate treatments., World Health OrganizationWorld Health Organization [001]

Background The promotion of household water treatment and handwashing with soap has led to large reductions in child diarrhoea in randomized efficacy trials. Currently, we know little about the health effectiveness of behaviour-based water and hygiene interventions after the conclusion of intervention activities. Methods We present an extension of previously published design (propensity score matching) and analysis (targeted maximum likelihood estimation) methods to evaluate the behavioural and health impacts of a pre-existing but non-randomized intervention (a 3-year, combined household water treatment and handwashing campaign in rural Guatemala). Six months after the intervention, we conducted a cross-sectional cohort study in 30 villages (15 intervention and 15 control) that included 600 households, and 929 children

Exposure to household wood smoke from cooking is a risk factor for chronic obstructive lung disease among women in developing countries. The Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) is a randomized intervention trial evaluating the respiratory health effects of reducing indoor air pollution from open cooking fires. A total of 504 rural Mayan women in highland Guatemala aged 15–50 years, all using traditional indoor open fires, were randomized to either receive a chimney woodstove (plancha) or continue using the open fire. Assessments of chronic respiratory symptoms and lung function and individual measurements of carbon monoxide exposure were performed at baseline and every 6 months up to 18 months. Use of a plancha significantly reduced carbon monoxide exposure by 61.6%. For all respiratory symptoms, reductions in risk were observed in the plancha group during follow-up; the reduction was statistically significant for wheeze (relative risk = 0.42, 95% confidence interval: 0.25, 0.70). The number of respiratory symptoms reported by the women at each follow-up point was also significantly reduced by the plancha (odds ratio = 0.7, 95% confidence interval: 0.50, 0.97). However, no significant effects on lung function were found after 12–18 months. Reducing indoor air pollution from household biomass burning may relieve symptoms consistent with chronic respiratory tract irritation.

To eliminate transmission of Onchocerca volvulus, semiannual mass treatment with ivermectin (Mectizan; donated by Merck & Co) has been underway in Guatemala since 2000. We applied the 2001 World Health Organization (WHO) elimination criteria in the Santa Rosa focus of onchocerciasis transmission in Guatemala (10,923 persons at risk). No evidence of parasite DNA was found in 2,221 Simulium ochraceum vectors (one-sided 95% confidence interval [CI], 0-0.086%), and no IgG4 antibody positives to recombinant antigen OV16 were found in a sample of 3,232 school children (95% CI, 0-0.009%). We also found no evidence of microfilariae in the anterior segment of the eye in 363 area residents (95% CI, 0-0.08%). Our interpretation of these data, together with historical information, suggest that transmission of O. volvulus is permanently interrupted in Santa Rosa and that ivermectin treatments there can be halted.

World Health Organization certification criteria for onchocerciasis elimination use anterior segment eye lesion prevalence as an indicator of mass ivermectin treatment program success. Lesions either contain visible microfilaria (noninflammatory punctate keratitis [PK] or microfilariae in anterior chamber [MFAC]), or microfilaria obscured by inflammation (inflammatory PK). To assess the utility of these disease indicators, two experienced ophthalmologists independently examined persons from endemic (N = 325) and nonendemic (N = 348) Guatemalan communities. Thirty-six (11.1%) and nine (2.6%) persons from endemic and nonendemic areas respectively had lesions found by either ophthalmologist (prevalence ratio = 4.3, 95% CI 2.1-8.8, P < 0.001). All lesions in nonendemic areas were inflammatory PK in whom no persons were seropositive for onchocerciasis. Overall, observer agreement was moderate (Kappa = 0.49), and most (61%) discordance occurred with inflammatory PK lesions. Our findings suggest that inflammatory punctate keratitis is neither a specific nor a reliable indicator of onchocercal eye disease. Future prevalence surveys should rely upon noninflammatory lesions as disease indicators.

The oral agent miltefosine has demonstrated a >95% cure rate in Indian visceral leishmaniasis. We performed a large, placebo-controlled study of miltefosine therapy (2.5 mg/kg per day orally for 28 days) against cutaneous leishmaniasis in Colombia and Guatemala. In regions in Colombia where Leishmania vianna panamensis is common, the per-protocol cure rates for miltefosine and placebo were 91% (40 of 44 patients) and 38% (9 of 24). These values are similar to historic values for the antimony standard of care and placebo. In regions in Guatemala where L. v. braziliensis and L. mexicana mexicana are common, the per-protocol cure rates were 53% (20 of 38) for miltefosine and 21% (4 of 19) for placebo. The miltefosine rate was lower than historic antimony cure rates of >90%. Miltefosine was well tolerated. Miltefosine is a useful oral agent against cutaneous leishmaniasis due to L. v. panamensis in Colombia but not against leishmaniasis due to L. v. braziliensis in Guatemala.

