Kala-azar in Nepal: public health evidence to support the elimination initiative

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Promoter:

Prof. Dr. Bruno DUJARDIN

Research Center "Policies and Health Systems – International Health"

School of Public Health Université libre de Bruxelles Brussels, Belgium

Kala-azar in Nepal: public health evidence to support the elimination initiative

Surendra Kumar URANW

Co-promoter(s):

Prof. Dr. Marleen BOELAERT Unit of Epidemiology and Control of Tropical Disease

Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium

Prof. Dr. Suman RIJAL

Department of Internal Medicine and Tropical & Infectious Disease Centre B.P. Koirala Institute of Health Sciences

Dharan, Nepal

Dépôt Légal : D/2013/Surendra Kumar URANW, Auteur-Éditeur

DoCToRAL THESIS PRESENTED To oBTAIN THE DEgREE of DoCToR IN PUBLIC HEALTH SCIENCES September 2013 U N I v E R S I T É L I B R E D E B R U x E L L E S – P ô L E S A N T É

É c o l e d e S a n t É P u b l i q u e

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Doctoral committee

Promoter

Prof. Dr. Bruno Dujardin,

Research Center: "Policies and Health Systems – International Health"

School of Public Health, Université Libre de Bruxelles, Belgium Co-promoter(s)

Prof. Dr. Marleen Boelaert,

Unit of Epidemiology and Control of Tropical Disease

Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium Prof. Dr. Suman Rijal,

Department of Internal Medicine and Tropical & Infectious Disease Center B.P. Koirala Institute of Health Sciences, Dharan, Nepal

Member of the Jury

Prof. Dr. Philippe Donnen (President of the Jury) Policies and Health Systems

School of Public Health, Université Libre de Bruxelles, Belgium Prof. Dr. M. Dramaix

Epidemiology and biostatistics

School of Public Health, Université Libre de Bruxelles, Belgium Prof. Dr. Isabelle Godin (Secretary of the Jury)

Social approaches to health

School of Public Health, Université Libre de Bruxelles, Belgium Prof. Dr. Philippe Goyens

Head of clinic, HUDERF Bruxelles, Belgium Prof. J. Macq

Faculty of Public Health, UCL Bruxelles, Belgium

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Dedicated to my beloved late mother (the fountain of inspiration)

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Kala-azar in Nepal: public health evidence to support the elimination initiative Visceral leishmaniasis (VL), also known as kala-azar, is a vector-borne parasitic disease caused by leishmania parasites that are transmitted through the bite of an infected female sand fly. The disease affects the visceral organs, causing chronic fever, weight loss, anemia, swelling of liver and spleen. Kala-azar is nearly always fatal if treatment is not provided timely. Kala-azar is a major publ ic he alth c oncern i n l arge pa rts of India, B angladesh, a nd Nepal. These c ountries, along with Sudan and Brazil, hold about 90% of the 200 000 – 400 000 e stimated annual VL cases worldwide. On the Indian subcontinent, VL is mainly caused by Leishmania donovani, and transmitted by a sand fly, Phlebotomus argentipes and the transmission is mostly anthroponotic (man to sand fly to man). Kala-azar is a significant public health problem in Nepal. Since 2005 the governments of India, Bangladesh and Nepal are engaged in a regional collaborative effort to control and eliminate VL from the region. Early diagnosis and prompt treatment, alongside with vector control are the two main pillars of the ongoing elimination programme. The target of this campaign is to reduce the annual incidence rate of VL to less than 1 per 10,000 population per year at district level by 2015.

Kala-azar is a focal disease and predominantly affects the poor and marginalized communities with limited access to healthcare services. To achieve the target of elimination initiative, it w ill require considerable efforts to b e imp lemented timely a nd effectively. Effective c ontrol w ill ultimately de pend on a number of public h ealth interventions i ncluding e arly di agnosis and prompt t reatment. However, l ack of ad equate ep idemiological and e conomical data is also considered as a major handicap in the proper implementation of the control programme. At the outset of m y t hesis w ork, t here a re still a num ber of i mportant know ledge gaps for V L elimination, some of which I chose as topics for my PhD research, such as the understanding of VL epidemiology, economical impact of VL on the households as well as the outcomes of the currently u sed an ti-VL dr ugs etc. By focusing on s ome of t hese knowledge g aps, we have wanted to g enerate ev idence and o ffer s ound recommendations f or policy development a nd implementation to contribute to the ongoing elimination initiative in the Indian subcontinent in general and in Nepal in particular.

