Guidelines for Treatment of Malaria

7/30/2019 Guidelines for Treatment of Malaria

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G U

S e c o n d e d i t i o n

I D E L I N E S

F O R T H E T R E A T M E N T O F M A L A R I A


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Guidelines forthe treatment of malaria

Second edition


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World Health Organization, 2010

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World

Health Organization, 20, avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791

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authors alone are responsible for the views expressed in this publication.

For technical information, please contact:

Dr P. Olumese

Global Malaria Programme

World Health Organization20, avenue Appia CH-1211 Geneva 27

Tel. +41 22 791 4424

Fax +41 22 791 4824

E-mail: [email protected]

WHO Library Cataloguing-in-Publication Data

Guidelines for the treatment of malaria -- 2nd edition.

1.Malaria drug therapy. 2.Malaria diagnosis. 3.Antimalarials administration and

dosage. 4. Drug therapy, Combination. 5.Guidelines. I.World Health Organization.

ISBN 978 92 4 154792 5 (NLM classification: WC 770)

Guidel ines for the t r eatment o f malar ia 2 nd edit ion


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Contents

iii

Glossary v

Abbreviations viii

Executive summary ix

1. Introduction 1

1.1 Background 1

1.2 Objectives and target audience 1

1.3 Methods used in developing the guidelines and recommendations 2

2. Clinical disease and epidemiology 4

3. Objectives of treatment 63.1 Uncomplicated malaria 6

3.2 Severe malaria 6

4. Resistance to antimalarial medicines 6

4.1 Impact of resistance 7

4.2 Global distribution of resistance 7

4.3 Assessing efficacy and resistance 7

5. Antimalarial treatment policy 8

5.1 Criteria for antimalarial treatment policy change 85.2 Therapeutic efficacy cut-offs for changing treatment policy 8

6. Diagnosis of malaria 9

6.1 Clinical diagnosis 9

6.2 Parasitological diagnosis 10

6.3 Where malaria transmission is low-to-moderate and/or unstable 11

6.4 In stable high-transmission settings 12

6.5 Malaria parasite species identification 12

6.6 In epidemics and complex emergencies 12

7. Treatment of uncomplicated P. falciparum malaria 13

7.1 Definition of uncomplicated malaria 13

7.2 Rationale for antimalarial combination therapy 13

7.3 ACT options 15

7.4 Management of treatment failures 17

7.5 Practical aspects of treatment with recommended ACTs 19

7.6 Incorrect approaches to treatment 21

7.7 Additional considerations for clinical management 22

7.8 Operational issues in treatment management 23

7.9 Treatment in specific populations and situations 26

7.10 Co-existing morbidities 32


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8. Treatment of severe P. falciparum malaria 35

8.1 Definition 35

8.2 Treatment objectives 36

8.3 Clinical assessment 36

8.4 Specific antimalarial treatment 37

8.5 Follow-on treatment 39

8.6 Pre-referral treatment options 39

8.7 Practical aspects of treatment 42

8.8 Adjunctive treatment 43

8.9 Continuing supportive care 44

8.10 Additional aspects of management 45

8.11 Treatment of severe malaria in special groups during pregnancy 47

9. Treatment of malaria caused by P. vivax, P. ovale or P. malariae 47

9.1 Diagnosis 48

9.2 Susceptibility ofP. vivax, P. ovale and P. malariae to antimalarials 48

9.3 Treatment of uncomplicated vivax malaria 49

9.4 Treatment of severe P. vivaxmalaria 52

9.5 Treatment of malaria caused by P. ovale and P. malariae 53

9.6 Monitoring therapeutic efficacy for vivax malaria 53

10. Mixed malaria infections 54

11. Complex emergencies and epidemics 54

11.1 Diagnosis 54

11.2 Management of uncomplicated falciparum malaria 55

11.3 Areas prone to mixed falciparum/vivax malaria epidemics 56

11.4 Areas prone to vivax malaria epidemics 56

11.5 Anti-relapse therapy in vivax malaria epidemics 56

11.6 Management of severe falciparum malaria 56

12. Case management in the context of malaria elimination 58

12.1 Use of gametocytocidal drugs to reduce transmission 58

12.2 Mass screening and treatment 58

13. Mass drug administration 59

Annexes 61

Annex 1. The guidelines development process 63

Annex 2. Adaptation of the WHO malaria treatment guidelines for use in countries 71

Annex 3. Pharmacology of antimalarial medicines 73

Annex 4. Antimalarials and malaria transmission 109

Annex 5. Malaria diagnosis 117

Annex 6. Resistance to antimalarial medicines 122

Annex 7. Uncomplicated P. falciparum malaria 134

Annex 8. Treatment of severe P. falciparum malaria 154

Annex 9. Treatment ofP. vivax, P. ovale and P. malariae infections 166

Index 188


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Glossary

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Glossary

Artemisinin-based combination therapy (ACT). A combination of artemisinin or oneof its derivatives with an antimalarial or antimalarials of a different class.

Asexual cycle. The life-cycle of the malaria parasite in host from merozoite invasion of

red blood cells to schizont rupture (merozoite ring stage trophozoite schizont merozoites). Duration approximately 48 h in Plasmodium falciparum, P. ovale and P. vivax;

72 h in P. malariae.

Asexual parasitaemia. The presence in host red blood cells of asexual parasites. Thelevel of asexual parasitaemia can be expressed in several different ways: the percentage

of infected red blood cells, the number of infected cells per unit volume of blood, thenumber of parasites seen in one microscopic field in a high-power examination of a thickblood film, or the number of parasites seen per 2001000 white blood cells in a high-power examination of a thick blood film.

Cerebral malaria. Severe P. falciparum malaria with cerebral manifestations, usually

including coma (Glasgow coma scale < 11, Blantyre coma scale < 3). Malaria with comapersisting for > 30 min after a seizure is considered to be cerebral malaria.

Combination treatment (CT). A combination of two or more different classes ofantimalarial medicines with unrelated mechanisms of action.

Cure. Elimination of the symptoms and asexual blood stages of the malaria parasite thatcaused the patient or caregiver to seek treatment.

Drug resistance. The World Health Organization (WHO) defines resistance to

antimalarials as the ability of a parasite strain to survive and/or to multiply despite theadministration and absorption of a medicine given in doses equal to or higher thanthose usually recommended but within the tolerance of the subject, provided drugexposure at the site of action is adequate. Resistance to antimalarials arises becauseof the selection of parasites with genetic mutations or gene amplifications that confer

reduced susceptibility.

Gametocytes. Sexual stages of malaria parasites present in the host red blood cells.

Hypnozoites. Persistent liver stages ofP. vivaxand P. ovale malaria that remain dormant

in host hepatocytes for an interval (most often 345 weeks) before maturing to hepaticschizonts. These then burst and release merozoites, which infect red blood cells.Hypnozoites are the source of relapses.


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Malaria pigment (haemozoin). A dark brown granular pigment formed by malariaparasites as a by-product of haemoglobin catabolism. The pigment is evident in mature

trophozoites and schizonts. They may also be present in white blood cells (peripheralmonocytes and polymorphonuclear neutrophils) and in the placenta.

Merozoites. Parasites released into the host bloodstream when a hepatic or erythrocyticschizont bursts. These then invade the red blood cells.

Monotherapy. Antimalarial treatment with a single medicine (either a single activecompound or a synergistic combination of two compounds with related mechanismof action).

Plasmodium.A genus of protozoan vertebrate blood parasites that includes the causalagents of malaria. Plasmodium falciparum,P. malariae, P. ovale and P. vivaxcause malaria

in humans. Human infections with the monkey malaria parasite, P. knowlesi have alsobeen reported from forested regions of South-East Asia.

Pre-erythrocytic development. The life-cycle of the malaria parasite when it firstenters the host. Following inoculation into a human by the female anopheline mosquito,

sporozoites invade parenchyma cells in the host liver and multiply within the hepatocytesfor 512 days, forming hepatic schizonts. These then burst liberating merozoites into the

bloodstream, which subsequently invade red blood cells.

Radical cure. In P. vivaxand P. ovale infections only, this comprises a cure as definedabove plus prevention of relapses by killing hypnozoites.

Rapid diagnostic test (RDT). An antigen-based stick, cassette or card test for malariain which a coloured line indicates that plasmodial antigens have been detected.

Recrudescence. The recurrence of asexual parasitaemia after treatment of the infectionwith the same infection that caused the original illness. This results from incomplete

clearance of parasitaemia due to inadequate or ineffective treatment. It is, therefore,different to a relapse in P. vivaxand P. ovale infections, and it differs from a new infectionor re-infection (as identified by molecular genotyping in endemic areas).

Recurrence. The recurrence of asexual parasitaemia following treatment. This can becaused by a recrudescence, a relapse (in P. vivaxand P. ovale infections only) or a new

infection.

Relapse. The recurrence of asexual parasitaemia in P. vivaxand P. ovale malaria deriving

from persisting liver stages. Relapse occurs when the blood stage infection has beeneliminated but hypnozoites persist in the liver and mature to form hepatic schizonts.

After variable intervals of weeks to months, the hepatic schizonts burst and liberatemerozoites into the bloodstream.



