**6. Asymptomatic malaria**

rate and risk of resistance for being commonly prescribed medicine by private practitioners and public sector alike [53]. In 2010, the program adopted ACT by combining it with SP, that is, artesunate + SP (AS + SP) for treatment of every single case of *P. falciparum* malaria in highrisk districts [54]. Mass scale introduction of this combination did result in appreciable transmission reduction in endemic communities formerly intractable. It continues to be in practice throughout India except in the northeast region where it has been replaced by yet another combination therapy, that is, artemether + lumefantrine (AL) in 2013 due to declining efficacy of AS + SP combination drug [55]. The emergence of artemisinin resistance in Southeast Asia [56]; however, is a matter of grave concern for its movement westwards to India for having it detected in Myanmar close to the Indian border in northeast [57]. Genomic studies have already detected mutations in the '*kelch 13*' propeller region (*Pfk 13*) linked to artemisinin resistance in north-eastern States, but to lesser frequency [58]. It is of utmost importance to periodically monitor the therapeutic efficacy of drug-regimen in force for radical cure and keep vigil on circulation of counterfeit drugs. The cost of spread of artemisinin-resistant

The Southeast Asian countries contribute most of the vivax cases (58%) in the World of which India is the largest contributor [1]. Historically, much of the control efforts continue to be focused on control of falciparum malaria due to its associated severity and critical illness; the vivax malaria remained a neglected parasite [59]. Paradoxically, control of falciparum malaria is rather measurable in relation to interventions due to development of gametocytaemia 9–10 days post primary infection; instead the formation of gametocytes in vivax malaria is concurrent within few days of initial infection even before the patient seeks treatment permitting uninterrupted transmission. This biological characteristic of vivax malaria along with intrinsic ability of formation of latent hibernating 'hypnozoites' has made control efforts a difficult proposition. Nevertheless, the control of vivax malaria is gaining eminence in the

The magnitude of vivax malaria is huge but grossly underestimated throughout India and continues to be neglected [61]. The transmission and distribution of vivax malaria varied across Indian States/UTs, but large concentrations of cases are occurring in urban metropolitan cities [7]. Although it remains highly susceptible to CQ therapy [62–66], its elimination is one difficult issue owing to latent stage 'hypnozoites' in the liver causing relapses amounting to extended morbidity over months/years. The only available anti-relapse drug 'primaquine (PQ)' does not guarantee radical cure much due to extended therapy over days coupled with poor compliance resulting in repeated episodes [67–69]. In addition, the administration of PQ is associated with several issues including contraindication in special groups, that is, infants, pregnant or lactating mothers, and inborn glucose-6-phosphate dehydrogenase (G6PD) deficiency syndromes due to associated hemolytic anemia; these population groups are excluded from primaquine therapy. There exists no diagnostics for detection of G6PD at point-of-care in the present surveillance system except few laboratories procedure for which

malaria would be colossal, threatening the control and elimination efforts.

**5.** *Plasmodium vivax* **malaria: the neglected parasite**

268 Towards Malaria Elimination - A Leap Forward

context of malaria elimination across the continents [60].

India is historically endemic for malaria with record of devastating epidemics in the pre-DDT era and varied population groups have been subject to repeated attacks of malarial bouts, resulting in acquired immunity and consequent build-up of asymptomatic sub-patent parasitemia in the endemic communities, serving as infectious reservoir for continued transmission. In India, the surveillance program is aimed at taking blood-smears from those who are either febrile (active surveillance) or presenting themselves (passive surveillance) for malaria diagnosis or treatment. There is no built-in mechanism to detect asymptomatic cases or even low-density/sub-patent parasitemia in the endemic communities. These infections may go undetected with conventional diagnostic techniques leaving them untreated, except for massblood surveys/mass-drug administrations that are conducted only to contain epidemics. Asymptomatic malaria is more abundant than assumed and have been reported in different endemic States of India; however, the extent and distribution vary corresponding to transmission intensities [74–77]. Asymptomatic parasitemia is often associated with gametocyte carriage and may persist infectious throughout the year to mosquito vectors. These gametocytes are unable to cause clinical symptoms of malaria, rather ensure the uninterrupted transmission of malaria in the presence of efficient vectors. Asymptomatic cases remain undetected and not accounted for disease incidence amounting to gross underestimates.