Water and sanitation interventions in developing countries have historically been difficult to evaluate. We conducted a seroepidemiologic study with the following goals: 1) to determine the feasibility of using antibody markers as indicators of waterborne pathogen infection in the evaluation of water and sanitation intervention projects; 2) to characterize the epidemiology of waterborne diarrheal infections in rural Guatemala, and 3) to measure the age-specific prevalence of antibodies to waterborne pathogens. Between September and December 1999, all children 6-36 months of age in 10 study villages were invited to participate. We collected sufficient serum from 522 of 590 eligible children, and divided them into six-month age groups for analysis (6-12, 13-18, 19-24, 25-30, and 31-36 months). The prevalence of antibodies was lowest in children 6-12 months old compared with the four older age groups for the following pathogens: enterotoxigenic Escherichia coli (48%, 81%, 80%, 77%, and 83%), Norwalk virus (27%, 61%, 83%, 94%, and 94%), and Cryptosporidium parvum (27%, 53%, 70%, 67%, and 73%). The prevalence of total antibody to hepatitis A virus increased steadily in the three oldest age groups (40%, 28%, 46%, 60%, and 76%). In contrast, the prevalence of antibody to Helicobacter pylori was relatively constant in all five age groups (20%, 19%, 21%, 25%, and 25%). Serology appears to be an efficient and feasible approach for determining the prevalence of infection with selected waterborne pathogens in very young children. Such an approach may provide a suitable, sensitive, and economical alternative to the cumbersome stool collection methods that have previously been used for evaluation of water and sanitation projects.

Now is a good time to reconsider research priorities as 2015 approaches, the target date originally set for elimination of visceral leishmaniasis. Visceral leishmaniasis is one of the most deadly parasitic diseases and disproportionately affects the poorest and most vulnerable populations. An estimated 200 000–400 000 people contract visceral leishmaniasis every year in developing countries. Spread by sandflies, visceral leishmaniasis can be fought with existing interventions, including treatment and vector control, but, similarly to every other human parasitic disease, no effective vaccine exists.

Summary Background To rapidly reduce the burden of visceral leishmaniasis for national elimination programmes, an acceptable, safe, and effective treatment is needed that can be delivered at primary health-care centres. We aimed to assess the tolerability, safety, and cure rate of single-dose liposomal amphotericin B (AmBisome, Gilead, USA) for visceral leishmaniasis treatment in such a setting in Bangladesh. Methods We enrolled patients who had been diagnosed with visceral leishmaniasis at Muktagacha upazila (subdistrict) hospital, Bangladesh. Eligible participants were at least 5 years old and had a history of fever for more than 2 weeks, splenomegaly, rK39 rapid test positivity, and haemoglobin concentrations of at least 50 g/L. Participants were provided a one-off intravenous infusion of liposomal amphotericin B (10 mg/kg bodyweight). Clinical assessments were done during treatment, before hospital discharge, and on days 30 and 180 after treatment. Cure was defined as resolution of fever, decrease in spleen size, and an increase in haemoglobin by 10% compared with baseline or to at least 100 g/L. We estimated efficacy in terms of initial cure (at day 30) and final cure (at 6 months), and safety in all patients who were enrolled (intention-to-treat analysis). We also assessed efficacy in all patients who completed treatment and 6 month follow-up after treatment with or without visceral leishmaniasis relapse (per protocol analysis). We assessed acceptability in terms of proportion of patients who consented to treatment. This study was registered with the Australian New Zealand Clinical Trial Registry, number CTRN12612000367842. Findings Between March 5, and Aug 14, 2012, 329 (55%) of 594 cases of suspected visceral leishmaniasis were confirmed. Of these cases, five patients did not consent to treatment and 24 were ineligible for treatment. In the intention-to-treat analysis, 261 (87%) of 300 patients achieved initial cure and 290 (97%) achieved final cure. In the per-protocol analysis, 260 (88%) of 296 patients achieved initial cure and 289 (98%) achieved final cure. One patient did not start treatment owing to an allergic reaction to liposomal amphotericin B. During treatment or within 2 h afterwards, 79 (26%) patients developed fever, 109 (36%) had fever with rigor, and 56 (19%) had hypotension. No patients needed referral to a tertiary hospital for management of adverse events. Interpretation Treatment of visceral leishmaniasis in a primary health-care facility with single-dose liposomal amphotericin B could safely and effectively be adopted by the national visceral leishmaniasis elimination programme in Bangladesh. Funding Neglected Tropical Diseases (WHO), Agencia Espanola de Cooperacion Internacional.

