Open Access

Made in Europe: will artemisinin resistance emerge in French Guiana?

  • Mathieu Nacher1, 2Email author,
  • Philippe J Guérin3,
  • Magalie Demar-Pierre2, 4,
  • Félix Djossou2, 4,
  • François Nosten5 and
  • Bernard Carme1, 2, 6
Malaria Journal201312:152

https://doi.org/10.1186/1475-2875-12-152

Received: 15 January 2013

Accepted: 29 April 2013

Published: 4 May 2013

Abstract

Resistance to artemisinin casts a shadow on the fight against malaria. Theimportance of illegal gold miners and of malaria in isolated regions of FrenchGuiana constitutes a threat that endangers the fight against malaria in theAmazon. The hurdles of French laws and the remoteness of the territory fromFrance make it impossible for the system to adapt to the problem of totalinaccessibility of an important part of the malaria problem. Transmission ishigh in these areas and gold miners self-medicate with erratic regimens ofartemisinin combinations, thus creating perfect conditions for the emergence ofresistance. What needs to be done is being done, but within the limits ofnational law, with some results. However, facing the same difficult problem,Suriname shows more flexibility and is doing much better than French Guianadespite having lower resources. Local authorities in French Guiana cannotoverrule the laws that block appropriate malaria care from reaching a third ofmalaria-exposed persons. Thus the health authorities in France should takeimmediate calibrated legislative and financial measures to avoid a predictabledisaster.

Background

Encouraged by the last decade’s funding efforts and significant successes,malaria elimination has become a serious goal. In the past, such efforts havestumbled on the rise of resistance to anti-malarials and insecticides that affectedthe sustainability of the progresses made. Now, the recent successes ofartemisinin-based combinations are increasingly threatened by the spread ofartemisinin resistance [1, 2], thus casting a shadow on recent optimism.

In the late 1950s, shortly after WHO embarked on the malaria eradication programme,resistance of Plasmodium falciparum to chloroquine emerged on theThai-Cambodia border and spread throughout Asia and then Africa within decades.Resistance to chloroquine also appeared independently in the Amazon Basin. The samepattern happened again for the next anti-malarial drug, sulphadoxine+pyrimethamine.The emergence was in Southeast Asia and it spread towards Africa. Again, resistanceindependently appeared in the Amazon Basin and spread to the subcontinent. Now thehopes of controlling and eliminating malaria are threatened by resistance againstartemisinin derivatives, which has emerged and is spreading in Southeast Asia [13]. There are reasons to fear that it will also emerge in the Amazon Basinwhich holds 98% of P. falciparum malaria cases in South America, andnotably the Guiana shield where the majority of cases are concentrated [4].

Looking for gold, finding malaria

Throughout the Amazon Basin, there has been remarkable progress in controllingmalaria. However, the problem of mobile populations, such as miners, poses achallenge in the region. An additional challenge is that these mobilepopulations cross borders, and thus interventions of the different countriesshould be coherent and coordinated in order to treat the problem globally. Thecommon features of Southeast Asia and the Amazon are that malaria transmissionoften affects remote forested areas where the reach of health care systems ischallenged. In addition, the people affected are often mobile and engaged inillegal activities, such as gold or gem mining, logging or fighting. In theseareas there is no vector control, and ill persons often self medicate witherratic drug regimens, often using single drugs of variable quality, althoughfor this the situation in South America seems to be better than in SoutheastAsia [5, 6].

There are reasons to believe that resistance to artemisinin will appear inEurope’s own back yard. Following the recent global economic meltdown, theprice of gold has sky rocketed, thus fuelling another gold rush. There are goldminers, and there is malaria in the Amazon and the Guianas. An estimated10,000-15,000 garimpeiros mostly originating from northern Brazilillegally operate in French Guiana with profound consequences on human health,the environment, security and the economy [7]. The garimpeiros’s health-seeking behaviour in FrenchGuiana is not uniform. First, they are often far away from health structures.Both Suriname [4] and Brazil report that a significant number of people cross theborder to get diagnosed and treated for malaria, allegedly to avoid beingarrested in French villages by the authorities. When they get malaria, part ofthe treatment they receive is taken and part is reportedly sold back on themining sites in exchange for gold. Remote health centres in French Guiana alsoreport treating garimpeiros with falciparum malaria using Riamet®(fixed combination of artemether-lumefantrine, Novartis). Finally, gold minersalso have access to artemisinin-based combination of unknown origin(Artecom® is neither commercialized in Suriname, in French Guiana nor inBrazil) on the gold mining sites, as was observed during “Harpie”operations by the French military.