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Glossary

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Ring stage. Young usually ring-shaped intra-erythrocytic malaria parasites, beforemalaria pigment is evident under microscopy.

Schizonts. Mature malaria parasites in host liver cells (hepatic schizonts) or red bloodcells (erythrocytic schizonts) that are undergoing nuclear division. This process is called

schizogony.

Selection pressure. Resistance to antimalarials emerges and spreads because of the

selective survival advantage that resistant parasites have in the presence of antimalarialsto which they are resistant. Selection pressure describes the intensity and magnitudeof the selection process; the greater the proportion of parasites in a given parasite

population exposed to concentrations of an antimalarial that allows proliferation of

resistant, but not sensitive parasites, the greater the selection pressure.

Severe anaemia. Haemoglobin concentration of < 5 g/100 ml (haematocrit < 15%).

Severe falciparum malaria. Acute falciparum malaria with signs of severity and/orevidence of vital organ dysfunction.

Sporozoites. Motile malaria parasites that are infective to humans, inoculated by afeeding female anopheline mosquito. The sporozoites invade hepatocytes.

Transmission intensity. The intensity of malaria transmission measured by the frequencywith which people living in an area are bitten by anopheline mosquitoes carryingsporozoites. This is often expressed as the annual entomological inoculation rate (EIR),

which is the number of inoculations of malaria parasites received by one person in oneyear.

Trophozoites. Stage of development of the malaria parasites within host red bloodcells from the ring stage and before nuclear division. Mature trophozoites contain visiblemalaria pigment.

Uncomplicated malaria. Symptomatic infection with malaria parasitaemia without signs

of severity and/or evidence of vital organ dysfunction.

Vectorial capacity. Number of new infections the population of a given vector would

distribute per case per day at a given place and time, assuming conditions of non-immunity.


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abbreviations

ACT artemisinin-based combination therapy

AL artemether plus lumefantrine combination

AQ amodiaquine

AS artesunate

AS+AQ artesunate plus amodiaquine combination

AS+MQ artesunate plus mefloquine combination

AS+SP artesunate plus sulfadoxine-pyrimethamine combination

BW body weightCI confidence interval

CQ chloroquine

DHA+PPQ dihydroartemisinin plus piperaquine combination

EIR entomological inoculation rate

GRADE Grading of Recommendations Assessment, Developmentand Evaluation

G6PD glucose-6-phosphate dehydrogenase

HIV/AIDS human immunodeficiency virus/acquired immunodeficiency syndrome

HRP2 histidine-rich protein 2

IC50 concentration providing 50% inhibition

IV intravenous

IM intramuscular

MIC minimum inhibitory concentration

MQ mefloquine

OR odds ratio

PCR polymerase chain reaction

PfHRP2 Plasmodium falciparum histidine-rich protein-2

pLDH parasite-lactate dehydrogenase

PQ primaquine

Pvdhfr Plasmodium vivaxdihydrofolate reductase

RCT randomized controlled trial

RDT rapid diagnostic testRR relative risk

SP sulfadoxine-pyrimethamine

WHO World Health Organization

WMD weighted mean difference



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Executive summary

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executive summary

Malaria case management remains a vital cmpnent f the malaria cntrl strategies.

This entails early diagnsis and prmpt treatment with effective antimalarial medicines.

The WHO Guidelines for the treatment of malaria, which were first published in 2006,

prvide glbal, evidence-based recmmendatins n the case management f malaria,

targeted mainly at plicy-makers at cuntry level, prviding a framewrk fr the

develpment f specific and mre detailed natinal treatment prtcls that take int

accunt lcal antimalarial drug resistance patterns and health service capacity in the

cuntry. This secnd editin f the guidelines revisits the recmmendatins based n

updated evidence. The same presentatin frmat frm the first editin has been mainly

kept based n feedback frm the end-users. A summary f the key recmmendatins

prvided in these guidelines is presented belw.

box 1.r hg h h Gdene (2006)

treatment of uncomplicated P. falciParummalaria

Artemisinin-based combination therapies (ACTs) are the recommended treatments foruncomplicated P. falciparummalaria.

The following ACTs are recommended:

artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, and artesunateplus sulfadoxine-pyrimethamine.

The choice of ACT in a country or region will be based on the level of resistance of the partnermedicine in the combination.

Artemisinin and its derivatives should not be used as monotherapy.

Second-line antimalarial treatment:

alternative ACT known to be effective in the region;artesunate plus tetracycline or doxycycline or clindamycin; any of these combinations to be given for

7 days;

quinine plus tetracycline or doxycycline or clindamycin; any of these combinations should be given for 7days.

treatment of uncomplicated P. falciParummalaria in special risk Groups

Pregnancy First trimester:

quinine plus clindamycin to be given for 7 days (artesunate plus clindamycin for 7 days is indicated if thistreatment fails);

an ACT is indicated only if this is the only treatment immediately available, or if treatment with 7-dayquinine plus clindamycin fails or uncertainty of compliance with a 7-day treatment.


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Second and third trimesters:

ACTs known to be effective in the country/region or artesunate plus clindamycin to be given for

7 days, or quinine plus clindamycin to be given for 7 days.Lactating women:

lactating women should receive standard antimalarial treatment (including ACTs) except for dapsone,

primaquine and tetracyclines.

Infants and young children:ACTs for first-line treatment in infants and young children with attention to accurate dosing and ensuring

the administered dose is retained.Travellers returning to non-endemic countries:

atovaquone-proguanil;

artemether-lumefantrine;

quinine plus doxycycline or clindamycin.

TreaTmenT of severe malaria

Severe malaria is a medical emergency. After rapid clinical assessment and confirmation ofthe diagnosis, full doses of parenteral antimalarial treatment should be started without delaywith whichever effective antimalarial is first available.

For adults, artesunate IV or IM: artemether or quinine is an acceptable alternative if parenteral artesunate is not available.

For children, artesunate IV or IM artemether or quinine is an acceptable alternative if parenteral artesunate is not available.

Give parenteral antimalarials in the treatment of severe malaria for a minimum of 24 h, oncestarted (irrespective of the patients ability to tolerate oral medication earlier) and, thereafter,complete treatment by giving a complete course of:

an ACT;

artesunate plus clindamycin or doxycycline;

quinine plus clindamycin or doxycycline.

If complete treatment of severe malaria is not possible, patients should be given pre-referraltreatment and referred immediately to an appropriate facility for further treatment. The followingare options for pre-referral treatment : rectal artesunate, quinine IM, artesunate IM, artemether IM.

TreaTmenT of uncomplicaTed P. vivaxmalaria

Chloroquine combined with primaquine is the treatment of choice for chloroquine-sensitiveinfections.

In mild-to-moderate G6PD deficiency, primaquine 0.75 mg base/kg body weight given once a weekfor 8 weeks. In severe G6PD deficiency, primaquine is contraindicated and should not be used.

Where ACT (exception AS+SP) has been adopted as the first-line treatment for P. falciparummalaria, it may also be used for P. vivaxmalaria in combination with primaquine for radical cure.Artesunate plus sulfadoxine-pyrimethamine is not effective against P. vivaxin many places.

Guidel ines f or the treatment o f malaria 2 nd edit ion


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1. Introduction

1

1. introduction

1.1 bg

Malaria is an imprtant cause f death and il lness in children and adults, especially in

trpical cuntries. Malaria cntrl requires an integrate apprach, including preventin

(primarily vectr cntrl) and prmpt treatment with effective antimalarials. Since the

publicatin f the first editin f the guidelines in 2006, mst f the cuntries where

P. falciparum is endemic have prgressively updated treatment plicies frm the failing

chlrquine (CQ) and sulfadxine-pyrimethamine (SP) t the recmmended artemisinin-based cmbinatin therapies (ACTs); this is the best current treatment fr uncmplicated

falciparum malaria. Unfrtunately, the implementatin f these plicies has lagged behind

due t varius factrs such as high csts.

The recmmendatins given in these guidelines aim t prvide simple and straightfrward

treatment recmmendatins based n sund evidence that can be applied even in

severely resurce-cnstrained settings. T achieve this gal, all relevant factrs are taken

int accunt with adjustments fr different areas where levels f drug resistance and

backgrund immunity vary. These factrs include the in vitr antimalarial susceptibilityand the pharmackinetic and pharmacdynamic prperties f the different antimalarial

medicines. Cst is a factr that shuld be taken int cnsideratin in antimalarial

treatment plicy and practices. Hwever, as there are increasing internatinal subsidies

fr antimalarials, efficacy and safety have taken precedence ver csts when making the

recmmendatins. The number f antimalarial drug trials published has cntinued t

increase ver the years, with the result that these guidelines have a firmer evidence base

than previus treatment recmmendatins. Inevitably, there are still infrmatin gaps,

s they will remain under regular review with updates every tw years and/r n an adhc basis as new evidence becmes available. The malaria treatment recmmendatins

in the main dcument are brief; fr thse wh may wish t study the evidence base in

mre detail, a series f annexes with linkages t the apprpriate sectins f the main

dcument is prvided.

