Malaria case management with prompt and effective treatment is critical to minimize morbidity and mortality, reduce transmission and to prevent the emergence and spread of anti-malarial drug ...resistance. India has the highest burden of malaria in South East Asia Region and has made impressive progress in the reduction of the malaria burden in recent years. Since the last revision to the Indian national malaria treatment policy in 2013, guidelines on new treatment strategies have been published for the control/ elimination of malaria by the World Health Organisation (WHO). The most recent update was in March 2023 based on the new evidence available. India's success is the Region's success. Therefore, to meet the national as well as regional targets of elimination, the Indian National Programme needs to consider WHO guidelines, deliberate with stakeholders and experts so as to tailor and adapt to the local context, and update National policies to incorporate the relevant ones. Technical aspects of new WHO guidelines which need to be considered for updating India's treatment policy are discussed.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but ...in P vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance. Methods We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria. Findings We identified 129 eligible clinical trials involving 21 694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P vivax . Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity. Interpretation Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P vivax , which is now present across most countries endemic for P vivax . Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. Funding Wellcome Trust (UK).
In recent years, Plasmodium falciparum histidine-rich protein 2 gene deletion has been reported in India. Such isolates are prone to selective transmission and thus form a challenge to case ...management. As most of the rapid malaria diagnostic tests are based on the detection of HRP2 protein in the blood, we attempted to use Glutamate Dehydrogenase (GDH) as a biomarker for the diagnosis of P. falciparum. Recombinant PfGDH was successfully cloned, expressed and purified using the Ni-NTA approach. Polyclonal antibodies were raised against full-length rPfGDH and its peptides. Antibodies for rPfGDH showed a strong immune response against the recombinant protein. However, antibody showed no affinity towards the peptides, which suggests they failed as antigen. Antibodies for rPfGDH significantly detected the GDH in human blood specimens. This is the first report where P. falciparum GDH was detected in malaria cases from various parts of India. The raised polyclonal antibodies had shown an affinity for PfGDH in quantitative ELISA and are capable to be exploited for RDTs. This research needs further statistical validation on a large number and different sample types from candidates infected with P. falciparum and other species.
In India, nine Anopheline vectors are involved in transmitting malaria in diverse geo-ecological paradigms. About 2 million confirmed malaria cases and 1,000 deaths are reported annually, although 15 ...million cases and 20,000 deaths are estimated by WHO South East Asia Regional Office. India contributes 77% of the total malaria in Southeast Asia. Multi-organ involvement/dysfunction is reported in both Plasmodium falciparum and P. vivax cases. Most of the malaria burden is borne by economically productive ages. The states inhabited by ethnic tribes are entrenched with stable malaria, particularly P. falciparum with growing drug resistance. The profound impact of complicated malaria in pregnancy includes anemia, abortions, low birth weight in neonates, still births, and maternal mortality. Retrospective analysis of burden of malaria showed that disability adjusted life years lost due to malaria were 1.86 million years. Cost-benefit analysis suggests that each Rupee invested by the National Malaria Control Program pays a rich dividend of 19.7 Rupees.
Chloroquine (CQ) resistance in Plasmodium falciparum is determined by the mutations in the chloroquine resistance transporter (Pfcrt) gene. The point mutation at codon 76 (K76T), which has been ...observed in more than 91% of P. falciparum isolates in India, is the major determinant of CQ resistance. To overcome the limitations and challenges of traditional methods, in this investigation we developed an easy to use loop mediated isothermal amplification (LAMP) protocol for rapid detection of the K76T mutation associated with CQ resistance in P. falciparum with naked eye visualization. In- house designed primers were synthesized and optimized to specifically distinguish the CQ resistant mutants of P. falciparum. The LAMP reaction was optimal at 61 °C for 60 min and calcein dye was added prior to amplification to enable visual detection. We demonstrate the detection limit of <2 ng/μl respectively, supporting the high sensitivity of this calcein based LAMP method. To the best of our knowledge this is the first report on the establishment of an easy, reliable and cost effective LAMP assay for rapid and specific detection of highly CQ resistance in P. falciparum malaria.