The general objective of this thesis was to provide evidence for more rational VL control to the ongoing elimination initiative in Nepal.

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The specific o bjectives in cluded in th is th esis are: (i) understanding the e pidemiology of Leishmania donovani infection and disease in high-transmission areas; (ii) understanding the risk factors for VL with regards to possible urban transmission; (iii) providing a better understanding on the health seeking behavior and economic burden of Kala-azar on households; (iv) monitoring clinical outcomes and patient adherence to currently used anti-VL drugs; and (v) estimating the prevalence, risk and risk factors of post-kala-azar dermal leishmaniasis among past treated VL patients in Eastern Nepal. The r esearch work on these s pecific objectives is framed i nto t wo sections: (i) epidemiology and economic aspects of VL; and (ii) treatment-related studies on VL in Nepal.

In chapter 4, we have compiled all six publications.

For t he f irst r esearch question “to understand t he e pidemiology of Leishmania donovani infection”, we obtained the data of bl ood s amples within t he f ramework of a c ommunity intervention trial of insecticide treated nets, named KALANET. Our study showed that overall 9% of the study population (n=5397) was positive for a Leishmania donovani serology test, used as a m arker of current or past infection, varying between 4.7% and 15.2% in between clusters.

Men had a higher percentage of L. donovani infection (9.9%) than women (8.3%). The odds of infection increased with a ge a nd decreased with a sset s core group. T he role of a symptomatic infections in the transmission of Kala-azar in the Indian subcontinent is not clear; thus, further research in this direction is needed from the elimination initiative.

The second research question, “Understanding the risk factors for VL with regards to possible urban transmission at Dharan town”, we conducted an outbreak investigation including a case- control s tudy among t he urban residents of Dharan t own. We f ound that cas es w ere s trongly clustered, with 70% r esiding i n 3 out of 19 n eighborhoods. Most affected w ere t he m ore peripheral wards of the town. These wards are typically a rural-urban interface as most residents depend on da ily manual labor for their livelihood, so individuals may have been exposed to L.

donovani infection elsewhere. However our study showed a very strong association between VL and certain housing f actors: those l iving i n a thatched houses without windows had 3-4 times higher odds of Kala-azar. Sleeping on a bed and upstairs were protective. Proximity to previous VL c ases w as a s trong r isk f actor f or V L. T hese as sociations ar e al l co nsistent w ith local transmission. The entomological data provided further evidence in support of local transmission of V L i nside t he D haran t own, as w e w ere ab le t o d emonstrate t he p resence as t he vector P.

argentipes, some of which infected w ith the p arasite L. donovani. These findings a re hi ghly

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relevant for pol icy m akers; i n V L endemic areas ap propriate s urveillance an d d isease control measures must be adopted not only in rural areas but in urban areas as well.

For the third research question we documented “the burden of VL on the households from the patients’ perspective”. We found that the median total cost of VL was US$ 165 per episode and that the economic burden of VL across all households was 11% of annual household income or 57% of median annual per capita income. These costs included both direct costs (medical and non-medical o ut-of-pocket e xpenditures) a nd i ndirect c osts ( productive t ime l osses due t o illness). Given the extreme poverty of the affected households, a VL episode is still catastrophic to most of them (51%) in Nepal. While free VL diagnosis and drugs at public health facilities have b een an imp ortant p olicy measure in N epal to lo wer f inancial b arriers and to improve access to VL diagnosis and care, the economic impact of VL is still considerable because of the duration of t reatment a nd l ength of hos pitalization. In a ddition hous eholds a lso incurred substantial c osts dur ing t he he alth s eeking pha se ( prior t o c orrect V L di agnosis) a s w ell a s through t he s trategies t hey us ed t o c ope w ith the c osts of i llness s uch a s l oans. Therefore, intensified efforts are needed to further reduce the burden of VL to affected households. These may i nclude s hortening the dur ation of s tay a t h ospital a nd e xpanding d emand-side f inancing mechanisms to cover a wider range of costs incurred by households.

