Drug resistance in malaria - - World Health Organization

WHO/CDS/CSR/DRS/2001.4ORIGINAL: ENGLISHDISTRIBUTION: GENERAL

Drug resistancein malariaPeter B. Bloland

World Health OrganizationCopies can be obtained from the CDS Information Resource CentreWorld Health Organization, 1211 Geneva 27, Switzerland

fax: +41 22 791 42 85 • email: [email protected]

WHO/CDS/CSR/DRS/2001.4ORIGINAL: ENGLISHDISTRIBUTION: GENERAL

Drug resistancein malariaPeter B. BlolandMalaria Epidemiology BranchCenters for Disease Control and PreventionChamblee, GA, United States of America

World Health Organization

A BACKGROUND DOCUMENT FOR

THE WHO GLOBAL STRATEGY

FOR CONTAINMENT OF

ANTIMICROBIAL

RESISTANCE

Acknowledgement

The World Health Organization wishes to acknowledge the support of the United States Agency for Inter-national Development (USAID) in the production of this document.

© World Health Organization 2001

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Designed by minimum graphicsPrinted in Switzerland

Contents

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WHO/CDS/CSR/DRS/2001.4 DRUG RESISTANC IN MALARIA

1. Introduction 1

2. Disease incidence and trends 22.1 Geographical distribution and populations at risk 22.2 Causative agents 32.3 Diagnosis 3

2.3.1 Microscopy 32.3.2 Clinical (presumptive) diagnosis 32.3.3 Antigen detection tests 52.3.4 Molecular tests 52.3.5 Serology 5

2.4 Drugs available for treatment of malaria 52.4.1 Quinine and related compounds 52.4.2 Antifolate combination drugs 92.4.3 Antibiotics 92.4.4 Artemisinin compounds 92.4.5 Miscellaneous compounds 92.4.6 Combination therapy with antimalarials 10

2.5 Current status of drug-resistant malaria 10

3. Causes of resistance 123.1 Definition of antimalarial drug resistance 123.2 Malaria treatment failure 123.3 Mechanisms of antimalarial resistance 12

3.3.1 Chloroquine resistance 123.3.2 Antifolate combination drugs 133.3.3 Atovaquone 13

3.4 Factors contributing to the spread of resistance 133.4.1 Biological influences on resistance 133.4.2 Programmatic influences on resistance 15

4. Detection of resistance 164.1 In vivo tests 164.2 In vitro tests 174.3 Animal model studies 174.4 Molecular techniques 174.5 Case reports and passive detection of treatment failure 18

5. Treatment 19

6. The future: prevention of drug resistance 206.1 Preventing drug resistance 20

6.1.1 Reducing overall drug pressure 216.1.2 Improving the way drugs are used 216.1.3 Combination therapy 21

7. Conclusions and recommendations 237.1 Priorities 23

8. Bibliography 24

Figure and tablesFigure 1. Approximate distribution of malaria 2Table 1. Comparative descriptions of available malaria diagnostic methods 4Table 2. Antimalarial drugs for uncomplicated malaria 6Table 3. Distribution of drug-resistant Plasmodium falciparum malaria 10

DRUG RESISTANCE IN MALARIA WHO/CDS/CSR/DRS/2001.4

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WHO/CDS/CSR/DRS/2001.4 DRUG RESISTANCE IN MALARIA

1. Introduction

of the greatest challenges facing malaria controltoday. Drug resistance has been implicated in thespread of malaria to new areas and re-emergence ofmalaria in areas where the disease had been eradi-cated. Drug resistance has also played a significantrole in the occurrence and severity of epidemics insome parts of the world. Population movement hasintroduced resistant parasites to areas previously freeof drug resistance. The economics of developingnew pharmaceuticals for tropical diseases, includ-ing malaria, are such that there is a great disparitybetween the public health importance of thedisease and the amount of resources invested indeveloping new cures (1, 2). This disparity comesat a time when malaria parasites have demonstratedsome level of resistance to almost every anti-malarial drug currently available, significantlyincreasing the cost and complexity of achievingparasitological cure.

The purpose of this review is to describe the stateof knowledge regarding drug- resistant malaria andto outline the current thinking regarding strategiesto limit the advent, spread, and intensification ofdrug-resistant malaria.

Malaria remains an important public healthconcern in countries where transmission occursregularly, as well as in areas where transmission hasbeen largely controlled or eliminated. Malaria is acomplex disease that varies widely in epidemiologyand clinical manifestation in different parts of theworld. This variability is the result of factors suchas the species of malaria parasites that occur in agiven area, their susceptibility to commonly usedor available antimalarial drugs, the distribution andefficiency of mosquito vectors, climate and otherenvironmental conditions and the behaviour andlevel of acquired immunity of the exposed humanpopulations. In particular, young children,pregnant women, and non-immune visitors tomalarious areas are at greatest risk of severe or fatalillness. Many malaria control strategies exist, butnone are appropriate and affordable in all contexts.Malaria control and prevention efforts need to bedesigned for the specific environment in which theywill be used and need to take into account thelocal epidemiology of malaria and the level of avail-able resources and political will.

Antimalarial drug resistance has emerged as one


2

2. Disease incidence and trends

(5) and the Medicines for Malaria Venture (6) ahistory of unpredictable support for malaria-relatedresearch and control activities in endemic countrieshave left many of these countries with little techni-cal capacity for malaria control activities.

Each year an estimated 300 to 500 million clini-cal cases of malaria occur, making it one of the mostcommon infectious diseases worldwide. Malaria canbe, in certain epidemiological circumstances, adevastating disease with high morbidity and mor-tality, demanding a rapid, comprehensive response.In other settings, it can be a more pernicious pub-lic health threat. In many malarious areas of theworld, especially sub-Saharan Africa, malaria isranked among the most frequent causes of mor-bidity and mortality among children and is oftenthe leading identifiable cause. WHO estimates thatmore than 90% of the 1.5 to 2.0 million deaths

2.1 Geographical distribution andpopulations at risk

Malaria occurs in over 90 countries worldwide.According to figures provided by the World HealthOrganization (3), 36% of the global population livein areas where there is risk of malaria transmission,7% reside in areas where malaria has never beenunder meaningful control, and 29% live in areaswhere malaria was once transmitted at low levelsor not at all, but where significant transmission hasbeen re-established (3). The development andspread of drug-resistant strains of malaria parasiteshas been identified as a key factor in this resur-gence and is one of the greatest challenges tomalaria control today. Although there is currentlyan increase in attention and resources aimed atmalaria, including such initiatives as Roll BackMalaria (4), the Multilateral Initiative on Malaria

FIGURE 1. APPROXIMATE DISTRIBUTION OF MALARIA

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attributed to malaria each year occur in Africanchildren (3). Other estimates based on a morerigorous attempt to calculate the burden of diseasein Africa support this level of mortality (7). Inaddition to its burden in terms of morbidity andmortality, the economic effects of malaria infectioncan be tremendous. These include direct costs fortreatment and prevention, as well as indirect costssuch as lost productivity from morbidity and mor-tality, time spent seeking treatment, and diversionof household resources. The annual economic bur-den of malaria infection in 1995 was estimated atUS$ .8 billion, for Africa alone (8). This heavy tollcan hinder economic and community developmentactivities throughout the region.

Malaria transmission occurs primarily in tropi-cal and subtropical regions in sub-Saharan Africa,Central and South America, the Caribbean islandof Hispaniola, the Middle East, the Indian subcon-tinent, South-East Asia, and Oceania (figure1). Inareas where malaria occurs, however, there is con-siderable variation in the intensity of transmissionand risk of malaria infection. Highland (>1500 m)and arid areas (<1000 mm rainfall/year) typicallyhave less malaria, although they are also prone toepidemic malaria when parasitaemic individualsprovide a source of infection and climate condi-tions are favourable to mosquito development (3).Although urban areas have typically been at lowerrisk, explosive, unplanned population growth hascontributed to the growing problem of urbanmalaria transmission (9).

2.2 Causative agents

In humans, malaria infection is caused by one ormore of four species of intracellular protozoan para-site. Plasmodium falciparum, P. vivax, P. ovale, andP. malariae differ in geographical distribution,microscopic appearance, clinical features (periodic-ity of infection, potential for severe disease, andability to cause relapses), and potential for devel-opment of resistance to antimalarial drugs. To date,drug resistance has only been documented in twoof the four species, P. falciparum and P. vivax.

2.3 Diagnosis (Table 1)

Direct microscopic examination of intracellularparasites on stained blood films is the current stand-ard for definitive diagnosis in nearly all settings.However, several other approaches exist or are indevelopment and will be described here.

2.3.1 Microscopy

Simple light microscopic examination of Giemsa-stained blood films is the most widely practised anduseful method for definitive malaria diagnosis.Advantages include differentiation between species,quantification of the parasite density, and abilityto distinguish clinically important asexual parasitestages from gametocytes which may persist with-out causing symptoms. These advantages can becritical for proper case-management and evaluat-ing parasitological response to treatment. Specificdisadvantages are that slide collection, staining, andreading can be time-consuming and microscopistsneed to be trained and supervised to ensure con-sistent reliability. While availability of microscopicdiagnosis has been shown to reduce drug use insome trial settings (10), in practice, results areoften disregarded by clinicians (11). Any pro-gramme aimed at improving the availability ofreliable microscopy should also retrain cliniciansin the use and interpretation of microscopicdiagnosis.