1.2 o g

1.2.1 Objectives

The purpse f these guidelines is t prvide glbal, evidence-based recmmendatins

n the treatment f malaria. Infrmatin is shwn n the treatment f:

uncmplicated malaria, including disease in special risk grups (yung children,

pregnant wmen, peple wh are HIV psitive, travellers frm nn-malaria endemic


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regins), and in epidemics and cmplex emergency situatins; and

severe malaria.

The guidelines prvide a framewrk fr the develpment f specific and mre detailednatinal treatment prtcls that take int accunt lcal antimalarial drug resistance

patterns and health service capacity in the cuntry (see Annex 2). They are nt intended

t prvide, r t be used, as a cmprehensive clinical management guide/manual fr the

treatment f malaria.

1.2.2 Taet audience

These guidelines are primarily targeted at plicy-makers in ministries f health, wh

frmulate cuntry specific treatment guidelines. Hwever, the fllwing grups shuldals find them useful:

public health and plicy specialists wrking in hspitals, research institutins, medical

schls, nngvernmental rganizatins and agencies wrking as partners in health r

malaria cntrl, the pharmaceutical industry and primary health-care services; and

health prfessinals (dctrs, nurses and paramedical fficers).

1.3 mh g h g

In the first editin f the WHO Guidelines for the treatment of malaria (2006), the

methdlgy fr identifying the questins, search and review f evidence is similar t

that used in this current update. Hwever, the Grading f Recmmendatins Assessment,

Develpment and Evaluatin (GRADE) methdlgy was nt applied then, rather in

frmulating recmmendatins, evidence was graded in rder f pririty as fllws:

frmal systematic reviews, such as Cchrane reviews, including mre than ne

randmized cntrl trial;

cmparative trials withut frmal systematic review;

bservatinal studies (e.g. surveillance, pharmaclgical data);

expert pinin/cnsensus.

Since the release f the first editin f the guidelines, the WHOs standard methds

fr guidelines develpment has evlved and, thus, this secnd editin was develped

in accrdance with the updated WHO standard methds fr guideline develpment.

This methdlgy incrprates a transparent link between research evidence and

recmmendatins. The GRADE system, which has been incrprated int this update,is a unifrm apprach that is being widely adpted. It emplys explicit methds,

develped by the GRADE Wrking Grup, t frmulate and t evaluate the strength f

a recmmendatin based n the rbustness f the evidence relating t a specific clinical

questin. Fr this secnd editin f the guidelines, nly new recmmendatins have been

subjected t the GRADE prcess (see Annex 1).



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1. Introduction

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The develpment, preparatin and printing f the guidelines is exclusively funded by the

WHO Glbal Malaria Prgramme. N external surces f funding either frm bilateral

technical partners, r frm industry, was slicited r used.

1.3.1 Method

The GRADE methodology involves a four-step process:

identification f the clinical questins, and the critical and imprtant utcmes t

answer these questins;

systematicreviews f the evidence (using Cchrane methdlgy) fcusing n these

utcmes;

construction f GRADE tables t summarize the data and t assess the quality (r

rbustness) f the evidence;

interpretation f the GRADE tables and the frmulatin f recmmendatins.

The first meeting of the Malaria Treatment Guidelines Panel identified several key areas

for review of existing recommendations:

cnsider adding dihydrartemisinin plus piperaquine t the recmmended list f

artemisinin-based cmbinatin therapies (ACTs) fr uncmplicated malaria;

cnsider remving amdiaquine plus sulfadxine-pyrimethamine frm the list f

recmmended antimalarials fr uncmplicated malaria;

recnsider the recmmendatin f artesunate plus meflquine in Africa, with specific

cncerns regarding txicity/vmiting in children;

cnsider the relative effectiveness f IV artesunate instead f quinine fr severe malaria;

assess the rle f ACTs in vivax malaria in areas with chlrquine-resistant P. vivax;

cnsider the best treatment fr radical cure fP. vivaxmalaria.

A sub-grup f the panel the GRADE sub-grup was frmed that prepared and

evaluated apprpriate, up-t-date systematic reviews and develped GRADE prfiles

related t these questins.

The quality f the evidence, as assessed byGRADE, is rated n a fur-pint scale:

HIGHquality: further research is very unlikely t change the cnfidence in the estimate

f effect;

MODERATE quality: further research is likely t have an imprtant impact n thecnfidence in the estimate f effect and may change the estimate;

LOW quality: further research is very likely t have an imprtant impact n the

cnfidence in the estimate f effect and is likely t change the estimate;

VERY LOWquality: uncertainty abut the estimate.


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Recmmendatins were frmulated based n the GRADE prfiles with the strength f

recmmendatins rated as:

weak: the panel cnsiders that the benefits f the interventin prbably utweigh therisks; r

strong: the panel is cnfident that the benefits f the interventin utweigh the risks.

The recmmendatins were mdified where necessary with further cnsideratin f

imprtant factrs beynd the scpe f evidence s that strongrecmmendatins may be

made n the basis flowquality evidence, and vice versa. These additinal values and

preferences cnsidered as imprtant t the panel are described alngside presentatin

f the tables.

1.3.2 Pesentation of evidence (ecommendations)

Fr clarity, these guidelines are presented in a simple descriptive frm with a central main

dcument cntaining the recmmendatins. Summaries f the recmmendatins are given

in bxes tgether with the summary f the GRADE prfiles, where available. In situatins

where a GRADE table has nt been cnstructed, it is s indicated in the recmmendatin

bx. Full reviews f the evidence, the cmplete GRADE tables and additinal references

are prvided in annexes apprpriately referenced in the main dcument.

2. clinical disease and epidemioloGy

Malaria is caused by infectin f red bld cells with prtzan parasites f the genus

Plasmodium. The parasites are inculated int the human hst by a feeding female anpheline

msquit. The fur Plasmodium species that infect humans are P. falciparum, P. vivax,

P. ovale and P. malariae. Increasingly, human infectins with the mnkey malaria parasite,

P. knowlesi, have als been reprted frm the frested regins f Suth-East Asia.

The first symptms f malaria are nnspecific and similar t the symptms f a minr

systemic viral illness. They cmprise: headache, lassitude, fatigue, abdminal discmfrt,

and muscle and jint aches, usually fllwed by fever, chills, perspiratin, anrexia,

vmiting and wrsening malaise. Malaria is, therefre, frequently ver-diagnsed n

the basis f symptms alne, especially in endemic areas, because f this nn-specificity

f symptmatlgy. At this early stage, with n evidence f vital rgan dysfunctin, the

patients can readily be treated with full rapid recvery prvided prmpt and effective

treatment is given. If, hwever, ineffective medicines are given r if treatment is delayed,

particularly in P. falciparum malaria, the parasite burden cntinues t increase and severe

malaria may ensue. It is a prgressin that may ccur within a few hurs. Severe malaria



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2. Cl inica l di sease and epidemiology

5

usually manifests with ne r mre f the fllwing: cma (cerebral malaria), metablic

acidsis, severe anaemia, hypglycaemia, acute renal failure r acute pulmnary edema.

By this stage f the disease, the case fatality in peple receiving treatment is typically1020%. Hwever, if left untreated, severe malaria is fatal in the majrity f cases.

The nature f malaria clinical disease depends greatly n the backgrund level f the

acquired prtective immunity, a factr which is the utcme f the pattern and intensity

f malaria transmissin in the area f residence.

Where the transmissin f malaria is stable, meaning where ppulatins are cntinuusly

expsed t a fairly cnstant, high rate f malarial inculatins (entmlgical inculatin

rate [EIR] >10 per year), partial immunity t the clinical disease and t its severe

manifestatin is acquired early in childhd. In such situatins, which prevail in muchf sub-Saharan Africa and parts f Oceania, the acute clinical disease described abve is

mstly cnfined t yung children, wh suffer high parasite densities and acute clinical

disease. If untreated, this can prgress very rapidly t severe malaria; adlescents and

adults are partially immune and seldm suffer clinical disease, althugh they may

cntinue t harbur lw bld-parasite densities. Immunity is, hwever, mdified in

pregnancy, and it is ften gradually lst, at least partially, when individuals mve ut f

the endemic areas fr lng duratins (usually many years).

In areas f unstable malaria, which prevails in much f Asia and Latin America, andthe remaining parts f the wrld where malaria is endemic, the rates f inculatin

fluctuate greatly ver seasns and years. Entmlgical inculatin rates are usually

< 5 per year and ften < 1 per year. This retards the acquisitin f immunity and results

in peple f all ages, adults and children alike, suffering acute clinical malaria, with a

high risk f prgressin t severe malaria if untreated. Epidemics may ccur in areas

f unstable malaria when inculatin rates increase rapidly due t a sudden increase

in msquit vectr densities. Epidemics manifest as a very high incidence f malaria in

all age grups and can verwhelm health services. Severe malaria is cmmn if prmpteffective treatment is nt made widely available. Nn-immune travellers t a malaria

endemic area are at a high risk f acquiring malaria, unless prtective measures are

taken, and f the disease prgressing t fatal severe malaria if infectins are nt treated

prmptly and effectively.

With effective malaria cntrl (as with a ppulatin-wide cverage with effective vectr

cntrl and large-scale deplyment f ACTs), the number f malaria inculatins can be

greatly reduced; this will be fllwed in time by a crrespnding change in the clinical

epidemilgical prfile in the area and a risk f epidemics, if cntrl measures are ntsustained.


