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For personal use. Only reproduce with permission from The Lancet Publishing Group. Since the first reports of chloroquine-resistant falciparum malaria in southeast Asia and South America almost half a century ago, drug-resistant malaria has posed a major problem in malaria control. By the late 1980s, resistance to sulfadoxine-pyrimethamine and to mefloquine was also prevalent on the Thai-Cambodian and Thai-Myanmar (Thai- Burmese) borders, rendering them established multid
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  For personal use. Only reproduce with permission from The Lancet Publishing Group. Since the first reports of chloroquine-resistant falciparummalaria in southeast Asia and South America almost half acentury ago, drug-resistant malaria has posed a major problem in malaria control. By the late 1980s, resistance tosulfadoxine-pyrimethamine and to mefloquine was alsoprevalent on the Thai-Cambodian and Thai-Myanmar (Thai-Burmese) borders, rendering them established multidrug-resistant (MDR) areas. Chloroquine resistance spreadacross Africa during the 1980s, and severe resistance is especially found in east Africa. As a result, more than ten African countries have switched their first-line drug to sulfadoxine-pyrimethamine. Of great concern is thefact that the efficacy of this drug in Africais progressively deteriorating, especiallyin foci in east Africa, which are classifiedas emerging MDR areas. Urgent efforts are needed to lengthen the lifespan of sulfadoxine-pyrimethamine and toidentify effective, affordable, alternativeantimalarial regimens. Molecular markersfor antimalarial resistance have beenidentified, including  pfcrt  polymorphismsassociated with chloroquine resistance and dhfr  and  dhps polymorphisms associated with sulfadoxine-pyrimethamineresistance. Polymorphisms in  pfmdr1 may also beassociated with resistance to chloroquine, mefloquine,quinine, and artemisinin. Use of such genetic informationfor the early detection of resistance foci and futuremonitoring of drug-resistant malaria is a potentially usefulepidemiological tool, in conjunction with the conventionalin-vivo and in-vitro drug-sensitivity assessments. Thisreview describes the various features of drug resistance in Plasmodium falciparum , including its determinants, currentstatus in diverse geographical areas, molecular markers,and their implications. Lancet Infect Dis 2002; 2: 209–18 Drug resistance in malaria is a vitally important public-health concern. Each year, an estimated 0·7–2·7 millionpeople die of malaria, and over 75% of them are Africanchildren. 1 Amid such a disease burden, the development of resistance has a significant influence on the control of malaria in affected countries.Resistance of Plasmodium falciparum to chloroquine, a4-aminoquinoline, was first observed almost 50 years ago.Today, chloroquine resistance occurs almost everywherethat P falciparum does. Strains of falciparum parasites havedeveloped resistance to most of the commonly usedantimalarials, including sulfadoxine-pyrimethamine(Fansidar) and mefloquine. Resistance commonly developswithin 10–15 years after an antimalarial is introduced (table 1). 2–6 The development of resistance to sulfadoxine-pyrimethamine in P falciparum in Africa is particularly serious, because this drug combination is the only affordable, effective, practical, and well-tolerated alternativeto 4-aminoquinolines.We review here the changing patterns of drug resistanceand our current understanding of its development,including molecular clues that have recently been elucidated.The resistance pattern in each geographical region providesuseful treatment guidance, because there are no bedsidemethods for assessment of antimalarial-drug susceptibility.Although drug resistance occurs in both P falciparum and Plasmodium vivax, only the former is discussed in this paperbecause it accounts for most of the disease burden. Weemphasise those areas where multidrug resistance isemerging. Resistance to chloroquine in P vivax largely concentrates in Papua New Guinea and Irian Jaya(Indonesia) with sporadic reports from elsewhere in Asiaand South America. No resistance has been documented for Plasmodium malariae  or Plasmodium ovale, theother speciesthat infect human beings. THE LANCET Infectious DiseasesVol 2 Xxxxxx 2002 http://infection.thelancet.com 209 Epidemiology of drug-resistant malaria Chansuda Wongsrichanalai, Amy L Pickard, Walther H Wernsdorfer, and Steven R Meshnick CW is an epidemiologist at the Armed Forces Research Institute ofMedical Sciences (AFRIMS), Bangkok, Thailand. ALP is a doctoralstudent and SRM is professor of epidemiology at the Department