A second method is a modification of lightmicroscopy called the quantitative buffy coatmethod (QBCTM, Becton-Dickinson). Originallydeveloped to screen large numbers of specimens forcomplete blood cell counts, this method has beenadapted for malaria diagnosis (12). The techniqueuses microhaematocrit tubes precoated with fluo-rescent acridine orange stain to highlight malariaparasites. With centrifugation, parasites are con-centrated at a predictable location. Advantages toQBC are that less training is required to operatethe system than for reading Giemsa-stained bloodfilms, and the test is typically quicker to performthan normal light microscopy. Field trials haveshown that the QBC system may be marginallymore sensitive than conventional microscopyunder ideal conditions (13, 14). Disadvantages arethat electricity is always required, special equipmentand supplies are needed, the per-test cost is higherthan simple light microscopy, and species-specificdiagnosis is not reliable.

2.3.2 Clinical (presumptive) diagnosis

Although reliable diagnosis cannot be made on thebasis of signs and symptoms alone because of thenon-specific nature of clinical malaria, clinicaldiagnosis of malaria is common in many malariousareas. In much of the malaria-endemic world,resources and trained health personnel are so scarcethat presumptive clinical diagnosis is the only real-


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TABLE 1. COMPARATIVE DESCRIPTIONS OF AVAILABLE MALARIA DIAGNOSTIC METHODS

Method Sensitivity/specificity Advantages Disadvantages Cost* References

Rapid diagnostic test sens: • Differentiates P. falciparum from non- • Cannot differentiate between non- 1.00based on pLDH: spec: falciparum infections. falciparum species.(OptiMal - Flow Inc) • Speed and ease of use; minimal training • Will not quantify parsitaemia

requirements to achieve reliable result. (+/- only).• Reportedly does not remain positive

after clearance of parasites.• No electricity, no special equipment

needed; could be used in communityoutreach programmes.

Rapid diagnostic stick sens: 84% –97% • Speed and ease of use; minimal training • Will not diagnose non-falciparum 0.80 to (23)test based on PfHRP-II: spec: 81%–100% requirements to achieve reliable results. malaria although subsequent 1.00(ParaSight-F – • No electricity, no special equipment generation tests will be able to do this.Becton – Dickinson; lower values probably needed; could be used at health post/ • Will not quantify parasitaemia (22)Malaria PfTest – due to low parasite community outreach. (+/- only).ICT Diagnostics) densities • Card format easier to use for individual • Can remain positive after clearance of

tests; dipstick test easier to use for parasites.batched testing.

Light microscopy Optimal conditions: • Species-specific diagnosis. • Requires relatively high degree of 0.03 to (22)sens: >90% • Quantification of parasitaemia aids training and supervision for reliable 0.08** (11)spec: 100% treatment follow-up. results.

• Sensitivity and specificity dependentTypical field conditions: on training and supervision.sens: 25%–100% • Special equipment and supplies needed.spec: 56%–100% • Electricity desirable.

• Time-consuming.

Fluorescent microscopy: AO: 42%–93% sens/ • Results attainable more quickly than • Special equipment and supplies needed. 0.03 (AO) (24)• Acridine orange [AO] 52–93% spec normal microscopy. • Sensitivity of AO poor with low parasite to 1.70 (22)

stained thick blood densities. (QBC)smears); • Electricity required.

• Quantitative Buffy QBC: 89% sens/ >95% • Unreliable species diagnosis; non-specificCoat (QBCTM) – spec staining of debris and non-parasitic cells.(Becton-Dickinson) • QBC will not quantify parasitaemia.

• Acridine orange is a hazardous material.

Clinical, especially Variable depending on • Speed and ease of use. • Can result in high degree of misdiagnosis Variable (111)based on formal level of clinical • No electricity, no special equipment and over-treatment for malaria. dependingalgorithm such as competency, training, needed beyond normal clinical • Requires close supervision and on (112)Integrated Manage- and malaria risk equipment (thermometer, stethoscope, retraining to maximize reliability. situation.ment of Childhood (endemicity): otoscope, timer).Illnesses (IMCI) or with IMCI:similar algorithm low risk: sens: 87%

spec: 8%high risk: sens: 100%

spec: 0%

Table modified from Stennies, 1999, CDC unpublished document.* Approximate or projected cost given in US dollars per test performed and reflects only cost of expendable materials unless otherwise noted.** Cost includes salaries of microscopists and expendable supplies; does not include cost of training, supervision, or equipment.

istic option. Clinical diagnosis offers the advantagesof ease, speed, and low cost. In areas where malariais prevalent, clinical diagnosis usually results in allpatients with fever and no apparent other causebeing treated for malaria. This approach can iden-tify most patients who truly need antimalarial treat-ment, but it is also likely to misclassify many whodo not (15). Over-diagnosis can be considerableand contributes to misuse of antimalarial drugs.Considerable overlap exists between the signs and

symptoms of malaria and other frequent diseases,especially acute lower respiratory tract infection(ALRI), and can greatly increase the frequency ofmisdiagnosis and mistreatment (16).

Attempts to improve the specificity of clinicaldiagnosis for malaria by including signs and symp-toms other than fever or history of fever have metwith only minimal success (17). The IntegratedManagement of Childhood Illnesses (IMCI) pro-gramme defined an algorithm that has been devel-

5


oped in order to improve diagnosis and treatmentof the most common childhood illnesses in areasrelying upon relatively unskilled health care work-ers working without access to laboratories orspecial equipment. With this algorithm, everyfebrile child living in a “high-risk” area for malariashould be considered to have, and be treated for,malaria. “High risk” has been defined in IMCIAdaptation Guides as being any situation where aslittle as 5% of febrile children between the ages of2 and 59 months are parasitaemic (18), a defini-tion that will likely lead to significant over-diagno-sis of malaria in areas with low to moderate malariatransmission.

2.3.3 Antigen detection tests (also known as rapidor “dipstick” tests)

A third diagnostic approach involves the rapiddetection of parasite antigens using rapid immuno-chromatographic techniques. Multiple experimen-tal tests have been developed targeting a variety ofparasite antigens (19‚ 20‚ 21). A number of com-mercially available kits (e.g. ParaSight-F®, Becton-Dickinson; Malaquick®, ICT, Sydney, New SouthWales, Australia) are based on the detection of thehistidine-rich protein 2 (HRP-II) of P. falciparum.Compared with light microscopy and QBC, thistest yielded rapid and highly sensitive diagnosis ofP. falciparum infection (22, 23). Advantages to thistechnology are that no special equipment is re-quired, minimal training is needed, the test andreagents are stable at ambient temperatures, andno electricity is needed. The principal disadvan-tages are a currently high per-test cost and aninability to quantify the density of infection.Furthermore, for tests based on HRP-II, detect-able antigen can persist for days after adequate treat-ment and cure; therefore, the test cannot adequatelydistinguish a resolving infection from treatmentfailure due to drug resistance, especially early aftertreatment (23). Additionally, a test based on detec-tion of a specific parasite enzyme (lactate dehydro-genase or pLDH) has been developed (OptiMAL®,Flow Inc. Portland, OR, USA) and reportedly onlydetects viable parasites, which if true, eliminatesprolonged periods of false positivity post-treatment(24, 25, 26). Newer generation antigen detectiontests are able to distinguish between falciparum andnon-falciparum infections, greatly expanding theirusefulness in areas where non-falciparum malariais transmitted frequently.

2.3.4 Molecular tests

Detection of parasite genetic material throughpolymerase-chain reaction (PCR) techniques isbecoming a more frequently used tool in the diag-nosis of malaria, as well as the diagnosis and sur-veillance of drug resistance in malaria. Specificprimers have been developed for each of the fourspecies of human malaria. One important use ofthis new technology is in detecting mixed infec-tions or differentiating between infecting specieswhen microscopic examination is inconclusive (27).In addition, improved PCR techniques could proveuseful for conducting molecular epidemiologicalinvestigations of malaria clusters or epidemics (28).Primary disadvantages to these methods are overallhigh cost, high degree of training required, needfor special equipment, absolute requirement forelectricity, and potential for cross-contaminationbetween samples.

2.3.5 Serology

Techniques also exist for detecting anti-malariaantibodies in serum specimens. Specific serologi-cal markers have been identified for each of the fourspecies of human malaria. A positive test generallyindicates a past infection. Serology is not useful fordiagnosing acute infections because detectablelevels of anti-malaria antibodies do not appearuntil weeks into infection and persist long afterparasitaemia has resolved. Moreover, the test is rela-tively expensive, and not widely available.

2.4 Drugs available for treatmentof malaria

There are only a limited number of drugs whichcan be used to treat or prevent malaria (Table 2).The most widely used are quinine and its deriva-tives and antifolate combination drugs.

2.4.1 Quinine and related compounds

Quinine, along with its dextroisomer quinidine, hasbeen the drug of last resort for the treatment ofmalaria, especially severe disease. Chloroquine is a4-aminoquinoline derivative of quinine first syn-thesized in 1934 and has since been the most widelyused antimalarial drug. Historically, it has been thedrug of choice for the treatment of non-severe oruncomplicated malaria and for chemoprophylaxis,although drug resistance has dramatically reducedits usefulness. Amodiaquine is a relatively widely


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TABLE 2. ANTIMALARIAL DRUGS FOR UNCOMPLICATED MALARIA

Drug name Use Half- Dosing (all per os) Contra- Cost Commentslife indications (US$)*(hours) Adult Paediatric

COMBINATION THERAPY

Mefloquine • Treatment of non- M: (14– 15 mg (base)/kg to 15 mg (base)/kg See under 3.90 • Safety of artemisinins & MQ+ severe falciparum 18 days) maximum of 1000 mg mefloquine on 2nd mefloquine during first trimester ofArtesunate infections thought mefloquine base on day of treatment monotherapy. pregnancy not established.

to be chloroquine Art: 0.5– second day of treat- followed by 10 mg/kg • Vomiting after mefloquineand SP resistant. 1.4 ment, followed by mefloquine on 3rd can be reduced by

10 mg (base)/kg to day. administering mefloquinemaximum of 500 mg on the second and third daymefloquine base on after an initial dose of3rd day. artesunate.

