Interventions for visceral leishmaniasis

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To compare the effects of different drugs, drug combinations and dosage regimens for the treatment of VL.

Background

Description of the condition

Leishmaniasis is an infection caused by protozoan parasites (single‐cell micro‐organisms) called leishmania that are transmitted by bites from infected sandflies. There are two modes of transmitting leishmaniasis: from humans to humans (anthroponotic) or from animals to humans (zoonotic). Leishmaniasis has many clinical presentations ranging from a subclinical (or non‐apparent) infection and localized skin lesions (solitary or limited cutaneous leishmaniasis) to disseminated infections (cutaneous, mucosal and visceral leishmaniasis or VL), which are associated with a variety of signs, symptoms and degrees of severity (Chappuis 2007). In this systematic review we shall focus on treatments for VL caused by the migration of the leishmania parasite into the internal organs.

Epidemiology

VL is endemic in South, Central and North America, the Mediterranean basin, central Asia, the Middle East and North and West Africa. The VL found in the Indian subcontinent and Africa is caused by Leishmania donovani and is transmitted to humans by the bite of an infected female sandfly, Phlebotomus argentipes. The VL found in north‐eastern Brazil is mostly caused by L. infantum (syn.L. chagasi) and is spread to humans by the vector Lutzomyia longipalpis. The VL in Colombia is caused by L. infantum and is spread to humans by Lutzomyia longipalpis and Lutzomyia evansi (Berman 2006).

According to the World Health Organization (WHO) among others, VL is ranked as the third most important parasitic disease after malaria and lymphatic filariasis in terms of disease burden (Desjeux 2004; WHO 2009). An estimated 2.5 million of people have VL in the world with half a million new cases of VL every year. People in 62 countries are at risk of developing VL (also called Kala azar or Black Fever, named after the dark coloration of the skin in this condition). In India alone 150 million people are estimated to be at risk. Eastern Africa (Sudan, Ethiopia, Kenya, Uganda and Somalia) has the second largest number of patients with VL after India, Bangladesh and Nepal (Chappuis 2007). More than 50,000 deaths occur from VL all over the world, though this figure is likely to be an underestimate due to inaccurate reporting in many regions of the world where the disease is endemic but also due to the scant health service coverage and access to health services or to misrecognition of VL as another parasitic disease. In India nearly 200 deaths are reported annually from VL out of the 20,000 patients, although the mortality rate reaches 5% or more. Malnutrition, immunosuppression, age, and immunogenetics (eg the human leukocyte antigen) are some risk factors associated with VL (Alvar 2006a; Collin 2006; WHO 2006).

Clinical features

When leishmania parasites are injected into the skin by the bite of a sandfly, they are rapidly phagocytosed by cells (neutrophils and macrophages) in the dermis. Once inside these cells, the parasite is transformed from its previously infectious promastigotic stage into another form (amastigotic) capable of surviving inside the host cells. These amastigotes replicate within the host's cells and are ultimately released into the tissue to invade adjacent cells. As a consequence of infection in the bone marrow and spleen individuals may become anaemic and further destruction of red and white blood cells may occur. This reduces the immunity of the person attacked, causing limited infection that may either spontaneously resolve or that may progress over weeks and months with persistent fever, anaemia, cough, abdominal pain, diarrhoea, enlargement of the liver and spleen (hepatosplenomegaly), weight loss, bleeding from the nose (epistaxis) due to decreased platelets (thrombocytopaenia), depleted blood counts (pancytopaenia), susceptibility to secondary infections, and also death. Differential diagnosis for VL includes malaria, syphilis, tuberculosis, typhoid fever, brucellosis, histoplasmosis, schistosomiasis, leukaemia, and lymphoma (Berman 2006; Chappuis 2007). VL may also lead to a cutaneous form of disease known as post‐Kala azar dermal leishmaniasis (PKDL) in East Africa and South Asia, the treatment of which is prolonged and expensive (Alvar 2006a).