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3. objectives of treatment

3.1 u

The bjective f treating uncmplicated malaria is t cure the infectin as rapidly as

pssible. Cure is defined as the eliminatin frm the bdy f the parasites that caused the

illness. This prevents prgressin t severe disease, and additinal mrbidity assciated

with treatment failure. In treatment evaluatins, it is necessary t fllw patients fr

sufficient time t apprpriately assess cures (see Sectin 5.1).

The public health gal f treatment is t reduce transmissin f the infectin t thers, i.e.

t reduce the infectius reservir and t prevent the emergence and spread f resistancet antimalarial medicines (see Annex 4). The adverse effect prfile and tlerability

f antimalarial medicines, and the speed f therapeutic respnse are als imprtant

cnsideratins.

3.2 s

The primary bjective f antimalarial treatment in severe malaria is t prevent death.

In treating cerebral malaria, preventin f neurlgical deficit is als an imprtantbjective. In the treatment f severe malaria in pregnancy, saving the life f the mther

is the primary bjective. In all cases f severe malaria, preventin f recrudescence and

avidance f minr adverse effects are secndary.

4. resistance to antimalarial medicines

Resistance t antimalarial medicines has been dcumented in all classes f antimalarials,

including the artemisinin derivatives, and it is a majr threat t malaria cntrl.

Widespread and indiscriminate use f antimalarials exerts a strng selective pressure

n malaria parasites t develp high levels f resistance. Resistance can be prevented,

r its nset slwed cnsiderably, by cmbining antimalarials with different mechanisms

f actin and ensuring very high cure rates thrugh full adherence t crrect dse

regimens. Further infrmatin n the emergence, spread and preventin f resistancet antimalarials is prvided in Annex 6.

1 Methods for surveillance of antimalarial drug efficacy. Geneva, World Health Organization, 2009.http://apps.who.int/malaria/docs/drugresistance/Protocol2009.pdf, accessed 29 October 2009).

2 Methods and techniques for clinical trials on antimalarial drug efficacy: genotyping to identify parasite populations.Informal consultation organized by the Medicines for Malaria Venture and cosponsored by the World HealthOrganization, 2931 May 2007, Amsterdam, the Netherlands. Geneva, World Health Organization, 2008http://apps.who.int/malaria/docs/drugresistance/MalariaGenotyping.pdf, accessed 29 October 2009).



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4. Res i s tance to antimalar ia l medic ines

7

4.1 i

Initially, at lw levels f resistance and with a lw prevalence f malaria, the impactf resistance t antimalarials is insidius. At the early nset f resistance, the initial

symptms f the infectin reslve and the patient appears t be better fr a shrt perid

f time; hwever, symptms recur (usually between three t six weeks after treatment),

anaemia may wrsen and there is a greater prbability f carrying gametcytes (which in

turn carry the resistance genes). The patient and the treatment prvider mstly interpret

these early features f resistance as a newly acquired infectin. Unless clinical drug trials

are cnducted at this stage, resistance may g unrecgnized. As resistance wrsens, the

interval between primary infectin and recrudescence shrtens; eventually symptms fail

t reslve fllwing treatment, with malaria incidence likely t rise in lw-transmissinsettings, and mrtality is likely t rise in all settings.

4.2 G

Resistance t antimalarials has been dcumented fr P. falciparum, P. malariae and

P. vivax. In P. falciparum, resistance has been bserved in all currently used antimalarials

(amdiaquine, chlrquine, meflquine, quinine, and sulfadxine-pyrimethamine) and,

mre recently, in artemisinin derivatives. The gegraphical distributins and rates f

spread have varied cnsiderably.

P. vivaxhas develped resistance rapidly t sulfadxine-pyrimethamine in many areas,

while resistance t chlrquine is cnfined largely t Indnesia, Papua New Guinea,

Timr-Leste and ther parts f Oceania. There are als reprts n resistance frm Brazil

and Peru. P. vivaxremains sensitive t chlrquine in mst f Suth-East Asia, the Indian

subcntinent, the Krean peninsula, the Middle East, nrth-east Africa, and mst f

Suth and Central America.

4.3 ag

The fllwing methds are available fr assessing efficacy and resistance t

antimalarials:

in viv assessment f therapeutic efficacy;1

mlecular gentyping t distinguish between re-infectins and recrudescence ;2

in vitr studies f parasite susceptibility t drugs in culture.3

mlecular markers.

3 Basco LK. Field application of in vitro assays for the sensitivity of human malaria parasites to antimalarial drugs.Geneva, World Health Organization, 2007http://apps.who.int/malaria/docs/drugresistance/OMS_FieldApplicationInVitroAssays.pdf, accessed 29 Oct. 2009).


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5. antimalarial treatment policy

Natinal antimalarial treatment plicies shuld aim t ffer antimalarials that are highly

effective.

5.1 c hg

The main determinant f antimalarial treatment plicy is the therapeutic efficacy f the

antimalarial medicines in use. Other imprtant determinants include: changing patterns

f malaria-assciated mrbidity and mrtality; cnsumer and prvider dissatisfactinwith the current plicy; and the availability f alternative medicines, strategies and

appraches. Therapeutic efficacy mnitring invlves the assessment f clinical and

parasitlgical utcmes f treatment ver at least 28 days fllwing the start f adequate

treatment t mnitr fr the reappearance f parasites in the bld. Reappearance f the

same gentype indicates reduced parasite sensitivity t the treatment drug.

Antimalarial treatment shuld be assessed n the basis f parasitlgical cure rates.

The duratin f pst-treatment fllw-up is based n the eliminatin half-life f the

antimalarial medicine being evaluated. The current recmmended duratin f fllw-upis a minimum f 28 days fr all antimalarial medicines, while it is extended fr lnger

perids f time depending n eliminatin half-life (42 days fr cmbinatins with

meflquine and piperaquine). When pssible, bld r plasma levels f the antimalarial

shuld als be measured in prspective assessments s that drug resistance can be

distinguished frm treatment failures due t inadequate drug expsure.

In high-transmissin settings re-infectin is inevitable, but the cure f malaria (i.e.

preventin f recrudescence) is imprtant; it benefits bth the patient, by reducing

anaemia, and the cmmunity, by reducing the parasite reservir and slwing theemergence and spread f resistance. Slwly eliminated antimalarials prvide the additinal

benefit f suppressing malaria infectins that are newly acquired during the perid in

which residual antimalarial drug levels persist in the bdy. On the ther hand, these

residual drug levels d prvide a selectin pressure fr resistance. In these treatment

recmmendatins, the curative efficacy f the antimalarials has taken precedence ver

the prvisin f a perid f prphylaxis.

5.2 th - hgg

A change f an antimalarial medicine recmmended in the natinal malaria treatment

plicy shuld be initiated if the ttal treatment failure prprtin is 10%, as assessed

thrugh in viv mnitring f therapeutic efficacy. The selectin f a new and/r



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alternative antimalarial medicine fr use at public health level within the cntext f

natinal treatment guidelines, shuld be based n an average cure rate f > 95%, as

assessed in clinical trials.

6. diaGnosis of malaria

Prmpt and accurate diagnsis f malaria is part f effective disease management. The

diagnsis f malaria is based n clinical suspicin and n the detectin f parasites in thebld (parasitlgical r cnfirmatry diagnsis). High sensitivity f diagnsis in malaria-

endemic areas is particularly imprtant fr the mst vulnerable ppulatin grups, such

as yung children and the nn-immune ppulatin, in whm the disease can be rapidly

fatal, while high specificity will reduce unnecessary treatment with antimalarials and

imprve diagnsis f ther febrile illnesses in all settings. Thus, high quality malaria

diagnsis is imprtant in all settings. Further infrmatin n the diagnsis f malaria

is prvided in Annex 5.

6.1 c g

The signs and symptms f malaria are nnspecific. Malaria is clinically suspected mstly

n the basis f fever r a histry f fever. Diagnsis based n clinical features alne has

very lw specificity and results in ver-treatment. Other pssible causes f fever and the

need fr alternative r additinal treatment must always be carefully cnsidered. The

WHO recmmendatins fr clinical diagnsis/suspicin f uncmplicated malaria in

different epidemilgical settings are as fllws:4

in settings where the risk f malaria is lw, clinical diagnsis f uncmplicated malaria

shuld be based n the pssibility f expsure t malaria and a histry f fever in the

previus three days with n features f ther severe diseases;

in settings where the risk f malaria is high, clinical diagnsis shuld be based n a

histry f fever in the previus 24 h and/r the presence f anaemia, fr which pallr

f the palms appears t be the mst reliable sign in yung children.

In all settings, clinical suspicin f malaria shuld be cnfirmed with a parasitlgical

diagnsis. Hwever, in settings where parasitlgical diagnsis is nt pssible, the decisint prvide antimalarial treatment must be based n the prir prbability f the illness

being malaria. Other pssible causes f fever and need fr alternative treatment must

always be carefully cnsidered.

4 WHO Expert Committee on Malaria. Twentieth report. Geneva, World Health Organization, 2000 in WHOTechnical Report Series, No. 892.