The fourth research question covers the treatment outcomes and patient adherence to miltefosine (MIL), the only oral drug for VL. We launched a prospective cohort study of 120 V L patients treated with MIL and followed them up f or up t o 12 m onths after the completion of therapy to document clinical outcomes. Drug compliance, parasite drug resistance, re-infection and a series of clinical parameters were assessed, and their potential role in treatment failure was explored.

We found the initial cure rate was 95.8% and cure rate at 6 months after treatment was 82.5%, which further dropped to 73.3% at 12 months after MIL treatment. The relapse rate at 6 and 12 months was 10.8% and 20.0% respectively. No significant clinical risk factors of relapse apart from age <12 years were found. Parasite fingerprints of pre-treatment and relapse bone marrow isolates within eight patients were similar, suggesting that clinical relapses were not due to re- infection w ith a n ew strain. T he m ean pr omastigote MIL susceptibility ( 50% i nhibitory concentration) of i solates f rom de finite c ures was s imilar t o t hat o f r elapses. M oreover Miltefosine blood levels at the end of treatment were similar in cured and relapsed patients. The reduced effectiveness of MIL observed in our study is an alarming signal for the VL elimination campaign, urging for further review and cohort monitoring.

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We also assessed patient adherence to unsupervised single-drug MIL treatment for VL at three different h ealthcare s ettings. W e found t hat patient adherence t o MIL was 83%. P redictors o f adherence were male sex and knowing the duration of treatment. Gastrointestinal side effects and negligence a fter t he r esolution of c linical s ymptoms of V L w ere t he m ain r easons f or poor adherence. Under t he c urrently c hosen policy of a mbulatory t reatment (which m akes d irectly observed t reatment (DOT) not a n opt ion), t he b est w ays t o i mprove adherence may be b etter counseling at the start of the treatment, including comprehensive informations on VL and on side effects and action of miltefosine, and on the importance of follow-up visits.

The fifth research question was to calculate the risk of PKDL in past treated VL patients and risk factors for PKDL development. PKDL patients are considered infectious to sand flies and may therefore play a role as a reservoir in episodes of absence of active VL cases. Our study shows that the occurrence of PKDL in patients with past treated VL was low (2.4%) in Nepal compared to ne ighboring c ountries India an d B angladesh. Overall, t he r isk t o de velop P KDL w as 1.4%

within 2 years after VL t reatment; 2.5% w ithin 4 years a nd 3.6 % w ithin 8 years. PKDL was more c ommon in th ose w ith in complete V L treatment a nd in s ettings w ith little tr eatment supervision. P olicy m akers should i nclude surveillance and case m anagement of P KDL i n t he ongoing VL elimination programme in Nepal.

In the last chapter of the thesis the main findings of the six studies are summarized, together with some fu rther in-depth discussions on pa rticular i ssues, s uch a s epidemiological di fferences between Nepal and the neighboring Indian state of Bihar, possible explanations for the observed male pr edominance i n L.donovani infection an d d isease r ates, an d av ailable s trategies f or improving adherence, with pros and cons in the context of the elimination initiative.

Though m aking pol icy r ecommendations i s be yond t he s cope of t his t hesis, w e c onclude t hat further efforts are n eeded t o: (i) i ncrease aw areness for t he changing ep idemiology o f V L for disease control, (ii) lower the financial barriers and improve the access to VL diagnosis and care, (iii) regular monitor the effectiveness of drug regimens and counseling the patients to optimize the treatment adherence, and (iv) improve PKDL surveillance and case management in ongoing control programme.

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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).

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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).

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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

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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 1^st 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.

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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.

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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

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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.

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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

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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

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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 southeastern 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

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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 2^nd 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

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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.

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1.3.3 References

__________________________

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Boelaert M, Meheus F, Sanchez A, Singh SP, Vanlerberghe V et al (2009) The poorest of the poor: a poverty appraisal of households affected by visceral leishmaniasis in Bihar, India.

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leishmaniasis: what are the needs for diagnosis, treatment and control? Nature Reviews Microbiology 5, 7-16.

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Desjeux P (1992) Human leishmaniasis: epidemiology and public health aspects. World Health Stat Q 45, 267-275.