Asymptomatic malaria in India remains entrenched in low-socioeconomic groupings living in forest-fringe communities, particularly along inter-border areas (both inter-province and international borders), which are largely inaccessible (marred with insurgent activities), wherein healthcare infrastructure is meager or even non-existent. Such areas are 'hot-spots' for explosive disease outbreaks due to mixing/importation of drug-resistant strains associated with illegal migration more so in the northeast (the gateway to India) that shares wide international border with Myanmar, a member country of GMS (an epicenter of multi-drug resistant malaria) and other WHO SEAR countries. Asymptomatic malaria has been documented for both *P. falciparum* and *P. vivax*, yet the magnitude was much higher for the former parasite species, more so in the winter months/dry-season, for example, in north-eastern State of Assam, for the high-risk districts surveyed, it varied from 7.1 to 31.1% in *P. falciparum* and 0.6–6.1% in *P. vivax* [78]. But on average, 12.8% of afebrile subjects were positive for malaria compared to 34.4% of those presenting with fever, and gametocyte carriage varied from 1.31 to 2.16%. Major bottleneck in eliminating asymptomatic malaria parasite is the absence of standard guidelines and diagnostic procedures aimed at targeting asymptomatic carriers. Malaria control program in practice is largely limited to the qualitative detection of parasite mostly in febrile human hosts and subsequently treating with suitable drugs; however, no attention is given on follow up for quantification of malaria parasite till radical cure. Moreover, a universally accepted parasite level for categorizing a patient as asymptomatic is also not available. Quantification and treating asymptomatic malaria has become increasingly important and relevant for disrupting transmission, requisite for achieving malaria elimination.

UTs [4, 7]. Utilizing the evidence-based intervention tools and large-scale implementation, India has registered notable decline in cases and malaria-attributable deaths in the preceding few years (**Figures 2** and **3**). Among these, roll-out of ACT for treatment of every single case of *P. falciparum* malaria, rapid diagnostics test (RDT) kits for on-the-spot diagnosis and largescale provision of long-lasting insecticidal nets (LLINs) for vector control have resulted in rich dividends in reducing disease transmission in areas formerly intractable. Malaria threat is seen receding presenting an unprecedented opportunity for upscaling interventions in achieving universal coverage for populations at any risk making elimination an achievable target. However, the logistics requirement is huge for which increased funding from donors (both national and international agencies) and political commitment for sustained allocation of resources is of paramount importance for strengthening healthcare services reaching the outreach population groups for equitable access. A humble beginning has been made under National Health Mission (NHM), which envisages achievement of universal access to equitable, affordable and quality healthcare services both in urban and rural India [85]. Much needed disease surveillance in the country is further strengthened by Integrated Disease Surveillance Programme (IDSP) to detect early warning signals for impending disease outbreaks instituting interventions to thwart the disease onslaught and spread [86]. Both these establishments have helped the program immensely in strengthening laboratory services averting disease outbreaks, as well as human resource development in providing training to State surveillance officers, rapid response teams and other medical and paramedical staffs. However, continuing education program is need of the hour for upgrading skills to keep pace with the changing technologies as well as to fill the void due to attrition of skilled workforce. The induction of Accredited Social Health Activists (ASHA) have proven boon to the program ensuring door-to-door surveillance raising new levels of confidence in the povertystricken communities. Host of Non-Governmental Organizations (NGOs)/media coverage have increased the reach of services in remote/inaccessible areas helping combating illness and saving lives. Collectively, communities today stand better informed and clearly benefit-

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ted by increased awareness on disease prevention and control.

