Declining Transmission of Malaria in India: Accelerating Towards Elimination

India is ecologically vast and has close to a billion-population living at risk of malaria. Given the evidence-based present-day intervention tools and large-scale implementation, India has recorded declining trends in disease transmission from 2 million cases in 2001 to close to a million cases in 2017 and embarked upon malaria elimination in keeping with the Global Technical Strategy by 2030. India is malaria endemic, but transmission intensities varied across its landscape with just few States of the east, central and northeast contributing bulk (80%) of total positive cases. Plasmodium falciparum and P. vivax are the predominant infections of which there has been steady increase in proportions of the former for constituting >60% of total cases what was 50:50 in 2001, a phenomenon attributed to emerging drug resistance. With the rolling out of the available intervention tools, malaria elimination is foreseeable yet there are multiple challenges which must be addressed to overcome the constraints. We strongly advocate continued disease surveillance and monitoring, universal coverage and intensification of core-interventions for prevention and treatment prioritizing high-risk States, strengthening cross-border collaborations for information sharing and coordinated activities, and above all sustained allocation of resources, creating the enabling environment to end malaria transmission

Molecular epidemiology of Plasmodium vivax anti-folate resistance in India

<p>Abstract</p> <p>Background</p> <p>Sulphadoxine and pyrimethamine are anti-folate drugs that show synergistic anti-malarial effect. Point mutations in <it>dihydrofolate reductase </it>(<it>dhfr</it>) and <it>dihydropteorate synthatase </it>(<it>dhps</it>) cause anti-folate drug resistance phenotype in human malaria parasites. This study presents pattern of point mutations in <it>dhfr/dhps </it>genes among Indian sub-continent.</p> <p>Methods</p> <p>Microscopically diagnosed one hundred <it>Plasmodium vivax </it>field isolates were collected from five widely separated geographical regions of India. <it>Dhfr </it>and <it>dhps </it>genes were PCR amplified and sequenced. Previously published mutations data were collected and analyzed using Chi square test to identify geographical cluster of mutant/wild type genotypes.</p> <p>Results</p> <p>Sequence analysis revealed single (S58R), double (S58R/S117N) and quadruple (F57L/S58R/T61M/S117T/) point mutations at <it>dhfr </it>and single (A383G) to double (A383G/A553G) mutations at <it>dhps </it>in <it>P. vivax </it>field isolates. In addition, three new mutations were also observed at <it>dhfr</it>. Both, <it>dhfr </it>and <it>dhps </it>genes revealed tandem repeat variations in field isolates. <it>Dhps </it>revealed very low mutation frequency (14.0%) compared to <it>dhfr </it>(50.70%). Comparative analysis revealed a progressive increase in frequency of quadruple mutant <it>dhfr </it>genotype (p < 0.001) within five years in north-eastern state (Kamrup, Assam). Frequency of <it>dhfr </it>genotypes revealed three distinct geographical clusters of wild (northern India), double mutant (southern India), and quadruple mutant (north-eastern and island regions of India) on the Indian sub-continent.</p> <p>Conclusion</p> <p>Study suggests that SP may be susceptible to <it>P. vivax </it>in India, except Andaman and north-eastern state. The distinction of geographical regions with sensitive and resistant parasite phenotypes would be highly useful for designing and administering national anti-malarial drug policy.</p

Malaria control in Bhutan: case study of a country embarking on elimination

<p>Abstract</p> <p>Background</p> <p>Bhutan has achieved a major reduction in malaria incidence amid multiple challenges. This case study seeks to characterize the Bhutan malaria control programme over the last 10 years.</p> <p>Methods</p> <p>A review of the malaria epidemiology, control strategies, and elimination strategies employed in Bhutan was carried out through a literature review of peer-reviewed and grey national and international literature with the addition of reviewing the surveillance and vector control records of the Bhutan Vector-Borne Disease Control Programme (VDCP). Data triangulation was used to identify trends in epidemiology and key strategies and interventions through analysis of the VDCP surveillance and programme records and the literature review. Enabling and challenging factors were identified through analysis of socio-economic and health indicators, corroborated through a review of national and international reports and peer-review articles.</p> <p>Findings</p> <p>Confirmed malaria cases in Bhutan declined by 98.7% from 1994 to 2010. The majority of indigenous cases were due to <it>Plasmodium vivax </it>(59.9%) and adult males are most at-risk of malaria. Imported cases, or those in foreign nationals, varied over the years, reaching 21.8% of all confirmed cases in 2006.</p> <p>Strategies implemented by the VDCP are likely to be related to the decline in cases over the last 10 years. Access to malaria diagnosis in treatment was expanded throughout the country and evidence-based case management, including the introduction of artemisinin-based combination therapy (ACT) for <it>P. falciparum</it>, increasing coverage of high risk areas with Indoor Residual Spraying, insecticide-treated bed nets, and long-lasting insecticidal nets are likely to have contributed to the decline alongside enabling factors such as economic development and increasing access to health services.</p> <p>Conclusion</p> <p>Bhutan has made significant strides towards elimination and has adopted a goal of national elimination. A major challenge in the future will be prevention and management of imported malaria infections from neighbouring Indian states. Bhutan plans to implement screening at border points to prevent importation of malaria and to targeted prevention and surveillance efforts towards at-risk Bhutanese and migrant workers in construction sites.</p

