CHAPTER 1: GENERAL INTRODUCTION
1.1 Visceral leishmaniasis, the disease 1.1.1 Etiology of Visceral leishmaniasis
Visceral leishmaniasis (VL), also known as Kala-azar, is a vector-borne parasitic disease caused by Leishmania parasites a nd tr ansmitted th rough th e b ite o f an in fected f emale phlebotomine sand fly (Bern et al. 2005; Barnett et al. 2005). The disease affects the visceral organs, causing chronic f ever, weight l oss, anemia, swelling of l iver and spleen. The di sease i s ne arly always fatal when untreated. Worldwide, the disease is caused by a parasite of the Leishmania donovani complex: Leishmania donovani in East Africa and in the Indian subcontinent, and Leishmania infantum in Europe, North Africa and Latin America (Lukes et al.2007). For L. donovani, man is the only known reservoir, whereas for L. infantum, the domestic dog is the main reservoir. Based on the transmission characteristics, there are two types of VL: (i) anthroponotic (man- vector- man transmission), and (ii) zoonotic ( animal – vector – human transmission). Anthroponotic L.
donovani transmission is prevalent i n a r elatively s mall but he avily po pulated a rea s panning northeastern India, southeastern Nepal and central Bangladesh which accounts for more than two thirds of all cases of VL in the world. The East Africa L. donovani focus, also with an important component of a nthroponotic t ransmission, i s t he s econd l argest focus of V L, w ith hi ghest incidence in Ethiopia and the Sudan. The other two important foci, both caused by zoonotic L.
infantum transmission, are the Mediterranean Basin, the Middle East and western Asia; and the New World, predominantly in Brazil (WHO 2010).
Post-kala-azar d ermal le ishmaniasis ( PKDL) is a la te c omplication o f VL is more c ommonly seen in inadequately treated kala-azar cases, usually appears several months after treatment of a VL episode. PKDL is seen in areas where L. donovani is endemic i.e. in Asia (India, Bangladesh and Nepal) and in East Africa (Ethiopia, Kenya and Sudan) (Zijlstra et al. 2003). It ma y also rarely occur in L.infantum endemic areas among immunosuppressed individuals. PKDL patients are considered infectious to sand flies and may therefore play a role as a reservoir in absence of active VL cases between epidemic cycles (Addy & Nandy 1992).
1.1.2. Pathogenesis and transmission cycle
Depending on th e tr ansmission c haracteristics, two types of V L can be di stinguished: an anthroponotic a nd a zoonotic f orm as m entioned ear lier. In t he f ormer, t here i s a n a nimal reservoir (dogs, f oxes, r odents) w here t he pa rasite i s m aintained with man be ing just a n occasional h ost, an d i n the l atter t he p arasite i s ex clusively m aintained i n a m an-vector-man cycle without animal reservoir (Ashford 1996; Alvar et al. 2004).
The life c ycle o f t he leishmania parasite has t wo m orphological f orms: a promastigote f orm (with flagella) moving extracellularly in the sand fly, and the amastigote form (oval, non-motile) located intracellularly i n t he v ertebrate h ost (figure 1 .1). After th e b iting of a f emale phlebotomine sand fly and inoculation of the promastigote leishmanial form in the skin (dermis), promastigotes a re pha gocytosed b y t he m acrophages a nd get c onverted t o a mastigotes and multiply within the vacuoles of macrophages. After multiplication, parasites disseminate through the lymphatic and vascular system and infect other monocytes and macrophages throughout the reticulo-endothelial s ystem, r esulting i n i nfiltration of bone m arrow, he patomegaly, splenomegaly and sometimes enlarged lymph nodes (lymphadenopathy).
Figure 1.1: Parasitic life cycle of Leishmania
The cl inical o utcome of Leishmania infection d epends o n t he s pecific cell-mediated immu ne response of the individuals. Symptomatic VL is due to the failure of the specific cell-mediated immunity l eading t o l ack of a ctivation of t he macrophages t o o vercome t he infection. Most infections remain asymptomatic in immunocompetent individuals but the risk of clinical disease drastically increases in cases of malnutrition or concomitant immunosuppressive diseases such as HIV infection (Murray, 1999).
1.1.3 The clinical features
VL is the severest form among the leishmaniases. Following an incubation period of generally 2 to 6 months, VL patients present with signs and symptoms of persistent systemic infection (prolonged irregular fever, weight loss, anemia, fatigue, loss of appetite and weakness) and parasite invasion of the blood and the reticulo-endothelial system (enlarged spleen and liver).