Neighbouring successes and French legal constraints

Fighting malaria in mobile populations, hidden in the tropical forest, is a verydifficult challenge, for all health delivery systems. The problem is compoundedby the fact that it affects border areas. Although there is an effort tocooperate in the region, countries have different strategies and differentconstraints, and different results. Facing the same problem as French Guiana,neighbouring Suriname has implemented an integrated comprehensive programmefunded by the global fund that has been followed by remarkable success, with theobjective of malaria elimination now in sight. However, the malaria problemoriginates largely outside of the Surinamese territory, with most of the malariacases reported in the Surinamese clinics in fact coming from French Guiana, thuspotentially threatening the sustainability of malaria control and derailing theobjective of elimination. With the “looking for gold, findingmalaria” programme, Suriname has used a community-based approach with 31malaria service deliverers working on the gold mining sites and trained inprevention, the use of rapid diagnostic tests, and the prompt delivery ofquality controlled artemisinin combinations for malaria patients; this programmehas been successful [8]. In addition, active case detection is performed which allows theinterruption of transmission. France, however, cannot reach these invisiblepopulations living in areas beyond the rule of law. Although malaria cases oftenseek treatment in Suriname or Brazil, some patients are treated by artemisinincombinations delivered by the health centres attached to Cayenne GeneralHospital. Patients can even benefit from costly helicopter evacuations (thefirst cause of emergency calls and evacuations is fever) and receive optimaltreatment by infectious disease specialists. However, the core of malariatransmission and of systematic self-medication is currently not tackled by thehealth system. While Suriname showed flexibility, with a special focus on mobilepopulations, by relying on malaria service deliverers, France is constrained bynational and European laws that are quite unfitting for the realities of thisparticular problem. In France, it is illegal for someone who is not a certifiedhealth professional to perform a rapid diagnostic test (in 2007, a decreeauthorized nurses or personnel from health centers to use the tests) or toprescribe a treatment. There have been various successful interventions relyingon community-based approaches with trained non-professionals delivering malariatreatment [911], but this is not yet feasible, because not authorized in FrenchGuiana. For health structures, sending health professionals to illegal goldmining sites is unlikely to ever take place: security there is not assured andit is probable that garimpeiros would believe public health workers tobe no different than the government that sends forces to dismantle gold miningsites, which could put them at risk.

Thus, the fight against malaria is bound to fail if it just continues to followthe current national laws and regulations.

Beyond the rule of law, research and action are unauthorized

The recent emergence of artemisinin resistance in P. falciparum inwestern Cambodia was detected by showing a significant reduction in parasiteclearance rates and increased failure rates following artemisinin combinationtreatment. In addition to treatment failures and pharmacokinetic data, WHOcurrently recommends measuring parasite density at day 0, day 2 and day 3. Theproportion of patients with a persistent parasitaemia at day 3 is a goodindicator to exclude the presence of resistance. However, it is not adapted todefine resistance because it depends on the initial parasite density, the timingof the sample and it requires large sample sizes. One of the pillars of theglobal plan to contain artemisinin resistance is to intensify monitoring andsurveillance [12]. There are no reliable genetic markers for artemisinin resistanceyet. For a precise assessment of resistance, a minimum of six to eight hourlymonitoring of malaria parasite clearance rate, plus a follow up for a minimum of28 days is required [13]. To do the same in France, as of today, it would be very expensive tooccupy expensive hospital beds to keep patients hospitalized and legallycomplicated, if not illegal. The public health law forbids the conduct ofinterventional research on patients that do not have health insurance because,theoretically, fear of not getting treatment could coerce patients toparticipate in research programmes. A new law, the Jardé law, relaxes thatbarrier. However, the application decrees are not published yet and, until then,the Institutional Review Board’s in France still follow the HurietSerusclat law that forbids biomedical research in persons without healthinsurance. For clinicians, who are in insufficient numbers in French Guiana, itseems unrealistic to expect them to decrypt the multilayered opaque Frenchregulations that thus stand in the way of a precise assessment ofresistance.

Why is it so difficult to do what needs to be done?

The voice of French Guiana does not weigh much when European and French laws arevoted. From Paris, it is hard to imagine that while at the European space portthe business is booming for Arianespace, Europe is also preparing the malariaparasites of tomorrow.

For malaria experts coming from areas where most malaria detection and treatmentis performed by non-doctors, the response to the malaria problem in FrenchGuiana, a rich country, often seems puzzling: why is there no active casedetection? Why does France make it so difficult to treat with primaquine(although the High Council for Public Health advising the Ministry of Healthrecommended it, it could only wish that a company would volunteer to initiatethe process for official approval… meanwhile, some paper work and, inpractice, 48 hours are necessary to obtain it), or to deal with the problem ofmalaria in gold miners? There is some schizophrenia in the state agencies withlaw enforcement clashing with public health. It is not that nothing is beingdone. Insecticide-treated bed nets have been funded and distributed; vectorcontrol teams are present in the villages; infectious disease specialists carefor the patients seen at the hospital, Institut Pasteur does in vitrosurveillance of drug resistance, the incidence of malaria has been divided bythree in the villages of French Guiana, the regional health agency has activelypursued a regional approach with neighbouring countries. But much of the problemoriginates from the illegal mining sites, and the legal framework of France isnot adapted for such a situation. Although the health regional agencies havebenefitted from decentralized powers, they do not have the power to bypass thelaw, even when it is obviously not adapted to the context.