We report Indian Plasmodium falciparum field isolates lacking both Pfhrp2 and Pfhrp3 genes. Lack of amplification of Pfhrp2, Pfhrp3 and their flanking genes in two P. falciparum field isolates of ...India. Row 1: Lanes 1 and 7=100bp marker, Lanes 6 and 12=negative control (distilled water), Lanes 2–5=Pfhrp2 gene, Lanes 8–11=Pfhrp3 gene. Row 2: Lanes 1 and 7=100bp marker, Lanes 6 and 12=negative control (distilled water), Lanes 2–5=upstream Pfhrp2 gene, Lanes 8–11=downstream Pfhrp2 gene. Display omitted
► Failure to express Pfhrp2 and Pfhrp3 due to gene deletion may contribute to variable performance of malaria RDTs. ► We report two Indian P. falciparum isolates lacking these genes. ► Genetic deletion of Pfhrp2 and Pfhrp3 may lead to false negative results in RDTs.
Genetic polymorphisms in diagnostic antigens are important factors responsible for variable performance of rapid diagnostic tests. Additionally, the failure of antigen expression due to gene deletion may also contribute to variable performance. We report Indian Plasmodium falciparum field isolates lacking both Pfhrp2 and Pfhrp3 genes leading to false negative results of rapid diagnostic tests. The study highlights need to determine the prevalence of P. falciparum isolates lacking these genes in larger field populations in India.
Malaria remains a global health problem despite availability of effective tools. For malaria elimination, drugs targeting sexual stages of Plasmodium falciparum need to be incorporated in treatment ...regimen along with schizonticidal drugs to interrupt transmission. Primaquine is recommended as a transmission blocking drug for its effect on mature gametocytes but is not extensively utilized because of associated safety concerns among glucose-6-phosphate dehydrogenase (G6PD) deficient patients. In present work, methylene blue, which is proposed as an alternative to primaquine is investigated for its gametocytocidal activity amongst Indian field isolates. An effort has been made to establish Indian field isolates of P. falciparum as in vitro model for gametocytocidal drugs screening.
Plasmodium falciparum isolates were adapted to in vitro culture and induced to gametocyte production by hypoxanthine and culture was enriched for gametocyte stages using N-acetyl-glucosamine. Gametocytes were incubated with methylene blue for 48 h and stage specific gametocytocidal activity was evaluated by microscopic examination.
Plasmodium falciparum field isolates RKL-9 and JDP-8 were able to reproducibly produce gametocytes in high yield and were used to screen gametocytocidal drugs. Methylene blue was found to target gametocytes in a concentration dependent manner by either completely eliminating gametocytes or rendering them morphologically deformed with mean IC
(early stages) as 424.1 nM and mean IC
(late stages) as 106.4 nM. These morphologically altered gametocytes appeared highly degenerated having shrinkage, distortions and membrane deformations.
Field isolates that produce gametocytes in high yield in vitro can be identified and used to screen gametocytocidal drugs. These isolates should be used for validation of gametocytocidal hits obtained previously by using lab adapted reference strains. Methylene blue was found to target gametocytes produced from Indian field isolates and is proposed to be used as a gametocytocidal adjunct with artemisinin-based combination therapy. Further exploration of methylene blue in clinical studies amongst Indian population, including G6PD deficient patients, is recommended.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The native gut microbiota of Anopheles mosquitoes is known to play a key role in the physiological function of its host. Interestingly, this microbiota can also influence the development of ...Plasmodium in its host mosquitoes. In recent years, much interest has been shown in the employment of gut symbionts derived from vectors in the control of vector-borne disease transmission. In this study, the midgut microbial diversity has been characterized among laboratory-reared adult Anopheles stephensi mosquitoes, from the colony created by rearing progeny of wild-caught mosquitoes (obtained from three different locations in southern India) for multiple generations, using 16S ribosomal RNA (rRNA) gene sequencing approach. Further, the influence of native midgut microbiota of mosquitoes on the development of rodent malaria parasite Plasmodium berghei in its host has been studied.
The microbial diversity associated with the midgut of An. stephensi mosquitoes was studied by sequencing V3 region of 16S ribosomal RNA (rRNA) gene. The influence of native midgut microbiota of An. stephensi mosquitoes on the susceptibility of the mosquitoes to rodent malaria parasite P. berghei was studied by comparing the intensity and prevalence of P. berghei infection among the antibiotic treated and untreated cohorts of mosquitoes.
The analysis of bacterial diversity from the midguts of An. stephensi showed Proteobacteria as the most dominant population among the three laboratory-reared strains of An. stephensi studied. Major genera identified among these mosquito strains were Acinetobacter, Pseudomonas, Prevotella, Corynebacterium, Veillonella, and Bacillus. The mosquito infectivity studies carried out to determine the implication of total midgut microbiota on P. berghei infection showed that mosquitoes whose native microbiota cleared with antibiotics had increased susceptibility to P. berghei infection compared to the antibiotic untreated mosquitoes with its natural native microbiota.