Co‐infection with human immunodeficiency virus (HIV)

The emergence of HIV in the last decades has made it more important to treat and control leishmaniasis as the two infections are closely associated in many parts of the world and issues of prevention and control are of global importance. VL is an opportunistic infection in HIV and other immunosuppressed patients (Cruz 2006). People with a VL and HIV co‐infection relapse repeatedly after apparently successful treatment and the outcome is fatal, with a life expectancy one‐third lower than it is for people with HIV who do not have leishmaniasis (WHO 2007a; Alvar 2008).

Costs

VL affects the poor as the vector breeds in unhygienic environmental conditions and the poor cannot afford personal protection against the bites. Poor nutrition among this vulnerable section of the population leads to their decreased immunity. Expensive diagnostic measures along with expensive treatments compound the difficulties in managing VL in economically disadvantaged groups. Farmers residing in areas characterized by high humidity, with ill ventilated dwellings that they share with animals are more at risk of being bitten by sandflies that thrive in unhygienic conditions.These socioeconomic factors drive the spread of the disease, and the lack of a financial return for industry‐sponsored research on new drugs leaves leishmaniasis a neglected disease. A policy to control, prevent, and treat VL will indirectly help to alleviate poverty, and to achieve the first of the Millennium Development Goals (Alvar 2006a).

Though cost‐effectiveness studies comparing various treatment regimes have been produced there is a shortage of information on the actual cost of leishmaniasis to people and to countries, although we know that, in some parts of Asia, infection with leishmaniasis increases the odds of plunging families into a vicious circle of disease‐poverty‐malnutrition‐disease (Ahluwalia 2003; Vanlerberghe 2007). The cost of treating VL worldwide was estimated to be around $250 million and the disease burden is estimated to account for 235,700,000 disability‐adjusted life years over a 10‐year period (Desjeux 2004; Alvar 2006a).

Diagnosis

VL can be suspected clinically in people with fever of more than two weeks' duration in endemic areas that does not respond to anti‐malarial drugs and antibiotics, substantial weight loss, anaemia and enlargement of the spleen with or without enlargement of the liver. So far, a definitive diagnosis has relied on the visual identification of the parasite under the microscope on aspirates from the lymph nodes, spleen, liver or bone marrow. The diagnostic yield is highest for splenic aspirates (98%) and this is often used for diagnosis in the field (Guerin 2002). However, in most district hospitals in endemic regions, there are no resources to collect and interpret invasive and risky spleen or bone marrow aspirates (eg the risk of haemorrhage and death in spleen aspirates) or even to perform skin tests; hence the need for rapid and easy‐to‐interpret techniques.

At present, three rapid diagnostic methods are available that are sensitive and specific for VL and that are being compared in field conditions in Africa and Asia. The rK39‐based immunochromatographic test, the direct agglutination test (DAT) and the latex agglutination test to detect the antigen in urine are more affordable than the conventional serological tests. The rK39‐based test, with a sensitivity of 97% to 100% and a specificity of 86% to 92%, was found to be accurate and reliable for diagnosis when used in combination with a clinical case definition, and has been adopted in some countries such as India, Bangladesh and Nepal as part of the strategy to eliminate VL (Chappuis 2007; Mondal 2009).

Description of the intervention

Treatment

The main factors for determining the choice of treatment for VL are efficacy, toxicity, cost (drug and hospitalization) and availability of the treatment (Alvar 2006b). The treatment for VL is the same for adults and children and the drugs used are pentavalent antimonials (sodium stibogluconate and meglumine antimoniate), pentamidine isethionate, amphotericin B, liposomal amphotericin B, miltefosine (the only oral intervention), and aminosidine (paromomycin). Most of the drugs available are toxic and potentially fatal, even in recommended therapeutic doses. Pentavalent antimonials, though effective in most parts of the world, can rarely cause fatal adverse events. Amphotericin B deoxycholate, used as a first line drug in Bihar, India and as a second line drug elsewhere, induces moderate to severe infusion reactions in most patients. In many instances, the side effects experienced during anti‐leishmanial treatment are reversible (Den Boer 2006).