• Artemisinin (10 mg/kg po4 mg/kg artesunate 4 mg/kg artesunate daily for 3 days) can bedaily for 3 days. daily for 3 days. substituted for artesunate.

Sulfadoxine/ • Treatment of non- S: 100– 25 mg/kg sulfa/1.25 By weight: Known SP 1.12 • This combination has notPyrimethamine severe falicparum 200 mg/kg pyrimethamine 25 mg/kg sulfa/1.25 allergy. been evaluated as+ infections thought per kg as single dose. mg/kg pyrimethamine extensively as MQ +Artesunate to be chloroquine P: 80– per kg as single dose. artesunate.

resistant. 100 Average adult dose: • Safety of artemisinin during3 tablets as a single By age: first trimester of pregnancy

Art: 0.5– dose (equivalent to • < 1 year: 2 tablet not established.1.4 1500 mg sulfa /75 mg • 1–3 years: 3/4 tablet • Artemisinin (10 mg/kg po

pyrimethamine). • 4–8 years: 1 tablet daily for 3 days) can be• 9–14 years: 2 tablets substituted for artesunate.• >14 years: 3 tablets

4 mg/kg artesunate 4 mg/kg artesunatedaily for 3 days. daily for 3 days.

Lumefantrine • Treatment of non- L: 3–6 Semi-immune patients: Tablets per dose by 7.30 • Fixed-dose combination+ severe falciparum days 4 tablets per dose at 0, body weight: (Cameroon with each tablet containingArtemether infections thought 8, 24, and 48 hours street 20 mg artemether and

to be chloroquine Art: 4–11 (total 16 tablet). 10–14 kg: 1 tablet price); 120 mg lumefantrine.Trade name: and SP resistant. 15–24 kg: 2 tablets • Safety during pregnancyCo-artem; Riamet Non-immune patients: 25–34 kg: 3 tablets 57 not established.

4 tablets per dose at 0 >34 kg: 4 tablets (Europe)and 8 hrs, then twicedaily for 2 more days given in same schedule(total 24 tablets) as for adults, depend-

ing on immune status.

SINGLE-AGENT THERAPY

Chloroquine (CQ) • Treatment of non- (41±14 • Treatment: 25 mg • Treatment: 25 mg 0.08 • Widespread resistance inTrade names: falciparum infections. days) base/kg divided over base/kg divided P. falciparum in mostNivaquine, • Treatment of P. falci- 3 days. over 3 days. regions.Malaraquine, parum infections in • Resistance in P. vivax occurs.Aralen, areas where chloro- Average adult: 1 g • Prophylaxis: 5 mg • Can cause pruritus in dark-many others quine remains chloroquine (salt), base/kg once per skinned patients, reducing

effective. followed by 500 mg week. compliance.• Chemoprophylaxis (salt) in 6-8 hours and

in areas where 500 mg (salt) daily forchloroquine remains 2 more days.effective.

• Prophylaxis: 500 mgsalt once per week.

7


TABLE 2 (continued)



Amodiaquine (AQ) • Treatment of non- • Treatment: 25 mg • Treatment: 25 mg 0.14 • Cross-resistance withTrade names: severe falciparum base/kg divided base/kg divided over chloroquine limits useful-Camoquine, infections thought to over 3 days. 3 days. ness in areas with high ratesothers be chloroquine of chloroquine resistance.

resistant. • Has been associated withtoxic hepatitis andagranulocytosis when usedas prophylaxis—risk whenused for treatmentunknown but likely to below.

Sulfadoxine/ • Treatment of non- SD: 100– 25 mg/kg sulfa/1.25 By weight: • Known sulfa 0.12 • Efficacy for vivax infectionspyrimethamine severe falciparum 200 mg/kg pyrimethamine 25 mg/kg sulfa/1.25 allergy may be poor.(SP); infections thought per kg as single dose. mg/kg pyrimethamine • Widespread resistance in

to be chloroquine SL: 65 per kg as single dose: P. falciparum in someSulfalene/ resistant. Average adult: regions.pyrimethamine P: 80–100 1500 mg sulfa/75 mg By age: • Can cause severe skin(Metakelfin) pyrimethamine as • < 1 year: 1/2 tablet disease when used prophy-

single dose. • 1–3 years: 3/4 tablet lactically; risk when used as• 4–8 years: 1 tablet treatment unknown but

(Equivalent to 3 tablets • 9–14 years: 2 tablets likely to be very low.as a single dose.) • >14 years: 3 tablets

Mefloquine (MQ) • Treatment of non- (14–18 • Treatment: 750 mg Treatment: 15 mg • Known 1.92 • Vomiting can be a commonTrade names: severe falciparum days) base to 1500 mg (base)/kg to 25 mg or suspected problem among youngLariam, infections thought to base depending on (base)/kg depending history of children.Mephaquine be chloroquine and local resistance pat- on local resistance neuro- • In some populations (e.g.

SP resistant. terns. Larger doses patterns. Larger doses psychiatric very young African• Chemoprophylaxis (>15 mg/ kg) best (>15 mg/kg) best disorder. children), unpredictable

in areas with chloro- given in split doses given in split doses • history of blood levels, even afterquine resistance. over 2 days. over 2 days. seizures appropriate dosing, can

• concomitant produce frequent• Prophylaxis: 250 mg • Prophylaxis: 5 mg use of treatment failure.

once per week. base/kg once per halofantrine. • Use of lower dose mayweek. facilitate development of

resistance.

Halofantrine • Treatment of 10–90 8 mg base/kg 8 mg base/kg every • Preexisting 5.31 • Cross-resistance withsuspected multidrug- every 6 hours for 6 hours for 3 doses. cardiac mefloquine has beenresistant falciparum. 3 doses. disease. reported.

• Congenital • Reported to have highlyAverage adult: prolongation variable bioavailability.1500 mg base of QT

c interval. • Risk of fatal cardiotoxicity.

divided into 3 doses • Treatment as above. with meflo-

quine withinprior 3 weeks.

• Pregnancy.

Quinine • Treatment of severe 10–12 • Non-severe malaria: • Non-severe malaria: 1.51 • Side-effects can greatlymalaria. 8 mg (base)/kg 3 8 mg (base)/kg 3 reduce compliance.

• Treatment of multi- times daily for 7 days. times daily for 7 days. • Used in combination withdrug-resistant • Average adult: • Severe: see section tetracycline, doxycycline,P. falciparum. 650 mg 3 times per on treatment of clindamycin, or SP (where

• Treatment of malaria day for 7 days. severe malaria. effective) and in areasduring 1st trimester • Severe: see section on where quinine resistanceof pregnancy. treatment of severe not prevalent; duration of

malaria. quinine dosage can bereduced to 3 days whenused in combination.


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TABLE 2 (continued)



Tetracycline • In combination with Tetra: 10 Tetra: 250 mg/kg Tetra: 5 mg/kg • Age less than • Used only in combination(tetra)/ Doxy- quinine, can increase 4 times per day for 4 times per day for 8 years. with a rapidly actingcycline (doxy) efficacy of treatment Doxy: 16 7 days. 7 days. • Pregnancy. schizonticide such as

in areas with quinine quinine.resistance and/or Doxy: 100 mg/kg Doxy: 2 mg/kgreduce likelihood of 2 times per day for twice per dayquinine-associated 7 days. for 7 days.side-effects byreducing duration of Prophylaxis: 100 mg Prophylaxis: 2 mg/kgquinine treatment. doxy per day. doxy per day up to

• Prophylaxis. 100 mg.

Clindamycin • For patients unable 3 300 mg 4 times per 20 to 40 mg/kg/day • Severe hepatic • Is not as effective asto take tetracycline. day for 5 days. divided in 3 daily or renal tetracycline, especially

• In combination with doses for 5 days. impairment. among non-immunequinine, can increase • History of patients.efficacy of treatment gastrointestinal • Used only in combinationin areas with quinine disease, with a rapidly actingresistance and/or especially schizonticide such asreduce likelihood of colitis. quinine.quinine-associatedside effects byreducing duration ofquinine treatment.

Atovaquone/ • Treatment of Atv: 59 1000 mg atovaquone No pediatric formula- 35.00 • Fixed dose combination.proguanil multidrug resistant + 400 mg proguanil tion currently available, • Reportedly safe in

P. falciparum Prog: 24 daily for 3 days. but for patients pregnancy and youngTrade name: infections. between 11 and 40 kg children.Malarone body weight: • Drug donation program

exists11–20 kg: 1/4 adult dose • Pediatric formulation in21–30 kg: 1/2 adult dose development.31–40 kg: 3/4 adult dose

Artesunate • Treatment of multi- 0.5–1.4 4 mg/kg on the first 4 mg/kg on the first 1.50–3.40 • Safety for use in pregnancydrug resistant day followed by day followed by not fully established,P. falciparum 2 mg/kg daily for 2 mg/kg daily for especially for use in firstinfections. total of 5 to 7 days. total of 5 to 7 days. trimester (available data

suggest relative safety forArtemisinin 2–7 20 mg/kg on the first 20 mg/kg on the first 1.50–3.40 second or third trimester).

day followed by 10 day followed by • Other artemisininmg/kg daily for 10 mg/kg daily for derivatives includetotal of 5 to 7 days. total of 5 to 7 days. arteether, dihydro-

artemisinin, artelinate.Artemether 4–11 4 mg/kg on the first 4 mg/kg on the first 3.60–4.80

day followed by day followed by2 mg/kg daily for 2 mg/kg daily fortotal of 5 to 7 days. total of 5 to 7 days.