The use of microbial symbiont to reduce the competence of vectors involved in disease transmission has gained much importance in recent years as an emerging alternative approach towards disease control. In this context, the present study was aimed to identify the midgut microbiota composition of An. stephensi, and its effect on the development of P. berghei. Interestingly, the analysis of midgut microbiota from An. stephensi revealed the presence of genus Veillonella in Anopheles species for the first time. Importantly, the study also revealed the negative influence of total midgut microbiota on the development of P. berghei in three laboratory strains of An. stephensi, emphasizing the importance of understanding the gut microbiota in malaria vectors, and its relationship with parasite development in designing strategies to control malaria transmission.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Comprehensive Case Management Project (CCMP), was a collaborative implementation research initiative to strengthen malaria early detection and complete treatment in Odisha State, India.
A two-arm ...quasi-experimental design was deployed across four districts in Odisha, representing a range of malaria endemicity: Bolangir (low), Dhenkanal (moderate), Angul (high), and Kandhamal (hyper). In each district, a control block received routine malaria control measures, whereas a CCMP block received a range of interventions to intensify surveillance, diagnosis, and case management. Impact was evaluated by difference-in-difference (DID) analysis and interrupted time-series (ITS) analysis of monthly blood examination rate (MBER) and monthly parasite index (MPI) over three phases: phase 1 pre-CCMP (2009-2012) phase 2 CCMP intervention (2013-2015), and phase 3 post-CCMP (2016-2017).
During CCMP implementation, adjusting for control blocks, DID and ITS analysis indicated a 25% increase in MBER and a 96% increase in MPI, followed by a -47% decline in MPI post-CCMP, though MBER was maintained. Level changes in MPI between phases 1 and 2 were most marked in Dhenkanal and Angul with increases of 976% and 287%, respectively, but declines in Bolangir (-57%) and Kandhamal (-22%). Between phase 2 and phase 3, despite the MBER remaining relatively constant, substantial decreases in MPI were observed in Dhenkanal (-78%), and Angul (-59%), with a more modest decline in Bolangir (-13%), and an increase in Kandhamal (14%).
Overall, CCMP improved malaria early detection and treatment through the enhancement of the existing network of malaria services which positively impacted case incidence in three districts. In Kandhamal, which is hyperendemic, the impact was not evident. However, in Dhenkanal and Angul, areas of moderate-to-high malaria endemicity, CCMP interventions precipitated a dramatic increase in case detection and a subsequent decline in malaria incidence, particularly in previously difficult-to-reach communities.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In 2013, the Comprehensive Case Management Programme (CCMP) was initiated to assess the impact of universal access to diagnosis and treatment and improved surveillance on malaria transmission in ...different settings in Odisha state, India.
Pairs of intervention and control sub-districts (blocks), matched on malaria incidence were selected in four districts with different transmission intensities. CCMP activities included training and supervision, ensuring no stock-outs of malaria tests and drugs, analysing verified surveillance data, stratifying areas based on risk factors, and appointing alternative providers to underserved areas. Composite risk scores were calculated for each sub-centre using principal component analysis. Post-pre changes (2013-2015 versus 2011-2012) for annual blood examination rates (ABER) and annual parasite incidence (API) across intervention and control groups were assessed using difference-in-difference (DID) estimates, adjusted for malaria transmission risk.
In the intervention sub-centres, the mean increase in ABER was 6.41 tests/sub-centre (95%CI 4.69, 8.14; p<0.01) and in API was 9.2 cases diagnosed/sub-centre (95%CI 5.18, 13.21; p<0.01). The control sub-centres reported lower increases in ABER (2.84 95%CI 0.35, 5.34; p<0.05) and API (3.68 95%CI 0.45, 6.90; p<0.05). The control-adjusted post-pre changes in API showed that 5.52 more cases (95%CI 0.34, 10.70; p<0.05) were diagnosed, and a 3.6 more cases (95%CI 0.58, 6.56; p<0.05) were tested per sub-centre in the intervention versus control areas. Larger differences in post-pre changes in API between intervention and control sub-centres were registered in the higher transmission-risk areas compared with the lower risk areas. All the changes were statistically significant.
Intensive intervention activities targeted at improved access to malaria diagnosis and treatment produced a substantial increase in blood examination and case notification, especially in inaccessible, hard-to-reach pockets. CCMP provides insights into how to achieve universal coverage of malaria services through a routine, state-run programme.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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