There is a debate about the acceptable dosage for pentavalent antimonials which still remain the mainstay of treatment in low‐income countries where this disease is prevalent (Berman 2006). However, resistance has been reported in around 60% of patients in parts of India, even when higher doses of the drug are used (Sundar 2001). A lack of response to the initial course of pentavalent antimony drug treatment is increasing in L. donovani‐endemic areas in Asia and Africa (Abdo 2003) and resistance to pentavalent antimonial drugs is emerging in other regions as well (Croft 2006; Vélez 2009). There is an emerging interest in drug combinations to treat VL as under these regimens there is less chance of parasite drug resistance to various antileishmanial drugs developing, a shorter duration of treatment, reduced costs and better compliance (Bryceson 2001; Mishra 2007).

Prevention

Difficulties in vector control in some endemic countries and the lack of an effective vaccine have hampered preventive strategies (Guerin 2002; Murray 2005). This further highlights the importance of effective and safe interventions in diagnosed cases. A Cochrane Review on prevention measures for all forms of leishmaniasis is underway.

How the intervention might work

Pentavalent antimonials

Sodium stibogluconate and meglumine antimoniate are the most frequently used pentavalent antimonials. Meglumine antimoniate is used in most Latin American and some central Asian countries (eg Iran). Its mode of action is not known with certainty but it seems that to execute its leishmanicidal action, the drug has to be converted into another chemical form either inside the macrophages or in the parasite itself. The WHO recommends a dosage of 20 mg/kg/day intramuscularly or intravenously for 20 to 30 days or more. Adverse effects include cardiotoxicity, myelosuppression, and liver and kidney damage but most are reversible (Mishra 2007). There is evidence of the emergence of antimonial‐resistant leishmania strain in India (Sundar 2000) and in East Africa, especially in Sudan, another anthroponotic focus of VL, with intense transmission (Abdo 2003).

Pentamidine isethionate

Pentamidine isethionate is administered intramuscularly or by slow intravenous injection for 5 to 25 weeks. Its use has been abandoned in India because of its relatively low efficacy and its serious side effects, which include insulin‐dependent diabetes mellitus. Acute adverse reactions are high and include cardiovascular collapse that frequently occurs after intravenous injections. Intramuscular injections alone cause local tissue necrosis. Other adverse effects include mental confusion, liver and kidney damage, and, rarely, cardiac arrhythmias (Croft 2006).

Amphotericin B

Amphotericin B deoxycholate is a very effective drug and was first developed as an anti‐fungal drug but its use has been limited because of its lengthy treatment and its adverse effects, like nephropathy, refractory hypokalaemia, myocarditis and death. It is administered as intravenous infusions on alternate days for a total of 20 days. It acts by altering the permeability of the cell membrane. Toxicity is high, with early acute reactions like chills, fever, aches, and pains. Severe adverse events like hypokalaemia, renal insufficiency, myocarditis and occasionally death might occur. The intensity of the reactions decreases with continued use (Mishra 2007).

Liposomal amphotericin B and other derivatives

Liposomal amphotericin B is a well‐tolerated drug and has been shown to be very effective in a single dose, it is the mainstay drug in Europe and the USA but it is an expensive option for low‐ and middle‐income countries (WHO 2007b; Den Boer 2009). The targeted drug delivery, especially to the macrophages in the liver and spleen where the amastigotes abound, makes this formulation more effective. It also has improved tolerability (mild acute reactions) and reduced nephrotoxicity and anaemia (Bern 2006).

Miltefosine

Miltefosine is the only oral treatment against VL. It was originally developed as an anti‐cancer drug and needs to be monitored very closely to avoid resistance to it. Its teratogenicity is a limiting factor for its use by women (Agrawal 2006). The mode of action of miltefosine in leishmaniasis has not been elucidated yet but might be complex. Miltefosine is associated with vomiting and diarrhoea in a small minority of patients (Berman 2008).

Aminosidine (paromomycin)

Paromomycin is an aminoglycoside which has been shown to have a good potential in trials and is affordable (Sundar 2007). The anti‐leishmanial action of paromomycin is likely to be its inhibition of protein synthesis, its induction of respiratory cell dysfunction, and the changes it makes in the mitochondrial membrane (Cruz 2009). It is administered intramuscularly in dosages of 11 mg/kg per day for 21 days. Adverse effects include the transient elevation of aspartate aminotransferase and transient reversible ototoxicity (Sundar 2008).