6. Diagnosi s of malar ia


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feasible. Micrscpy has further advantages in that it can be used fr speciatin and

quantificatin f parasites, and t assess respnse t antimalarial treatment. Micrscpy

can als be used in the identificatin f ther causes f fever. Hwever, a majr drawbackf light micrscpy is its requirement fr well-trained, skilled staff and, usually, an energy

surce t pwer the micrscpe.

In many areas, malaria patients are treated utside f the frmal health services, e.g. in

the cmmunity, in the hme r by private prviders; micrscpy is generally nt feasible

in many such circumstances, but RDTs may be pssible. Althugh RDTs fr detectin f

parasite antigen are generally mre expensive, their deplyment may be cnsiderably cst

effective in many f these settings. The sensitivities and specificities f RDTs are variable,

and their vulnerability t high temperatures and humidity is an imprtant cnstraint.Despite these cncerns, RDTs make it pssible t expand the use f cnfirmatry

diagnsis. Practical experience and peratinal evidence f best practices frm large-scale

implementatin, thugh still limited, shuld guide wide-scale deplyment f RDTs n

a prgrammatic level.

In the diagnsis f severe malaria cases, micrscpy is a preferred ptin; it nt nly

prvides the diagnsis f malaria, but it is useful in assessing ther imprtant parameters

in a severely ill patient. In situatins where an RDT has been used t cnfirm malaria,

this allws fr a rapid institutin f antimalarial treatment, hwever, where pssible amicrscpic examinatin is recmmended t enhance the verall management f the

patient.

6.3 Wh w-- /

Parasitlgical cnfirmatin f the diagnsis f malaria is strngly recmmended. This

shuld be prvided by high quality micrscpy r, where this is nt available, by RDTs.

Lw-t-mderate transmissin settings6 include mst areas utside Africa. In Africa,this includes many urban areas that have effective malaria cntrl prgrammes; during

the lw-transmissin seasn, it includes areas with seasnal malaria.

In settings where malaria incidence is very lw, parasitlgical diagnsis fr all fever

cases may lead t cnsiderable expenditure t detect nly a few patients wh are actually

suffering frm malaria. In such settings, health wrkers shuld be trained t identify

patients that may have been expsed t malaria (e.g. recent travel t a malaria endemic

area, r lack f effective preventive measures) and have symptms that may be attributable

t malaria befre they cnduct a parasitlgical test.

6 Transmission intensity is conventionally expressed in terms of EIR (see Section 2). There is as yet no consensuson criteria for determining the thresholds between high- and low-to-moderate transmission settings. Suggestedcriteria include: the proportion of all children under 5 years of age with patent parasitaemia, and the incidenceof individuals with the spleen palpable below the umbilicus in children aged 29 years. The IMCI guidelinesrecommend that areas in which fewer than 5% of young children with fever have malaria parasitaemia should beconsidered as low-transmission settings.

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6.4 i hgh- g

Parasitlgical cnfirmatin f the diagnsis f malaria prvided by high-qualitymicrscpy r, where this is nt available, by RDTs is recmmended fr all suspected

cases f malaria. High-transmissin settings include mst areas in sme parts f Oceania

and sub-Saharan Africa. In these settings, slide psitivity rate in children under five years

f age with fever is mre than 5%.

A parasitlgical cnfirmatin f malaria in stable high-transmissin settings is

recmmended; it imprves the differential diagnsis f fever, imprves fever case

management, and reduces unnecessary use f antimalarial medicines. Antimalarial

treatment n the basis f clinical suspicin f malaria shuld nly be cnsidered insituatins where a parasitlgical diagnsis is nt accessible. This cnsideratin is f high

significance particularly in vulnerable ppulatins (e.g. children under five years f age,

pregnant wmen, suspected severe malaria cases, and in settings with a high prevalence f

HIV/AIDS where the patients present with fever r a histry f fever and n ther bvius

cause f the fever is present) in whm the disease can rapidly becme fatal.

6.5 m

In areas where tw r mre species f malaria parasites are cmmn, nly the

parasitlgical methd will permit a species diagnsis. Where mn-infectin with

P. vivaxis cmmn and micrscpy is nt available, it is recmmended that a cmbinatin

RDT, which cntains a pan-malarial antigen, is used. Where P. vivax, P. malariae r

P. ovale ccur, almst always as a c-infectin with P. falciparum, an RDT detecting

P. falciparum alne may be sufficient; the treatment fr nn-falciparum malaria is given

nly t cases with a negative test result and where n ther bvius cause f illness is

present. Anti-relapse treatment with primaquine shuld nly be given t cases with

cnfirmed diagnsis fP. vivaxr P. ovale malaria, and in the absence f cntraindicatins

such as glucse-6-phsphate dehydrgenase (G6PD) deficiency.

6.6 i g

In epidemic and cmplex emergency situatins, facilities fr parasitlgical diagnsis may

be unavailable r inadequate t cpe with the case-lad. In such circumstances, it may

be impractical and unnecessary t demnstrate parasites befre treatment in all cases ffever (see details in Sectin 11.1).



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7. Treatment of uncomplicated P. fa l c iparum malar ia

13

box 6.1

Summary of recom mendati ons o n parasitoloGical diaGnosis

p g , rdt, .

t h h wh gg .

7. treatment of uncomplicated P. falciParummalaria

T cunter the threat f resistance fP. falciparum t mntherapies, and t imprve

treatment utcme, WHO recmmends that artemisinin-based cmbinatin therapies

be used fr the treatment f uncmplicated P. falciparum malaria (see als Annex 7).

Althugh the evidence base cnfirming the benefits f artemisinin-based cmbinatins

has grwn substantially in recent years, there is still substantial gegraphic variability in

the efficacy f available ACT ptins, underlining the imprtance f cuntries regularlymnitring the efficacy f the ACTs in use t ensure that the apprpriate ACT ptin(s)

is being deplyed.

7.1 d

Uncmplicated malaria is defined as symptmatic malaria withut signs f severity r

evidence (clinical r labratry) f vital rgan dysfunctin. The signs and symptms funcmplicated malaria are nnspecific. Malaria is, therefre, suspected clinically mstly

n the basis f fever r a histry f fever.

7.2 r h

Antimalarial cmbinatin therapy is the simultaneus use f tw r mre bld

schizntcidal medicines with independent mdes f actin and, thus, different

bichemical targets in the parasite. The ratinale is twfld: i) the cmbinatin is ftenmre effective; and ii) in the very rare event that a mutant parasite resistant t ne f the

medicines arises de novo during the curse f the infectin, this resistant parasite will be

killed by the ther antimalarial medicine. This mutual prtectin is thught t prevent r

t delay the emergence f resistance. T realize the tw advantages, the partner medicines

in a cmbinatin must independently be sufficiently efficacius in treating malaria.


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7.2.1 Non-atemisinin based combination theap

Nn-artemisinin based cmbinatin treatments include sulfadxine-pyrimethamine

plus chlrquine (SP+CQ) r amdiaquine (SP+AQ). The prevailing high levels fresistance t these medicines as mntherapy have cmprmised their efficacy even

in cmbinatins. There is n cnvincing evidence that chlrquine plus sulfadxine-

pyrimethamine prvides any additinal benefit ver SP, s this cmbinatin is nt

recmmended; amdiaquine plus sulfadxine-pyrimethamine can be mre effective than

either drug alne; but it is usually inferir t ACTs, and it is n lnger recmmended fr

the treatment f malaria.

box 7.1

recommendation: withdrawal of non-ACTs for treatment of uncomplicated falciparum malaria

a- h h q

-h h P. p .

Strong recommendation, moderate quality evidence

GraDE eton (see Annex 7, tables A7.1.1A7.1.4)

In trials comparing AQ+SP to the recommended ACTs, the performance of AQ+SP is highly variable.

Treatment failure rates at day 28 (after polymerase chain reaction [PCR] adjustment) are as high as 16%in Uganda and 24% in Rwanda. In addition, AQ+SP is less effective at reducing gametocyte carriage than

combinations containing an artemisinin derivative. AQ+SP performed adequately in trials from Senegal in

2003, Burkina Faso in 2005, and Madagascar in 2006.

Othe ondeton

The panels view is that the continued spread of amodiaquine and sulfadoxine-pyrimethamine resistance

is likely to reduce the effectiveness of this combination in most African countries and, thus, their use as

partners in ACT combinations.

7.2.2 Atemisinin-based combination theap

These are cmbinatins in which ne f the cmpnents is artemisinin and its derivatives

(artesunate, artemether, dihydrartemisinin). The artemisinins prduce rapid clearance

f parasitaemia and rapid reslutin f symptms, by reducing parasite numbers 100- t

1000-fld per asexual cycle f the parasite (a factr f apprximately 10 000 in each 48-h

asexual cycle), which is mre than the ther currently available antimalarials achieve.Because artemisinin and its derivatives are eliminated rapidly, when given alne r in

cmbinatin with rapidly eliminated cmpunds (tetracyclines, clindamycin), a 7-day

curse f treatment with an artemisinin cmpund is required (see Annex 3 fr details).

