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EDITORIAL
Year : 2017  |  Volume : 35  |  Issue : 2  |  Page : 155-156
 

Molecular monitoring of antimalarial drug resistance in India


Department of Molecular Parasitology, National Institute of Malaria Research, ICMR, Bengaluru, Karnataka, India

Date of Web Publication5-Jul-2017

Correspondence Address:
Susanta Kumar Ghosh
Department of Molecular Parasitology, National Institute of Malaria Research, ICMR, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_15_548

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How to cite this article:
Ghosh SK. Molecular monitoring of antimalarial drug resistance in India. Indian J Med Microbiol 2017;35:155-6

How to cite this URL:
Ghosh SK. Molecular monitoring of antimalarial drug resistance in India. Indian J Med Microbiol [serial online] 2017 [cited 2017 Nov 23];35:155-6. Available from: http://www.ijmm.org/text.asp?2017/35/2/155/209568


Emergence and widespread antimalarial drug resistance in malaria parasites especially in Plasmodium falciparum is a cause of public health concern. Routine monitoring of antimalarial drug resistance is an integral part in the national programme for management of drug resistance. The study in reference to Arunachal Pradesh and Assam reported that the presence of high incidence of P. falciparum chloroquine-resistance transporter (Pfcrt) mutation confirms the high degree of chloroquine resistance in this area.[1]

It is important to know the susceptibility status of malaria parasites to the antimalarial drugs used in the national programme. The National Vector Borne Disease Control Programme in collaborations with the National Institute of Malaria Research jointly conducts 'therapeutic efficacy of antimalarial drugs in India'.[2] The results of these multicentric studies help the authorities to decide on the future national drug policy. Thus, artemisinin monotherapy for treatment and management of P. falciparum malaria was withdrawn,[2] and treatment confirmed that P. falciparum was advocated to treat with artemisinin-based combination therapy (ACT) replacing chloroquine. On the other hand, all confirmed Plasmodium vivax cases would be treated with chloroquine since it showed adequate response to this parasite, barring few cases of resistance.[2]

Resistance to chloroquine is the most disturbing factor since this is an affordable and the cheapest antimalarial drug. Genetic diversity and genetic sweep revealed six originating foci in Africa, Southeast Asia (old world) and Latin America (new world).[3] Studies on molecular mechanism of drug resistance have been able to find out several mutations on certain protein or enzyme of the parasite. Such mutations are used as molecular signatures for monitoring and management of drug resistance. In the therapeutic efficacy studies, molecular markers Pfcrt, Pfmdr1 (for chloroquine) and dhfr and dhps (for pyrimethamine and sulfadoxine) are analysed for polymerase chain reaction correction.[2]

The Pfcrt gene is located on a 36 kb segment of chromosome 7 and associated with CQ resistance.[4] The other gene P. falciparum multidrug resistance 1 (Pfmdr1) located on chromosome 5 encoding P glycoprotein homologue 1 has also been linked to the CQ resistance, but its association with the resistance could not be substantiated.[4] Haplotypes (amino acid residues) of these two molecular markers determine the status of CQ resistance. In case of Pfcrt, mutations at K76T of 72–76 residues have been proven to be associated with the CQ resistance whereas mutations at N86Y, Y184F, S1034C, N1042D and D1246Y of Pfmdr1 gene are generally linked to the resistance.[4]

In the Pfcrt gene, four main haplotypes CVIET, CVMNT, CVMET and SVMNT are indicators of resistance, and CVMNK is a wild variant (susceptible). In general, CQ-resistant strains in the old world correspond to CVIET haplotype whereas SVMNT haplotype to new world. On the other hand, irrespective of geographic origin, CQ-susceptible strains are characterised by wild-type haplotype CVMNK. The widespread prevalence of SVMNT haplotype across different geographic zones in India did not support a presumed geographic spread from contiguous Southeast Asia.[5] The study in reference to Assam and Arunachal Pradesh also confirms this phenomenon.[1]

Recent reports have come out with two important aspects. First, return of chloroquine-sensitive P. falciparum in some African countries is a good sign,[6] but it could not sustain even 2 days post-chloroquine treatment where CVIET haplotype (resistant) was replaced with CVMNK (sensitive) one.[7] Second, the correlation of molecular signatures with the therapeutic outcomes is not always positive. Almost all reports indicated positive correlation between CQ-resistance and presence of Pfcrt; a recent report clearly showed the absence of Pfcrt mutation (CVMNK CQ-susceptible haplotype) in a therapeutic study in Eastern India (West Bengal) where Pfmdr1 presented double mutations, contrast to the lack of association of CQ resistance with Pfmdr1, as mentioned earlier.[4] We also observed complete absence of Pfmdr1 in a therapeutic study on CQ in Karnataka in 2008 (unpublished report).