Fever is usually associated with chills and rigor and may be intermittent.
As in tuberculosis, only a fraction of those infected with L. donovani or L.infantum progress to clinical d isease (Singh et al. 2002). Few prospective s tudies ha ve do cumented t he r atio of asymptomatic infection to clinical disease by estimating the number of incident sero-conversions to incident new VL cases due to L. donovani. Bern et al. (2007) in Bangladesh used Leishmanin Skin Test (LST) and rK39 dipstick test as markers of infection and found a 4 to 1 ratio between incident infection and disease. Ostyn et al. (2011), using the Direct Agglutination Test (DAT) found a r atio o f 9 t o 1 i n B ihar, India. A lthough r atios m ay b e s kewed be cause s ome of these”asymptomatically in fected” individuals c ould pr ogress t o di sease, the majority d oes not (Gidwani et al. 2009). Even if asymptomatically infected individuals can be assumed to be far less infectious to the biting sand fly, they might be able to drive the epidemic as they outnumber the active VL cases, as demonstrated by mathematical modeling (Stauch, 2011). The exact role of these asymptomatic infections in the transmission of disease is thus not well understood.
In contrast t o V L, P KDL is c haracterized b y a spectrum of s kin l esions r anging from h ypo- pigmented macules, papules to nodules or combinations over the face and trunk (Zijlstra et al.
2003). Persons w ith PKDL do not f eel s ick and as the d isease h as usually only co smetic significance for the individual, diagnosis and treatment is rarely sought.
1.1.4 Diagnosis
Visualization of the amastigotes form of the parasite by microscopic examination of the tissue aspirate from bon e m arrow a nd o r s pleen pun cture i s t he c lassical c onfirmatory t ests for V L.
Although the specificity of microscopy is high, its sensitivity varies, being higher for spleen (93- 99%) than for bone marrow (53-86%). Spleen aspiration can be complicated by life-threatening hemorrhage in about 0.1% of individuals and therefore requires strict precautions, training and technical e xperts, a s w ell a s f acilities f or nur sing s urveillance, bl ood t ransfusion a nd s urgery.
The detection of parasite DNA b y pol ymerase chain reaction (PCR) in blood or bone marrow aspirates is s ubstantially more s ensitive th an microscopic e xamination, a lthough its u se i s
currently r estricted t o r eferral h ospital an d r esearch cen ter ( WHO 2 010).Because o f its h igh sensitivity, PCR detects more asymptomatic infections than microscopic examinations.
Serological t ests ba sed on i ndirect immunofluorescent a ntibody t est ( IFAT), enzyme l inked immunosorbent assay (ELISA) or western blotting have shown good diagnostic accuracy in most studies but r equire e quipment t hat i s poor ly adapted t o f ield s ettings. T he f ormol ge l ( or aldehyde) test is obsolete and should no longer be used for diagnosis. Two serological tests- the direct a gglutination t est a nd t he r K39 a ntigen-based i mmunochromatographic t est- were specifically developed for field use and have shown good diagnostic accuracy in most endemic areas (Bern et al. 2000; Sundar et al. 2006; Chappuis et al. 2007).The rK39-based tests are easy to pe rform, qui ck, c heap a nd g ive r eproducible r esults a nd c an t herefore be us ed for e arly diagnosis of VL at both peripheral and central level. It improves the access of patients with VL to care in poor rural areas where most of them live.
As t he v ast m ajority o f cas es o f P KDL occur in pa tients w ith pr evious c oncomitant V L i n endemic rural areas, the diagnosis is mainly clinical. The diagnosis of PKDL can be confirmed by finding parasites in skin lesion samples obtained by biopsy or scraping of skin slit
1.1.5 Treatment
VL remains a challenging disease due to the limited therapeutic options. Pentavalent antimonials (sodium s tibogluconate, SSG ) ha ve be en t he first l ine t reatment f or V L for ov er 70 years.
Antimonials ar e t oxic d rugs w ith f requent ad verse s ide ef fects s uch as c ardio-, hepato-, and nephrotoxicity (Ballou et al. 1987). In India and Nepal, antimonials are no longer in use due to increasing reports of treatment failure and drug resistance (Sundar 2001; Rijal et al. 2003). As an alternative opt ion, four highly e ffective drugs ar e now available f or V L: Miltefosine, Amphotericin B deoxycholate, Liposomal amphotericin B and Paromomycin (Murray 2000).