In India, some States (Sikkim and Himachal Pradesh) and UTs (Lakshadweep, Daman & Diu and Puducherry) are already reporting <100 cases, while others recorded substantial decrease (>50%) in cases over past few years, for example, Assam and Karnataka (**Table 1**). Given the reducing transmission levels, malaria elimination at sub-national level is seemingly achievable. However, the emergence of artemisinin-resistant malaria and possible spread, coupled with multiple insecticide resistance in disease vectors (**Table 2**), could reverse the gains for which disease surveillance, monitoring and evaluation should be the corner-stone activity. *P. vivax* and asymptomatic malaria continue to be unattended and should be accorded priority for reducing parasite reservoir in the endemic communities. Priority should be accorded for strengthening healthcare services in high-risk States of eastern, central and north-eastern States helping mitigate disease onslaught and deter entry and spread of drug-resistant strains in India. Inter-sectoral linkages with research establishments and medical colleges for developing innovative newer interventions (possibly vaccines), assessing therapeutic efficacy of

**9. The way forward**

### **7. Cross-border malaria**

India shares vast international border with Nepal, Bhutan and China to the North, Myanmar to the East, Bangladesh to the South and Pakistan to the West. Among these, borders with Myanmar and Bangladesh are of immediate concern for their high endemicity and common disease vectors and ecology in the adjoining vicinity on either side of the border [79, 80]. These border areas are porous for cross-migration and have high forest cover inhabited by indigenous tribes living in impoverished conditions. These communities have poor access to healthcare services and are at high-risk to disease outbreaks attributed to drug-resistant strains originating from the GMS countries. These populations are largely marginalized and just as reluctant to seek treatment amounting to unattended parasite reservoirs. Border with Myanmar in particular is believed to be the corridor for entry of drug-resistant strains to northeast India for onward spread. The detection of artemisinin-resistant malaria in closer proximity to Indian border is seen as threat for making its way to India and beyond, similar to the path that was followed by CQ-resistant malaria [48, 49]. Cross-border malaria transmission from neighboring endemic countries can be daunting task and has regional implications jeopardizing the elimination efforts [81, 82]. For example, most cases reported in Bhutan (a country that is heading for malaria elimination), are imported from adjoining districts of Assam seeking treatment on other side of the border. Labor migration across borders engaged in developmental projects is unstoppable for want of livelihood and there exists every possibility of re-entry of malaria given the similar vectors and ecology. It is important to characterize the imported malaria strains enabling interventions well in place and time to prevent re-establishment of local transmission in declared malaria-free territories [83]. Inter-country coordinated efforts are deemed essential to maintain vigil and strengthening border-posts (entry/exit doors) with capacity to detect and treat malaria in the migrant/itinerant labor force at the earliest available opportunity. In keeping the same mandate, India has joined hands with the Asia Pacific Malaria Elimination Network (APMEN) countries for shared experiences and coordinated action to achieve malaria elimination by 2030 [84]. Mitigating cross-border malaria should be accorded priority in context of malaria elimination.

#### **8. Strengthening health systems**

India has a well-structured vector-borne disease control program in place providing logistics support along with guidance and monitoring/evaluation services to malaria endemic States/

