Long-lasting Insecticidal Nets to Prevent Visceral Leishmaniasis in the Indian Subcontinent; Methodological Lessons Learned from a Cluster Randomised Controlled Trial

In a recent paper, Nagpal et al. voiced concerns about the limited or biased use of scientific evidence to support public health interventions to control neglected tropical diseases (NTDs). Visceral leishmaniasis (VL), also known as kala-azar, is one of the major NTDs and does not escape this problem. Transmission is vector-borne and the Indian subcontinent is the region reporting most of the VL cases worldwide. In this region, the main causative species is Leishmania donovani and Phlebotomus argentipes is the vector. Transmission is considered anthroponotic and peridomestic—occurring at night when female sand flies bite people sleeping inside their house. The World Health Organization and the governments of India, Nepal, and Bangladesh set out in 2005 to eliminate VL from the region by 2015 through a combination of early treatment of cases and vector control. However, while recent advances in diagnostic tools and drugs have significantly improved case management strategies, the available vector control tools against P. argentipes remain limited. The elimination initiative promotes the use of indoor residual spraying (IRS) of households and cattle sheds to reduce vector density, but the evidence underpinning the effectiveness of IRS in this region is scanty. Historical observations show that L. donovani transmission declined concomitantly with dichlorodiphenyltrichloroethane (DDT) spraying during the 1950s–60s to eradicate malaria. In the aftermath of this malaria eradication campaign, very few VL cases were observed in endemic regions until the mid-seventies, when there was resurgence of a VL epidemic in India. To date, there are no randomized trials showing the effect of IRS on the incidence of clinical VL, though some studies showed a reduction in vector density. When the VL elimination initiative was launched in 2005, there were no clear alternatives for IRS as a vector control strategy. Insecticide treated nets (ITNs) were proposed as an alternative or complement to IRS on the basis of analogy arguments regarding their given efficacy against malaria or on data from observational studies suggesting ITNs reduce the risk of VL; but as for IRS, there were no randomized trials evaluating the effect of ITNs on L. donovani transmission. In this context, a number of field studies were conducted in the Indian subcontinent in the past decade to evaluate the effectiveness and impact of ITNs and other vector control tools on VL. Most of these studies have been reviewed in detail in two recent papers. The only two studies evaluating the impact of vector control interventions on clinical outcomes found conflicting results. First, the KALANET project, a cluster randomised controlled trial (CRT) in India and Nepal, showed that mass-distribution of ITNs did not reduce the risk of L. donovani infection or clinical VL. Then, an intervention trial in Bangladesh suggested that widespread bed net impregnation with slow-release insecticide may reduce the frequency of VL. Technical (e.g., type of nets and insecticides, lack of replicas and randomisation in Bangladesh) and biological factors (e.g., insecticide susceptibility and sand fly behaviour) may explain the different results observed. This apparent contradiction raises the question about the role that ITN may play in controlling VL in the Indian subcontinent but has also triggered a lot of discussion on methodology and evidence levels required when evaluating vector control tools for VL. In this paper, we would like to summarise the lessons learned from the KALANET CRT in terms of methodology to inform the generation of future evidence and discuss interpretation of findings against this background

Longlasting insecticidal nets for prevention of Leishmania donovani infection in India and Nepal: paired cluster randomised trial

Objective To test the effectiveness of large scale distribution of longlasting nets treated with insecticide in reducing the incidence of visceral leishmaniasis in India and Nepal

Insecticide Susceptibility of Phlebotomus argentipes in Visceral Leishmaniasis Endemic Districts in India and Nepal

Visceral leishmaniasis (VL), also know as kala azar, is one of the major public health concerns India, Nepal and Bangladesh. In the Indian subcontinent, VL is caused by Leishmania donovani which is transmitted by Phlebotomus argentipes. To date, Indoor Residual Spraying (IRS) campaigns have been unable to control the disease. Vector resistance to the insecticides used has been postulated as one of the possible reasons explaining this failure. A number of studies in the region have shown a variable degree of resistance to DDT in areas where this insecticide has been widely used for IRS (mainly India). However there is no coordinated and standardized program to monitor resistance to insecticides in the region. In this study we tested P. argentipes susceptibility to DDT and deltamethrin in VL endemic villages in India and Nepal. The results confirmed the DDT resistance in India and in a border village of Nepal. P. argentipes from both countries were in general susceptible to deltamethrin, an insecticide used in some long lasting insecticidal nets

Domestic Animals and Epidemiology of Visceral Leishmaniasis, Nepal

Proximity of Leishmania donovani–positive goats is a risk factor for human infection

Do Size and Insecticide Treatment Matter? Evaluation of Different Nets against Phlebotomus argentipes, the Vector of Visceral Leishmaniasis in Nepal.