Since 2005, M iltefosine ha s be en a dded t o t he a rmamentarium a s 1st line therapy f or V L elimination initiative in the Indian subcontinent (Van Griensven et al. 2010). Miltefosine is the first o ral d rug for VL and w as o riginally d eveloped as an an ti-cancer dr ug. T he dr ug i s administered orally for 28 days, but possibly teratogenic and cannot be administered to pregnant women or women of childbearing age that refuse the use of contraceptives (Sundar et al. 2002).
Amphotericin B de oxycholate is a dministered i ntravenously with 15 -20 s low i nfusions o f 1mg/kg/body w eight given e ither on a da ily or alternate ba sis, t hus r equiring hospitalization (Bhattacharya et al. 2004). Amphotericin B is the second line of choice for VL treatment in the Indian subcontinent.
Liposomal a mphotericin B (Ambisome; G ilead), a lip id f ormulation o f a mphotericin B , is considered the best monotherapy for anthroponotic VL (WHO 2010). A single dose of liposomal amphotericin B d elivered i ntravenously, w as shown t o be ve ry e ffective i n t he Indian subcontinent a nd r esulted i n l ess s ide-effects co mpared t o o ther an ti-leishmanial tr eatment (Sundar et al. 2010).
Aminosidine ( paromomycin), an a ntibiotic w ith g ood a nti-leishmanial act ivity h as b een registered in India since 2006. It is administered intramuscularly for 21 days, has few side effects and is very cheap. At a dosage of 15mg per kg per day it has been shown to be effective in India (Sundar et al. 2007).
For t he t reatment of P KDL, antimonials, amphotericin B , liposomal a mphotericin B and miltefosine are used, but studies on efficacy and effectiveness of these treatments are still lacking (WHO 2012).
1.2 Epidemiology of Visceral leishmaniasis 1.2.1 Global epidemiology
Visceral leishmaniasis is reported in large areas of the tropics, subtropics and the Mediterranean region (79 countries) (figure 1.2), primarily in the developing world with 200 million people at risk ( Desjeux 1996) . R ecently, W orld H ealth O rganization e stimated t hat a bout 200,000 t o 400,000 new cases of VL worldwide and 50,000 to 60,000 de aths occur annually. It has been estimated that more than 90% of VL is concentrated in only six countries: Bangladesh, Brazil, Ethiopia, India, Nepal and Sudan (WHO 2010; Alvar et al. 2012).
However, due t o a lack of reliable d ata t here i s m uch unc ertainty on reported f igures o f V L incidence. In p articular, mortality d ata a re ex tremely s parse an d generally r epresent h ospital- based deaths only. In the Indian subcontinent, the current officially reported figures are obtained through pa ssive case d etection ( i.e. onl y t hose who pr esent t hemselves t o t he publ ic he alth facilities) in government health services and usually do not include cases detected by the private for-profit sector, which constitute a majority of the VL care providers in India and Bangladesh.
Therefore, these figures are largely underestimating the actual number of cases (Desjeux 1992).
Extrapolation from the official data sources is also difficult due to the focal distribution of VL cases ( Bern et al. 2008). A num ber of s tudies have e stimated t he de gree of unde rreporting, although these studies were limited to specific geographical areas. For example, Desjeux (1992) found a 1: 5 r atio of r eported t o unde rreported of V L c ases i n a c ommunity s urveys i n India.
Singh et al. ( 2006) doc umented unde rreporting b y a f actor of e ight i n a c ommunity i n Muzzafarpur di strict i n B ihar, India i n 2001 -2003 a nd m ore r ecently Singh et al. (2010) estimated underreporting by a factor of four in Vaishali district, also in Bihar, India.
Figure 1.2: The distribution of visceral leishmaniasis worldwide (Chappuis et al. 2007) The majority of VL cases occur in just six countries: Bangladesh, Brazil, Ethiopia, India, Nepal and Sudan.
1.2.2 VL in the Indian subcontinent
Kala-azar i s en demic i n t he Indian s ubcontinent, affecting t he G angetic plains o f Bangladesh, India, and Nepal (figure 1.3). The annual VL incidence in this focus is estimated at 160,000 – 315,000 c ases, or 80% of t he w orldwide V L b urden ( Alvar et al. 2012).The w hole r egion i s considered as d omestic “heartland” for VL ( Bern et al. 2008). About 190 m illion pe ople a re considered at risk of VL (Sundar et al. 2008). There is a huge gap between the reported and the estimated incidence due to the underreporting of VL cases.