Desjeux P (1996) Leishmaniasis. Public health aspects and control. Clin Dermatol 14, 417-423.

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Joshi A, Narain JP, Prasittisuk C, Bhatia R, Hasim G, Alvar J et al (2008) Can visceral

leishmaniasis be eliminated from Asia? Journal of Vector Borne Diseases 45, 105-111.

Kumar V, Kesari S, Dinesh DS, et al. (2009) A report on the indoor residual spraying (IRS) in the control of Phlebotomus argentipes, the vector of visceral leishmaniasis in Bihar (India): an initiative towards total elimination targeting 2014 (series-1). J Vector Borne Dis 46, 225-229.

Kishore K, Kumar V, Kesari S, Dinesh DS, Kumar AJ, Das P, Bhattacharya SK (2006) Vector control in leishmaniasis. Indian Journal of Medical Research 123, 467-472.

Lukes J, Mauricio IL, Schönian G, Dujardin JC, Soteriadou K, Dedet JP et al. (2007) Evolutionary and geographical history of the Leishmania donovani complex with a revision of current taxonomy. Proc Natl Acad Sci USA 29, 9375-9380.

Meheus F, Boelaert M, Baltussen R, Sundar S (2006) Costs of patient management of visceral leishmaniasis in Muzaffarpur, Bihar, India.Tropical Medicine and Internationl Health 11,1715-24.

Mondal D, Nasrin KN, Huda MM, Kabir M, Hossain MS et al (2010) Enhanced case detection and improved diagnosis of PKDL in a kala-azar endemic area of Bangladesh. PLoS Neglected Tropical Diseases 4, e832.

Moral L, Rubio EM & Moya M (2002) A leishmanin skin test survey in the human population of l’Alacanti region (Spain): implication for the epidemiology of Leishmania infantum infection in southern Europe. Transactions of the Royal Society of Tropical Medicine and Hygiene 96, 129-132.

Murray HW (1999) Kala-azar as an AIDS-related opportunistic infection. AIDS Patient Care STDS 13, 459-465.

Murray HW (2000) Treatment of visceral leishmaniasis (kala-azar): a decade of progress and future approaches. International Journal of Infectious Diseases 65, 193-196.

Ostyn B, Gidwani K, Khanal B, Picado A, Chappuis F, Singh SP et al (2011) Incidence of symptomatic and asymptomatic Leishmania donovani infections in high-endemic foci in India and Nepal: a prospective study. PLoS Neglected Tropical Diseases 5:e1284.

Picado A, Singh SP, Rijal S, Sundar S, Ostyn B, Chappuis F et al. (2010) Longlasting insecticidal nets for prevention of Leishmania donovani infection in India and Nepal:

paired cluster randomised trial. BMJ 341, c6760.

Picado A, Das ML, Kumar V et al. (2010) Phlebotomus argentipes seasonal patterns in India and Nepal. Journal of Medical Entomology 47,283-286.

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Rahman KM, Islam S, Rahman MW, Kenah E, Galive CM et al (2010) Increasing incidence of post-kala-azar dermal leishmaniasis in a population based study in Bangladesh. Clinical Infectious Diseases 50:73-76

Ramesh V, Mukherjee A (1995) Post-kala-azar dermal leishmaniasis. International Journal of Dermatology 34: 85-91.

Rijal S, Chappuis F, Singh R, Bovier PA, Acharya P, Karki BMS et al (2003) Treatment of visceral leishmaniasis in south-eastern Nepal: decreasing efficacy of sodium

stibogluconate and need for a policy to limit further decline. Transactions of the Royal Society of Tropical Medicine and Hygiene 97, 350-354.

Rijal S, Koirala S, Van der Stuyft P, Boelaert M (2006) The economic burden of visceral leishmaniasis for households in Nepal. Transactions of the Royal Society of Tropical Medicine and Hygience 100, 838-841.

Schaefer KU, Kurtzhals JA, Gachihi GS, Muller AS, Kager PA (1995) A prospective sero- epidemiological study of visceral leishmaniasis in Baringo District, Rift Valley Province, Kenya, Transactions of the Royal Society of Tropical Medicine and Hygiene 89, 471-475.