ofEpidemiology, University of North Carolina School of Public Health,Chapel Hill, NC, USA. WHW is professor at the Department ofSpecific Prophylaxis and Tropical Medicine, Institute ofPathophysiology, University of Vienna, Vienna, Austria. Correspondence: Dr Chansuda Wongsrichanalai, AFRIMS, 315/6Rajvithi Road, Bangkok 10400, Thailand. Tel +66 (0) 2 644 5775; fax +66 (0) 2 644 4784; email chansudaw@thai.amedd.army.mil Reviews Table 1. Dates of introduction and first reports of antimalarial drug resistance  Antimalarial drugIntroducedFirst reported Difference Refsresistance(years) Quinine163219102782Chloroquine19451957123Proguanil1948194912,4Sulfadoxine-pyrimethamine1967196702,4Mefloquine1977198255 Atovaquone1996199606  For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Infectious DiseasesVol 2 April 2002 http://infection.thelancet.com 210 Historical perspectives Quinine is one of the oldest malaria remedies known,although its use has never been as widespread as that of more contemporary drugs. Quinine occurs naturally in thebark of cinchona trees in South America. Cinchona bark wasintroduced into Europe as a treatment for “the ague” in theearly 17th century. In 1820, the alkaloid quinine was isolatedfrom cinchona bark. 7,8 Chloroquine was first synthesised in Germany but wasnot recognised as a potent antimalarial until the 1940s aspart of the US World War II military effort. By 1946, it wasfound to be far superior to other contemporary syntheticantimalarials. 9 It became the cornerstone of antimalarialchemotherapy for the next 40 years. However, the advent of chloroquine resistance led to the development of otherdrugs such as mefloquine, sulfadoxine-pyrimethamine,artemisinin derivatives, and atovaquone-proguanil(Malarone). 7,8 Subsequently, resistance has developed tomany of the newer drugs.In China, infusions prepared from wormwood( Artemisia annua  ) were used for treating fever over athousand years ago. The efficacy of the infusions has beenascribed to the sesquiterpene lactone, artemisinin. As aresult of increasing drug-resistant malaria, artemisinin fromwormwood and semisynthetic derivatives of this substancehave become a very important antimalarial drug group.  Assessment of  P falciparum antimalarialsusceptibility  P falciparum susceptibility to antimalarial drugs iscommonly assessed by therapeutic response (in-vivo test).In-vivo response to drugs was srcinally defined by WHO interms of parasite clearance (sensitive [S] and three degrees of resistance [RI, RII, RIII]). 10 This classification remains validfor areas with low or no malaria transmission, but it isdifficult to apply to areas with intensive transmission, wherenew infections may be mistaken for recrudescences.Therefore, WHO introduced in 1996 a modified protocolbased on clinical outcome (adequate clinical response, early treatment failure, and late treatment failure) targeted at apractical assessment of therapeutic responses in areas withintense transmission, where parasitaemia in the absence of clinical signs or symptoms is common. 10,11 The protocol hasalso been adapted for use in areas of low to moderateendemicity, taking into consideration that the objectives of malaria treatment are both parasite clearance anddisappearance of symptoms. A summary of the srcinal andmodified protocols is shown in table 2. If not otherwiseindicated, the term “resistance” in this review is based ontherapeutic response according to one of these establishedprotocols.Antimalarial-drug susceptibility can also be assessed by in-vitro assays measuring the intrinsic sensitivity of P falciparum from the inhibition of growth or schizontmaturation. 3,11 Recently, the use of molecular markers hasbeen proposed as an additional tool for the early detection of drug resistance in malaria. 12 Each assessment method has itsadvantages and disadvantages, and the results may not bedirectly comparable with each other. In-vitro test results, inparticular, do not necessarily correspond to in-vivooutcomes, largely owing to the role of host immunity in thelatter. In addition, pharmacokinetic information may berequired for differentiation between true resistance andfailure to achieve adequate drug concentration profiles. 13 Determinants of antimalarial resistance Many factors contribute to the development and spread of resistance. Gene mutations conferring resistance toantimalarial drugs do occur in nature, independently of drug effect (the common antimalarial drugs are notmutagenic). Although the natural proportion of suchmutants in the parasite population is low, and malariaisolates from populations andindividuals show heterogeneity,selection of the most “fit” parasitesoccurs under drug pressure. Single ormultiple point mutations in theplasmodium genome may conferresistance in the face of chemotherapy.Reasons for the development andspread of drug resistance involve the interaction of drug-use patterns,characteristics of the drug itself, humanhost factors, parasite characteristics,and vector and environmental factors(table 3). 