Nepal(lowlands) India (Bihar) Sudan
High endemicity in VL foci
Brazil
Bangladesh Ethiopia
Figure 1.3: VL endemic areas in Indian subcontinent (highlighted)
VL is a major public health concern in large parts of the India, Bangladesh, and Nepal (Alvar et al. 2008; Das et al. 2009; Boelaert et al. 2009). In the Indian subcontinent, VL is mainly due to Leishmania donovani, transmitted by a sand fly, Phlebotomus argentipes and the transmission is mostly anthroponotic. Kala-azar has been reported in this region for more than 100 years and believed t o ha ve b een i ntroduced f rom E ast A frica t o t he Indian s ubcontinent, w here i t ha s infected m ostly hum ans. The a nnual r eported nu mber of V L c ases i n t hese t hree co untries i s shown in figure 1.4. India has experienced recurrent epidemics in 1977 ( ~100 000 c ases) with the recent ones in 1991-1992 (~250 000 cases) (Thakur et al. 2008). More than 90% of all cases in India a re r eported f rom B ihar s tate. Bangladesh h as r eported a p rogressive i ncrease i n V L incidence from the mid-1990s. In Nepal, the first officially recorded case of VL was in 1980 from one district and now 12 l owland districts situated in south-eastern Nepal are affected with estimated 8.5 million population at risk (total population: 29 million). In recent years (since 2006 and 2007) however, the country-wise case load of VL in Nepal is in decreasing trend.
Figure 1.4: VL cases in the Indian sub-continent (Source: Country profile 2010)
PKDL patients may have a major epidemiological importance as they are considered a reservoir for VL transmission (Zijlstra et al. 2003). The incidence of PKDL varies from country to country for reasons that are not entirely clear. In India, PKDL is reported in 5-10% of patients treated for VL usually after an interval of 2 t o 4 years (Ramesh & Mukherjee 1995). In Bangladesh, it is seen in 6-10% of patients usually occurring within 36 months after VL treatment (Rahman et al.
2010; M ondal et al. 2010). P KDL i s not a s erious c linical c ondition but t he l esions h arbor abundant parasites infectious to sandflies, and are the putative ‘reservoir’ in anthroponotic VL between epidemic cycles (Addy & Nandy, 1992). So far, there is no systematic epidemiological data on PKDL from Nepal.
Economic burden of VL on households
Kala-azar i s a di sease o f pove rty a ffecting t he poor a nd marginalized communities, g enerally living in th e r emote v illages ( Boelaert et al. 2009). The di sease is mo stly e ndemic in th e s o- called “l east d eveloped countries” ( e.g. N epal) or i n t he poor est r egions of “ middle i ncome”
countries ( e.g. B ihar s tate i n India). Several s tudies of t he c ost or b urden of i llness ha ve addressed the economic burden of VL on households. On the Indian subcontinent, the median
total expenditure by a patient on VL treatment was 1.2 to 1.4 times the annual per capita income (Rijal et al. 2006, M eheus et al. 2006). A dhikari et al. (2009) r eported t hat up t o 26% of previously non -poor ho useholds w ere pus hed i nto pove rty as a di rect r esult of out -of-pocket expenditures o n V L car e w hile R ijal et al. 2006 s howed t hat t he ( median) di rect a nd i ndirect costs of a VL episode were equal to one year of median per capita income.
The economic burden of VL on household is measured in terms of two broad categories of cost components. These include the direct costs (medical & non-medical) associated with accessing VL ca re (e.g. consultation f ee, investigations, transportation) an d t he i ndirect co sts as sociated with loss of productivity due to VL illness, which measures into income loss to the households (Meheus et al. 2006). Details on the economic burden of VL are presented in chapter 4.
1.3 VL control in the Indian subcontinent 1.3.1 VL control options
VL t ransmission i s m aintained i n a c omplex bi ological s ystem i nvolving t he hum an hos t, the parasite, the sand f ly vector a nd i n s ome s ituations a n a nimal r eservoir. T herefore, c ontrol i s unlikely to be achieved by a single intervention. In the absence of a vaccine, a combination of early diagnosis and case management strategies, integrated vector control and, if relevant, animal reservoir control is required and should be tailored to each context (Boelaert et al. 2000, WHO 2010).