Background.For the treatment of visceral leishmaniasis in Bangladesh, single dose liposomal amphotericin B (ambisome) is supposed to be the safest and most effective treatment. Specific needs for application and storage raise questions about feasibility of its implementation and acceptance by patients and health staff.Methods.The study was carried out in the most endemic district of Bangladesh. Study population includes patients treated with ambisome or miltefosine, hospital staff, and a director of the national visceral leishmaniasis program. Study methods include direct observation (subdistrict hospitals), open interviews (heath staff and program personnel), structured questionnaires, and focus group discussions (patients).Results.Politicalcommitment for ambisome is strong; the general hospital infrastructure favours implementation but further strengthening is required, particularly for drug storage below 25°C (refrigerators), back-up energy (fuel for generators), and supplies for ambisome administration (like 5% dextrose solution). Ambisome created high satisfaction in patients and hospital staff, less adverse events, and less income loss for patients compared to miltefosine.Conclusions.High political commitment, general capacities of subdistrict hospitals, and high acceptability favour the implementation of ambisome treatment in Bangladesh. However, strengthening of the infrastructure and uninterrupted supplies of essential accessories is mandatory before introducing sLAB in Bangladesh.

Ten rural communities in the northern area of Guatemala where cutaneous leishmaniasis (CL) is endemic were investigated to determine the residents' knowledge of the disease, their related concepts and practices, and their treatment preferences, and to identify the communication channels they use to acquire information. Of 425 heads of household interviewed, 96.7% could accurately describe a typical CL lesion. CL was found to be the fourth most frequently mentioned disease (in studies based on a free list format) and to be considered the sixth most serious (in studies based on paired comparisons). A series of three-way comparisons, used to analyse the subjects' concepts about the similarities of various discases, indicated that CL was considered to be most closely related to skin problems and to be different from any other group of diseases. All interviewees believed that it was necessary to receive treatment for CL, because without treatment the disease would progress, reach the bone, and take years to heal. More than half (55%) of the respondents knew about meglumine antimonate (Glucantime), the most commonly prescribed drug for treating CL in Guatemala. Only a few communication channels that were used by respondents to receive information were identified; the use of radio broadcasts and direct communication via the community leaders appeared to be the most effective.

The polymerase chain reaction (PCR) assay has been reported for the diagnosis of cutaneous leishmaniasis (CL). Real-time (RT) PCR offers several advantages over traditional PCR, including faster processing time and decreased risk of contamination. Enhanced portability is another benefit that expands the applicability of the assay. A portable RT-PCR assay was transported from the United States to Guatemala for comparison with traditional diagnostic modalities. With the clinical diagnosis of CL as the gold standard, RT-PCR was positive in 86% (37 of 43) versus 53% (20 of 38) for microscopy and 72% (28 of 39) for culture. Negative RT-PCR samples (6) were also negative by traditional diagnostic methods (although subsequently determined to be positive by a nested kDNA PCR). Sixty-four percent (9 of 14) of cases tested and negative by microscopy and/or culture were positive by RT-PCR. This study demonstrates that a RT-PCR assay can be successfully deployed to offer enhanced sensitivity for the diagnosis of CL.

The current evidence-base for recommendations on the treatment of cutaneous leishmaniasis (CL) is generally weak. Systematic reviews have pointed to a general lack of standardization of methods for the conduct and analysis of clinical trials of CL, compounded with poor overall quality of several trials. For CL, there is a specific need for methodologies which can be applied generally, while allowing the flexibility needed to cover the diverse forms of the disease. This paper intends to provide clinical investigators with guidance for the design, conduct, analysis and report of clinical trials of treatments for CL, including the definition of measurable, reproducible and clinically-meaningful outcomes. Having unified criteria will help strengthen evidence, optimize investments, and enhance the capacity for high-quality trials. The limited resources available for CL have to be concentrated in clinical studies of excellence that meet international quality standards., Author Summary Solid evidence is needed to decide how to treat conditions. In the case of cutaneous leishmaniasis, the diversity of clinical conditions, combined with the heterogeneity and weaknesses of the methodologies used in clinical trials, make it difficult to derive robust conclusions as to which treatments should be used. There also other imperatives - ethical (not exposing patients to treatments that cannot be assessed adequately) and financial (optimize use of limited resources for a neglected condition). This paper is meant to provide clinical investigators with guidance for the design, conduct, analysis and report of clinical trials to assess the efficacy and safety of treatments of this condition.