Why it is important to do this review

VL is a worldwide health problem and there is currently a unique political and social commitment to controlling it, including a Resolution to combat it by the World Health Assembly (WHO 2006). Since 1990 no updated recommendations have been produced by the WHO on the treatment of leishmaniasis apart from advice on specific topics. The WHO Leishmaniasis Expert Panel meeting on the "Control of Leishmaniasis" in October 2009 and the subsequent WHO Report Series in 2010, constituting an update of effective treatments in leishmaniasis, require reliable evidence on which to base recommendations. The rational use of the existing drugs either as a monotherapy, or ideally as a combined therapy, justifies a systematic review to underpin such recommendations.

The Ministers of Health of Bangladesh, India and Nepal embarked in 2005 on an ambitious programme to eliminate leishmaniasis by 2015 or earlier, based on the fact that humans are the sole reservoir for the transmission of VL; the susceptibility to insecticides of the only sandfly species that transmits the disease in the region (Phlebotomus argentipes); the availability of a rapid diagnostic test; and the limited and concentrated geographical distribution of the disease, which affects 94 districts in all three countries ( WHO 2005a; WHO 2005b). However, for this programme to succeed, apart from the massive input required in terms of actively identifying patients and strengthening the public health system (Mondal 2009), reliable and up‐to date evidence of effective, safe and affordable intervention strategies would be required (Olliaro 2005).

Two Cochrane Systematic Reviews have evaluated the efficacy and safety of interventions for cutaneous and muco‐cutaneous leishmaniasis (González 2008; González 2009). This review hopes to contribute reliable and timely evidence to aid the global effort to eliminate VL.

Objectives

To compare the effects of different drugs, drug combinations and dosage regimens for the treatment of VL.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials.

Quasi‐randomized trials in which the method of randomization permits the prediction of allocation to treatment arms (eg alternation) will be excluded.

Types of participants

People of all ages, with or without HIV infection, with a proven diagnosis of VL together with parasitological or serological confirmation.

The clinical characteristics are persistent fever (of two weeks or more) not due to malaria, tuberculosis or other infections (ie not responsive to a course of antibiotics), splenomegaly and weight loss.

The parasitological confirmation should be based on a microscopic demonstration of the parasite by identifying it morphologically or in cultures from aspirates of the liver, spleen, bone marrow, lymph nodes (the later is possible mainly in East Africa), together with molecular biological methods such as polymerase chain reaction.

Serological confirmation should be based on specific anti‐leishmanial antibodies (such as an immunofluorescence antibody test, enzyme‐linked immunoabsorption assay DAT or rk39‐based immunochromatographic test), or on antigen‐detection tests such as the the latex agglutination test to detect the antigen in urine.

Types of interventions

Intervention:

• sodium stibogluconate;

• meglumine antimoniate;

• pentamidine isethionate;

• pentamidine mesylate;

• pentamidine methanesulfonate;

• amphotericin B (deoxycholate);

• liposomal amphotericin B;

• other amphotericin B lipidic carriers;

• miltefosine;

• aminosidine (paromomycin); and

• any other therapeutic intervention or a combination of the above drugs used concurrently or sequentially.

Control:

• no intervention or placebo;

• different doses of any of the above interventions; and

• different combination of drugs used concurrently or sequentially

Types of outcome measures

Primary outcomes

• Percentage of participants cured at least 6 months after the end of treatment.

We define 'cured' as eradication of parasites (in bone marrow or spleen aspirates or culture) and resolution of clinical signs and symptoms (anaemia, defervescence, weight gain, and decrease in spleen size) and absence of clinical signs and symptoms attributable to VL or PKDL.