Theoretically, control of anthroponotic VL can be done at three levels: (i) preventing individuals from g etting bitten b y s andflies (vector c ontrol), ( ii) a v accine f or h uman protecting a gainst Leishmania infection, a nd ( iii) appropriate and pr ompt t reatment of V L and P KDL patients (early diagnosis and treatment). Preventing of vector bites can be achieved b y indoor residual spraying (IRS) of insecticides or avoiding human-vector contact using bed nets i.e. long lasting insecticide-treated nets (ITN). IRS is th e mo st widely u sed i ntervention a nd i s i mplemented routinely in India and Nepal by spraying houses twice yearly in villages where a case of VL had been reported in the year before. IRS has been shown to effective in reducing sand fly density in India and N epal w here the sand f ly (Phlebotomus argentipes) i s e ndophilic a nd r ests i nside cracks an d crevices o f mud p lastered w all ( Das et al. 2008; K umar et al. 2009).The m alaria eradication campaigns of the 1950s as a collateral effect also wiped out the VL epidemics for several years in India an d B angladesh. V L d id n ot r eappear i n t he areas w here IRS w as continued in the 1970’s-1980’s (Joshi et al. 2006). However, the results of IRS have been less convincing during recent years, and emerging resistance to insecticides is a concern, definitely in
India w here dichloordifenyltrichloorethane (DDT) is s till in u se. In N epal, IRS is b ased o n synthetic pyrethroids a nd is li mited to h igh V L tr ansmission f oci which a re identified f rom routine surveillance data.
Insecticide t reated nets ( ITNs) ha ve be en di stributed i n India and N epal, t he e vidence on t he effectiveness o f ITNs i s m ixed, though several observational studies showed sleeping und er a bed nets to be a protective factor against VL (Bern et al. 2000; 2005). However a recent evidence from a community in tervention tr ial o f lo ng la sting in secticidal n ets ( LLINs) in th e Indian subcontinent resulted i n a 25% r eduction i n ve ctor de nsity but did not l ead to a reduced V L incidence compared to control areas, where commercially available bed net use was high (Picado et al. 2010).
1.3.2 VL elimination programme in the Indian subcontinent
Since 2005, t he government of B angladesh, India a nd N epal are e ngaged i n a regional collaborative effort to control and eliminate VL from the region. The target of this campaign is to reduce the annual incidence rate of VL to below 1 per 10,000 population at district level by the year 2015 (WHO 2005).
The elimination of the disease is deemed feasible due to its unique features: firstly, the disease is anthroponotic in nature, with man as the only known reservoir of infection and P. argentipes the only known vector. Secondly, new tools for diagnosis i.e. rK39 dipstick and availability of an effective oral drug miltefosine, have facilitated decentralized c ase m anagement including effective ve ctor c ontrol methods i f a pplied c orrectly (WHO 2005; B hattacharya et al. 2006).
Thirdly, the occurrence of VL is relatively well circumscribed and limited to 56 districts in India, i.e. the adjacent states of Bihar, Jharkhand, West Bengal and Uttar Pradesh, 12 districts in south- eastern Nepal, and 31 districts in Bangladesh (Huda et al. 2011). Last but not least, a high level of political commitment exists in the three countries for this regional initiative.
The VL elimination initiative is based upon five main strategies (WHO 2005, Joshi et al. 2008) 1. Early diagnosis and complete case management
2. Integrated vector management and vector surveillance
3. Effective disease surveillance through passive and active case detection 4. Social mobilization and building partnerships
5. Clinical and operational research.
In t he a bsence of anti-leishmanial v accines at present, early di agnosis and case m anagement strategies including integrated vector control are the main strategies of the ongoing elimination programme. To achieve early diagnosis and complete case management, rK39 dipstick test and
miltefosine are b eing m ade freely available at public h ealth f acilities in the endemic ar eas.
Amphotericin B a nd l ipid f ormulations of a mphotericin B ( Ambisome) ar e k ept as 2nd line treatment; paromomycin as possible alternative (WHO 2005).
Integrated v ector control ( IRS and ITNs) is one of t he pi llars of the current V L e limination programme, alongside early case detection and treatment. The aim of vector control programme is to reduce or interrupt transmission of disease. An effective strategy for reducing VL incidence is to control sand fly vectors, especially in domestic and peridomestic transmission habitats. A number of control methods are available, including chemicals, environmental management and personal protection (WHO 2010). VL control has often been integrated with that of other vector- borne disease. For example, after intensive attempts to eradicate malaria in the 1950s and 1960s by IRS with DDT, the prevalence of VL fell dramatically in many countries. In this approach, integrated ve ctor m anagement pr ogrammes c ombine i nterventions a nd r esources a nd t arget several v ector-borne d iseases ( e.g. m alaria, d engue, filariasis) i n o ne a rea. H owever, t here ar e number of reports about DDT resistance in sandflies (Kishore et al. 2006).
