SP Resistance Data Access Group

The sulphadoxine-pyrimethamine (SP) resistance Data Access Group’s aim is to provide maps and open access to the most recent data on molecular markers of SP resistance to help policy makers make informed decisions with regard to use of SP for intermittent preventive treatment of malaria in pregnancy (IPTp) or seasonal malaria chemoprevention (SMC).

Update and overview

Data curation will remain open for all prospective contributions submitted for inclusion on the surveyor, and data provided under open access terms will be used to populate the interactive map platform. This facility will be publicised at the beginning of 2017.

Rationale

Malaria in pregnancy can have devastating consequences.1 The World Health Organization (WHO) currently recommends IPTp for prevention of malaria in pregnant women by administering treatment doses of an efficacious antimalarial drug during the second and third trimesters of pregnancy at predefined intervals at least a month apart. Sulphadoxine-pyrimethamine (SP) is the only antimalarial currently recommended for IPTp. However, high-level parasite resistance to SP threatens the efficacy of the strategy.

In East and Southern Africa, the effectiveness of IPTp with SP to clear peripheral parasitaemia and prevent low birthweight (LBW) decreases with increasing population prevalence of the Plasmodium falciparum dihydropteroate synthase (Pf dhps) K540E mutation, which is a proxy of the quintuple pfdhfr/pfdhps mutant.2 Nevertheless, some beneficial effect on birthweight remains even in areas with high clinical resistance to SP (defined as >90% prevalence of parasites carrying pfdhfr 51I/59R/108N and pfdhps 437G/540E).2, 3 However, IPTp with SP fails to inhibit parasite growth among pregnant women infected with ‘sextuple’ mutant parasites (pfdhps-581G in combination with the quintuple mutant),3, 4, 5, 6 defined as super-resistant parasites.

The continued use of SP in these highly resistant areas has been a topic of recent debate, reflecting the pressing need for an effective, safe and affordable alternative to SP.6, 8, 9, 10 Meanwhile the World Health Organization (WHO), National Malaria Programmes and other policy makers need information at national and sub-national levels to inform strategy decisions and help define the prevalence thresholds of certain mutations above which the IPTp-SP strategy is compromised. Ideally, these data need to be openly accessible without restrictions, in the form of user-friendly tools such as maps which show the thresholds for policy change accompanied with relevant alternative policy recommendations.

Similarly, SP is used in combination with amodiaquine (AQ) for seasonal malaria chemoprevention (SMC) in children in the Sahel regions.11 Population level data on prevalence of molecular markers of resistance to SP are required to obtain a better understanding of the impact on the evolution and spread of SP resistance of the widespread use SP-AQ for SMC, and conversely, the impact of parasite resistance on the effectiveness of SMC with this regimen. Data on markers of resistance to AQ will be observed on the WWARN pfcrt/ pfmdr1 Molecular Surveyor.

Aim and Objectives

The SP Resistance Data Access Group’s aim is to provide open access to the most recent data on SP resistance to inform policy decisions on the clinical effectiveness of intermittent preventive treatment of malaria in pregnancy (IPTp) with SP and SMC with SP-amodiaquine (AQ). Specifically, we will provide up-to-date information to WHO and WHO’s Technical Expert Group (TEG) on Drug Efficacy and Response such that up to date results can be shared early with the relevant policy makers. WWARN will act as the data host and curator.

The long term goal is to maintain an open access interactive map (the ‘surveyor’) and associated data which can be accessed by policy makers and programme managers in endemic countries for national or sub-national level data to inform decisions on recommendations for use of preventive strategies based on prevailing levels of SP resistance.

To achieve these important goals, we have curated published data (to June 2016) on SP resistance from all available sources into the WWARN Data Repository and updated WWARN’s pfdhfr/pfdhps Molecular Surveyor

The specific objective is to:

Provide a platform to continuously update the database and map of molecular markers of SP resistance for sub-Saharan Africa for use by researchers and by WHO and other international and national policy makers.           