UTs [4, 7]. Utilizing the evidence-based intervention tools and large-scale implementation, India has registered notable decline in cases and malaria-attributable deaths in the preceding few years (**Figures 2** and **3**). Among these, roll-out of ACT for treatment of every single case of *P. falciparum* malaria, rapid diagnostics test (RDT) kits for on-the-spot diagnosis and largescale provision of long-lasting insecticidal nets (LLINs) for vector control have resulted in rich dividends in reducing disease transmission in areas formerly intractable. Malaria threat is seen receding presenting an unprecedented opportunity for upscaling interventions in achieving universal coverage for populations at any risk making elimination an achievable target. However, the logistics requirement is huge for which increased funding from donors (both national and international agencies) and political commitment for sustained allocation of resources is of paramount importance for strengthening healthcare services reaching the outreach population groups for equitable access. A humble beginning has been made under National Health Mission (NHM), which envisages achievement of universal access to equitable, affordable and quality healthcare services both in urban and rural India [85]. Much needed disease surveillance in the country is further strengthened by Integrated Disease Surveillance Programme (IDSP) to detect early warning signals for impending disease outbreaks instituting interventions to thwart the disease onslaught and spread [86]. Both these establishments have helped the program immensely in strengthening laboratory services averting disease outbreaks, as well as human resource development in providing training to State surveillance officers, rapid response teams and other medical and paramedical staffs. However, continuing education program is need of the hour for upgrading skills to keep pace with the changing technologies as well as to fill the void due to attrition of skilled workforce. The induction of Accredited Social Health Activists (ASHA) have proven boon to the program ensuring door-to-door surveillance raising new levels of confidence in the povertystricken communities. Host of Non-Governmental Organizations (NGOs)/media coverage have increased the reach of services in remote/inaccessible areas helping combating illness and saving lives. Collectively, communities today stand better informed and clearly benefitted by increased awareness on disease prevention and control.

#### **9. The way forward**

compared to 34.4% of those presenting with fever, and gametocyte carriage varied from 1.31 to 2.16%. Major bottleneck in eliminating asymptomatic malaria parasite is the absence of standard guidelines and diagnostic procedures aimed at targeting asymptomatic carriers. Malaria control program in practice is largely limited to the qualitative detection of parasite mostly in febrile human hosts and subsequently treating with suitable drugs; however, no attention is given on follow up for quantification of malaria parasite till radical cure. Moreover, a universally accepted parasite level for categorizing a patient as asymptomatic is also not available. Quantification and treating asymptomatic malaria has become increasingly important and rel-

India shares vast international border with Nepal, Bhutan and China to the North, Myanmar to the East, Bangladesh to the South and Pakistan to the West. Among these, borders with Myanmar and Bangladesh are of immediate concern for their high endemicity and common disease vectors and ecology in the adjoining vicinity on either side of the border [79, 80]. These border areas are porous for cross-migration and have high forest cover inhabited by indigenous tribes living in impoverished conditions. These communities have poor access to healthcare services and are at high-risk to disease outbreaks attributed to drug-resistant strains originating from the GMS countries. These populations are largely marginalized and just as reluctant to seek treatment amounting to unattended parasite reservoirs. Border with Myanmar in particular is believed to be the corridor for entry of drug-resistant strains to northeast India for onward spread. The detection of artemisinin-resistant malaria in closer proximity to Indian border is seen as threat for making its way to India and beyond, similar to the path that was followed by CQ-resistant malaria [48, 49]. Cross-border malaria transmission from neighboring endemic countries can be daunting task and has regional implications jeopardizing the elimination efforts [81, 82]. For example, most cases reported in Bhutan (a country that is heading for malaria elimination), are imported from adjoining districts of Assam seeking treatment on other side of the border. Labor migration across borders engaged in developmental projects is unstoppable for want of livelihood and there exists every possibility of re-entry of malaria given the similar vectors and ecology. It is important to characterize the imported malaria strains enabling interventions well in place and time to prevent re-establishment of local transmission in declared malaria-free territories [83]. Inter-country coordinated efforts are deemed essential to maintain vigil and strengthening border-posts (entry/exit doors) with capacity to detect and treat malaria in the migrant/itinerant labor force at the earliest available opportunity. In keeping the same mandate, India has joined hands with the Asia Pacific Malaria Elimination Network (APMEN) countries for shared experiences and coordinated action to achieve malaria elimination by 2030 [84]. Mitigating cross-border malaria should be accorded priority in context of malaria elimination.

India has a well-structured vector-borne disease control program in place providing logistics support along with guidance and monitoring/evaluation services to malaria endemic States/

evant for disrupting transmission, requisite for achieving malaria elimination.