Indoor residual spraying is one the main means for controlling endophilic sand fly vectors and should b e ta rgeted to lo calities w ith a ctive tr ansmission ( focal s pray). T herefore, g ood knowledge of t he e pidemiology of V L a nd l ocal ve ctor b ehavior a nd e cology i s ne eded.
Insecticide-treated nets are an effective, relatively cheap, sustainable method for sand fly control.
The t erm co vers b oth n ets t hat ar e i mpregnated at r egular i ntervals a nd l ong-lasting n ets, in which insecticide is incorporated or coated on the fibre and which remain effective for 2-3 years.
Under i deal c onditions, i nsecticide-treated n ets with p eople s leeping u nder t hem a ct as b aited traps th at k ill sandflies. S everal c ommunity t rials i n a reas i n e ndemic f or V L also s howed reductions in vector density in clusters where insecticide-treated nets w ere used (Picado et al.
2010). T he effectiveness of l ong-lasting ne ts on reducing c linical out comes of V L (infection, disease) is being evaluated in several countries (WHO 2010).
The r emaining t hree components of the s trategy, d isease s urveillance, s ocial mo bilization a nd operational research a re ma inly aimed at s upporting th e f irst tw o c omponents. D isease surveillance should include s urveillance o f P KDL because o f its r eservoir r ole in th e d isease transmission during inter-epidemic period. VL surveillance includes detection of passive cases at government health facilities, which is complemented by active case detection at least once a year in t he be ginning a nd i f possible t wo t imes pe r year. This w ill b ecome more imp ortant a s th e number o f c ases r eported b y passive d etection d eclines an d will es timate t he t rue d isease prevalence to achieve the elimination target. However, complete and adequate surveillance data
for VL in the sub-continent has been lacking mainly due to underreporting and under-diagnosis (Desjeux 2001; Singh et al. 2006). In Nepal, VL is mainly treated at public health facilities and access to treatment is provided free of charge in the public health structures, and is not available in private sector. Thus, only those patients attending the public health facility are recorded in the ministry o f h ealth s urveillance ( Bista 1998) . But th ere is a different s cenario for PKDL as persons with PKDL do not feel sick, the disease has only cosmetic significance for the individual and t reatment i s r arely sought at primary h ealthcare level an d t hey preferred t o s eek car e at dermatologist.
Social mobilization is also an important element in the elimination of VL and for the success of early di agnosis a nd t reatment. Similarly, e ffective behavioral change communication can al so help in promoting early VL care seeking and adherence to treatment. Community participation at family and i ndividual l evel i n i ndoor r esidual s praying i s ne cessary to r educe m an-vector contact, a nd t herefore s ocial m obilization i s c onsidered a s a n in tegral p art o f th e e limination programme right from the inception. Moreover, (i) partnership at different levels such as district and state levels, at national level and with international stakeholders, (ii) networking, and (iii) collaboration with other health-related programmes can also further support the implementation of the elimination programme.
Operational research helps to include new treatment strategies and diagnostic techniques during the elimination programme. These studies should allow a rapid assessment and mapping of the disease f or m onitoring the e ffectiveness of i ntervention s trategies. In a ddition, ope rational research i s g enerally r ecommended t o e stablish mechanisms t o m onitor drug r esistance, dr ug efficacy and quality of drugs used in the programme. Research is also needed in searching for cases of PKDL and its treatment. Implementation research is required in pilot districts where the programme s hould be monitored c losely t o i dentify constraints, l esson l earnt a nd pos sible solutions to overcome obstacles in health care delivery and disease control programmes.
1.3.3 References
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Bern C, Maguire JH, Alvar J (2008) Complexities of assessing the disease burden attributable to Leishmaniasis. PLoS Neglected Tropical Diseases 2,e313.
Bhattacharya SK, Jha TK, Sundar S, Thakur CP, Engel J, Sindermann H (2004) Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India. Clinical Infectious Disease 15, 217-221.
Bhattacharya SK, Sur D, Sinha PK, Karbwang J (2006) Elimination of leishmaniasis (kala-azar) from the Indian subcontinent is technically feasible and operationally achievable. Indian Journal of Medical Research 123, 195-196.
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