3,5,14–16 Characteristics of the drug areimportant determinants of resistance.First, drugs with a long eliminationhalf-life, such as mefloquine, may exertsubstantial residual selection on new infections contracted after thetreatment of the primary infectionwhen the drug persists atsubtherapeutic concentrations in the Review Epidemiology of drug-resistant malaria Table 2. Classifications of in-vivo antimalarial-drug sensitivity test outcomesaccording to the srcinal WHO protocol and the modification (1996) for areas withsubstantial malaria transmission 10 ClassificationDefinitionOriginal classification S (sensitive)Reduction to <25% of initial parasitaemia on day 2 with smears negative for malaria from day 7 to the end of follow-up (28 days or longer for drugs with a long half-life, such as mefloquine)RI responseInitial clearance of parasitaemia, a negative smear on day 7, followed by recrudescence 8 or more days after treatmentRII responseInitial clearance or substantial reduction of parasitaemia (<25% of the initial count on day 2) but with persistence or recrudescence of parasitaemia during days 4–7RIII responseNo significant reduction of parasitaemia Modified classification (1996) Early treatment failure (ETF)Aggravation or persistence of clinical symptoms in the presence of parasitaemia during the first 3 days of follow-upLate treatment failure (LTF)Reappearance of symptoms in the presence of parasitaemia during days 4–14 of follow-up Adequate clinical response (ACR)Absence of parasitaemia on day 14 irrespective of fever, or absence of clinical symptoms irrespective of parasitaemia, in patients not meeting ETF or LTF criteria  For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Infectious DiseasesVol 2 April 2002 http://infection.thelancet.com 211 plasma, 16 especially in areas withintense malaria transmission. Second,the maintenance of adequate drugconcentrations over a long enoughtime is important for clearing the entirepopulation of parasites within a given individual. Subtherapeutic drugconcentrations eliminate the mostsusceptible parasites and leave thosethat may be more fit to recover andreproduce. As a result, the necessary therapeutic dose may increase beyondthe maximum tolerated, and manifestdrug resistance will emerge. Third,widespread use of drugs at highintensity serves to increase drugpressure and is a determinant for selection of resistant parasitepopulations.More potent immune responsesincrease the efficacy of chemotherapy.A semi-immune patient might be curedby a drug despite the fact that hisparasites are partially drug resistant.Individuals who are naive to malariagenerate a non-specific immuneresponse that is not as effective as thespecific immunity elicited by repeatedinfections. Thus, the introduction of resistant malaria into non-immune populations such as refugeesor migrants increases the opportunity for manifestation andspread of resistance, because parasites with low or moderateresistance would be cleared in semi-immune populations.Level of transmission influences the rate of developmentand spread of drug resistance but its exact role is complex andis most probably multifactorial. Increased risk of drug-resistance development has been postulated to occur in areasof both low  17 and high 15 transmission . The generalobservations that resistance developed earlier in areas of low transmission (such as Thailand and Brazil) and is still moreprevalent in such areas than in those with higher transmissiontend to support the low-transmission hypothesis. As anexample of the high transmission hypothesis, full chloroquineresistance in children occurred and spread within 2·5 years inan area of high transmission in east Africa that had beenunder massive chloroquine pressure. 18 Finally, vector and environmental factors may influence theproliferation of resistant parasites. For example, chloroquine-resistant parasites may be more fit for reproduction in certainanopheline mosquitoes than non-resistant strains. 16 Description of drug resistance worldwide Chloroquine Chloroquine resistance has been reported from whereverfalciparum malaria is endemic, except Central America andthe Caribbean. 3,10 In the late 1950s, resistance to chloroquinewas noted on the Thai-Cambodian border and in Colombia. 