Primaquine • Treatment of P. vivax 6 • 14 mg base per day • 0.3 mg (base)/kg • G6PD • Primaquine has also beeninfections (reduce for 14 days. daily for 14 days. deficiency. investigated for prophy-likelihood of relapse). • 45 mg once per • Pregnancy. laxis use.

• Gametocytocidal week for 8 weeks. • Shorter courses have beenagent. used for falciparum

infections for gameto-cytocidal action.

* Cost is given for a full adult (60kg) treatment course. Prices have been derived from a variety of sources including Management Sciences for Health, World HealthOrganization, drug companies, published reports, and personal communication and are presented for relative comparison purposes only—actual local prices maydiffer greatly.

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available compound closely related to chloroquine.Other quinine-related compounds in common useinclude primaquine (specifically used for eliminat-ing the exoerythrocytic forms of P. vivax and P. ovalethat cause relapses), and mefloquine (a quinoline-methanol derivative of quinine).

2.4.2 Antifolate combination drugs

These drugs are various combinations of dihydro-folate-reductase inhibitors (proguanil, chlorpro-guanil, pyrimethamine, and trimethoprim) andsulfa drugs (dapsone, sulfalene, sulfamethoxazole,sulfadoxine, and others). Although these drugs haveantimalarial activity when used alone, parasitologi-cal resistance can develop rapidly. When used incombination, they produce a synergistic effect onthe parasite and can be effective even in the pres-ence of resistance to the individual components.Typical combinations include sulfadoxine/pyrimethamine (SP or Fansidar1), sulfalene-pyrimethamine (metakelfin), and sulfametho-xazole-trimethoprim (co-trimoxazole).

A new antifolate combination drug is currentlybeing tested in Africa. This drug, a combination ofchlorproguanil and dapsone, also known as Lap-Dap, has a much more potent synergistic effect onmalaria than existing drugs such as SP. Benefits ofthis combination include 1) a greater cure rate, evenin areas currently experiencing some level of SPresistance, 2) a lower likelihood of resistance devel-oping because of a more advantageous pharmaco-kinetic and pharmacodynamic profile, and 3)probable low cost (currently estimated at less thanUS$ 1 per adult treatment course) (29).

2.4.3 Antibiotics

Tetracycline and derivatives such as doxycycline arevery potent antimalarials and are used for both treat-ment and prophylaxis. In areas where response toquinine has deteriorated, tetracyclines are often usedin combination with quinine to improve cure rates.Clindamycin has been used but offers only limitedadvantage when compared to other available anti-malarial drugs. Parasitological response is slow toclindamycin and recrudescence rates are high (30,31). Its efficacy among non-immune individualshas not been fully established.

2.4.4 Artemisinin compounds

A number of sesquiterpine lactone compounds havebeen synthesized from the plant Artemisia annua(artesunate, artemether, arteether). These com-pounds are used for treatment of severe malaria andhave shown very rapid parasite clearance times andfaster fever resolution than occurs with quinine. Insome areas of South-East Asia, combinations ofartemisinins and mefloquine offer the only reliabletreatment for even uncomplicated malaria, due tothe development and prevalence of multidrug-resistant falciparum malaria (32). Combinationtherapy (an artemisinin compound given in com-bination with another antimalarial, typically along half-life drug like mefloquine) has reportedlybeen responsible for inhibiting intensification ofdrug resistance and for decreased malaria transmis-sion levels in South-East Asia (32, 33) (see section6.1.3).

2.4.5 Miscellaneous compounds (not exhaustive)

Halofantrine is a phenanthrene-methanol com-pound with activity against the erythrocytic stagesof the malaria parasite. Its use has been especiallyrecommended in areas with multiple drug-resist-ant falciparum. Recent studies have indicated, how-ever, that the drug can produce potentially fatalcardiac conduction abnormalities (specifically,prolongation of the PR and QT interval), limitingits usefulness (34). Atovaquone is a hydroxynaptho-quinone that is currently being used most widelyfor the treatment of opportunistic infections inimmunosuppressed patients. It is effective againstchloroquine-resistant P. falciparum, but because,when used alone, resistance develops rapidly,atovaquone is usually given in combination withproguanil (35, 36). A new fixed dose antimalarialcombination of 250 mg atovaquone and 100 mgproguanil (MalaroneTM) is being brought tomarket worldwide and is additionally being distrib-uted through a donation programme (37, 38). Twodrugs originally synthesized in China are currentlyundergoing field trials. Pyronaridine was report-edly 100% effective in one trial in Cameroon (39);however, it was only between 63% and 88% effec-tive in Thailand (40). Lumefantrinel, a fluoro-methanol compound, is being produced as a fixedcombination tablet with artemether (41, 42).

1 Note: Use of trade names is for identification only and doesnot imply endorsement by the Public Health Service or bythe US Department of Health and Human Services.


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2.4.6 Combination therapy with antimalarials

The use of two antimalarials simultaneously,especially when the antimalarials have differentmechanisms of action, has the potential for inhib-iting the development of resistance to either of thecomponents. The efficacy of a combination of a4-aminoquinoline drug (either chloroquine or amo-diaquine) with sulfadoxine/pyrimethamine hasbeen reviewed (43). The results of this review sug-gested that the addition of either chloroquine oramodiaquine to SP marginally improvedparasitological clearance (compared with SP alone).The studies reviewed were mostly done in areas andat times when both SP and chloroquine/amodi-aquine retained a fair amount of efficacy, and it isnot clear from these studies how well such acombination would act in areas where one of thecomponents was significantly compromised.Additionally, to date, there are no data to suggestwhether this slightly improved clearance would

translate into prolonged useful life span for eitherdrug.

Another combination therapy approach, com-bining an artemisinin derivative with other, longerhalf-life antimalarials, is discussed in section6.1.3.

2.5 Current status of drug-resistantmalaria

Resistance to antimalarial drugs has been describedfor two of the four species of malaria parasite thatnaturally infect humans, P. falciparum and P. vivax.P. falciparum has developed resistance to nearly allantimalarials in current use, although the geo-graphical distribution of resistance to any singleantimalarial drug varies greatly (Table 3). P. vivaxinfection acquired in some areas has been shownto be resistant to chloroquine and/or primaquine(44, 45).

Chloroquine-resistant P. falciparum malaria has

TABLE 3. DISTRIBUTION OF DRUG-RESISTANT PLASMODIUM FALCIPARUM MALARIA

Region Resistance reported1 Comments

CQ SP MQ Others

PL ASMODIUM FALCIPARUM INFECTIONS

Central America (Mexico, N N N North-west of Panama Canal onlyBelize, Guatemala, Honduras,El Salvador, Nicaragua,Costa Rica, NW Panama)

Caribbean (Haiti and N N NDominican Republic only)

South America (SE Panama, Y Y Y QN Resistance to MQ and QN, although reported, is considered to occur infrequentlyColumbia, Venezuela,Ecuador, Peru, Brazil, Bolivia, )

Western Africa Y Y Y Incidence of resistance to CQ variable, but very common in most areas

Eastern Africa Y Y N Incidence o f resistance to SP highly variable, with some reports of focally high incidence,but generally uncommon

Southern Africa Y Y N Resistance to SP, although reported, is considered to be generally uncommon

Indian Subcontinent Y N N

South-East Asia and Oceania Y Y Y HAL, Border areas of Thailand, Cambodia, and Myanmar highest risk for multiple-drug-resistantQN infections; in other areas, incidence of resistance to SP and MQ highly variable and absent

in many areas

East Asia (China) Y Y ? Resistance greatest problem in southern China

1 Reports of resistance to a given agent occurring in an area does not necessarily mean that occurrence is frequent enough to pose a significant public health risk.Bold “Y” indicates agents to which significant resistance occurs in a given area (although actual risk may be highly focal, e.g. South-East Asia, where MQ resistance,while very frequent in some limited areas, is infrequent or absent in most others). Regular “Y” indicates that, while resistance to agent has been reported, it is notbelieved to occur frequently enough to pose a significant public health risk.

CQ = chloroquine QN = quinine SP = sulfadoxine-pyrimethamine HAL = halofantrine MQ = mefloquine

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been described everywhere that P. falciparummalaria is transmitted except for malarious areas ofCentral America (north-west of the PanamaCanal), the island of Hispaniola, and limited areasof the Middle East and Central Asia. Sulfadoxine-pyrimethamine (SP) resistance occurs frequently inSouth-East Asia and South America. SP resistanceis becoming more prevalent in Africa as that drug

is increasingly being relied upon as a replacementfor chloroquine. Mefloquine resistance is frequentin some areas of South-East Asia and has beenreported in the Amazon region of South Americaand sporadically in Africa (46). Cross-resistancebetween halofantrine and mefloquine is suggestedby reduced response to halofantrine when used totreat mefloquine failures (47).


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3. Causes of resistance

incorrect dosing, non-compliance with duration ofdosing regimen, poor drug quality, drug interac-tions, poor or erratic absorption, and misdiagnosis.Probably all of these factors, while causing treat-ment failure (or apparent treatment failure) in theindividual, may also contribute to the developmentand intensification of true drug resistance throughincreasing the likelihood of exposure of parasitesto suboptimal drug levels.