Assessment of therapeutic efficacy of chloroquine and sulphadoxine-pyrimethamine in uncomplicated falciparum malaria

A standardised protocol has been developed by World Health Organization (CDS/RBM/2002) toassess the efficacy of common antimalarials in the treatment of clinically manifested infection withuncomplicated P. falciparum malaria for areas with low to moderate transmission. The therapeuticefficacy protocol is based on clinical and parasitological responses of the patients and it has thepurpose of determining the practical efficacy of the drug regimen in study areas with the ultimateobjective of ascertaining its continued usefulness or the necessity for replacing it in the routinetreatment. Present study has been conducted at seven sites—Kathiatali and Simonabasti of DistrictNowgaon, Assam; Sonapur and Boko of District Kamrup, Assam; Keonjhar Town, Padampur andBasudebpur of District Keonjhar, Orissa. In order to reduce the patient recruitment time, health centreclose to well-defined community was identified to conduct the activities at peak malaria seasonby selecting local pockets and organising mobile clinics. Microscopically confirmed cases of P. falciparumwere enrolled according to the criteria for inclusion and exclusion. Treatment with recommendeddrug was given under supervision and a follow-up schedule at various intervals for 28days was maintained. In chloroquine (CQ) study areas, wherever patients showed treatment failure,they were treated with second line drug—sulphadoxine-pyrimethamine (SP) combination and thenfollowed-up as per study protocol. It was observed that 30% cases showed treatment failure to CQin District Nowgaon, where revised drug policy has already been introduced. In Kamrup district,treatment failure with CQ was found to be less than 25%, which denotes the said regimen is still effective.Almost all the patients from Padampur and Basudebpur of District Keonjhar responded toCQ, treatment failure was noticed only in two patients (3%). The antifolate combination found to befully effective as second line and also as first line wherever revised drug policy has been introduced

Plasmodium vivax lineages: geographical distribution, tandem repeat polymorphism, and phylogenetic relationship

Background: Multi-drug resistance and severe/ complicated cases are the emerging phenotypes of vivax malaria, which may deteriorate current anti-malarial control measures. The emergence of these phenotypes could be associated with either of the two Plasmodium vivax lineages. The two lineages had been categorized as Old World and New World, based on geographical sub-division and genetic and phenotypical markers. This study revisited the lineage hypothesis of P. vivax by typing the distribution of lineages among global isolates and evaluated their genetic relatedness using a panel of new mini-satellite markers. Methods: 18S SSU rRNA S-type gene was amplified from 420 Plasmodium vivax field isolates collected from different geographical regions of India, Thailand and Colombia as well as four strains each of P. vivax originating from Nicaragua, Panama, Thailand (Pak Chang), and Vietnam (ONG). A mini-satellite marker panel was then developed to understand the population genetic parameters and tested on a sample subset of both lineages. Results: 18S SSU rRNA S-type gene typing revealed the distribution of both lineages (Old World and New World) in all geographical regions. However, distribution of Plasmodium vivax lineages was highly variable in every geographical region. The lack of geographical sub-division between lineages suggests that both lineages are globally distributed. Ten mini-satellites were scanned from the P. vivax genome sequence; these tandem repeats were located in eight of the chromosomes. Mini-satellites revealed substantial allelic diversity (7-21, AE = 14.6 +/- 2.0) and heterozygosity (He = 0.697-0.924, AE = 0.857 +/- 0.033) per locus. Mini-satellite comparison between the two lineages revealed high but similar pattern of genetic diversity, allele frequency, and high degree of allele sharing. A Neighbour-Joining phylogenetic tree derived from genetic distance data obtained from ten mini-satellites also placed both lineages together in every cluster. Conclusions: The global lineage distribution, lack of genetic distance, similar pattern of genetic diversity, and allele sharing strongly suggested that both lineages are a single species and thus new emerging phenotypes associated with vivax malaria could not be clearly classified as belonging to a particular lineage on basis of their geographical origin

Therapeutic efficacy of artemether-lumefantrine in uncomplicated falciparum malaria in India

