THE USE OF ANTIMALARIAL DRUGS
Report of an Informal Consultation
CONTENTS

Introduction

PART I - POLICY IMPLICATIONS

1. Current status of antimalarial drug resistance
   1.1 Development of resistance
   1.2 Assessment of antimalarial drug susceptibility
   1.3 Plasmodium falciparum resistance
   1.4 Plasmodium vivax resistance
   1.5 Regional responses to antimalarial drug resistance
2. Combination
   2.1 Definitions
   2.2 Rationale for the use of combination therapy
   2.3 Artemisinin-based combination therapy
   2.4 Implementation of combination therapy - operational issues
3. Chemoprophylaxis and treatment of malaria in special groups
   3.1 Chemoprophylaxis and intermittent treatment of malaria in pregnancy
   3.2 Chemoprophylaxis and stand-by treatment in travellers
   3.3 Management of severe malaria
   3.4 Vivax malaria
   3.5 Formulations for paediatric use
4. Antimalarial treatment policies
   4.1 Definition
   4.2 Purpose
   4.3 Development
   4.4 Factors influencing antimalarial treatment policies
   4.5 Health-seeking behaviour
   4.6 Criteria for changing treatment policy
   4.7 Process of changing treatment policy: country examples
   4.8 Implementation and access to antimalarial drugs in endemic countries
5. Conclusions and recommendations
   5.1 General
   5.2 Future research and other activities

PART II - ANTIMALARIAL DRUGS

1. Antimalarial drugs for malaria prevention and treatment
   Chloroquine
   Amodiaquine
   Antifolate drugs (sulfa drug-pyrimethamine combinations)
   Proguanil
   Mefloquine
   Quinine, quinidine and related alkaloids
   Halofantrine
   Artemisinin and its derivatives
   Primaquine
   Antibiotics used as antimalarial drugs
   Atovaquone-proguanil
   Chloroquine-proguanil
   Artemether-lumefantrine
   Mefloquine-sulfadoxine-pyrimethamine
2. Status and potential of combination therapies
   2.1 Past or present co-administered (non-fixed) combinations
   2.2 Combinations undergoing consideration or trial
   2.3 Potential combinations under consideration or trial with not yet available drugs

References

Annex 1. List of participants
Annex 2. Guidance on the selection of drugs for national antimalarial treatment policies
Annex 3. Common antimalarial drugs that should be considered in drug selection

 

THE USE OF ANTIMALARIAL DRUGS

ABBREVIATIONS

ACR    adequate clinical response
ACT    artemisinin-based combination therapy
AIDS    acquired immunodeficiency syndrome
AQ    amodiaquine
ART    artemisinin
ASU    artesunate
AT    atovaquone
ATM    artemether
AUC    area under curve (time-concentration)
Cmax    maximum plasma concentration
CD    clindamycin
CNS    Central Nervous System
CQ    chloroquine
CT    combination therapy
D    doxycycline
DHFR    dihydrofolate reductase
DHPS    dihydropteroate synthetase
EANMAT    East African Network for Monitoring Antimalarial Treatments
ETF    early treatment failure
GI    Gastro-intestinal   G6PD    glucose-6-phosphate dehydrogenase
HAL    halofantrine
HIV    human immunodeficiency virus
HPLC-ECD    high-performance liquid chromatography-electron capture detection
LTF    late treatment failure
LUM    lumefantrine
MQ    mefloquine
P. falciparum    Plasmodium falciparum
P. ovale    Plasmodium ovale
P. malariae    Plasmodium malariae
P. vivax    Plasmodium vivax

PAHO    Pan American Health Organization
PQ    primaquine
Q    quinine
RDT    rapid diagnostic test
SP    sulfadoxine-pyrimethamine
T    tetracycline
WHO    World Health Organization

 

INTRODUCTION

The WHO Informal Consultation on the Use of Antimalarial Drugs was held from 13 to 17 November 2000 in Geneva, Switzerland. The participants reflected a broad range of expertise in the development and use of antimalarial drugs, and in the implementation and adaptation of antimalarial treatment policies (see Annex 1 for List of participants).

Early diagnosis and prompt treatment are fundamental components of the WHO global strategy for malaria control (1). Correct use of an effective antimalarial drug will not only shorten the duration of malaria illness but also reduce the incidence of complications and the risk of death. Antimalarial drug resistance has spread and intensified over the last 15-20 years (2-4), however, leading to a dramatic decline in the efficacy of the most affordable antimalarial drugs. Development of new drugs is not keeping pace (5), and problems related to the distribution and use of these drugs have compounded the situation. In many malarious areas, a majority of the population does not have ready access to antimalarial drugs and to reliable and consistent information about malaria treatment and prevention (6). Moreover, those drugs that are available are frequently obtained from informal sources and may be counterfeit; they are of variable quality, may be partially or completely ineffective against local parasite strains, and are often used in inappropriate dosages (7).

Many endemic countries are beginning to face a situation in which there are no affordable, effective antimalarial drugs available. Combination therapy offers hope for preserving the efficacy of antimalarial drugs and prolonging their useful therapeutic life (8-11), although it may not necessarily provide better treatment for consumers. The development of artemisinin and its derivatives--the most rapidly acting of all the current antimalarial drugs--and recognition of their potential role as a component of combination therapy (8, 9, 12, 13) have led to several large trials aimed at assessing different combinations of existing drugs, and to the specific development of new combination drugs. In addition, several countries have felt the need to evaluate, as potential first-line treatments, drug combinations that do not include artemisinin. These changes have provided an impetus for updating and rationalizing antimalarial treatment policies.

National antimalarial treatment policies are essential to provide countries with a framework for the safe and effective treatment of uncomplicated and severe malaria as well as for the prevention of malaria in travellers and in vulnerable groups, such as pregnant women and young children. As a general principle, such policies should aim at the greatest possible reduction of malaria mortality and morbidity, while containing the development of resistance and remaining compatible with limited national health budgets and health care infrastructures. All health care providers in both the public and private health sectors must be aware of, understand the rationale for, and implement the national policy. Such national policies should be updated to take account of the development of antimalarial drug resistance in the country. A framework for this purpose has been developed for use in Africa (14).

The treatment of severe malaria is covered comprehensively in the Transactions of the Royal Society of Tropical Medicine and Hygiene supplement Severe falciparum malaria (15). The use of antimalarial drugs for chemoprophylaxis and the prevention and treatment of uncomplicated malaria was last reviewed at a WHO informal consultation in September 1995 (16), which also considered diagnosis and the principles of clinical management. Since then, considerable additional experience has been gained in the use of existing and new antimalarial drugs, alone and in combination.

In view of the new evidence available on malaria prevention and treatment and on the further spread of resistance to antimalarial drugs, WHO considered it timely to convene an informal consultation to:

The informal consultation took the form of presentations of prepared papers, followed by discussions during which specific conclusions and recommendations were agreed. The proceedings of the consultation and the working papers form the basis of this report.

The report is aimed at managers of national malaria control programmes and those involved in implementing antimalarial treatment policies. Part I provides information on the current status of antimalarial resistance throughout the world, considers the potential for combination therapy, updates recommendations on the prevention and treatment of malaria in specific target groups, and outlines the development and implementation of an antimalarial treatment policy. Part II describes the antimalarial drugs and recommended regimens in current use for malaria prevention and for the treatment of uncomplicated malaria. It also covers antimalarial drugs under development. The report also presents options for different treatment scenarios according to specific epidemiological situations. Individual countries will need to adapt the recommendations made in this report to their own epidemiological and health care context.

The Use of Antimalarial Drugs: Table of Contents