3.3 Mechanisms of antimalarial resistance

In general, resistance appears to occur throughspontaneous mutations that confer reduced sensi-tivity to a given drug or class of drugs. For somedrugs, only a single point mutation is required toconfer resistance, while for other drugs, multiplemutations appear to be required. Provided themutations are not deleterious to the survival orreproduction of the parasite, drug pressure willremove susceptible parasites while resistant para-sites survive. Single malaria isolates have been foundto be made up of heterogeneous populations ofparasites that can have widely varying drug responsecharacteristics, from highly resistant to completelysensitive (51). Similarly, within a geographical area,malaria infections demonstrate a range of drug sus-ceptibility. Over time, resistance becomes estab-lished in the population and can be very stable,persisting long after specific drug pressure is re-moved.

The biochemical mechanism of resistance hasbeen well described for chloroquine, the antifolatecombination drugs, and atovaquone.

3.3.1 Chloroquine resistance

As the malaria parasite digests haemoglobin, largeamounts of a toxic by-product are formed. Theparasite polymerizes this by-product in its foodvacuole, producing non-toxic haemozoin (malariapigment). It is believed that resistance ofP. falciparum to chloroquine is related to an in-creased capacity for the parasite to expel chloro-quine at a rate that does not allow chloroquine to

3.1 Definition of antimalarial drugresistance

Antimalarial drug resistance has been defined as the“ability of a parasite strain to survive and/or multi-ply despite the administration and absorption of adrug given in doses equal to or higher than thoseusually recommended but within tolerance of thesubject”. This definition was later modified tospecify that the drug in question must “gain accessto the parasite or the infected red blood cell for theduration of the time necessary for its normal action”(48). Most researchers interpret this as referring onlyto persistence of parasites after treatment doses ofan antimalarial rather than prophylaxis failure, al-though the latter is a useful tool for early warningof the presence of drug resistance (49).

This definition of resistance requires demonstra-tion of malaria parasitaemia in a patient who hasreceived an observed treatment dose of an antima-larial drug and simultaneous demonstration ofadequate blood drug and metabolite concentrationsusing established laboratory methods (such as highperformance liquid chromatography) or in vitrotests (see section 4.2). In practice, this is rarely donewith in vivo studies. In vivo studies of drugs forwhich true resistance is well known (such as chlo-roquine) infrequently include confirmation of drugabsorption and metabolism; demonstration of per-sistence of parasites in a patient receiving directlyobserved therapy is usually considered sufficient.Some drugs, such as mefloquine, are known to pro-duce widely varying blood levels after appropriatedosing and apparent resistance can often be ex-plained by inadequate blood levels (50).

3.2 Malaria treatment failure

A distinction must be made between a failure toclear malarial parasitaemia or resolve clinical dis-ease following a treatment with an antimalarial drugand true antimalarial drug resistance. While drugresistance can cause treatment failure, not all treat-ment failure is due to drug resistance. Many fac-tors can contribute to treatment failure including

13


reach levels required for inhibition of haem polym-erization (52). This chloroquine efflux occurs at arate of 40 to 50 times faster among resistant para-sites than sensitive ones (53). Further evidence sup-porting this mechanism is provided by the fact thatchloroquine resistance can be reversed by drugswhich interfere with this efflux system (54). It isunclear whether parasite resistance to other quino-line antimalarials (amodiaquine, mefloquine,halofantrine, and quinine) occurs via similar mecha-nisms (52).

3.3.2 Antifolate combination drugs

Antifolate combination drugs, such as sulfadoxine+ pyrimethamine, act through sequential andsynergistic blockade of 2 key enzymes involved withfolate synthesis. Pyrimethamine and related com-pounds inhibit the step mediated by dihydrofolatereductase (DHFR) while sulfones and sulfonamidesinhibit the step mediated by dihydropteroatesynthase (DHPS) (48). Specific gene mutationsencoding for resistance to both DHPS and DHFRhave been identified. Specific combinations of thesemutations have been associated with varying de-grees of resistance to antifolate combination drugs(55).

3.3.3 Atovaquone

Atovaquone acts through inhibition of electrontransport at the cytochrome bc1 complex (56).Although resistance to atovaquone develops veryrapidly when used alone, when combined with asecond drug, such as proguanil (the combinationused in MalaroneTM) or tetracycline, resistance de-velops more slowly (35). Resistance is conferred bysingle-point mutations in the cytochrome-b gene.

3.4 Factors contributing to the spreadof resistance

Numerous factors contributing to the advent,spread, and intensification of drug resistance exist,although their relative contribution to resistance isunknown. Factors that have been associated withantimalarial drug resistance include such disparateissues as human behaviour (dealt with in detail else-where), vector and parasite biology, pharmacoki-netics, and economics. As mentioned previously,conditions leading to malaria treatment failure mayalso contribute to the development of resistance.

3.4.1 Biological influences on resistance

Based on data on the response of sensitive parasitesto antimalarial drugs in vitro and the pharma-cokinetic profiles of common antimalarial drugs,there is thought to always be a residuum of para-sites that are able to survive treatment (57). Undernormal circumstances, these parasites are removedby the immune system (non-specifically in the caseof non-immune individuals). Factors that decreasethe effectiveness of the immune system in clearingparasite residuum after treatment also appear toincrease survivorship of parasites and facilitate de-velopment and intensification of resistance. Thismechanism has been suggested as a significant con-tributor to resistance in South-East Asia, whereparasites are repeatedly cycled through populationsof non-immune individuals (58, 59); the non-specific immune response of non-immune individu-als is less effective at clearing parasite residuum thanthe specific immune response of semi-immuneindividuals (60). The same mechanism may alsoexplain poorer treatment response among youngchildren and pregnant women (60).

The contribution to development and intensi-fication of resistance of other prevalent immuno-suppressive states has not been evaluated. Amongrefugee children in the former Zaire, those who weremalnourished (low weight for height) had signifi-cantly poorer parasitological response to bothchloroquine and SP treatment (61). Similarly, evi-dence from prevention of malaria during pregnancysuggests that parasitological response to treatmentamong individuals infected with the humanimmunodeficiency virus (HIV) may also be poor.HIV-seropositive women require more frequenttreatment with SP during pregnancy in order tohave the same risk of placental malaria as is seenamong HIV-seronegative women (62). Para-sitological response to treatment of acute malariaamong HIV-seropositive individuals has not beenevaluated. The current prevalence of malnutritionamong African children under 5 years has been es-timated to be 30% and an estimated 4 to 5 millionchildren are expected to be infected with HIV atthe beginning of this new century (63). If it isproven that malnutrition or HIV infection plays asignificant role in facilitating the development orintensification of antimalarial drug resistance, theprevalence of these illnesses could pose a tremen-dous threat to existing and future antimalarialdrugs.

Some characteristics of recrudescent or drug-resistant infections appear to provide a survival


14

advantage or to facilitate the spread of resistanceconferring genes in a population (32). In one study,patients experiencing chloroquine treatment fail-ure had recrudescent infections that tended to beless severe or even asymptomatic (64). Schizontmaturation may also be more efficient among re-sistant parasites (65, 66).

There is some evidence that certain combina-tions of drug-resistant parasites and vector speciesenhance transmission of drug resistance, while othercombinations inhibit transmission of resistant para-sites. In South-East Asia, two important vectors,Anopheles stephensi and A. dirus, appear to be moresusceptible to drug-resistant malaria than to drug-sensitive malaria (67, 68). In Sri Lanka, research-ers found that patients with chloroquine-resistantmalaria infections were more likely to havegametocytaemia than those with sensitive infectionsand that the gametocytes from resistant infectionswere more infective to mosquitos (64). The reverseis also true—some malaria vectors may be some-what refractory to drug-resistant malaria, whichmay partially explain the pockets of chloroquinesensitivity that remain in the world in spite of verysimilar human populations and drug pressure (e.g.Haiti).

Many antimalarial drugs in current usage areclosely related chemically and development ofresistance to one can facilitate development of re-sistance to others. Chloroquine and amodiaquineare both 4-aminoquinolines and cross-resistancebetween these two drugs is well known (69, 70).Development of resistance to mefloquine may alsolead to resistance to halofantrine and quinine.Antifolate combination drugs have similar actionand widespread use of sulfadoxine/ pyrimethaminefor the treatment of malaria may lead to increasedparasitological resistance to other antifolate com-bination drugs (29). Development of high levels ofSP resistance through continued accumulation ofDHFR mutations may compromise the useful lifespan of newer antifolate combination drugs suchas chlorproguanil/dapsone (LapDap) even beforethey are brought into use. This increased risk ofresistance due to SP use may even affect non-malarial pathogens; use of SP for treatment ofmalaria increased resistance to trimethoprim/sufa-methoxazole among respiratory pathogens (71).

There is an interesting theory that developmentof resistance to a number of antimalarial drugsamong some falciparum parasites produces a levelof genetic plasticity that allows the parasite torapidly adapt to a new drug, even when the new

drug is not chemically related to drugs previouslyexperienced (72). The underlying mechanism ofthis plasticity is currently unknown, but thiscapacity may help explain the rapidity with whichSouth-East Asian strains of falciparum developresistance to new antimalarial drugs.

The choice of using a long half-life drug (SP,MQ) in preference to one with a short half-life (CQ,LapDap, QN) has the benefit of simpler, single-dose regimens which can greatly improve compli-ance or make directly observed therapy feasible.Unfortunately, that same property may increase thelikelihood of resistance developing due to prolongedelimination periods. The relative contribution oflow compliance versus use of long half-life drugsto development of resistance is not known.