Objective Standard treatment of Indian post-kala-azar dermal leishmaniasis (PKDL) is unsatisfactory because to achieve therapeutic effectiveness, heroic courses of parenteral and toxic agents have to be administered. Our objective was to evaluate oral miltefosine for its potential to provide effective as well as tolerable treatment for this disease. Method Open-label, randomised, parallel-group multicentric trial. Miltefosine, 100 mg/day to all but one patient, was administered for 12 weeks or 8 weeks, with a target of 18 patients in each treatment group. Key endpoints were tolerance during treatment and efficacy at 12 months of follow-up. Results The ITT and per-protocol cure rates after 12 months of follow-up for patients receiving 12 weeks of therapy were 78% (14 of 18 patients: 95% CI = 61–88%) and 93% (14 of 15 patients: 95% CI = 71–95%), respectively, after 12 months of follow-up. The ITT and per-protocol cure rates for patients receiving 8 weeks of therapy were 76% (13 of 17 patients: 95% CI = 53–90%) and 81% (13 of 16 patients: 95% CI = 57–93%), respectively. Gastrointestinal and other adverse events were rare. Conclusions This study suggests that oral miltefosine for 2–3 months can be considered a treatment of choice for Indian PKDL. Objectif Le traitement standard de la leishmaniose cutanee post kala-azar (LDPKA) indienne n'est pas satisfaisant car pour obtenir une efficacite therapeutique, des regimes eprouvants d'agents parenteraux et toxiques doivent etre administres. Notre objectif etait d’evaluer la miltefosine par voie orale pour sa capacite a fournir un traitement efficace et tolerable pour cette maladie. Methode Etude ouverte, randomisee, multicentrique, en groupes paralleles. La miltefosine a 100 mg par jour a ete administree a tous les patients sauf un, pendant 12 semaines ou 8 semaines, avec un objectif de 18 patients dans chaque groupe de traitement. Les principaux parametres etaient la tolerance au cours du traitement et l'efficacite a 12 mois de suivi. Resultats Les taux de guerison ITT et par protocole apres 12 mois de suivi chez les patients recevant 12 semaines de traitement etaient de 14 sur 18 patients (78%; IC95%: 61–88%) et 14 sur 15 patients (93%; IC95%: 71–95%), respectivement. Les taux de guerison ITT et par protocole pour les patients recevant 8 semaines de traitement etaient de 13 sur 17 patients (76%; IC95%: 53–90%) et 13 sur 16 patients (81%; IC95%: 57–93%), respectivement. Les effets indesirables gastro-intestinaux et autres etaient rares. Conclusions Cette etude suggere que la miltefosine orale pendant 2–3 mois peut etre consideree comme un traitement de choix pour la LDPKA indienne. Objetivo El tratamiento estandar de la leishmaniasis cutanea post kala-azar (LCPK) en la India no es satisfactorio, puesto que para conseguir una eficacia terapeutica, es necesario administrar dosis altas de agentes parenterales y toxicos. Nuestro objetivo era evaluar el potencial de la miltefosina oral como tratamiento efectivo y tolerable para esta enfermedad. Metodos Ensayo abierto, aleatorizado, de grupos paralelos y multicentrico. Se suministro 100 mg por dia de Miltefosina a todos, excepto un paciente, durante 8 o 12 semanas, con un objetivo de 18 pacientes por cada grupo de tratamiento. Los principales criterios de valoracion eran la tolerancia durante el tratamiento y la eficacia a los 12 meses de seguimiento. Resultados La intencion de tratar (ITT) y las tasas de curacion segun protocolo tras 12 meses de seguimiento para aquellos pacientes recibiendo 12 semanas de tratamiento eran 14 de 18 pacientes (78%: IC 95% =61-88%) y 14 de 15 pacientes (93%: IC 95% =71-95%), respectivamente. La ITT y tasas de curacion segun protocolo para los pacientes recibiendo 8 semanas de tratamiento eran 13 de 17 pacientes (76%: IC 95% CI=53-90%) y 13 de 16 pacientes (81%: IC 95% =57-93%), respectivamente. La presencia de eventos adversos gastrointestinales y de otro tipo fueron raros. Conclusiones El presente estudio sugiere que la miltefosina oral durante 2–3 meses podria considerarse como una tratamiento alternativo para la LCPK en la India.