This lng duratin f treatment with the artemisinins can be reduced t 3 days when given



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in cmbinatin with slwly eliminated antimalarials. With this shrter 3-day curse, the

cmplete clearance f all parasites is dependent n the partner medicine being effective and

persisting at parasiticidal cncentratins until all the infecting parasites have been killed.Thus, the partner cmpunds need t be relatively slwly eliminated. This als results in

the artemisinin cmpnent being prtected frm resistance by the partner medicine, while

the partner medicine is als partly prtected by the artemisinin derivative.

An additinal advantage frm a public health perspective is the ability f the artemisinins

t reduce gametcyte carriage and, thus, the transmissibility f malaria. This cntributes

t malaria cntrl, particularly in areas f lw-t-mderate endemicity.

T eliminate at least 90% f the parasitaemia, a 3-day curse f the artemisinin is required

t cver up t three pst-treatment asexual cycles f the parasite. This ensures that nlyabut 10% f the parasitamia is present fr clearance by the partner medicine, thus reducing

the ptential fr develpment f resistance. Shrter curses f 12 days f the artemisinin

cmpnent f the ACTs wuld lead t a larger prprtin f parasitaemia fr clearance by

the partner medicine; this is nt recmmended fr the fllwing additinal reasns:

they are less efficacius (except when the partner drug is highly effective),

they have less f an effect n gametcyte carriage,

they prvide less prtectin f the slwly eliminated partner antimalarial.

b 7.2

recommendation: duration of artemisinin component in combination treatment of uncomplicatedP. falciparum malaria

act h 3 wh .

Strong recommendation, high quality evidence

GraDE eton (see Annex 7, Table A7.2.1)In trials comparing the addition of 3 days of artesunate to sulfadoxine-pyrimethamine with adding 1 day

of artesunate, there was a significant reduction in treatment failure at day 28 with the 3-day combination

(5 trials, 1634 participants; relative risk [RR] 0.62, 95% confidence interval [CI] 0.550.69).

7.3 act

Althugh there are sme minr differences in ral absrptin and biavailabilitybetween the different artemisinin derivatives, there is n evidence that these differences

are clinically significant in currently available frmulatins. It is the prperties f the

partner medicine that determine the efficacy and chice f cmbinatin. Resistance t

the artemisinins partner medicines cmprmises the efficacy f the ACT.


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In additin t the fur ACT cmbinatins artemether plus lumefantrine (AL), artesunate

plus amdiaquine (AS+AQ), artesunate plus meflquine (AS+MQ), and artesunate

plus sulfadxine-pyrimethamine (AS+SP) already recmmended fr the treatmentf uncmplicated P. falciparum malaria there is nw sufficient evidence n safety and

efficacy f dihydrartemsinin plus piperaquine (DHA+PPQ) fr its additin t the list

f ACTs ptins recmmended fr the treatment f uncmplicated falciparum malaria

(see Annex 7, Sectin A7.1).

box 7.3

recommendation: DHA+PPQ as a first-line treatment for uncomplicatedP. falciparum malaria

dHa+ppQ act - P. p

ww.Strong recommendation, high quality evidence

GraDE eton (see Annex 7, tables A7.3.1A7.3.3)

In clinical trials directly comparing DHA+PPQ and the currently recommended ACTs, DHA+PPQ was at

least as effective at treating uncomplicated P. falciparum malaria (as measured by PCR adjusted treatment

failure) as:

artesunate plus mefloquine in Asia (day 63, 3 trials, 1182 participants; RR 0.39, 95% CI 0.190.79;

high quality evidence); artemether plus lumefantrine worldwide (day 42, 4 trials, 1492 participants; RR 0.42, 95% CI 0.260.67;

high quality evidence);

artesunate plus amodiaquine worldwide (day 28, 2 trials, 679 participants; RR 0.47, 95% CI 0.230.94;

moderate quality evidence).

Othe ondeton

At the time of publication, no DHA+PPQ product has been prequalified by WHO or registered by any

stringent medicine regulatory authority.

In summary, the ACT options now recommended for treatment of uncomplicated

falciparum malaria in alphabetical order are:

artemether plus lumefantrine,

artesunate plus amodiaquine,

artesunate plus mefloquine,

artesunate plus sulfadoxine-pyrimethamine,7

dihydroartemisinin plus piperaquine.

7 A similar medicine with tablets containing 500 mg of sulfalene and 25 mg pyrimethamine is considered analternative to sulfadoxine-pyrimethamine.



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7.3.1 Deploment consideations affectin choice

Fixed-dse cmbinatin (FDC) frmulatins are strngly preferred and recmmended

ver blistered c-packaged r lse tablets cmbinatins t prmte adherence ttreatment and t reduce the ptential selective use f the medicines as mntherapy.

Fixed-dse cmbinatin frmulatins are nw available fr all recmmended ACTs, except

artesunate plus SP. Fixed-dse cmbinatins may cntribute t delaying artemisinin

resistance as they avid artemisinin mntherapies being distributed (as lse tablets

r in c-packaged blisters). As frmulating FDCs f ACTs is technically difficult, it is

essential that generic FDCs are shwn t have satisfactry ingredient cmpatibility,

stability, and similar absrptin rates and ral biavailability t the separate tablets r

benchmark reference FDCs.Resistance and tlerability t the partner medicines f artemisinins in ACTs may affect

chice. In many cuntries, artemether plus lumefantrine, artesunate plus meflquine r

dihydrartemisinin plus piperaquine may give the highest cure rates. The main reasn

fr restricting the use f AS+MQ in African children s far has been excessive vmiting

assciated with meflquine at the recmmended dse f 25 mg/kg. Hwever, a recent

study8 fund that in children weighing 1020 kg (mean age f the study ppulatin was

4.5 1.7 years) the tlerability f AS+MQ is as gd as with artemether-lumefrantrine.

The lw levels f resistance t AQ and SP in sme parts f Africa still makes artesunate plusamdiaquine r sulfadxine-pyrimethamine effective ptins. Hwever, amdiaquine

and sulfadxine-pyrimethamine remain widely available as mntherapies prviding

cntinued selectin pressure, and it is likely that resistance will cntinue t wrsen despite

the deplyment f crrespnding ACTs.

7.4 mg

Recurrence fP. falciparum malaria can be the result f a re-infectin, r a recrudescence

(i.e. failure). In an individual patient, it may nt be pssible t distinguish recrudescence

frm re-infectin, althugh if fever and parasitaemia fail t reslve r recur within tw

weeks f treatment then this is cnsidered a failure f treatment. Treatment failures

may result frm drug resistance, pr adherence r inadequate drug expsure (frm

under-dsing, vmiting r unusual pharmackinetic prperties in that individual) r

substandard medicines. It is imprtant t determine frm the patients histry whether

he r she vmited the previus treatment r did nt cmplete a full curse.

Wherever pssible, treatment failure must be cnfirmed parasitlgically preferably by

bld slide examinatin (as P. falciparum histidine-rich prtein-2 (PfHRP2)-based tests

8 Babacar Faye et.al. A Randomized trial of artesunate mefloquine versus artemether lumefantrine for the treatmentof uncomplicated Plasmodium falciparum malaria in Senegalese children. Am. J. Trop. Med. Hyg. 82(1), 2010,140-144.


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(usually n the secnd day) fllwed by 10 mg/kg ne day later, r as a daily dse f

8.3 mg/kg fr 3 days. (see Annex 3, Sectins A3.5, A3.6.3,)

7.5.4 Atesunate plus sulfadoxine-pimethamine

This is currently available as separate scred tablets cntaining 50 mg f artesunate and

tablets cntaining 500 mg f sulfadxine and 25 mg f pyrimethamine.9

Tpc s.A target dse f 4 mg/kg/day artesunate given nce a day fr 3 days

and a single administratin f 25/1.25 mg/kg sulfadxine-pyrimethamine n day 1, with

a therapeutic dse range between 210 mg/kg/day artesunate and 2570/1.253.5 mg/kg

sulfadxine-pyrimethamine.

This cmbinatin was sufficiently efficacius nly where 28-day cure rates with sulfadxine-

pyrimethamine alne exceeded 80%. Resistance is likely t wrsen with cntinued

widespread use f sulfadxine-pyrimethamine, sulfalene plus pyrimethamine and

ctrimxazle (trimethprim plus sulfamethxazle) (see Annex 3, sectins A3.3A3.4,

A3.6.3).

7.5.5 Dihdoatemisinin plus pipeaquine

This is currently available as a fixed-dse cmbinatin with tablets cntaining 40 mg fdihydrartemisinin and 320 mg f piperaquine.

Therapeutic dose. A target dse f 4 mg/kg/day dihydrartemisinin and 18 mg/kg/day

piperaquine nce a day fr 3 days, with a therapeutic dse range between 210 mg/kg/day

dihydrartemisinin and 1626 mg/kg/dse piperaquine (see Annex 3, Sectin A3.6.4).

7.5.6 Atesunate plus tetaccline o doxccline o clindamcin

There are n blister c-packaged frms f any f these cmbinatin ptins. These are

reserved fr very rare ccasins f treatment failures t the recmmended ACTs andin sme special grups, e.g. pregnant wmen failing ACT treatment. They are dsed

separately and shuld nly be used in a hspital setting.