Secondary outcomes

• Percentage of participants cured at the end of treatment or up to six months thereafter

• Recurrence: duration of remission and/or percentage of cured participants who recur after six months, 12 months, and one, two and three years

• Percentage of participants with a parasitological cure (identified in the field or laboratory and assessed by parasitology)

• Percentage of deaths (all causes)

• Compliance, defined as the percentage of participants with any deviation in the recommended therapeutic regimens. Any method of measurement will be considered

• Percentage of participants with PKDL at least six months after the end of treatment

• Duration of hospitalization

• Percentage of participants with adverse events including fever, chills and/or rigor, pain at the injection site, cardiotoxicity, vomiting, diarrhoea, audiometric shifts, elevated liver enzymes (hepatitis), elevated creatinine and urea (nephrotoxicity), congenital anomaly or birth defects, chemical pancreatitis, etc.

Search methods for identification of studies

We will attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).

Electronic searches

We will search the following databases: Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; and LILACS, using the search terms detailed in Appendix 1. We will also search the metaRegister of Controlled Trials and the WHO Clinical Trials Search Portal using 'leishmania*"' or 'kala‐azar' as search terms

Searching other resources

Researchers, organizations, and pharmaceutical companies

For unpublished reports we will contact individual researchers working in the field, the World Health Organization TDR, and pharmaceutical companies, research agencies and non‐governmental organizations including GlaxoSmithKline , Paladin (formerly  Aeterna Zentaris, and previously AstraZeneca), Sanofi‐Aventis, Albert David Ltd, Gilead Sciences,Institute for One World Health, Drugs for Neglected Diseases initiative, Médecins Sans Frontières ‐Holland, Médecins Sans Frontières ‐Spain, National Institutes of Health.

Reference lists

We will also check the reference lists of all trials and relevant articles identified by the above methods.

Data collection and analysis

Selection of studies

Six authors (UG, MP, SK, MH, IV, and SS) will independently screen all citations and abstracts identified by the search strategy to identify potentially eligible studies. Full articles of potentially eligible studies will be obtained and assessed independently for inclusion in the review by the same authors, using a pre‐designed eligibility form based on the inclusion criteria. We will contact the authors of trials for clarification if it is unclear whether a trial is eligible for the review. We will resolve any differences in opinion with the remaining author (JA). We will check for multiple publications of the same data and will identify the main source but include all relevant data for review, taking care to avoid duplication. We will document the reason for the exclusion of reports that do not meet inclusion criteria.

Data extraction and management

Four authors (SK, MH, IV, and SS) will independently extract data using pre‐tested data extraction forms. For all included trials we will extract information on the number and characteristics of patients randomized and the number for which outcome(s) were measured. We will extract the number of events and the number of patients in each treatment arm for dichotomous outcomes, together with the arithmetic means and standard deviations, and the number of patients in each group for continuous outcomes. If medians have been reported we shall extract ranges or interquartile ranges. If count data are reported in trials, we will extract the total number of events in each group and the total amount of person‐time at risk in each group. We will also record the total number of participants in each group. If this information is not available, we shall attempt to extract alternative summary statistics such as rate ratios and confidence intervals, if available. If count data are presented as dichotomous outcomes we will extract the number of participants in each intervention group and the number of participants in each intervention group who experienced at least one event. We will resolve any inadequacies or discrepancies between the extracted data by discussion, and if necessary by contacting the trial authors.

Assessment of risk of bias in included studies

Six authors (UG, MP, SK, MH, IV, and SS) will independently assess the risk of bias in the included trials. We will assess the following six components for each of the trials: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases. For each of these components, we will assign a judgment regarding the risk of bias as "yes', 'no' or 'unclear' (Higgins 2008). We will contact the trial authors for clarification if any of the six components is unclear or is not stated in the report. We will record the results in the standard table in Review Manager 5 (Review Manager 2008), and we will summarize the findings as a 'risk of bias' table or graph.

Measures of treatment effect

All authors will be involved in data synthesis. We will compare dichotomous outcomes using risk ratios and their 95% confidence intervals. We will calculate the numbers needed to treat to benefit or harm various control group event rates and display them in a table. We will combine continuous data reported as arithmetic means and standard deviations, using the mean difference. Count outcomes will be summarized using rate ratios.

