GTMcover-production.pdf 11.1.2006 7:10:05 GUIDELINES FOR THE TREATMENT O F M A L A R I A GUIDELINES FOR THE TREATMENT OF MALARIA Guidelines for the treatment of malaria Guidelines for the treatment of malaria WHO Library Cataloguing-in-Publication Data Guidelines for the treatment of malaria/World Health Organization. Running title: WHO guidelines for the treatment of malaria. 1. Malaria – drug therapy. 2. Malaria – diagnosis. 3. Antimalarials – administration and dosage. 4. Drug therapy, Combination. 5. Guidelines. I. Title. II. Title: WHO guidelines for the treatment of malaria. ISBN 92 4 154694 8 (NLM classification: WC 770) ISBN 978 92 4 154694 2 WHO/HTM/MAL/2006.1108 © World Health Organization, 2006 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 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either express or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication. For technical information, please contact: Dr P. Olumese Global Malaria Programme World Health Organization 20, avenue Appia – CH-1211 Geneva 27 Tel. +41 22 791 4424 Fax +41 22 791 4824 E-mail: [email protected] Printed in Switzerland Design: B. Duret – Cover: T. Cailler ii Contents Glossary v Abbreviations viii 1. Introduction 1 1.1 Background 1 1.2 Objectives and target audience 2 1.3 Methods used in developing the guidelines and recommendations 3 2. The clinical disease 5 3. Treatment objectives 7 3.1 Uncomplicated malaria 7 3.2 Severe malaria 7 4. Diagnosis of malaria 8 4.1 Clinical diagnosis 8 4.2 Parasitological diagnosis 9 4.3 Where malaria transmission is low–moderate and/or unstable 10 4.4 In stable high-transmission settings 10 4.5 Malaria parasite species identification 11 4.6 In epidemics and complex emergencies 11 5. Resistance to antimalarial medicines 12 5.1 Impact of resistance 12 5.2 Global distribution of resistance 12 5.3 Assessing resistance 13 6. Antimalarial treatment policy 14 6.1 Assessment of in vivo therapeutic efficacy 14 6.2 Criteria for antimalarial treatment policy change 15 7. Treatment of uncomplicated P. falciparum malaria 16 7.1 Assessment 16 7.2 Antimalarial combination therapy 16 7.3 The choice of artemisinin based combination therapy options 20 7.4 Practical aspects of treatment with recommended ACTs 23 7.5 Incorrect approaches to treatment 26 7.6 Additional aspects of clinical management 27 7.7 Operational issues in treatment management 29 7.8 Management of treatment failures 31 7.9 Treatment in specific populations and situations 32 7.10 Coexisting morbidities 38 iii Guidelines for the treatment of malaria 8. Treatment of severe falciparum malaria 41 8.1 Definition 41 8.2 Treatment objectives 41 8.3 Clinical assessment 42 8.4 Specific antimalarial treatment 42 8.5 Practical aspects of treatment 47 8.6 Follow-on treatment 48 8.7 Pre-referral treatment options 49 8.8 Adjunctive treatment 51 8.9 Continuing supportive care 53 8.10 Additional aspects of clinical management 54 8.11 Treatment during pregnancy 58 8.12 Management in epidemic situations 59 8.13 Hyperparasitaemia 60 9. Treatment of malaria caused by P. vivax, P. ovale or P. malariae 62 9.1 Diagnosis 62 9.2 Susceptibility of P. vivax, P. ovale and P. malariae to antimalarials 63 9.3 Treatment of uncomplicated vivax malaria 63 9.4 Treatment of severe vivax malaria 66 9.5 Treatment of malaria caused by P. ovale and P. malariae 66 9.6 Monitoring therapeutic efficacy for vivax malaria 66 10. Mixed malaria infections 68 11. Complex emergencies and epidemics 69 11.1 Diagnosis 69 11.2 Use of rapid diagnostic tests in epidemic situations 69 11.3 Management of uncomplicated malaria in epidemics 70 11.4 Areas prone to mixed falciparum/vivax malaria epidemics 70 11.5 Use of gametocytocidal drugs to reduce transmission 71 11.6 Anti-relapse therapy in vivax malaria epidemics 71 11.7 Mass treatment 71 Annexes Annex 1. The guidelines development process 77 Annex 2. Adaptation of WHO malaria treatment guidelines for use in countries 83 Annex 3. Pharmacology of antimalarial drugs 87 Annex 4. Antimalarials and malaria transmission 133 Annex 5. Malaria diagnosis 147 Annex 6. Resistance to antimalarials 