Tpc s. Artesunate (2 mg/kg nce a day) plus tetracycline (4 mg/kg fur times

a day r dxycycline (3.5 mg/kg nce a day) r clindamycin (10 mg/kg twice a day). Any

f these cmbinatins shuld be given fr 7 days.

7.6 i h

Artemisinins shuld nt be used as mntherapy, as this will prmte resistance t this

critically imprtant class f antimalarials. Wherever pssible, artemisinins shuld be used

9 A similar medicine with tablets containing 500 mg of sulfalene and 25 mg of pyrimethamine is considered to beequivalent to SP.


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shuld be used if cre temperatures > 38.5 oC. Paracetaml (acetaminphen) 15 mg/kg

every 4 hurs is widely used; it is safe and well tlerated, given rally r as a suppsitry.

Ibuprfen (5 mg/kg) has been used successfully as an alternative in malaria and therchildhd fevers, althugh there is less experience with this cmpund. Acetylsalicylic

acid (aspirin) shuld nt be used in children because f the risks f Reyes syndrme.

7.7.3 Use of antiemetics

Vmiting is cmmn in acute malaria and may be severe. Antiemetics are widely used.

There have been n studies f their efficacy in patients with malaria, and n cmparisns

between different antiemetic cmpunds; there is n evidence that they are harmful

thugh they can mask severe malaria. Patients that vmit everything, including themedicines, shuld be managed as severe malaria (see Sectins 8.48.7).

7.7.4 Manaement of seizues

Generalized seizures are mre cmmn in children with P. falciparum malaria than in

thse with the ther malarias. This suggests an verlap between the cerebral pathlgy

resulting frm malaria and febrile cnvulsins. As seizures may be a prdrme f

cerebral malaria, patients with repeated seizures (mre than tw seizures within a

24 h perid) shuld be treated as fr severe malaria (see Sectins 8.48.7). If the seizure

is nging, the airway shuld be maintained and anticnvulsants given (parenteral r

rectal benzdiazepines r intramuscular paraldehyde). If it has stpped, the child shuld

be treated as indicated in Sectin 7.7.2, if cre temperature is abve 38.5 oC. There is n

evidence that prphylactic anticnvulsants are beneficial in therwise uncmplicated

malaria, and they are nt recmmended.

7.8 o g

Individual patients derive the maximum benefit frm ACTs, if they can access thesewithin 2448 hurs f the nset f malaria symptms. At a ppulatin level, their impact

in terms f reducing transmissin and delaying resistance depends n high cverage rates.

Thus, t ptimize the benefit f deplying ACTs, their deplyment shuld target the public

health delivery system, the private sectr and the cmmunity r husehld. It shuld

als ensure that there is n financial r physical barrier t universal access. The strategy

t secure full access (including hme-based management f malaria) must be based n

an analysis f the natinal and lcal health systems, and this may require legislative

change and regulatry apprval with additinal lcal adjustment based n prgrammemnitring and peratinal research. The disseminatin f natinal treatment guidelines

with clear recmmendatins, prductin and use f apprpriate infrmatin, educatin

and cmmunicatin materials, mnitring bth f the deplyment prcess, access and

cverage, and prvisin f adequately packaged (user-friendly) antimalarials are needed

t ptimize the benefits f prviding effective treatments widely.


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s h :

ACTb known to be effective in the country/region or artesunate plus clindamycin to be given for 7 days or

quinine plus clindamycin to be given for 7 days.Pharmacovigilance programmes need to be established to continually monitor safety of antimalarial

medicines in all trimesters, including inadvertent exposures in the early first trimester.

a. If clindamycin is unavailable or unaffordable, then the monotherapy should be given.b. With the exception of DHA+PPQ for which there is insufficient information in second and third trimesters of pregnancy to use as first-

line therapy.

7.9.2 Lactatin women

The amunts f antimalarials that enter breast milk and are cnsumed by the breastfeedinginfant are relatively small. Tetracycline is cntraindicated in breastfeeding mthers

because f its ptential effect n the infants bnes and teeth. Primaquine shuld nt

be used in nursing wmen, unless the breastfed infant has been determined nt t be

G6PD-deficient.

box 7.6

recommendation: treatment for lactating women with uncomplicated falciparum malaria

lg w h h (g act),

q .

7.9.3 Infants and oun childen

7.9.3.1 Choice of antimalarial drug

There are imprtant differences in the pharmackinetic parameters f many medicines

in yung children. Accurate dsing is particularly imprtant in infants. Despite this, nly

a few clinical studies have fcused specifically n this age range; this is partly because

f ethical cnsideratins relating t the recruitment f very yung children t clinical

trials, and it is als because f the difficulty f repeated bld sampling. In the majrity

f clinical studies, subgrup analysis is nt used t distinguish between infants and lder

children. As a result, the available evidence in yung infants (< 5 kg) is insufficient fr

cnfident recmmendatins fr any f the ACTs, t the extent that many f the drugscarry label restrictins that they shuld nt be used. Furthermre, dsing is ften difficult

where paediatric frmulatins are unavailable.

The artemisinin derivatives are safe and well tlerated by yung children, and s

the chice f ACT will be determined largely by the safety and tlerability f the



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partner drug. Sulfadxine-pyrimethamine shuld be avided in the first weeks f life

because it cmpetitively displaces bilirubin with the ptential t aggravate nenatal

hyperbilibinemia. Primaquine shuld als be avided in the first mnth and tetracyclinesavided thrughut infancy and in children < 8 years f age. With these exceptins there

is n evidence fr specific serius txicity fr any f the ther currently recmmended

antimalarial treatments in infancy.

Delay in treating P. falciparum malaria in infants and yung children may have fatal

cnsequences, particularly fr mre severe infectins. The uncertainties nted abve

shuld nt delay treatment with the mst effective drugs that are available, with attentin

t accurate dsing and ensuring the administered dse is retained, as infants are mre

likely t vmit r regurgitate antimalarial treatment than lder children r adults.Taste, vlume, cnsistency and gastrintestinal tlerability are imprtant determinants

f whether the child retains the treatment. Mthers ften need advice n techniques f

medicine administratin and the imprtance f administering the drug again if it is

regurgitated within an hur f administratin. Because deteriratin in infants can be

rapid, there shuld be a much lwer threshld fr the use f parenteral treatment.

7.9.3.2 Dosing

Althugh dsing based n bdy area is recmmended fr many drugs in yung children,fr the sake f simplicity, dsing f antimalarials has traditinally been based n

administering a standard dse per kg bdy weight fr all patients (including yung

children and infants); hwever, the dispsitin f many medicines are different frm

that f lder children and adults. The currently recmmended dses f lumefantrine,

piperaquine, sufladxine-pyrimethamine and chlrquine achieve substantially lwer

drug cncentratins in yung children than lder patients. Small studies did nt find

any effect f age n plasma cncentratins f amdiaquine r meflquine. Althugh the

absrptin and dispsitin f many drugs differ between infants and yung children,

there are very limited data n antimalarial pharmackinetics in the first year f life.

Fr the majrity f antimalarials, the lack f an infant frmulatin necessitates the

divisin f adult tablets; this leads t inaccurate dsing. There are nw paediatric

frmulatins and paediatric tablet strengths fr sme f the antimalarial medicines.

These have the ptential fr imprving the effectiveness and accuracy f ACT dsing in

yung children.

In situatins where it is nt pssible t give parenteral treatment, such as severely sick

infants that vmit antimalarial drug treatment repeatedly, r are t weak t swallw,artesunate shuld be given by the rectal rute prir t transfer t a facility where

parenteral treatment is pssible. Evidence frm recent studies demnstrates that in

situatins where parenteral medicatin is nt pssible, using a single dse f rectal

artesunate as pre-referral treatment reduces the risk f death r permanent disability

(as lng as this initial treatment is fllwed up with apprpriate parenteral antimalarial


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lg w

Lactating women should receive standard antimalarial treatment (including ACTs) except for dapsone,

primaquine and tetracyclines, which should be withheld during lactation.

i g h

ACTs for first-line treatment in infants and young children with attention to accurate dosing and ensuring

the administered dose is retained.

Referral to a health centre or hospital is indicated for young children who cannot swallow antimalarial

medicines reliably. If referral is expected to take more than 6 hours, pre-referral treatment with rectal

artesunate is indicated.

t g -

Uncomplicated falciparum malaria:

atovaquone plus proguanil,

artemether plus lumefantrine,

dihydroartemisinin plus piperaquine,

quinine plus doxycyclinec or clindamycin; all drugs to be given for 7 days.

Severe malaria:

the antimalarial treatment is the same as shown in Section 8.

a. If clindamycin is unavailable or unaffordable, then the monotherapy should be given.b. With the exception of DHA+PPQ for which there is insufficient information in second and third trimesters of pregnancy to

use as first-line therapy.c. Doxycycline should not be used in children under 8 years of age.