Background Active case detection (ACD) significantly contributes to early detection and treatment of visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) cases and is cost effective. This paper evaluates the performance and feasibility of adapting ACD strategies into national programs for VL elimination in Bangladesh, India and Nepal. Methods The camp search and index case search strategies were piloted in 2010-11 by national programs in high and moderate endemic districts / sub-districts respectively. Researchers independently assessed the performance and feasibility of these strategies through direct observation of activities and review of records. Program costs were estimated using an ingredients costing method. Results Altogether 48 camps (Bangladesh-27, India-19, Nepal-2) and 81 index case searches (India-36, Nepal-45) were conducted by the health services across 50 health center areas (Bangladesh-4 Upazillas, India-9 PHCs, Nepal-37 VDCs). The mean number of new case detected per camp was 1.3 and it varied from 0.32 in India to 2.0 in Bangladesh. The cost (excluding training costs) of detecting one new VL case per camp varied from USD 22 in Bangladesh, USD 199 in Nepal to USD 320 in India. The camp search strategy detected a substantive number of new PKDL cases. The major challenges faced by the programs were inadequate preparation, time and resources spent on promoting camp awareness through IEC activities in the community. Incorrectly diagnosed splenic enlargement at camps probably due to poor clinical examination skills resulted in a high proportion of patients being subjected to rK39 testing. Conclusion National programs can adapt ACD strategies for detection of new VL/PKDL cases. However adequate time and resources are required for training, planning and strengthening referral services to overcome challenges faced by the programs in conducting ACD.

Background. National VL Elimination Programs in India, Nepal and Bangladesh face challenges as home-based Miltefosine treatment is introduced.Objectives. To study constraints of VL management in endemic districts within context of national elimination programs before and after intervention.Methods. Ninety-two and 41 newly diagnosed VL patients were interviewed for clinical and provider experience in 2009 before and in 2010 after intervention (district training and improved supply of diagnostics and drugs). Providers were assessed for adherence to treatment guidelines. Facilities and doctor-patient consultations were observed to assess quality of care.Results. Miltefosine use increased from 33% to 59% except in Nepal where amphotericin was better available. Incorrect dosage and treatment interruptions were rare. Advice on potential side effects was uncommon but improved significantly in 2010. Physicians did not rule out pregnancy prior to starting Miltefosine. Fever measurement or spleen palpation was infrequently done in Bangladesh but improved after intervention (from 23% to 47%). Physician awareness of renal or liver toxicity as Miltefosine side effects was lower in Bangladesh. Bio-chemical monitoring was uncommon. Patient satisfaction with services remained low for ease of access or time provider spent with patient. Health facilities were better stocked with rK39 kits and Miltefosine in 2010.

Miltefosine (target dose of 2.5 mg/kg/day for 28 days) is the recommended treatment for visceral leishmaniasis (kala-azar) in Bangladesh on the basis of data from India. We evaluated miltefosine in a phase IV trial of 977 patients in Bangladesh. At the six-month final follow up, 701 were cured. 24 showed initial treatment failure, and 95 showed treatment failure at 6 months, although 73 of the 95 showed treatment failure solely by the criterion of low hemoglobin values. One hundred twenty-one patients were not assessable. With the conservative assumption that all low hemoglobin values represented treatment failure, the final per protocol cure rate was 85%. Of 13 severe adverse events, 6 led to treatment discontinuation and 7 resulted in deaths, but only 1 death (associated with diarrhea) could be attributed to drug. Nearly all non-serious adverse events were gastrointestinal: vomiting in 25% of patients and diarrhea in 8% of patients. Oral miltefosine is an attractive alternative to intramuscular antimony and intravenous amphotericin B for treatment of kala-azar in Bangladesh.