3 All endemic areas in South America were affected by 1980 andalmost all in Asia and Oceania by 1989.In Africa, chloroquine resistance was first documentedin the east in 1978. Resistance spread to the central andsouthern parts of the continent before arriving in west Africain 1983. By 1989, chloroquine resistance was widespread insub-Saharan Africa. Extensive reviews of the spread of chloroquine resistance have been published by Wernsdorferand Payne 3 and Peters. 2 In general, resistance is currently lesssevere in west and central Africa than in east Africa, but evenin west Africa, its intensity varies from an advanced stagewith severe effects on mortality and morbidity in focal areasof Senegal, 19,20 to a moderate degree in Ghana 21 andCameroon, 22 and a low level in Mali. 23 Owing to high-intensity chloroquine resistance, more than ten countries in Africa have already switched their first-line treatment to sulfadoxine-pyrimethamine or a combination of chloroquine and sulfadoxine-pyrimethamine.Chloroquine-resistant parasites in Africa were thoughtby some to share the same srcin as the Indochina strains,but by others to have developed locally as a result of massdrug administration plus intrinsic entomological,epidemiological, and parasitological factors that promotedlocal resistance selection. 3,16 Current molecular studiessuggest the Asian srcin of African isolates, but at least fourdifferent foci of chloroquine resistance have so far beenidentified. 12 Polymorphisms in two genes of the P falciparum genomeare the focus of studies on the molecular basis of chloroquine resistance (panel 1). The  pfcrt  gene 24 is locatedon chromosome 7, and codes for PfCRT, a vacuolarmembrane transporter protein. Many polymorphisms that Review Epidemiology of drug-resistant malaria Table 3. Determinants of antimalarial-drug resistance Factor and characteristicsExampleDrug Half-lifeResistance to LAPDAP (short half-life) develops more slowly than that to sulfadoxine-pyrimethamine (long half-life) 14 DosingUse of subtherapeutic doses in self-treatment such as with antifolate drugs in Thailand in the 1970s; poor drug compliance; mass drug administration with subtherapeutic doses; use of chloroquinised salt 3 Non-target drug pressurePresumptive use of antimalarial drugs without laboratory diagnosis or for indications other than malariaPharmacokineticsUse of drug formulations with reduced bioavailabilityCross-resistanceSulfadoxine-pyrimethamine and sulfamethoxazole-trimethoprim Human Host immunityNon-immune, migrant gem-miners and resistance to mefloquine on the Thai-Cambodian border 5 Maintenance of resistantNon-detection of drug failureparasite reservoir Parasite Genetic mutationsSee panel 1 Transmission levelWhether low or high transmission has more influence on drug resistance is debatable; prevalence of drug resistance is higher in regions of low transmission, whereas a model suggests the benefits of transmission control in delaying resistance development 15  Vector and environment  Vector affinity of parasitesIncreased infectivity and productivity of chloroquine-resistant parasites in  Anopheles dirus and the propagation of chloroquine resistance in southeast Asia and western Oceania 16 LAPDAP=chlorproguanil plus dapsone.  For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Infectious DiseasesVol 2 April 2002 http://infection.thelancet.com 212 are associated with chloroquine resistance have beenidentified, but the substitution of threonine for lysine incodon 76 was recently shown in vitro to associate absolutely with resistance in isolates from Africa, South America, Asia,and Papua New Guinea. 23,25 Findings from an in-vitro study of isolates from various srcins 26 and several clinical studiesin diverse geographical areas support the associationbetween the Thr76 mutation and chloroquine resistance inAfrica (Mali, 23 Cameroon, 27 Sudan, 28 Mozambique 29 ), Asia(Laos, 30 Thailand 31 ), and South America (Brazil 32 ). However,one study in Uganda, where chloroquine resistance ismoreprevalent thanin west Africa, reported no association. 33 Most of the studies reporting an association note that,although the Thr76 mutation may be essential for theresistant phenotype, it is also present to a lesser degree inchloroquine-sensitive strains, suggesting that otherpolymorphisms in  pfcrt  are necessary or that several genesare involved. Additionally, host immunity is known to havea significant role in parasite clearance, therefore chloroquinetreatment success in semi-immune individuals even in thepresence of chloroquine-resistant parasites with the Thr76mutation is not unexpected. Djimde and colleagues 23 foundthat the lack of the Thr76 mutation was highly predictive of chloroquine treatment success, whereas its presenceaccounted for only a third of treatment failures.Another gene,  pfmdr1, which is located