Parasites from new infections or recrudescentparasites from infections that did not fully clear willbe exposed to drug blood levels that are high enoughto exert selective pressure but are insufficient toprovide prophylactic or suppressive protection (57).When blood levels drop below the minimum in-hibitory concentration (the level of drug that fullyinhibits parasite growth), but remain above the EC5(the concentration of drug that produces 5% inhi-bition of parasite growth), selection of resistantparasites occurs. This selection was illustrated inone study in Kenya that monitored drug sensitiv-ity of parasites reappearing after SP treatment. Para-sites reappearing during a period when blood levelswere below the point required to clear pyrimeth-amine-resistant parasites, but still above that levelrequired to clear pyrimethamine-sensitive parasites,were more likely to be pyrimethmaine-resistant thanthose reappearing after levels had dropped belowthe level required to clear pyrimethamine-sensitiveparasites (73). This period of selective pressure lastsfor approximately one month for mefloquine,whereas it is only 48 hours for quinine (57).

In areas of high malaria transmission, the prob-ability of exposure of parasites to drug during thisperiod of selective pressure is high. In Africa, forinstance, people can be exposed to as many as 300infective bites per year (in rare cases, even as muchas 1000 infective bites per year), and during peaktransmission, as many as five infective bites pernight (74, 75).

Mismatched pharmacokinetics can also play arole in facilitating the development of resistance.The elimination half-life of pyrimethamine is be-tween 80 and 100 hours, and is between 100 and200 hours for sulfadoxine, leaving an extendedperiod when sulfadoxine is “unprotected” by

15


synergy with pyrimethamine (73). This sort of mis-matched pharmacokinetics is even more apparentin the mefloquine-sulfadoxine-pyrimethamine(MSP) combination used in Thailand (mefloquinehas an elimination half-life of approximately 336to 432 hours (48, 76).

It is not clear what the relationship betweentransmission intensity and development of resist-ance is, although most researchers agree that thereseems to be such an association. It is apparent thatthere are more genetically distinct clones per per-son in areas of more intense transmission than inareas of lower transmission (77). However, the in-terpretation of this and its implications for devel-opment of resistance has variously been describedas resistance being more likely in low-transmissionenvironments (78, 79), high-transmission environ-ments (80, 77, 81), or either low- or high- but notintermediate-transmission environments (82, 83).This relationship between transmission intensityand parasite genetic structure is obviously complexand subject to other confounding/contributingfactors (84, 83). What is clear is that the rate atwhich resistance develops in a given area is sensi-tive to a number of factors beyond mere intensityof transmission (such as initial prevalence of muta-tions, intensity of drug pressure, populationmovement between areas, the nature of acquiredimmunity to the parasite or its strains, etc.), butthat reducing the intensity of transmission willlikely facilitate prolonging the useful life span ofdrugs (81, 85).

3.4.2 Programmatic influences on resistance

Programmatic influences on development of anti-malarial drug resistance include overall drug pres-sure, inadequate drug intake (poor compliance orinappropriate dosing regimens), pharmacokineticand pharmacodynamic properties of the drug ordrug combination, and drug interactions (86).Additionally, reliance on presumptive treatment canfacilitate the development of antimalarial drugresistance.

Overall drug pressure, especially that exerted byprogrammes utilizing mass drug administration,probably has the greatest impact on developmentof resistance (86, 87). Studies have suggested thatresistance rates are higher in urban and periurbanareas than rural communities, where access to anduse of drug is greater (88).

Confusion over proper dosing regimen has beendescribed. In Thailand, the malaria control pro-

gramme recommended 2 tablets (adult dose) of SPfor treating malaria based on studies suggesting thatthis was effective. Within a few years, this was nolonger effective and the programme increased theregimen to 3 tablets. Although unproven, this mayhave contributed to the rapid loss of SP efficacythere. Similar confusion over the proper SP dosingregimen exists in Africa. To simplify treatment,many programmes dose children based on agerather than weight and, depending on the regimenbeing recommended, this has been shown to pro-duce systematic underdosing among children ofcertain weight and age groups (ter Kuile, unpub-lished data, 1997).

The use of presumptive treatment for malariahas the potential for facilitating resistance by greatlyincreasing the number of people who are treatedunnecessarily but will still be exerting selective pres-sure on the circulating parasite population. In someareas and at some times of the year, the number ofpatients being treated unnecessarily for malaria canbe very large (15).

Concurrent treatment with other drugs can in-crease the likelihood of treatment failure and maycontribute to development of drug resistance. Folateadministration for treatment of anaemia and pos-sibly when used as a routine supplement duringpregnancy (CDC, unpublished data,1998), canincrease treatment failure rates (89). Similarly,concurrent illness may have an influence, as wasmentioned previously with regard to malnourish-ment.

Drug quality has also been implicated in in-effective treatment and possibly drug resistance.Either through poor manufacturing practices, in-tentional counterfeiting, or deterioration due toinadequate handling and storage, drugs may notcontain sufficient quantities of the active ingredi-ents. In an analysis of chloroquine and antibioticsavailable in Nigeria and Thailand, between 37%and 40% of samples assayed had substandardcontent of active ingredients, mostly from poormanufacturing practices (90). Another study inAfrica found chloroquine stored under realistictropical conditions lost at least 10% of its activityin a little over a year (91).


16

4. Detection of resistance

Of the available tests, in vivo tests most closelyreflect actual clinical or epidemiological situations(i.e. the therapeutic response of currently circulat-ing parasites infecting the actual population inwhich the drug will be used). Because of the influ-ence of external factors (host immunity, variationsof drug absorption and metabolism, and potentialmisclassification of reinfections as recrudescences),the results of in vivo tests do not necessarily reflectthe true level of pure antimalarial drug resistance.However, this test offers the best information onthe efficacy of antimalarial treatment under closeto actual operational conditions—what can be ex-pected to occur among clinic patients if providerand patient compliance is high.

The original methods for in vivo tests requiredprolonged periods of follow-up (minimum of 28days) and seclusion of patients in screened roomsto prevent the possibility of reinfection. Thesemethods have since been modified extensively andthe most widely used methods now involve shorterperiods of follow-up (7 to 14 days) without seclu-sion, under the assumption that reappearance ofparasites within 14 days of treatment is more likelydue to recrudescence than reinfection (92). Addi-tional modifications reflect the increased emphasison clinical response in addition to parasitologicalresponse. Traditionally, response to treatment wascategorized purely on parasitological grounds asSensitive, RI, RII, and RIII (48). Later modifica-tions have combined, to varying extent, para-sitological and clinical indicators (93).

Because anaemia can be a major component ofmalaria illness, in vivo methodologies allow inves-tigation of haematological recovery after malariatherapy (94). This is obviously not possible with invitro or molecular techniques. Failure of completeparasitological clearance, even in situations whererecurrence of fever is rare, can be associated withlack of optimal haematological recovery amonganaemic patients.

Unfortunately, these methodologies, whiletermed “standardized” are, in practice, not stand-ardized. Major differences in sample size, enrolment

In general, four basic methods have been routinelyused to study or measure antimalarial drug resist-ance: in vivo, in vitro, animal model studies, andmolecular characterization. Additionally, less rig-orous methods have been used, such as case reports,case series, or passive surveillance. Much discus-sion has occurred regarding the relative merits ofone test over another, with the implication alwaysbeing that one type of test should be used prefer-entially. Careful consideration of the types ofinformation each yields should indicate, however,that these are complementary, rather than compet-ing, sources of information about resistance.

Recognition of drug resistance (or, more appro-priately, treatment failure) in individual patients ismade difficult in many settings by operationalissues, such as availability and quality of microscopy.Especially in Africa, where presumptive diagnosisand treatment for malaria is the rule, detection oftreatment failures also tends to be presumptive (per-sistence or reappearance of clinical symptoms in apatient recently receiving malaria treatment).Because of the non-specific nature of clinical signsand symptoms of malaria and the many other causesof febrile disease, this can lead to a false sense thata particular drug is not working when it is, or,potentially, that an ineffective drug is working whenit is not. In cases where microscopy is used, pres-ence of parasitaemia in a supposedly fully treatedpatient may indicate treatment failure, but is notnecessarily evidence of drug resistance, as explainedin section 3.1.

4.1 In vivo tests

An in vivo test consists of the treatment of a groupof symptomatic and parasitaemic individuals withknown doses of drug and the subsequent monitor-ing of the parasitological and/or clinical responseover time. One of the key characteristics of in vivotests is the interplay between host and parasite.Diminished therapeutic efficacy of a drug can bemasked by immune clearance of parasites amongpatients with a high degree of acquired immunity(60).

17


criteria, exclusion criteria, length and intensity offollow-up, loss-to-follow-up rates, and interpreta-tion and reporting of results are apparent in pub-lished papers on in vivo trials. These differences areat times so dramatic, that it is difficult, if not im-possible, to compare results from one study toanother with any level of confidence (CDC, un-published data, 1999).

The methodology currently being used andpromoted, especially in sub-Saharan Africa, is asystem that emphasizes clinical response overparasitological response (95). Close adherence tothis protocol does provide comparable data; how-ever, these data are not readily comparable to datacollected using other in vivo methods. Althoughnot called for in the protocol, categorization of theparasitological response using the standard WHOdefinitions (95) would allow some ability to com-pare to historical levels and provide useful para-sitological results that would aid in interpreting theclinical results.

4.2 In vitro tests

From the point of view of a researcher interested inpure drug resistance, in vitro tests avoid many ofthe confounding factors which influence in vivotests by removing parasites from the host andplacing them into a controlled experimental envi-ronment. In the most frequently used procedure,the micro-technique, parasites obtained from afinger-prick blood sample are exposed in microtitreplates to precisely known quantities of drug andobserved for inhibition of maturation into schizonts(96).