Singh S, Kumari V, Singh N (2002) Predicting kala-azar disease manifestations in asymptomatic patients with latent Leishmania donovani infection by detection of antibody against recombinant Rk39 antigen. Clinical and Diagnostic Laboratory Immunology 9, 568-572.

Singh S, Reddy DCS, Rai M, Sundar S (2006) Serious underreporting of visceral leishmaniasis through passive case reporting in Bihar, India. Tropical Medicine and International Health 11; 899-905.

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Sundar S, Maurya R, Singh RK et al. (2006) Rapid, non-invasive diagnosis of visceral leishmaniasis in India: comparison of two immunochromatographic strip test for detection of anti-K39 antibody. Journal of Clinical Microbiology 44, 251-253

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and Nepal-the challenges for diagnosis and treatment. Tropical Medicine and International Health 13, 2-5.

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CHAPTER 2: RATIONALE AND OBJECTIVES OF THE THESIS 2.1 Rationale of the research

As stated in the previous chapter, Kala-azar is an important public health problem in Nepal and the country p articipates in a r egional collaborative ef fort to e liminate VL from t he Indian subcontinent. To control, or even elimination of VL to be successful, it will require number of considerable efforts that needs to be implemented over the longer term. Effective control of VL will depend on the integration of public health interventions and research evidences that need to be translated into a ction. However, t he s carcity of ad equate d ata, b oth ep idemiological an d economic, c ontributes t o t he l ow a ttention a nd p riority given b y n ational c ontrol pr ogrammes and international donors also. At the outset of my thesis work, there are number of important knowledge gaps that are particular interest to the elimination initiative in Nepal (figure 2.1).

1. There was little community-based epidemiological information on Leishmania infections and disease available from Nepal except for two small surveys from eastern Nepal (Koirala et al. 1998;2004; Schenkel et al. 2006). Lack of epidemiological data is also considered as a major handicap in the proper implementation of the control programme (Bista 1998).

2. VL is a r ural d isease an d associated w ith precarious hous ing conditions (mud pl astered house) and the environment (humid soil and organic debris) of the poor communities. The proliferation of the vector is enhanced by poor housing conditions which provide excellent breeding sites for sandflies and increased the risk of infection through the bite of vector or increased human-vector contact (Singh et al. 2010). More recently, questions were raised about possible urban transmission and it is becoming a p eri-urban disease. This should be verified and needs to be investigated.

3. VL is a disease of poverty affecting the poorest of the poor (Alvar et al. 2006; Boelaert et al. 2009) but l imited i nformation on the bur den of V L on affected hous eholds after t he intensified i mplementation of V L c ontrol e fforts. T here ar e few s tudies qua ntifying t he economic burden of VL on households conducted prior to the elimination initiative showed the profound impact of a VL episode on the socio-economic status of the household (Rijal et al. 2006; Meheus et al. 2006; Adhikari et al.2009). The median total expenditure by a patient on V L treatment was 1.2 t o 1.4 t imes the annual per capita income (WHO 2010).

After the intensified implementation of VL control efforts, the economic burden of VL on households could be expected to be reduced, but neither data nor monitoring existed.

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4. Miltefosine, the onl y oral d rug fo r V L, i s c urrently t he 1 ^st line th erapy in th e V L elimination programme of t he Indian s ubcontinent and s o f ar little a ttention is g iven to monitor the clinical outcomes and patient adherence (Hasker et al. 2010; Malaviya et al.

2011). Although m iltefosine s howed an ex cellent ef ficacy i n p hase t hree clinical tr ials (Sundar et al. 2002), a recent data indicate increased failure rates after a decade of use in Bihar, India (Sundar et al. 2012) and five years of use in Nepal (Rijal et al. 2013). Given the h igh p revalence o f gastrointestinal s ide effects o f m iltefosine ( >60%, S undar et al.

2012) on one h and and the relatively fast r esolution of clinical s ymptoms of V L on t he other, patient may lose their motivation to complete the 28 da ys of miltefosine treatment.

Therefore, treatment outcomes and patient compliance to treatment is a key factor worth monitoring. S o f ar, no f ormal e valuation of adherence t o M iltefosine has b een r eported from Nepal or from any other region.

5. Last but not least, there is a risk of re-emergence of VL if the issue of PKDL is ignored since PKDL patients could act as a reservoir of infection within the population (Zijlstra et al. 2003). No data on PKDL epidemiology and burden existed from Nepal.