Presently, about 30,000 legal residents live in the endemic areas of FrenchGuiana, but there are up to 15,000 illegal miners. Thus, although WHO recommends100% coverage of exposed populations by appropriate interventions, in FrenchGuiana it is more like two thirds of the population benefitting from a malariaprogramme with appropriate interventions. The rest are attempting to selfmedicate the problem away. Cross border efforts are not proportional. On oneside of the border Suriname is following the WHO policy, on the other sideFrance is not. Therefore, if the status quo is maintained it would be illusoryto think that malaria will ever be eliminated from French Guiana, thus from theneighbouring countries of Brazil and Suriname. In the past, despite greatermalaria incidence, little has been done to tackle this problem. The recentdecline of malaria incidence in the villages of French Guiana will definitelynot be a stimulant to make some changes: everything seems to be going well,while an invisible third of the problem is out of control.

What could be done? Special derogations, special funds and specialimplementing structures for a special problem

What needs to be done is known but it cannot be done in France, under nationallaws.

Reaching populations

If the health system cannot go to the gold mines, and since the gold miners wouldprobably not spontaneously go to the military health professionals, there needsto be some way to improve detection and treatment of malaria on site. NGOs couldbe a solution to fill that gap. Given the number of mining sites, and theirscattered locations, to cover all the ground simultaneously would be difficultand costly. Médecins du Monde, which already operates in French Guianadelivering health care for urban migrants, or Médecins sansFrontières, could be better suited to approach this problem than theofficial health system and its constraints. But these French NGOs may not bewilling to intervene, and probably even less so in the absence of specificfunds. If “professional” NGOs do not intervene, exceptional measuresshould allow local health authorities to implement community-based actions evenif they go against some of the laws voted far away from the forests of FrenchGuiana. Exceptional measures now, not in five years.

WHO recommends universal coverage with appropriate interventions for the entirepopulation at risk, for prevention, diagnosis and treatment. It also emphasizesa special effort to ensure that the most vulnerable populations are covered. WHOalso recommends strong leadership at the ministerial level (funding,regulations). For French Guiana, the Ministry is in Paris, malaria may not be apressing problem there, but there should be a calibrated response to thefinancial and regulatory barriers that prevent the fight against malaria toreach universal coverage.

Implementing structure

Perhaps the dispersion of health and research professionals in differentinstitutions with different scientific pursuits and a variety of other problemsto deal with is detrimental to achieve a clear focus and timely response towardsthe goal of controlling malaria in gold mining areas. The interventions to reachthese populations should be a cross border effort since garimpeiros arehighly mobile. The absence of a programme manager also complicates theinternational coordination with other national malaria programmes dealing withthe same problem. The creation of an implementing structure with a voice, staff,and sufficient funds to achieve strategic goals with regards to malaria couldhence facilitate this task. However, if the legal obstacles for the healthsystem to reach gold miners remain, the added value would be marginal, because athird of the malaria problem, the most difficult third, would still not beproperly dealt with.

There has been enduring concern about the emergence of unknown new pathogens fromthe Amazonian biodiversity hotspot [14]. One that is likely to emerge is artemisinin-resistant P.falciparum. Something should be done about it. Something should havebeen done about it much earlier because neither malaria, gold mining norresistance to anti-malarials are particularly new [15]. In November 2012, it was reported that in Suriname, near the borderwith French Guiana, up to 31% of patients still had detectable parasites at day3 after Coartem® treatment [16, 17]. This needs to be confirmed, but the fear may have become reality andfurther delays would be disastrous.