155 Annex 7. Uncomplicated P. falciparum malaria 185 Annex 8. Malaria treatment and HIV/AIDS 198 Annex 9. Treatment of severe P. falciparum malaria 207 Annex 10. Treatment of P. vivax, P. ovale and P. malariae infections 225 Index 240 iv Glossary GLOSSARY Artemisinin-based combination therapy (ACT). A combination of artemisinin or one if its derivatives with an antimalarial or antimalarials of a different class. Asexual cycle. The life-cycle of the malaria parasite in host red blood cells (intra- erythrocytic development) from merozoite invasion to schizont rupture (merozoite → ring stage → trophozoite → schizont → merozoites). Duration approximately 48 h in Plasmodium falciparum, P. ovale and P. vivax;72h in P. malariae. Asexual parasitaemia. The presence in host red blood cells of asexual para- sites. The level 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, the number of parasites seen in one microscopic field in a high-power examination of a thick blood film, or the number of parasites seen per 200–1000 white blood cells in a high-power examination of a thick blood film. Cerebral malaria. Severe falciparum malaria with coma (Glasgow coma scale <11, Blantyre coma scale <3). Malaria with coma persisting for >30 min after a seizure is considered to be cerebral malaria. Combination treatment (CT). A combination of two or more different classes of antimalarial medicines with unrelated mechanisms of action. Cure. Elimination of the symptoms and asexual blood stages of the malaria parasite that caused the patient or carer to seek treatment. Drug resistance. Reduced susceptibility of the causal agent to a drug. WHO defines resistance to antimalarials as the ability of a parasite strain to survive and/or multiply despite the administration and absorption of a medicine given in doses equal to – or higher than – those usually recommended but within the tolerance of the subject, with the caveat that the form of the drug active against the parasite must be able to gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action. Resistance to antimalarials arises because of 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, which are infective to the anopheline mosquito. v Guidelines for the treatment of malaria Hypnozoites. Persistent liver stages of P. vivax and P. ovale malaria that remain dormant in host hepatocytes for a fixed interval (3–45 weeks) before maturing to hepatic schizonts. These then burst and release merozoites, which infect red blood cells. Hypnozoites are the source of relapses. Malaria pigment (haemozoin). A dark brown granular pigment formed by malaria parasites as a by-product of haemoglobin catabolism. The pigment is evident in mature trophozoites and schizonts. Merozoites. Parasites released into the host bloodstream when a hepatic or erythrocytic schizont bursts. These then invade the red blood cells. Monotherapy. Antimalarial treatment with a single medicine (either a single active compound or a synergistic combination of two compounds with related mechanism of action). Plasmodium. A genus of protozoan vertebrate blood parasites that includes the causal agents of malaria. Plasmodium falciparum, P. malariae, P. ovale and P. vivax cause malaria in humans. Pre-erythrocytic development. The life-cycle of the malaria parasite when it first enters the host. Following inoculation into a human by the female anopheline mosquito, sporozoites invade parenchyma cells in the host liver and multiply within the hepatocytes for 5–12 days, forming hepatic schizonts. These then burst liberating merozoites into the bloodstream, which subse- quently invade red blood cells. Radical cure. In P. vivax and P. ovale infections only, this comprises cure as defined above plus prevention of relapses. Rapid diagnostic test (RDT). An antigen-based stick, cassette or card test for malaria in which a coloured line indicates that plasmodial antigens have been detected. Recrudescence. The recurrence of asexual parasitaemia after treatment of the infection with the same infection that caused the original illness (in endemic areas now defined by molecular genotyping).