Based on the above knowledge gaps, the following objectives for the thesis were derived.

2.2 Objectives General objective:

The m ain obj ective of t he thesis was t o provide evidence for more rational V L control to the ongoing elimination initiative in the Indian subcontinent in general and in Nepal in particular.

Specific objectives:

1. Describe the e pidemiology of Leishmania donovani infection a nd di sease in hi gh- transmission areas

2. Understand the risk factors for VL with regards to possible urban transmission 3. Assess the health seeking behavior and economic burden of VL on households.

4. Monitor the treatment outcomes and patient adherence to currently used anti-VL drugs.

5. Estimate the prevalence, risk and risk factors of PKDL in patients treated for VL.

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Page | 35 Figure 2.1: Gaps of knowledge for VL elimination leading to the topics for PhD research

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2.3 References

__________________________

Adhikari SR, Maskay NM, Sharma BP (2009) Paying for hospital-based care of Kala-azar in Nepal: assessing catastrophic, impoverishment and economic consequences. Health Policy Plan 24, 129-139.

Alvar J, Yactayo S, Bern C (2006) Leishmaniasis and Poverty. Trends Parasitol 22, 552-557.

Bista MB (1998) National overview of kala-azar in Nepal. In: kala-azar in Nepal: principles, practice and public health perspectives (eds Bastola S, Karki P, Rijal S & Gautam A) EDCD/BPKIHS/WHO, Kathamandu, pp. 1-5.

Boelaert M, Meheus F, Sanchez A, Singh SP, Vanlerberghe V, Picado A, Meessen B, Sundar S (2009) The poorest of the poor: a poverty appraisal of households affected by visceral leishmaniasis in Bihar, India. Trop Med Int Health 14, 639-644.

Hasker E, Singh SP, Malaviya P et al. (2010) Management of visceral leishmaniasis in rural primary health care services in Bihar, India. Trop Med Int Health 15 suppl2, 55-62.

Malaviya P, Singh RP, Singh SP et al. (2011) Monitoring drug effectiveness in kala-azar in Bihar, India: cost and feasibility of periodic random surveys vs. a health service-based reporting system. Trop Med Int Health 16, 1159-1166.

Meheus F, Boelaert M, Baltussen R, Sundar S (2006) Costs of patient management of visceral leishmaniasis in Muzaffarpur, Bihar, India.Tropical Medicine and Internationl Health 11,1715-24.

Koirala S, Parija SC, Karki P, Das ML (1998) Knowledge, attitudes, and practices about kala- azar and its sandfly vector in rural communities of Nepal. Bull World Health Organ 76, 485-490.

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CHAPTER 3: METHODS AND PRESENTATION OF THE PUBLISHED WORK 3.1 Setting

Nepal is a c ountry of 2 9.9 million in habitants w ith a p opulation growth r ate is 1.35%

(Population census 2011). It i s a l andlocked country of 147,181 s quare kilometers bordering India to the south, east and west and China to the north, at the southern flank of the Himalayas.

Nepal is e cologically di vided f rom nor th t o s outh i nto t hree distinct e cological z ones: the Mountains to the north, the Hills in the middle and the plains (lowlands) to the south, which is the continuation of the Ganges plain of India (figure 3.1). Though Nepal is better known for its mountain range than for its tropical plains, this land-locked country is endemic for almost all the tropical diseases. The plains of Nepal are known as the “Terai” and are endemic for vector borne diseases like malaria,, dengue, kala-azar, filariasis and Japanese encephalitis (JE). The eco-system of terai region is very favorable for the breeding of sandflies, the proven vector of VL in Nepal.

The terai is adjacent to the VL endemic districts of Bihar and Uttar Pradesh of India and cross- border migration is very frequent due to the open border.

Figure 3.1: Geographical map of Nepal highlighting12 VL endemic districts in Nepal

Kala-azar in Nepal: public health evidence to support the elimination initiative

Kala-azar in Nepal: public health evidence to support the elimination initiative

Surendra Kumar URANW

É c o l e d e S a n t É P u b l i q u e

Table of Contents

CHAPTER 1: GENERAL INTRODUCTION

N N E E P P A A L L