**7. Cross-border malaria**

270 Towards Malaria Elimination - A Leap Forward

**8. Strengthening health systems**

In India, some States (Sikkim and Himachal Pradesh) and UTs (Lakshadweep, Daman & Diu and Puducherry) are already reporting <100 cases, while others recorded substantial decrease (>50%) in cases over past few years, for example, Assam and Karnataka (**Table 1**). Given the reducing transmission levels, malaria elimination at sub-national level is seemingly achievable. However, the emergence of artemisinin-resistant malaria and possible spread, coupled with multiple insecticide resistance in disease vectors (**Table 2**), could reverse the gains for which disease surveillance, monitoring and evaluation should be the corner-stone activity. *P. vivax* and asymptomatic malaria continue to be unattended and should be accorded priority for reducing parasite reservoir in the endemic communities. Priority should be accorded for strengthening healthcare services in high-risk States of eastern, central and north-eastern States helping mitigate disease onslaught and deter entry and spread of drug-resistant strains in India. Inter-sectoral linkages with research establishments and medical colleges for developing innovative newer interventions (possibly vaccines), assessing therapeutic efficacy of antimalarials and upgradation of drug-treatment policy, human resource development and field-evaluation of newer technologies, including innovative vector control approaches, are vital before these are incorporated in the control program. Disease epidemiology is rapidly changing in the face of fast urbanization, deforestation and anomalous weather conditions opening new vistas, which must be watched for targeting interventions in place and time. Mosquito vectors are invading new territories, and adapting to altered ecology establishing outdoor transmission in response to strengthening insecticide interventions, which are largely based on indoor residual applications. We strongly advocate the judicious mix of technologies used in an integrated manner to overcome the challenges of outdoor transmission and growing insecticide resistance threatening the efficacy of present day intervention tools. There remains of scope of newer interventions in Indian geo-epidemiological conditions, namely, eave tubes, attractive sugar baits, nano-synthesized pesticides loaded with microbial- and plant-borne compounds, for trapping adult mosquito vectors and population reduction presently being put to field evaluation in African countries (Beier, personal communication). It is the high time to strengthen the entomological component at the State/Zonal level for monitoring vector densities and insecticide resistance targeting interventions averting impending disease outbreaks. Above all, educating communities and stakeholders on disease prevention and control should be the guiding principle for increased compliance and harmonious action. Increased allocation of resources (both from State and Central assistance), for ensuring universal coverage of interventions, should be given utmost priority in reducing parasite reservoir much below threshold density disrupting transmission [87]. It is time accelerating towards elimination and let there be no complacency at various echelons of operation for keeping disease at bay. Outside Africa, Southeast Asia is the largest contributor of cases and source of spread of drug-resistant malaria for which it is strongly advocated that larger share of global investments in this part of the World would go a long way in alleviating poverty and malaria. In summary, given the enormity of disease burden and myriad of issues, odds are all against, yet concerted efforts should be made in rendering malaria a thing of the past; together we can beat malaria.

AL artemether lumefantrine API annual parasite incidence

CQ chloroquine

APLMA Asia Pacific Leaders Malaria Alliance

ASHA Accredited Social Health Activist

DDT dichloro-diphenyl-trichloroethane

GMS Greater Mekong Subregion

ITS-2 internal transcribed spacer-2 LLIN long-lasting insecticidal nets

NHM National Health Mission

PCR polymerase chain reaction

Pfk 13 *Plasmodium falciparum kelch 13*

SEAR WHO Southeast Asia Region SP sulfadoxine-pyrimethamine

WHO World Health Organization

SCAR Sequence Characterized Amplified Region

Pf *Plasmodium falciparum*

RBM roll back malaria

r-DNA ribosomal-DNA

UT Union Territory

RDT rapid diagnostic test

NGO Non-Governmental Organization

NVBDCP National Vector Borne Disease Control Programme

IRS indoor residual spray ITN insecticide treated nets

G6PD glucose-6-phosphate dehydrogenase

IDSP Integrated Disease Surveillance Project

APMEN Asia-Pacific Malaria Elimination Network

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AS + SP artesunate + sulfadoxine-pyrimethamine