The combination of one intravenous administration of 5mg/kg Ambisome and oral administration of miltefosine, 2.5mg/kg/day for 14 days, was evaluated in 135 Indian patients with kala-azar. The Intent-to-Treat cure rate at 6 months was 124 of the 135 enrolled patients (91.9%: 95% CI = 86-96%), and the per protocol cure rate was 124 of 127 evaluable patients (97.6%: 95% CI = 93-100%). Side effects could be attributed to each drug separately: fevers, rigors and back pain due to Ambisome; gastrointestinal side effects due to miltefosine. This combination is attractive for reasons of efficacy, tolerance, and feasibility of administration, although the gastrointestinal side effects of miltefosine require medical vigilance. Clinical Trials.gov identification number: NCT00371995.

To determine the relative efficacy and toxicity of stibogluconate and ketoconazole for the treatment of cutaneous leishmaniasis, we conducted a comparative trial in which 120 Guatemalan men with parasitologically proven cutaneous leishmaniasis were randomly divided into three treatment groups: sodium stibogluconate (20 mg of antimony per kg per day intravenously for 20 days); ketoconazole (600 mg per day orally for 28 days); and placebo. Stibogluconate was associated with occasional moderate but manageable adverse effects, including abnormal electrocardiograms and elevated transaminase values. Treatment outcome was influenced by species. Among patients infected with Leishmania braziliensis, 24 (96%) of 25 in the stibogluconate group responded. Among L. mexicana-infected patients, only four (57%) of seven in the stibogluconate group but eight (89%) of nine in the ketoconazole group responded. These differences emphasize the importance of specification in the treatment of leishmaniasis.

Onchocerciasis (river blindness), which is close to being eliminated from Guatemala through semiannual administration of ivermectin, is still transmitted in one area of the country that coincidentally receives an annual influx of migrant workers to harvest coffee. Migrant workers generally are not included in semiannual ivermectin treatments, but if infected could serve as a reservoir. We report on two studies undertaken to measure the exposure to onchocerciasis (presence of IgG4 antibodies to a recombinant Onchocerca volvulus antigen, OV-16) among migrant workers. During two coffee harvest seasons, 170 migrant workers with a history of working in the disease-endemic area were tested and 1 (0.6%, 95% confidence interval = 0–3.2%) was seropositive. This low rate of exposure in migrant workers indicates that they are unlikely to play a significant role in transmission of onchocerciasis and may indicate that transmission in the last remaining disease-endemic area of Guatemala is decreasing significantly.

Before recommending the skin-test use at national level in Guatemala of an antigen prepared from Leishmania major (a Leishmania species not found in the New World), we conducted a study in 100 Guatemalans to determine its sensitivity and specificity. The antigen consisted of 0·1 mL of a solution that contained 5 × 106 promastigotes of L. major (MRHO/IR/75/VAX). Positive leishmanin skin test (LST) reactions at 48 h were observed in 16 (80%) of 20 patients with proven active cutaneous leishmaniasis (CL), 18 (90%) of 20 with previously treated proven CL, and in 18 (90%) of 20 with a history and compatible scar of previously suspected but unconfirmed CL. None of 20 healthy controls or 20 patients with skin lesions due to causes other than CL had positive reactions to the LST, giving a sensitivity of 85% and specificity of 100%. There were no statistically significant differences in ethnic group, age, duration of the lesion, lesion size or Leishmania species between the 34 persons with true positive reactions. Even though it will be necessary to test this antigen on a larger number of patients, these preliminary results show that this antigen is specific and reasonably sensitive in identifying current or past CL and that it is a reasonable choice for epidemiological studies on CL in Guatemala.

Endosymbionic Wolbachia bacteria inside adult Onchocerca volvulus worms (causing river blindness) are necessary for female worm fertility. We evaluated whether rifampin and/or azithromycin used in a five-day course could kill Wolbachia. In an open-label trial in Guatemala, 73 patients with 134 palpable onchocercal nodules were randomized into four treatment groups: rifampin, azithromycin, a combination of the two drugs, and controls (multivitamins). After five days of antibiotic treatment, all participants received a single dose of ivermectin on day 6. Nine months after treatment, the nodules were removed and the worms were examined. Skin snips to determine microfilariae were obtained at baseline and nine months. There were no significant differences between any of the treatment groups in the condition of the worms in the nodules, the presence of Wolbachia surface protein, or the number of microfilariae in skin. Short courses with these antibiotics will not clear Wolbachia from O. volvulus.