In the Indian subcontinent, Leishmania donovani, the parasite causing visceral leishmaniasis (VL) is transmitted by the sand fly vector Phlebotomus argentipes. Long lasting insecticide treated nets (LN) have been postulated as alternative or complement to Indoor Residual Spraying but there are few field studies evaluating the entomological efficacy of different nets against this vector. We conducted two crossover trials in a VL endemic area in Nepal to compare the barrier effect of (1) LN with different mesh sizes (156 holes/inch2 vs 625 holes/inch2) and (2) alpha-cypermethrin treated LN and untreated nets having the same mesh size (156 holes/inch2). Each crossover trial had two arms consisting of a sequence of two different nets for 8 nights. We used 10 cattle sheds per trial. A cow placed under the net was used as bait. CDC light traps placed inside the nets were used to evaluate the number of P. argentipes crossing the net barrier. Negative binomial generalized estimating equation (GEE) population-averaged models adjusted by night and sequence were used to estimate the barrier effect of the different nets. The crossover trials conducted in a rural village in Morang district (South-eastern Nepal) demonstrated that reducing the size of the holes in treated nets (625 holes/inch2) increased the barrier effect of LN by 77% (95% confidence interval (CI): 56%-88%) compared with treated nets with larger holes (156 holes/inch2). Treating nets with alpha-cypermethrin reduced the number of P. argentipes captured inside the nets by 77% (95% CI: 27%-93%) compared with untreated nets. The effectiveness and acceptability of finer mesh pyrethroid treated LN should be tested for VL prevention in a randomized controlled trial

Research priorities for elimination of visceral leishmaniasis

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

Spatial analysis of Leishmania donovani exposure in humans and domestic animals in a recent kala azar focus in Nepal.

SUMMARY: Visceral leishmaniasis (VL) is a major public health problem in the Indian subcontinent where the Leishmania donovani transmission cycle is described as anthroponotic. However, the role of animals (in particular domestic animals) in the persistence and expansion of VL is still a matter of debate. We combined Direct Agglutination Test (DAT) results in humans and domestic animals with Geographic Information System technology (i.e. extraction maps and scan statistic) to evaluate the exposure to L. donovani on these 2 populations in a recent VL focus in Nepal. A Poisson regression model was used to assess the risk of infection in humans associated with, among other factors, the proportion of DAT-positive animals in the proximities of the household. The serological results showed that both humans and domestic animals were exposed to L. donovani. DAT-positive animals and humans were spatially clustered. The presence of serologically positive goats (IRR=9.71), past VL cases (IRR=2.62) and the proximity to a forest island dividing the study area (IRR=3.67) increased the risk of being DAT-positive in humans. Even if they are not a reservoir, domestic animals, and specially goats, may play a role in the distribution of L. donovani, in particular in this new VL focus

Toolkit for monitoring and evaluation of indoor residual spraying for visceral leishmaniasis control in the Indian subcontinent: application and results.

Background. We field tested and validated a newly developed monitoring and evaluation (M&E) toolkit for indoor residual spraying to be used by the supervisors at different levels of the national kala-azar elimination programs in Bangladesh, India and Nepal. Methods. Methods included document analysis, in-depth interviews, direct observation of spraying squads, and entomological-chemical assessments (bioassay, susceptibility test, chemical analysis of insecticide residues on sprayed surfaces, vector density measurements at baseline, and three follow-up surveys). Results. We found that the documentation at district offices was fairly complete; important shortcomings included insufficient training of spraying squads and supervisors, deficient spray equipment, poor spraying performance, lack of protective clothing, limited coverage of houses resulting in low bioavailability of the insecticide on sprayed surfaces, and reduced vector susceptibility to DDT in India, which limited the impact on vector densities. Conclusion. The M&E toolkit is a useful instrument for detecting constraints in IRS operations and to trigger timely response

Residual activity and integrity of PermaNet® 2.0 after 24 months of household use in a community randomised trial of long lasting insecticidal nets against visceral leishmaniasis in India and Nepal.

The World Health Organization (WHO) recommends several brands of long lasting insecticidal net (LN) for protection against insect vectors but also advises national programmes to monitor and evaluate performance under local conditions to help them select the most suitable LN for their setting. During the course of a community randomised trial of LNs against visceral leishmaniasis in northern India and Nepal, opportunity arose to assess the efficacy of PermaNet 2.0 (Vestergaard-Frandsen, Denmark) after two years of use against sandfly vectors. Between 63% (India) and 78% (Nepal) of LNs became holed over the course of two years, deltamethrin residues fell from 55 mg/m(2) to an average of 11.6 mg/m(2) (India) and 27.9 mg/m(2) (Nepal), but on the basis of bioassay criteria all LNs tested still met the WHO Pesticide Evaluation Scheme standard for LN effectiveness. Nets had on average only been washed 2.5 times (India) and 0.6 times (Nepal) by householders over the course of two years. The loss of insecticide was attributed to factors which had little or nothing to do with washing, such as handling, friction and torsion during daily use. Under conditions pertaining in this region of south Asia, and for two years at least, this brand of net continues to meet the criteria established by WHO for LNs