**4. Drug-resistant malaria**

studied for its sibling species composition (A, B, C, D and E), distribution range, seasonal prevalence, larval ecology, feeding and breeding behavior and disease transmission relationships [26]. Species E is the most efficient malaria vector of all having predilection for human host, while species B is a poor vector for its zoophilic characteristics. The other three species (A, C and D) are responsible for local transmission in areas of their predominance [27]. This taxon is the most abundant rural vector in plains of mainland India generating about 65% of cases annually and held responsible for focal disease outbreaks associated with build-up of vector density. It is regarded as highly adaptive species for its diverse breeding habitats and invading new territories in degraded forests of north-eastern India evidenced by records of rising density and incrimination [28–30]. Its control has become a formidable challenge for having grown multi-resistant virtually to all available insecticides including pyrethroids opening new vistas for research on newer

*An. fluviatilis* complex is just as widespread and have overlapping distribution with *An. culicifacies* throughout India [20]. Among its sibling species, that is, S, T, U and form 'V'; it is species S which is highly anthropophilic and responsible for maintaining hyperendemic malaria predominantly in foothills of eastern India contributing ~15% of reported cases [34]. It shares similar bionomical characteristics with yet another efficient malaria vector species *An. minimus s.s* for breeding in foothill seepage water streams and resting indoors in human dwellings [35]. Both are highly susceptible to residual insecticides. *An. minimus* instead is the most predominant vector species of north-eastern States of India and has long history of disappearance and re-appearance stymying the control authorities. It is reckoned as the most efficient vector species for its high anthropophily (human blood index > 90%) and fulminating focal disease outbreaks taking heavy toll of human lives [36]. It is a perennial species and widely incriminated practically all months of the year with average sporozoite infection rate of 3% [37]. This species exhibits high behavioral plasticity for avoiding sprayed surfaces for weeks and establishing extra-domiciliary transmission in response to indoor residual spraying (IRS). While this species has staged comeback in eastern State of Odisha after lapse of 45 years [38], the populations of *An. minimus* once again are reported diminishing in erstwhile domains of its distribution in northeast India corroborated by evidence of reducing disease transmission [35]. It presents an unprecedented opportunity to strengthen interventions to keep populations of this species at

interventions that are sustainable, cost-effective and community-based [31–33].

266 Towards Malaria Elimination - A Leap Forward

bay helping achieve malaria elimination specific to the region at sub-national level.

Within the *An. dirus* complex, *An. baimaii* is the only vector occurring in India with a wide prevalence in the north-eastern States and has been recorded in high densities and incriminated in range of its distribution [39]. It is just as efficient vector species with strong predilection for human host but distinct from *An. minimus* for its breeding and resting characteristics [40, 41]. It is a forest dweller affecting forest-fringe human settlements along inter-country and inter-state border areas causing devastating disease outbreaks often in conjunction with *An. minimus*; together they contribute 10% of reported cases in the country [42]. Its control has become difficult for peak biting activity during second quartile (21:00–00:00) of the night as well as exophilic resting behavior avoiding sprayed surfaces. Its populations along with that of *An. minimus* are also depleting owing to deforestation and urbanization [29, 30]. However, niche thus vacated by both these species is accessed by *An. culicifacies s.l.* and has established foothold erstwhile recorded in lowdensity [26, 28]. Among sibling species of the *An. sundaicus* complex, cytotype species D has been characterized with a regional importance presently confined to Andaman and Nicobar Islands [43]. It is a brackish water species, largely zoophilic and susceptible to residual insecticides.

Of the two prevalent malaria parasite species, the rising proportions of *P. falciparum* is of grave concern for presently constituting >60% of total reported cases in the country [5, 7]. Rising trends of *P. falciparum* are largely attributed to fast emerging drug-resistance over space and time in parallel with phenomenon happening in countries of the Greater Mekong Subregion (GMS) of Southeast Asia [47]. Historically, chloroquine (CQ) was the most commonly used drug for treatment ever since inception of the control program in 1953 for its efficacy and affordability. It had become obsolete since its first report of treatment failure in Assam (northeast India) way back in 1973 [48]. Subsequently, drug-resistant foci had multiplied for which northeast is considered corridor for spread to rest of peninsular India resulting in steady rise in proportions of *P. falciparum* what was 13% in 1978 to 65% in present day malaria [49]. Northeast India shares wide border with Myanmar contiguous with GMS countries which is porous for cross-border migration, facilitating entry of drug-resistant strains enroute to the rest of India and beyond. Malaria transmission along this border is intense vectored by *An. minimus* and *An. baimaii* (the two most efficient vector species), and healthcare access is inadequate resulting in indiscriminate and sub-optimal doses *inter-alia*, poor vector control, illiteracy and treatment-seeking behavior; all contributing to propagation and spread of drug-resistant malaria strains [50]. Chloroquine therapy was subsequently upgraded to sulfadoxine-pyrimethamine (SP) in 2004 as first-line treatment in selected districts reporting CQ-resistant malaria [51]. The therapeutic efficacy of SP was short lived resulting in substantial rise in cases in the following years [52]. It was in 1990s that the development of artemisinin-derivatives raised new hopes for treatment of drug-resistant malaria for its fast acting schizontocidal properties. Initially, artemisinin was used as monotherapy for treatment of severe and complicated clinical malaria, discontinued in 2009 due to high recrudescence 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 malaria would be colossal, threatening the control and elimination efforts.

it is time consuming and impractical in field conditions where the problem exists. Further, given the available technologies, the detection of latent hypnozoites and sub-patent parasit-

Declining Transmission of Malaria in India: Accelerating Towards Elimination

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The primary attack of vivax malaria is invariably associated with acute paroxysm presenting classical symptoms but treatable and rarely fatal [70–72]; although few sporadic cases of CQ-resistant cases have been reported in India and several other countries [73]. There is acute need of alternative 8-aminoquinolines, which are safe and universally applicable for radical cure across all population groups preventing relapses. As of today, we stand ill equipped to tackle this stubborn parasite calling for renewed attack both on parasite and disease vectors

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

emia is presently not built in the disease surveillance.

**6. Asymptomatic malaria**

in reducing parasite reservoir which is likely to persist for long.

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

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 context of malaria elimination across the continents [60].

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 it is time consuming and impractical in field conditions where the problem exists. Further, given the available technologies, the detection of latent hypnozoites and sub-patent parasitemia is presently not built in the disease surveillance.

The primary attack of vivax malaria is invariably associated with acute paroxysm presenting classical symptoms but treatable and rarely fatal [70–72]; although few sporadic cases of CQ-resistant cases have been reported in India and several other countries [73]. There is acute need of alternative 8-aminoquinolines, which are safe and universally applicable for radical cure across all population groups preventing relapses. As of today, we stand ill equipped to tackle this stubborn parasite calling for renewed attack both on parasite and disease vectors in reducing parasite reservoir which is likely to persist for long.