This test more accurately reflects “pure” anti-malarial drug resistance. Multiple tests can be per-formed on isolates, several drugs can be assessedsimultaneously, and experimental drugs can betested. However, the test has certain significant dis-advantages. The correlation of in vitro response withclinical response in patients is neither clear nor con-sistent, and the correlation appears to depend onthe level of acquired immunity within the popula-tion being tested. Prodrugs, such as proguanil,which require host conversion into active meta-bolites cannot be tested. Neither can drugs thatrequire some level of synergism with the host’s im-mune system. Although adaptation of erythrocyticforms of P. vivax to continuous culture has beenachieved, non-falciparum erythrocytic parasitesgenerally cannot be evaluated in vitro (97). Inaddition, because parasites must be cultured, dif-

ferential die-off of parasites can occur. If, for in-stance, resistant strains are less likely to adapt, theresults would be biased towards sensitive responses.Because venous blood is typically needed, resist-ance in the more vulnerable younger age groups isoften not studied. Finally, these tests are techno-logically more demanding and relatively expensive,which makes them potentially more difficult toadapt successfully to routine work in the field.

4.3 Animal model studies

This type of test is, in essence, an in vivo test con-ducted in a non-human animal model and, there-fore, is influenced by many of the same extrinsicfactors as in vivo tests. The influence of host im-munity is minimized by using lab-reared animalsor animal-parasite combinations unlikely to occurin nature, although other host factors would stillbe present. These tests allow for the testing of para-sites which cannot be adapted to in vitro environ-ments (provided a suitable animal host is available)and the testing of experimental drugs not yetapproved for use in humans. A significant disad-vantage is that only parasites that can grow in, orare adaptable to, non-human primates can beinvestigated.

4.4 Molecular techniques

These tests are in the process of being developedand validated, but offer promising advantages tothe methods described above. Molecular tests usepolymerase chain reaction (PCR) to indicate thepresence of mutations encoding biological resist-ance to antimalarial drugs (98). Theoretically, thefrequency of occurrence of specific gene mutationswithin a sample of parasites obtained from patientsfrom a given area could provide an indication ofthe frequency of drug resistance in that area analo-gous to information derived from in vitro meth-ods. Advantages include the need for only smallamounts of genetic material as opposed to live para-sites, independence from host and environmentalfactors, and the ability to conduct large numbersof tests in a relatively short period of time. Disad-vantages include the obvious need for sophisticatedequipment and training, and the fact that genemutations that confer antimalarial drug resistanceare currently known or debated for only a limitednumber of drugs (primarily for dihydrofolatereductase inhibitors [pyrimethamine], dihydro-pteroate synthase inhibitors [sulfadoxine], andchloroquine) (98, 99). Confirmation of the asso-


18

ciation between given mutations and actual drugresistance is difficult, especially when resistanceinvolves more than one gene locus and multiplemutations. If these complexities can be resolved,molecular techniques may become an extremelyvaluable surveillance tool for monitoring theoccurrence, spread, or intensification of drug re-sistance.

4.5 Case reports and passive detectionof treatment failure

Additional methods for identifying or monitoringantimalarial drug resistance include the use of casereports or case series of spontaneously reportedtreatment failure. In general, these methods requirefar less investment in time, money, and personneland can be done on an ongoing basis by individualhealth care centres. They suffer, however, from pre-senting a potentially biased view of drug resistanceprimarily because denominators are typically un-known and rates of resistance cannot be calculated.Nonetheless, case reports can be useful and mayindicate a problem that should be confirmed usingone of the other methods. In the United States, forinstance, case reports, especially when occurring inclusters, of prophylaxis failure have been used to

help formulate recommendations for chemo-prophylaxis of non-immune travellers to endemicareas (100).

Another method that has been used is passivedetection of treatment failure. In this system,patients are treated following usual treatment guide-lines and told to come back to the clinic or hospi-tal if symptoms persist or return. Those cases whichdo return are considered to represent the popula-tion of treatment failures. Because this system doesnot ensure compliance with treatment regimensthrough directly observed therapy and does notattempt to locate and determine the outcome ofpatients who do not return on their own, data areseriously biased. In one study conducted in Ethio-pia and Eritrea using this method, only 1706/39824 (4.6%) patients returned to clinic (101). Theassumption was that those patients who did notreturn did not have resistant parasites, yielding avery low prevalence of resistance (1.8% to 4.8%,depending on region). These results contrastdramatically with results from standard 7-day invivo trials conducted at two sites in Eritrea in 1994(CDC, unpublished data,1994) and one site inEthiopia in 1993–1994 which found between 58%and 86% RII/RIII level resistance (102).

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5. Treatment

Multidrug resistance (typically referring to re-sistance to both chloroquine and SP, but may alsoinclude resistance to other compounds as well)occurs frequently in Amazonia and South-East Asia.In these areas, a wide range of treatment optionsare used. Quinine, either alone or in combinationwith tetracyclines, or mefloquine tend to be thedrugs of choice for multidrug-resistant malaria,although declining quinine efficacy and high ratesof mefloquine resistance have been reported in someareas of South-East Asia. In limited areas of Thai-land, where falciparum is resistant to many of theavailable drugs, a combination of high-dosemefloquine (25 mg/kg in a divided dose) andartesunate (4 mg/kg daily for 3 days) or 7 days ofartesunate alone is required to achieve reliable clear-ance of parasites.

Table 2 summarizes various treatment options,not all of which would be available or necessarilyappropriate in all contexts. One of the primary lim-iting factors to the use of a highly effective antima-larial and a willingness to change policy to facilitateits use, is the cost of the drug itself. Although anumber of evaluations have been able to show thecost-effectiveness of changing between certaindrugs, in many cases, the total cost associated withuse of a given drug may be prohibitively high (103).Additional costs of interventions to improve use ofdrugs or patients’ adherence to treatment regimens(such a provider and user training, innovative pack-aging) would further add to the total cost of usingsome drugs or drug combinations.

In theory, recommended treatment regimens shouldbe tailored specifically to a given region based onresistance patterns found in that area. Other con-siderations include cost, cost-effectiveness, availabil-ity, ease of administration, capabilities of the healthcare infrastructure (i.e. do health care workers havethe equipment and training to safely use parenteralroutes of administration?), perceived efficacy, andreal and perceived safety of the drug (acceptabilityof the drug by the population). In practice, cur-rently recommended treatment regimens often donot reflect the current state of antimalarial drugresistance.

Chloroquine remains the drug of choice fortreatment of non-falciparum infections and non-severe falciparum infections acquired in areas ofknown chloroquine sensitivity. Because drug resist-ance is not an all-or-nothing phenomenon, chlo-roquine still retains adequate efficacy even in areasof known resistance for continued use to be justifi-able for the time being (for instance, some areas ofWest Africa continue to use chloroquine success-fully, although efficacy rates are declining). Muchof Africa, however, is currently investigating alter-natives to chloroquine. Malawi, Kenya, SouthAfrica, and Botswana have moved away from chlo-roquine and are using sulfadoxine/ pyrimethamine(SP) extensively or exclusively for treatment of non-severe falciparum infections. The United Republicof Tanzania recently indicated that it is movingtowards SP as first-line treatment of malaria, andEthiopia, Eritrea, Uganda, and others are in theprocess of considering similar policy changes.


20

6. The future: prevention of drug resistance

household level (104). This approach is gainingsupport internationally. This approach is also indirect conflict with the primary methods for in-hibiting development of drug resistance, limitedaccess to and judicious use of chemotherapeuticagents. Clearly, some middle ground will need tobe identified that will improve access to antimalar-ial drugs for those who need to be treated while atthe same time reducing the inappropriate use ofthose same drugs.

Prevention strategies can be divided into thoseaimed specifically at preventing malaria infectionand those aimed at reducing the likelihood of de-velopment of drug resistance. Reduction of overallmalaria infection rates or transmission rates havean indirect impact on development of drug resist-ance by reducing the number of infections need-ing to be treated (and therefore, overall drugpressure) and by reducing the likelihood that re-sistant parasites are successfully transmitted to newhosts. Full discussion of these strategies is beyondthe scope of this review but they include the use ofinsecticide-treated bednets, indoor residual insec-ticide spraying, environmental control (mosquitobreeding site or “source” reduction), other personalprotection measures (e.g. use of repellent soap orscreening windows) and chemoprophylaxis indefined populations (use of mass prophylaxis is typi-cally not recommended). An effective and deliver-able vaccine would also be greatly beneficial.

6.1 Preventing drug resistance

Interventions aimed at preventing drug resistance,per se, generally focus on reducing overall drugpressure through more selective use of drugs; im-proving the way drugs are used through improvingprescribing, follow-up practices, and patient com-pliance; or using drugs or drug combinations whichare inherently less likely to foster resistance or haveproperties that do not facilitate development orspread of resistant parasites.

The future of antimalarial drug resistance andefforts to combat it is defined by a number ofassumptions. First, antimalarial drugs will continueto be needed long into the future. No strategy inexistence or in development, short of an unfore-seen scientific breakthrough or complete eradica-tion, is likely to be 100% effective in preventingmalaria infection. Second, as long as drugs are used,the chance of resistance developing to those drugsis present. P. falciparum has developed resistance tonearly all available antimalarial drugs and it is highlylikely that the parasite will eventually developresistance to any drug that is used widely. Theadvent of P. vivax resistant to chloroquine and pri-maquine may, in time, result in a resurgence of vivaxmalaria as has been seen with P. falciparum. Third,development of new drugs appears to be takinglonger than development of parasitological resist-ance. The development of resistance to antimalar-ial drugs in South-East Asia has been far quickerthan the estimated 12 to 17 years it takes to de-velop and market a new antimalarial compound(2). Fourth, affordability is an essential considera-tion for any strategy to control drug-resistantmalaria, especially in Africa.