on chromosome5 and codes for P-glycoprotein homologue 1 (Pgh1), hasgenerated interest in resistance to chloroquine and otherantimalarials. The aspartic acid to tyrosine point mutationin codon 86 has been associated with chloroquine resistancein some clinical and in-vitro studies (Mali, 23 The Gambia, 34 Sudan, 28 Uganda, 35 Thailand, 36 Brazil 37 ), but not in others(Uganda, 33 Laos, 30 Thailand, 38 Brazil 39 ). Several other  pfmdr1 polymorphisms, notably Phe184, Cys1034, Asp1042, andTyr1246, have been implicated to varying degrees inchloroquine resistance (table 4). Although evidence for theassociation of  pfmdr1 with chloroquine resistance has notbeen as convincing as for  pfcrt  , a recent parasite transfectionexperiment showed that polymorphisms in the  pfmdr1 genemodulate susceptibility to chloroquine (as well as tomefloquine and the structurally related compounds quinineand halofantrine). 49 Linkage disequilibrium between  pfcrt  Thr76 and  pfmdr1 Tyr86 has been noted in Africa (Nigeria 50 and Sudan 28 ) andprovides support for a convergence of polymorphismsnecessary for a resistance phenotype. The slow developmentof chloroquine resistance may signal such a multifactorialmechanism. 12 Sulfadoxine-pyrimethamine Resistance to sulfadoxine-pyrimethamine was first noted onthe Thai-Cambodian border in the mid-1960s, 4 and itbecame an operational problem in the same area within afew years of its introduction to the malaria-controlprogramme in 1975. 51 Currently, high-level resistance isfound in a large part of southeast Asia, southern China, andthe Amazon Basin. 10,46,52 Lower degrees and frequencies of resistance are observed on the Pacific coast of SouthAmerica, southern Asia east of Iran, and western Oceania. 11 In Africa, sulfadoxine-pyrimethamine sensitivity starteddeclining in the late 1980s. Resistance is rapidly gainingground on this continent, more so in the east than in thewest. In east Africa, the degree of resistance is variable. Highpercentages of RII/RIII responses were documented inchildren in an endemic area of Tanzania as early as 1994. 53 This finding was thought to be attributable to previous drugpressure due to the use of pyrimethamine-dapsoneprophylaxis. The 1999–2000 data from the East AfricanNetwork for Monitoring Antimalarial Treatment indicatedthat the proportion of clinical failures (combined late andearly treatment failures) at some sentinel sites in Kenya wasalready more than 25%, and the proportion of parasitological failures at day 7 in children has reached 45%at one site in Tanzania. Focal areas of low to moderatesulfadoxine-pyrimethamine resistance exist throughoutAfrica. 21,54–56 Resistance is likely to progress geographically and in its intensity at an alarming rate if nothing is done tointerrupt its course.An in-vitro study in Kenya showed low sensitivity toboth pyrimethamine and sulfadoxine from the late 1980s tothe early 1990s and the presence of pyrimethamine-resistantisolates in the late 1980s, even before sulfadoxine-pyrimethamine was widely used. 57 In-vitro sulfadoxine-pyrimethamine resistance was documented across sub-Saharan Africa, varying in prevalence from 13–30%: inTanzania in 1994, 58 Equatorial Guinea in 1990–92, 59 Gabonin 1994, 60 and Ghana in 1991. 21 Cross-resistance betweentrimethoprim and pyrimethamine in P falciparum wasrecently demonstrated . 61 Therefore, widespread use of trimethoprim-sulfamethoxazole for prophylaxis againstopportunistic in people with AIDS in Africa might furthershorten the useful lifespan of sulfadoxine-pyrimethamine.The molecular basis of resistance to sulfadoxine-pyrimethamine is the best characterised of all antimalarialresistance. Specific mutations in P falciparum that lead toresistance to both sulfadoxine and pyrimethamine have Review Epidemiology of drug-resistant malaria Panel 1. Molecular markers of antimalarialresistance Chloroquine  pfcrt  Thr76 strongly associated  pfmdr1 Tyr86, Phe184, Cys1034, Asp1042, Tyr1246 possiblyassociated Sulfadoxine-pyrimethamine Principal mutations in codons 108, 51, 59, and 164 of dhfrgene and codons 436, 437, 540, 581, and 623 of dhps gene dhfr   Asn108 essential for pyrimethamine resistanceDegree of resistance increases with additional mutations,Leu51 and Arg59, or triple mutation Absolute resistance conferred by the addition of Leu164, thusquadruple mutation, irrespective of dhps mutations Mefloquine, quinine Genetic basis of resistance not yet clearly understood  pfmdr1 polymorphism may modulate mefloquine and quininesusceptibilityPoint mutations being explored at positions 86, 184, 1034,1042, and 1246 of  pfmdr1 .  Artemisinin No clinically relevant resistance as yet.

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