Background: Indoor air pollution (IAP) from combustion of biomass fuels represents a global health problem, estimated to cause 1.6 million premature deaths annually. Aims: RESPIRE (Randomised Exposure Study of Pollution Indoors and Respiratory Effects) Guatemala is the first randomised controlled trial ever performed on health effects from solid fuel use. Its goal is to assess the effect of improved stoves (planchas) on exposure and health outcomes in a rural population reliant on wood fuel. Methods: Questions about symptoms were asked at baseline and periodically after the intervention, to an initial group of 504 women (259 randomly assigned to planchas (mean (standard deviation) age 27.4 (7.2) years) and 245 using traditional open fires (28.1 (7.1) years)). Levels of carbon monoxide (CO) in exhaled breath, a biomarker of recent exposure to air pollution from biomass combustion, were measured at each visit. In addition to reducing IAP levels, the plancha may also have a positive health effect by changing the working posture to an upright position. Results: A high prevalence of eye discomfort, headache and backache was found. The odds of having sore eyes and headache were substantially reduced in the plancha group relative to the group using open fires for the follow-up period (odds ratio (OR) 0.18, 95% confidence interval (CI) 0.11 to 0.29 and (OR) 0.63, 95% CI 0.42 to 0.94, respectively). Median CO in breath among women in the intervention trial was significantly lower than controls. Conclusion: In addition to reducing discomfort for women, tangible improvements in symptoms experienced by a substantial proportion of women may help to gain acceptance and wider use of planchas.

Cutaneous Leishmaniasis (CL) is a tropical parasitic disease in humans, transmitted by sandflies. CL causes lesions on exposed parts of the body, potentially leaving life-long scars. The disease manifestations vary significantly, depending on parasite species. An estimated 0.7 - 1.3 million new cases occur worldwide annually. Recommendations on the treatment of CL currently have a weak evidence base: not only are treatment options limited, but also have systematic reviews pointed to a lack of methodological standardization in the conduct and analysis of clinical trials of CL interventions. Standardized clinical trial methodologies would provide clinical investigators with guidance for the design, conduct, analysis and report of future clinical trials of treatments for CL. This includes the definition of measurable, reproducible and clinically meaningful outcomes. In order for both current and newer treatments to be adequately assessed, standardised methodologies are needed which can be applied generally, while at the same time allowing the flexibility required to cover the diverse disease manifestations. A guidance document on the methodology of clinical trials assessing CL interventions was published and provides the basis for further refinement. For this project, an iterative online Delphi consensus methodology is used. It involves stakeholders in order to agree on a set of core outcomes and eligibility criteria for CL treatment trials. The targeted stakeholder groups are researchers and health care providers (physicians and nurses) working with CL, and treating CL patients. Additional input is being sought from patients via interviews, to reflect their perspectives. CL is used as a case-study to assess whether the key stakeholders, most of them in disease endemic countries, can be identified and encouraged to collaborate using an innovative, participatory approach. The project is in progress; preliminary results will be presented.

World Health Organization certification criteria for onchocerciasis elimination use anterior segment eye lesion prevalence as an indicator of mass ivermectin treatment program success. Lesions either contain visible microfilaria (noninflammatory punctate keratitis [PK] or microfilariae in anterior chamber [MFAC]), or microfilaria obscured by inflammation (inflammatory PK). To assess the utility of these disease indicators, two experienced ophthalmologists independently examined persons from endemic (N = 325) and nonendemic (N = 348) Guatemalan communities. Thirty-six (11.1%) and nine (2.6%) persons from endemic and nonendemic areas respectively had lesions found by either ophthalmologist (prevalence ratio = 4.3, 95% CI 2.1-8.8, P0.001). All lesions in nonendemic areas were inflammatory PK in whom no persons were seropositive for onchocerciasis. Overall, observer agreement was moderate (Kappa = 0.49), and most (61%) discordance occurred with inflammatory PK lesions. Our findings suggest that inflammatory punctate keratitis is neither a specific nor a reliable indicator of onchocercal eye disease. Future prevalence surveys should rely upon noninflammatory lesions as disease indicators.