Declarations

Authors’ Affiliations

(1)
Centre d’Investigation Clinique Epidémiologie Clinique AntillesGuyane, Cayenne General Hospital
(2)
Equipe EPaT EA3593 Epidémiologie des Parasitoses et Mycoses Tropicales, Universite Antilles Guyane
(3)
World Wide Antimalarial Resistance Network (WWARN) and Nuffield Department ofClinical Medicine, University of Oxford
(4)
Unité des Maladies Infectieuses et Tropicales, Centre Hospitalier de Cayenne
(5)
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit
(6)
Centre Hospitalier de Cayenne, Laboratoire Hospitalo Universitaire de Parasitologie Mycologie

References

  1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ: Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009, 361: 455-467. 10.1056/NEJMoa0808859.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, ler Moo C, Al-Saai S, Dondorp AM, Lwin KM, Singhasivanon P, Day NP, White NJ, Anderson TJ, Nosten F: Emergence of artemisinin-resistant malaria on the western border of Thailand:a longitudinal study. Lancet. 2010, 379: 1960-1966.View ArticleGoogle Scholar
  3. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM: Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008, 359: 2619-2620. 10.1056/NEJMc0805011.View ArticlePubMedGoogle Scholar
  4. Hiwat H, Hardjopawiro LS, Takken W, Villegas L: Novel strategies lead to pre-elimination of malaria in previously high-riskareas in Suriname, South America. Malar J. 2011, 11: 10.View ArticleGoogle Scholar
  5. Pribluda VS, Barojas A, Anez A, Lopez CG, Figueroa R, Herrera R, Nakao G, Nogueira FH, Pianetti GA, Povoa MM, Viana GM, Gomes MS, Escobar JP, Sierra OL, Norena SP, Veloz R, Bravo MS, Aldas MR, Hindssemple A, Collins M, Ceron N, Krishnalall K, Adhin M, Bretas G, Hernandez N, Mendoza M, Smine A, Chibwe K, Lukulay P, Evans L: Implementation of basic quality control tests for malaria medicines in AmazonBasin countries: results for the 2005–2010 period. Malar J. 2012, 11: 202. 10.1186/1475-2875-11-202.PubMed CentralView ArticlePubMedGoogle Scholar
  6. Evans L, Coignez V, Barojas A, Bempong D, Bradby S, Dijiba Y, James M, Bretas G, Adhin M, Ceron N, Hinds-Semple A, Chibwe K, Lukulay P, Pribluda V: Quality of anti-malarials collected in the private and informal sectors inGuyana and Suriname. Malar J. 2012, 11: 203. 10.1186/1475-2875-11-203.PubMed CentralView ArticlePubMedGoogle Scholar
  7. Tabor D: Like butterflies in the jungle: the quest for the new El Dorado. Harpers magazine. 2011, 45-54.Google Scholar
  8. Breeveld FJ, Vreden SG, Grobusch MP: History of malaria research and its contribution to the malaria controlsuccess in Suriname: a review. Malar J. 2012, 11: 95. 10.1186/1475-2875-11-95.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Ruebush TK, Zeissig R, Klein RE, Godoy HA: Community participation in malaria surveillance and treatment. II. Evaluationof the volunteer collaborator network of Guatemala. AmJTrop Med Hyg. 1992, 46: 261-271.Google Scholar
  10. Cunha ML, Piovesan-Alves F, Pang LW: Community-based program for malaria case management in the BrazilianAmazon. Am J Trop Med Hyg. 2001, 65: 872-876.PubMedGoogle Scholar
  11. Pang LW, Piovesan-Alves F: Economic advantage of a community-based malaria management program in theBrazilian Amazon. Am J Trop Med Hyg. 2001, 65: 883-886.PubMedGoogle Scholar
  12. Talisuna AO, Karema C, Ogutu B, Juma E, Logedi J, Nyandigisi A, Mulenga M, Mbacham WF, Roper C, Guerin PJ, D'Alessandro U, Snow RW: Mitigating the threat of artemisinin resistance in Africa: improvement ofdrug-resistance surveillance and response systems. Lancet Infect Dis. 2012, 12: 888-896. 10.1016/S1473-3099(12)70241-4.PubMed CentralView ArticlePubMedGoogle Scholar
  13. Flegg JA, Guerin PJ, White NJ, Stepniewska K: Standardizing the measurement of parasite clearance in falciparum malaria:the parasite clearance estimator. Malar J. 2011, 10: 339. 10.1186/1475-2875-10-339.PubMed CentralView ArticlePubMedGoogle Scholar
  14. Leport C, Guégan JF: Les maladies infectieuses émergentes : état de la situation etperspectives. 2011, Paris: Haut conseil de la santé publique La DocumentationFrançaise,Google Scholar
  15. Question au gouvernement: [http://questions.assemblee-nationale.fr/q12/12-21120QE.htm]
  16. Jitan JK, Vreden SG, Adhin MR: Emerging Coartem resistance assessed by day three parasitemia in Suriname. Proceedings of the American Society of Tropical Medicine Meeting 2012,Atlanta, USA. Abstract 1326,Google Scholar
  17. Adhin MR, Labadie-Bracho M, Vreden SG: Status of potential PfATP6 molecular markers for artemisinin resistance inSuriname. Malar J. 2012, 11: 322. 10.1186/1475-2875-11-322.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Nacher et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), whichpermits unrestricted use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.

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