The future, especially in Africa, will also be de-fined by how well the central tenets of malaria con-trol can be reconciled with the central tenets ofcontrol of drug resistance. One of the cornerstonesof the current approach to malaria control is theprovision of prompt, effective malaria treatment.In much of Africa, easy access to public sector healthcare is limited and when it is accessible, health carestaff are often inadequately trained, insufficientlysupplied and supported, ineffectively supervisedand/or poorly motivated. One response to this situ-ation has been the intentional liberalization ofaccess to drugs; instead of relying so heavily on theformal public sector to distribute antimalarial drugs,some people are suggesting that the best way toreduce the time between onset of illness and firsttreatment with an antimalarial drug is by makingthese drugs widely available on the open market,from unofficial sources of health care, and at the

21


6.1.1 Reducing overall drug pressure.

Because overall drug pressure is thought to be thesingle most important factor in development of re-sistance, following more restrictive drug use andprescribing practices would be helpful, if notessential, for limiting the advent, spread, and in-tensification of drug resistance. This approach hasgained support in North America and Europe forfighting antibacterial drug resistance (105, 106).

The greatest decrease in antimalarial drug usecould be achieved through improving the diagno-sis of malaria. Although programs such as IMCIaim to improve clinical diagnosis through well-designed clinical algorithms, a large number ofpatients will continue to receive unnecessary anti-malarial therapy, especially in areas of relatively lowmalaria risk (18). Basing treatment on the resultsof a diagnostic test, such as microscopy or a rapidantigen test, however, would result in the greatestreduction of unnecessary malaria treatments anddecrease the probability that parasites are exposedto subtherapeutic blood levels of drug.

There are notable exceptions to this, however.Presumptive therapy with SP during pregnancy hasbeen shown to be an operationally sustainable in-tervention that offers significant protection fromlow birth weight associated with placental malaria(62). There may be a role for presumptive treat-ment or even mass drug administration in responseto an epidemic, although its cost-effectiveness hasnot been proven. Prophylaxis programmes, how-ever, should be used only among populations wherecompliance is likely to be high and where a highlyeffective prophylactic drug can be used.

6.1.2 Improving the way drugs are used

Other disease control programmes, such as for TB,STDs, and HIV, have begun to rely heavily ondirectly observed therapy (DOT) as a way to en-sure a high degree of compliance. While this hasnot yet received serious consideration for malaria,the use of drugs with single-dose regimens (SP,mefloquine) could potentially make DOT possi-ble. The benefits of using single-dose DOT needto be weighed against the costs of using drugs withlong half-lives.

Another approach that has not been widelyadopted is the close follow-up and re-treatment, ifnecessary, of patients. The success of this approachis dependant on availability of reliable microscopy(to diagnose the illness initially as well as to con-firm treatment failure), and either an infrastruc-

ture to locate patients in the community or a com-munity willing to return on a given date, regardlessof whether they feel ill or not. With this system,patients who fail initial treatment, for whateverreason, are identified quickly and re-treated untilparasitologically cured, decreasing the potential forspread of resistant parasites (107).

6.1.3 Combination therapy

A strategy that has received much attention recentlyis the combination of antimalarial drugs, such asmefloquine, SP, or amodiaquine, with anartemisinin derivative (108). Artemisinin drugs arehighly efficacious, rapidly active, and have actionagainst a broader range of parasite developmentalstages. This action apparently yields two notableresults. First, artemisinin compounds, used in com-bination with a longer acting antimalarial, can rap-idly reduce parasite densities to very low levels at atime when drug levels of the longer acting antima-larial drug are still maximal. This greatly reducesboth the likelihood of parasites surviving initialtreatment and the likelihood that parasites will beexposed to suboptimal levels of the longer actingdrug (32). Second, the use of artemisinins has beenshown to reduce gametocytogenesis by 8- to18-fold (33). This reduces the likelihood thatgametocytes carrying resistance genes are passedonwards and potentially may reduce malaria trans-mission rates. Use of combination therapy has beenlinked to slowing of the development of mefloquineresistance and reductions in overall malaria trans-mission rates in some parts of Thailand and hasbeen recommended for widespread use in sub-Saharan Africa (108). This interpretation and therecommendation for rapid adoption of combina-tion therapy in Africa, however, has been questioned(109, 110).

It should be noted that this argument contra-dicts a previously mentioned argument in that itpromotes the use of a drug combination withgrossly mismatched half-lives. Theoretically, inareas where malaria transmission rates are quite low,such as where this strategy has been most inten-sively studied in Thailand, this is of minimal con-cern (i.e. the likelihood of being bitten by aninfective mosquito during the period when druglevels are suboptimal is very low). In areas wheretransmission rates are very high (for example,Africa where inoculation rates can be as high as fiveinfective bites per night), this likelihood is very high.The relative contribution to development of resist-


22

ance of parasites surviving initial malaria treatmentcompared with new parasites being exposed to sub-optimal drug levels is unknown.

As second concern about combination therapyis the extent to which the components might beused for monotherapy outside official health serv-ices. Already, artemisinin compounds are availablein the pharmacies and markets of Africa. As supplyincreases and the price drops, these drugs will beused increasingly for the treatment of fever and,because of the rapidity of action, they may in factbecome the community’s drug of choice. It is un-likely, in this scenario, that they would be used incombination with another drug, whether SP ormefloquine. Similarly, in Africa, SP is both widelyavailable and inexpensive and may continue to beused alone. Any benefits of combination therapyin preventing development or intensification ofresistance may be lost due to unofficial and incor-rect use of the component drugs outside of officialhealth services.

In the future, antimalarial therapy may be ex-panded by combining chemotherapy with vaccines(or other drugs) specifically designed to inhibittransmission of malaria. These “transmission-block-ing” vaccines or drugs could reduce the potentialfor onward transmission of gametocytes carryingresistance genes, even if a relatively large numberof parasites survive initial treatment. This couldwork through using drugs or vaccines with a highdegree of specific antigametocytocidal activity (suchas primaquine and related drugs), drugs that non-specifically reduce the likelihood of gametocytesdeveloping (such as appears to be the case with theartemisinins), or drugs or vaccines that interferewith sexual reproduction and infection of the para-site within the mosquitos when taken up with ablood meal (although short acting, the combina-tion of atovaquone and proguanil has this type ofactivity).

23


7. Conclusions and recommendations

face of high levels of self-treatment and un-official use of component drugs (or relatedcompounds) as monotherapy and in variousepidemiological contexts (especially high-transmission areas).

3. Investigate how a combination therapy strat-egy could be financed. This strategy, if provencost-effective, will nonetheless be more ex-pensive than current strategies. What mecha-nisms might be developed to assist countriesin adopting this strategy?

B. Invest significantly in identifying strategies toimprove acceptance of and compliance withdrug regimens, especially a combination therapystrategy, at all levels of official and unofficialhealth care systems, private sector, and com-munity. Similarly, investigate to teach conceptsof judicious use of antimicrobials (includingantimalarial drugs) to health care providers.

C. Investigate ways to improve effectiveness of drugregulatory systems and ability to control intro-duction of new antimalarials within endemiccountries. This is required to avoid uncontrolleduse of new antimalarials resulting in develop-ment of resistance before they are needed whichcould significantly compromise their efficacywhen they are needed.

D. Support new drug development. Investigatenew approaches to drug delivery, such as time-released formulations or novel delivery systemsthat would allow use of short half-life drugswhile optimizing compliance. Investigate drugs(or vaccines?) that have transmission-blockingeffect that could be used in combination withdrugs active against blood-stage parasites.

E. Improve access to and use of definitive diagno-sis-based treatment.

F. Support more widespread use of insecticide-treated materials or other appropriate vectorcontrol strategies to reduce frequency of clini-cal illness (and therefore, treatment) as well asoverall malaria transmission.

Because of the realities of health care infrastructureand the influence of the private sector, approachesto malaria therapy, especially in sub-SaharanAfrica, will probably favour increased access todrugs (and, therefore, loss of control over how theyare used) over restricted access (and, therefore, morecontrol over how they are used). If this proves tobe true, while only minor advances against anti-malarial drug resistance can be expected, short-termreductions in malaria morbidity and mortality maybe achieved.

Long-term success of this strategy, however, willdepend on a continuous supply of new and afford-able drugs and on the development of effective andimplementable control measures to reduce overallburden of disease. A more cautious approach wouldbe to avoid placing too much faith in future scien-tific advances and technology and to invest in meth-ods to improve the way people and antimalarialdrugs interact in an environment of essentiallyuncontrolled use. The objective of this investmentwould be to prolong the useful life span of drugsenough to increase the likelihood that new drugsor other methods of malaria control will indeed bedeveloped and implemented.

Significant advances against antimalarial drugresistance is probably unlikely without majorchange in health infrastructure leading to higher-quality services that are more readily available.

7.1 Priorities

A. Investigate combination therapy:

1. Fast-track a chlorproguanil/dapsone/artesunate fixed dose formulation. From atheoretical basis, this would offer the bestcombination of overall efficacy, synergy be-tween the antifolate-sulfa components, shorthalf-life, reasonably well-matched pharma-cokinetics, and probable cost. Because ofgrowing use of and resistance to SP, anurgency exists to field this promising agent.

2. Investigate effectiveness of combinationtherapy in terms of robustness of strategy in


24

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