<p>Abstract</p> <p>Background</p> <p>Artemisinin-based combination therapy (ACT) is the treatment of choice for uncomplicated falciparum malaria. Artemether-lumefantrine (AL), a fixed dose co-formulation, has recently been approved for marketing in India, although it is not included in the National Drug Policy for treatment of malaria. Efficacy of short course regimen (4 × 4 tablets of 20 mg artemether plus 120 mg lumefantrine over 48 h) was demonstrated in India in the year 2000. However, low cure rates in Thailand and better plasma lumefantrine concentration profile with a six-dose regimen over three days, led to the recommendation of higher dose globally. This is the first report on the therapeutic efficacy of the six-dose regimen of AL in Indian uncomplicated falciparum malaria patients. The data generated will help in keeping the alternative ACT ready for use in the National Programme as and when required.</p> <p>Methods</p> <p>One hundred and twenty four subjects between two and fifty-five years of age living in two highly endemic areas of the country (Assam and Orissa) were enrolled for single arm, open label prospective study. The standard six-dose regimen of AL was administered over three days and was followed-up with clinical and parasitological evaluations over 28 days. Molecular markers <it>msp</it>-<it>1 </it>and <it>msp</it>-2 were used to differentiate the recrudescence and reinfection among the study subjects. In addition, polymorphism in <it>pfmdr</it>1 was also carried out in the samples obtained from patients before and after the treatment.</p> <p>Results</p> <p>The PCR corrected cure rates were high at both the sites viz. 100% (n = 53) in Assam and 98.6% (n = 71) in Orissa. The only treatment failure case on D7 was a malnourished child. The drug was well tolerated with no adverse events. Patients had pre-treatment carriage of wild type codons at positions 86 (41.7%, n = 91) and 184 (91.3%, n = 91) of <it>pfmdr1 </it>gene.</p> <p>Conclusion</p> <p>AL is safe and effective drug for the treatment of acute uncomplicated falciparum malaria in India. The polymorphism in <it>pfmdr</it>1 gene is not co-related with clinical outcome. However, treatment failure can also occur due to incomplete absorption of the drug as is suspected in one case of failure at D7 in the study. AL can be a viable alternative of artesunate plus sulphadoxine/pyrimethamine (AS + SP), however, the drug should be used rationally and efficacy needs to be monitored periodically.</p

Genetic structure of Plasmodium falciparum field isolates in eastern and north-eastern India

<p>Abstract</p> <p>Background</p> <p>Molecular techniques have facilitated the studies on genetic diversity of <it>Plasmodium </it>species particularly from field isolates collected directly from patients. The <it>msp-1 </it>and <it>msp-2 </it>are highly polymorphic markers and the large allelic polymorphism has been reported in the block 2 of the <it>msp-1 </it>gene and the central repetitive domain (block3) of the <it>msp-2 </it>gene. Families differing in nucleotide sequences and in number of repetitive sequences (length variation) were used for genotyping purposes. As limited reports are available on the genetic diversity existing among <it>Plasmodium falciparum </it>population of India, this report evaluates the extent of genetic diversity in the field isolates of <it>P. falciparum </it>in eastern and north-eastern regions of India.</p> <p>Methods</p> <p>A study was designed to assess the diversity of <it>msp-1 </it>and <it>msp-2 </it>among the field isolates from India using allele specific nested PCR assays and sequence analysis. Field isolates were collected from five sites distributed in three states namely, Assam, West Bengal and Orissa.</p> <p>Results</p> <p><it>P. falciparum </it>isolates of the study sites are highly diverse in respect of length as well as sequence motifs with prevalence of all the reported allelic families of <it>msp-1 </it>and <it>msp-2</it>. Prevalence of identical allelic composition as well as high level of sequence identity of alleles suggest a considerable amount of gene flow between the <it>P. falciparum </it>populations of different states. A comparatively higher proportion of multiclonal isolates as well as multiplicity of infection (MOI) was observed among isolates of highly malarious districts Karbi Anglong (Assam) and Sundergarh (Orissa). In all the five sites, R033 family of <it>msp-1 </it>was observed to be monomorphic with an allele size of 150/160 bp. The observed 80–90% sequence identity of Indian isolates with data of other regions suggests that Indian <it>P. falciparum </it>population is a mixture of different strains.</p> <p>Conclusion</p> <p>The present study shows that the field isolates of eastern and north-eastern regions of India are highly diverse in respect of <it>msp-1 </it>(block 2) and <it>msp-2 </it>(central repeat region, block 3). As expected Indian isolates present a picture of diversity closer to southeast Asia, Papua New Guinea and Latin American countries, regions with low to meso-endemicity of malaria in comparison to African regions of hyper- to holo-endemicity.</p