7.10 c-g

7.10.1 HIV infection

There is cnsiderable gegraphic verlap between malaria and HIV, resulting in substantial

numbers f individuals with c-infectin. Wrsening HIV-related immunsuppressin

may lead t mre severe manifestatins f malaria. In HIV-infected pregnant wmen,

the adverse effects f placental malaria n birth weight are increased. In stable endemic

areas, HIV-infected patients with partial immunity t malaria may suffer mre frequent

and higher density infectins; while in areas f unstable transmissin, HIV infectin is

assciated with an increased risk f severe malaria and malaria-related deaths. There islimited infrmatin at present n hw HIV infectin mdifies the therapeutic respnses t

ACTs r n interactins between antimalarial medicines and antiretrvirals. Early studies

with less effective regimens suggested that increasing HIV-related immunsuppressin

was assciated with decreased treatment respnse, increased parasite burdens and

reduced hst immunity. Bth f these are nw knwn t ccur with HIV infectin



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and are assciated with increased treatment failure rates. At the current time there is

insufficient infrmatin t mdify the general malaria treatment recmmendatins fr

patients with HIV/AIDS.Patients infected with HIV may be receiving ther medicatins, such as ctrimxazle

(trimethprim plus sulfamethxazle) as prphylaxis, fr pprtunistic infectins

and/r antiretrviral medicines. There is limited infrmatin n drug interactins

between antiretrviral therapies with ACTs. In ne study, treatment f uncmplicated

malaria with artesunate plus amdiaquine was highly effective in bth HIV-infected

and HIV-uninfected children. Imprtantly, hwever, there was a significant 78-fld

increased risk f neutrpenia 14 days after initiatin f treatment amng HIV-infected

children cmpared t uninfected children. Abut ne fifth f the episdes in the HIV-infected grup were severe r life threatening. Amng the HIV-infected children, the

risk f neutrpenia was significantly higher amng thse n antiretrviral regimens

cntaining zidvudine. Hepattxicity has been dcumented when efavirenz was given

tgether with artesunate plus amdiaquine. Given this limited but wrrying infrmatin,

treatment f malaria in HIV-infected patients receiving zidvudine r efavirenz shuld,

if pssible, avid amdiaquine-cntaining ACT regimens. Althugh HIV-infectin and

ctrimxazle may als depress neutphil cunts, there is insufficient infrmatin n

the interactin f amdiaquine cntaining ACT regimens with ctrimxazle r HIV

infectin t make recmmendatins.

box 7.10

recommendations: treatment for HIV-infected patients with uncomplicatedP. falciparum malaria

p wh Hiv wh h ,

g h h g.

t wh -h h

g Hiv- g z (h hz)

h.

t Hiv- z z h, ,

q-g act g.

7.10.2 Sevee malnutition

Malaria and malnutritin frequently cexist. There are nly a few studies f antimalarial

drug dispsitin in peple with malnutritin, althugh many antimalarial drug efficacy

studies have been cnducted in ppulatins and settings where malnutritin was prevalent

(see Annex 3, Sectin A3.15.2).


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8. Treatment of severe P. fa l c iparum malar ia

35

8. treatment of severe P. falciParummalaria

8.1 d

In a patient with P. falciparum asexual parasitaemia and n ther bvius cause f

symptms, the presence f ne r mre f the fllwing clinical r labratry features

classifies the patient as suffering frm severe malaria (see also Annex 8):13

Clinical features:

impaired cnsciusness r unrusable cma prstratin, i.e. generalized weakness s that the patient is unable walk

r sit up withut assistance

failure t feed

multiple cnvulsins mre than tw episdes in 24 h

deep breathing, respiratry distress (acidtic breathing)

circulatry cllapse r shck, systlic bld pressure < 70 mm Hg in adults

and < 50 mm Hg in children

clinical jaundice plus evidence f ther vital rgan dysfunctin

haemglbinuria

abnrmal spntaneus bleeding

pulmnary edema (radilgical)

Laboratory findings:

hypglycaemia (bld glucse < 2.2 mml/l r < 40 mg/dl)

metablic acidsis (plasma bicarbnate < 15 mml/l) severe nrmcytic anaemia (Hb < 5 g/dl, packed cell vlume < 15%)

haemglbinuria

hyperparasitaemia (> 2%/100 000/l in lw intensity transmissin areas r > 5%

r 250 000/l in areas f high stable malaria transmissin intensity)

hyperlactataemia (lactate > 5 mml/l)

renal impairment (serum creatinine > 265 ml/l).

13Full details of the definition and prognostic factors are provided in: World Health Organization. Severe falciparummalaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000:94(Suppl. 1):190, andManagement of severe malaria: a practical handbook, 2nd ed. Geneva, World Health Organization, 2000.


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with signs of meningeal irritation (neck stiffness, photophobia or Kernig sign), but the

patient may be opistotonic. As untreated bacterial meningitis is almost invariably fatal, a

diagnostic lumbar puncture should be performed to exclude this condition. There is alsoconsiderable clinical overlap between septicaemia, pneumonia and severe malaria and

these conditions may coexist. In malaria endemic areas, particularly where parasitaemia

is common in the young age group, it is often impossible to rule out septicaemia in a

shocked or severely ill obtunded child. Where possible, blood should always be taken on

admission for culture and, if there is any doubt about the diagnosis, empirical antibiotic

treatment should be started immediately along with antimalarial treatment.

8.4 Spf r r

It is essential that effective, parenteral (or rectal) antimalarial treatment in full doses is

given promptly in severe malaria. Two classes of medicines are available for the parenteral

treatment of severe malaria: the cinchona alkaloids (quinine and quinidine) and the

artemisinin derivatives (artesunate, artemether and artemotil). Parenteral chloroquine

is no longer recommended for the treatment of severe malaria, because of widespread

resistance. Intramuscular sulfadoxine-pyrimethamine is also not recommended.

8.4.1 Artemisinin derivatives

Various artemisinin derivatives have been used in the treatment of severe malaria,

including artemether, artemisinin, artemotil and artesunate. Randomized trials

comparing artesunate and quinine from South-East Asia show clear evidence of benefit

with artesunate. In a multi-centre trial, which enrolled 1461 patients (including 202

children < 15 years old), mortality was reduced by 34.7% in the artesunate group when

compared to the quinine group. The results of this and smaller trials are consistent and

suggest that artesunate is the treatment of choice for adults with severe malaria.Until recently there was insufficient evidence to make a similar recommendation in

children, from high transmission settings, so the guidelines for this important patient

group did not recommend artesunate above treatment with either artemether or quinine.

This has now changed with the publication of the AQUAMAT trial*, a multi-centre

study conducted in African children hospitalized with severe malaria. This very large

randomized controlled trial, which enrolled 5425 children < 15 years of age across

Africa, showed a significant mortality reduction by 22.5% in the artesunate group when

compared to the quinine group. The incidence of convulsions, coma, and hypoglycaemiadeveloping after hospital was also significantly reduced. Importantly there was no

significant difference in the incidence of severe neurological sequelae.

8. Treatment of severe P. fa l c iparum malar ia

* Artesunate vs. quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label randomized trial. Lancet2010; 376: 164757


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it is recommended that patients be treated with the first dose of one of the recommended

treatments before referral (unless the referral time is less than 6 h). Recommended pre-

referral treatment options include intramuscular artesunate, artemether, or quinine, orrectal artesunate (see Annex 8, Section A8.5). Evidence from recent studies demonstrates

that in situations where parenteral medication is not possible and intramuscular injection

impractical, using a single dose of rectal artesunate as pre-referral treatment reduces the

risk of death or permanent disability in young children.

Box 8.2

Recommendation:pr e-referr al tr eatm en t for severe P. falciparum malaria

if p r fr sr r (s r S 8.4) s pssb,ps wh sr r sh b g pr-rfrr r rfrr y

pprpr fy fr frhr r.

The following are options for pre-referral treatment:

rectal artesunate quinineIM artesunateIM artemether IM.

In young children of less than 5 years of age, the use of rectal artesunate (10 mg/kg) has been shown

to reduce the risk of death and permanent disability.

8.6.1 Pre-referral and continued treatment with rectal artemisinins

The administration of an artemisinin derivative by the rectal route as pre-referral

treatment is feasible and acceptable even at the community level.

There is insufficient evidence to show whether rectal artesunate is as good as intravenous

or intramuscular options in the management of severe malaria. The recommendation,

therefore, is to use artesunate or artemisinin suppositories only as pre-referral treatment

and to refer the patient to a facility where complete parenteral treatment with artesunate,quinine or artemether can be instituted. If, however, referral is impossible, rectal

treatment should be continued until the patient can tolerate oral medication; at this

point, a full course of the recommended ACT for uncomplicated malaria in the locality

can be administered.

8.6.2 Dosing for antimalarials given by rectal route

8.6.2.1 Initial (pre-referral) treatment with rectal artesunate

The 10 mg/kg body weight single dose of artesunate suppository should be administered

rectally as soon as the presumptive diagnosis of severe malaria is made. In the event

that an artesunate suppository is expelled from the rectum within 30 min of insertion,

a second suppository should be inserted and, especially in young children, the buttocks

should be held together for 10 min to ensure retention of the rectal dose of artesunate.



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8.6.2.2 Artemether

Doses used have been variable and empiric: 1040 mg/kg body weight (at 0, 4 or 12, 24, 48 and

72 h). Some studies have given a maintenance dose of one to two thirds of the initial dose.

8.6.2.3 Quinine

Th

Guidelines for Treatment of Malaria

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