Trials of environmental risk factors and acute lower respiratory infections (ALRI) face a double challenge: implementing sufficiently sensitive and specific outcome assessments, and blinding. We evaluate methods used in the first randomized exposure study of pollution indoors and respiratory effects (RESPIRE): a controlled trial testing the impact of reduced indoor air pollution on ALRI, conducted among childrenor= 18 months in rural Guatemala.Case-finding used weekly home visits by fieldworkers trained in integrated management of childhood illness methods to detect ALRI signs such as fast breathing. Blindness was maintained by referring cases to study physicians working from community centres. Investigations included oxygen saturation (SaO2), respiratory syncytial virus (RSV) antigen test and chest X-ray (CXR).Fieldworkers referred90% of children meeting ALRI criteria, of whom about 70% attended a physician. Referrals for cough without respiratory signs and self-referrals contributed 19.0% and 17.9% of physician-diagnosed ALRI cases respectively. Intervention group attendance following ALRI referral was 7% higher than controls, a trend also seen in compliance with RSV tests and CXR. There was no evidence of bias by intervention status in fieldworker classification or physician diagnosis. Incidence of fieldworker ALRI (1.12 episodes/child/year) is consistent with high sensitivity and low specificity; incidence of physician-diagnosed ALRI (0.44 episodes/child/year) is consistent with comparable studies.The combination of case-finding methods achieved good sensitivity and specificity, but intervention cases had greater likelihood of reaching the physician and being investigated. There was no evidence of bias in fieldworkers classifications despite lack of concealment at home visits. Pulse oximetry offers practical, objective severity assessment for field studies of ALRI.

Water and sanitation interventions in developing countries have historically been difficult to evaluate. We conducted a seroepidemiologic study with the following goals: 1) to determine the feasibility of using antibody markers as indicators of waterborne pathogen infection in the evaluation of water and sanitation intervention projects; 2) to characterize the epidemiology of waterborne diarrheal infections in rural Guatemala, and 3) to measure the age-specific prevalence of antibodies to waterborne pathogens. Between September and December 1999, all children 6-36 months of age in 10 study villages were invited to participate. We collected sufficient serum from 522 of 590 eligible children, and divided them into six-month age groups for analysis (6-12, 13-18, 19-24, 25-30, and 31-36 months). The prevalence of antibodies was lowest in children 6-12 months old compared with the four older age groups for the following pathogens: enterotoxigenic Escherichia coli (48%, 81%, 80%, 77%, and 83%), Norwalk virus (27%, 61%, 83%, 94%, and 94%), and Cryptosporidium parvum (27%, 53%, 70%, 67%, and 73%). The prevalence of total antibody to hepatitis A virus increased steadily in the three oldest age groups (40%, 28%, 46%, 60%, and 76%). In contrast, the prevalence of antibody to Helicobacter pylori was relatively constant in all five age groups (20%, 19%, 21%, 25%, and 25%). Serology appears to be an efficient and feasible approach for determining the prevalence of infection with selected waterborne pathogens in very young children. Such an approach may provide a suitable, sensitive, and economical alternative to the cumbersome stool collection methods that have previously been used for evaluation of water and sanitation projects.

In support of the National Program for Chagas Disease Control, we conducted a cross-sectional study to estimate the seroprevalence rate of Trypanosoma cruzi infection across the five Departments (Chiquimula, Jalapa, Zacapa, Jutiapa, and Santa Rosa) that are believed to comprise the entire principal endemic area in Guatemala. Also, so that the results could be used to identify areas of active transmission, we conducted the survey in school-aged children. We used an experimental enzyme-linked immunosorbent assay with blood samples obtained by finger prick to estimate the seroprevalence of T. cruzi. This assay has been previously tested and showed good sensitivity and specificity. Overall, the seropositivity rate for T. cruzi infection was 5.28% (235 of 4,450). Of 173 communities evaluated, 35 (20.23%) had a seropositive rate ranging from 10% to 45%. A number of parameters, including but not limited to living conditions, were examined for possible association with seropositivity. While there are several associations, the strongest association with seropositivity is living in a house with a thatch roof. The survey results will permit the Ministry of Health to stratify T. cruzi-endemic communities, enabling local health authorities to efficiently focus on vector control operations.

In the present study, domestic dogs in a Leishmania endemic area in the Peten Region of Guatemala were sampled to determine if they are a potential reservoir for Leishmania parasites. Blood from 100 dogs from six villages was tested with two different antibody-capture assays for Leishmania-specific antibodies and a 28% seroprevalence was determined. Tissue scrapings from six dogs presenting with chronic lesions characteristic of Leishmania infection were sampled and four dogs were positive by a genus-specific fluorogenic PCR assay. Histopathology by giemsa stain confirmed the presence of amastigotes in one of these dogs. These findings support the hypothesis that dogs may play an important role in the transmission of Leishmania in a region where no mammal has ever been implicated as a reservoir.