Dealing with missing data

We shall attempt to obtain missing data from trial authors. Where possible, we shall extract data to allow an intention‐to‐treat analysis in which all randomized participants are analysed in the groups to which they were originally assigned. If there is discrepancy in the number randomized and the numbers analysed in each treatment group, we shall calculate the percentage loss to follow‐up in each group and report this information.

Assessment of heterogeneity

We will assess heterogeneity between the trials by visual examination of the forest plot to check for overlapping confidence intervals, using the chi²statistic test for heterogeneity using a 10% level of significance, and the I² statistic. A value of I²  of 50% or greater will be used to denote significant heterogeneity. If this value is substantial (75% or greater) we shall not attempt data synthesis if heterogeneity cannot be explained by the clinical or methodological features of the trial or by subgroup analyses.

Data synthesis

Every individual drug or combination will be analysed separately in the meta‐analysis. Three authors (UG, SS, JA) will analyse the data using Review Manager 5. Primarily, we will stratify the analyses by the comparison made. Dichotomous data will be synthesized using the Mantel Haensel meta‐analysis method and continuous data will be combined using the generic inverse variance method.

Subgroup analysis and investigation of heterogeneity

We will use a fixed‐effect model to synthesize data when there is no heterogeneity. We will combine the trials using a random‐effects model where heterogeneity is present, but not substantial (I² > 50% but less than 75%), and cannot be explained by subgroup analyses or in terms of clinical or methodological features of the trials and the participants. If substantial heterogeneity is present or there are substantial differences across the trials in terms of clinical or methodological features, we would present the trials in a forest plot but would not combine the trials in a meta‐analysis.

If data permit, we shall attempt subgroup analysis for:

• HIV infected individuals;

• duration of follow up greater than six months versus less than six months;

• severity of infection;

• distinct Leishmania species;

• geographical region (Asia, Africa, Mediterranean basin,and South America);

• different time periods.

Sensitivity analysis

We will conduct sensitivity analyses to investigate the robustness of the results for the primary outcome by excluding trials at high risk of bias. We will also undertake sensitivity analyses if trials report drop‐out rates of 10% or greater, to ascertain differences in outcomes of intention‐to‐treat analysis. We will also assess the robustness of the results to the use of definitive criteria to diagnose VL (parasitological conformation).

Appendices

Appendix 1. Search strategy for MEDLINE (OVID)

1. randomised controlled trial.pt. 2. controlled clinical trial.pt. 3. randomized.ab. 4. placebo.ab. 5. clinical trials as topic.sh. 6. randomly.ab. 7. trial.ti. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. visceral leishmaniasis.mp. or exp Leishmaniasis, Visceral/ 10. leishmaniasis visceral.mp. 11. kala azar.mp. 12. treatment.mp. or exp *Therapeutics/ 13. exp *Drug Therapy/ 14. 11 or 10 or 9 or 12 15. 13 or 14 16. 8 and 16 and 15

What's new

Date	Event	Description
16 August 2017	Amended	This protocol is being withdrawn from The Cochrane Library. The authors have made no progress with this protocol in seven years. The protocol is out of date and does not meet the current methodological standards of Cochrane.

Contributions of authors

All authors were involved in the development and drafting of the protocol.

Sources of support

Internal sources

• Office of Control of Neglected Tropical Diseases (WHO/CDS/NTD/IDM), Communicable Disease Cluster, World Health Organization, Switzerland.

• Hospital Plató, c/ Plató 21 08006 Barcelona, Spain.

• Agencia Española de Cooperación Internacional para el Desarrollo (AECID), Spain.

• South Asian Cochrane Network & Centre, Vellore, India.

• Christian Medical College, Vellore, India.

External sources

• Effective Health Care Alliance Research Partnership Consortium, Liverpool School of Tropical Medicine, UK.

• Department for International Development (DFID), UK.

Declarations of interest

None known.

Notes

This protocol is being withdrawn from The Cochrane Library. The authors have made no progress with this protocol in seven years. The protocol is out of date and does not meet the current methodological standards of Cochrane.

Withdrawn from publication for reasons stated in the review