Currently, artemisinin is the most potent antimalarial drug, for which the 2015 Nobel Prize for Medicine or Physiology was awarded to the Chinese scientist Tu Youyou. Even this potent drug is showing reduced susceptibility to P. falciparum. The presence of kelch13 molecular marker (present on chromosome 13) of P. falciparum is an indication of reduced susceptibility for artemisinin under the ACT regime in Northeast Sates of India.[8] Earlier, resistance to the partner drugs, sulfadoxine-pyrimethamine, led to change the one arm of ACT regime from artemisinin-sulfadoxine-pyrimethamine to artemisinin-lumefantrine.[2] However, reduced susceptibility of P. falciparum to artemisinin is a cause of great concern.

So far, it is a good sign that P. vivax is still susceptible to CQ in India, but emergence of resistance to this drug elsewhere is also a matter of concern.[6]

In conclusion, in vivo therapeutic studies need to be carried out where molecular markers may play a pre-emptive role for predicted prevalence of resistance and predicted prevalence of failure calculating the genotype-resistance index (GRI) and genotype-failure index (GFI), where GRI = prevalence of molecular marker/prevalence of parasitological resistance, and GFI = prevalence of molecular marker/prevalence of therapeutic failure.[9]



 
 ~ References Top

1.
Sharma J, Soni M, Dutta P, Khan SA, Mahanta J. Mutational prevalence of chloroquine resistance transporter gene among Plasmodium falciparum field isolates in Assam and Arunachal Pradesh, India. Indian J Med Microbiol 2016;34:193-7.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Anvikar AR, Arora U, Sonal GS, Mishra N, Shahi B, Savargaonkar D, et al. Antimalarial drug policy in India: Past, present & future. Indian J Med Res 2014;139:205-15.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, Baruch DI, et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 2002;418:320-3.  Back to cited text no. 3
    
4.
Das S, Mahapatra SK, Tripathy S, Chattopadhyay S, Dash SK, Mandal D, et al. Double mutation in the pfmdr1 gene is associated with emergence of chloroquine-resistant Plasmodium falciparum malaria in Eastern India. Antimicrob Agents Chemother 2014;58:5909-15.  Back to cited text no. 4
    
5.
Keen J, Farcas GA, Zhong K, Yohanna S, Dunne MW, Kain KC. Real-time PCR assay for rapid detection and analysis of PfCRT haplotypes of chloroquine-resistant Plasmodium falciparum isolates from India. J Clin Microbiol 2007;45:2889-93.  Back to cited text no. 5
    
6.
Mekonnen SK, Aseffa A, Berhe N, Teklehaymanot T, Clouse RM, Gebru T, et al. Return of chloroquine-sensitive Plasmodium falciparum parasites and emergence of chloroquine-resistant Plasmodium vivax in Ethiopia. Malar J 2014;13:244.  Back to cited text no. 6
    
7.
Gadalla NB, Elzaki SE, Mukhtar E, Warhurst DC, El-Sayed B, Sutherland CJ. Dynamics of pfcrt alleles CVMNK and CVIET in chloroquine-treated Sudanese patients infected with Plasmodium falciparum. Malar J 2010;9:74.  Back to cited text no. 7
    
8.
Mishra N, Prajapati SK, Kaitholia K, Bharti RS, Srivastava B, Phookan S, et al. Surveillance of artemisinin resistance in Plasmodium falciparum in India using the kelch13 molecular marker. Antimicrob Agents Chemother 2015;59:2548-53.  Back to cited text no. 8
    
9.
Plowe CV. Monitoring antimalarial drug resistance: Making the most of the tools at hand. J Exp Biol 2003;206:3745-52.  Back to cited text no. 9
    




 

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