Variables for molecular data

Data on molecular makers of SP resistance in P. falciparum required for each submitted dataset:

  • Alleles assessed, total number of samples and number of mutant alleles identified
  • Prevalence or frequency of molecular resistance marker genotype(s)
  • Fraction of the isolates that were polyclonal infections and how those isolates were included in the prevalence calculations
  • Sample collection date and Geo-position of the site

Desirable for each submitted dataset:

  • Information on haplotypes (pfdhfr 51I/59R/108N and/or pfdhps 437G/540E and/or 437G/540E/581G)
  • Genotyped microsatellites in regions flanking resistance markers

Data standardisation and analysis

Once uploaded into the WWARN Data Repository, datasets will be standardised according to the WWARN Surveyor protocols and displayed on the SP molecular surveyor.

The Access Group Coordinator for MiP is Dr Jenny Hill Jenny [dot] Hill [at] lstmed [dot] ac [dot] uk and for SMC is Dr Magatte Ndiaye magatte1 [dot] ndiaye [at] ucad [dot] edu [dot] sn

For further information, email clinical [at] wwarn [dot] org  

References

1.       Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD, 2007. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 7: 93-104.

2.       Desai M, Gutman J, Taylor SM, Wiegand RE, Khairallah C, Kayentao K, Ouma P, Coulibaly SO, Kalilani L, Mace KE, Arinaitwe E, Mathanga DP, Doumbo O, Otieno K, Edgar D, Chaluluka E, Kamuliwo M, Ades V, Skarbinski J, Shi YP, Magnussen P, Meshnick S, Ter Kuile FO, 2016. Impact of Sulfadoxine-Pyrimethamine Resistance on Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy at Clearing Infections and Preventing Low Birth Weight. Clin Infect Dis 62: 323-33.

3.       Chico RM, Cano J, Ariti C, Collier TJ, Chandramohan D, Roper C, Greenwood B, 2015. Influence of malaria transmission intensity and the 581G mutation on the efficacy of intermittent preventive treatment in pregnancy: systematic review and meta-analysis. Trop Med Int Health 20: 1621-33.

4.       Harrington WE, Mutabingwa TK, Muehlenbachs A, Sorensen B, Bolla MC, Fried M, Duffy PE, 2009. Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment. Proc Natl Acad Sci U S A 106: 9027-32.

5.       Minja DT, Schmiegelow C, Mmbando B, Bostrom S, Oesterholt M, Magistrado P, Pehrson C, John D, Salanti A, Luty AJ, Lemnge M, Theander T, Lusingu J, Alifrangis M, 2013. Plasmodium falciparum mutant haplotype infection during pregnancy associated with reduced birthweight, Tanzania. Emerg Infect Dis 19.

6.       Gutman J, Kalilani L, Taylor S, Zhou Z, Wiegand RE, Thwai KL, Mwandama D, Khairallah C, Madanitsa M, Chaluluka E, Dzinjalamala F, Ali D, Mathanga DP, Skarbinski J, Shi YP, Meshnick S, ter Kuile FO, 2015. The A581G Mutation in the Gene Encoding Plasmodium falciparum Dihydropteroate Synthetase Reduces the Effectiveness of Sulfadoxine-Pyrimethamine Preventive Therapy in Malawian Pregnant Women. J Infect Dis 211: 1997-2005.

7.       Naidoo I, Roper C, 2013. Mapping 'partially resistant', 'fully resistant', and 'super resistant' malaria. Trends Parasitol 29: 505-15.

8.       Harrington WE, Fried M, Duffy PE, 2016. Defending the Use of Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment for Malaria in Pregnancy: A Short-Sighted Strategy. J Infect Dis 213: 496-7.

9.       Harrington W, McGready R, Muehlenbachs A, Fried M, Nosten F, Duffy P, 2012. Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: the times they are a-changin'. Clin Infect Dis 55: 1025-6; author reply 1026-7.

10.     Gutman J, Taylor S, Meshnick SR, Ter Kuile FO, 2016. Reply to Harrington et al. J Infect Dis 213: 497-8.

11.     Somé, A.F., et al., Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso. Antimicrobial Agents and Chemotherapy, 2014. 58(7): p. 3660-3665.