/malaria by Global Health Council

Reducing Malaria’s Burden Evidence of Effectiveness for Decision Makers

TECHNICAL REPORT — DECEMBER 2003

Malaria’s Challenge: Saving Lives By Applying Existing Knowledge Malaria in Children and Pregnant Women Indoor Residual Spraying and Insecticide-Treated Nets The Role of Artemisinin-based Combination Therapy in Malaria Management Challenges in Monitoring the Impact of Interventions against Malaria Using Diagnostics Effective Delivery Methods for Malaria Treatment

Global Health Council

Global Health Council Published by Global Health Council 1701 K Street, NW - Suite 600 Washington, DC 20006 Tel: (202) 833-5900 Fax: (202) 833-0075

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Editors: Colleen Murphy, Karin Ringheim, Sara Woldehanna — Global Health Council Jimmy Volmink — University of Cape Town

Cover photo by D.N. Baraskar

Reducing Malaria’s Burden Evidence of Effectiveness for Decision Makers TABLE

CONTENTS

Acronyms and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Foreword, Jeffrey D. Sachs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Malaria’s Challenge: Saving Lives by Applying Existing Knowledge . . . . . . . . . . . . . 4 Colleen Murphy, Jimmy Volmink and Sara Woldehanna Malaria in Children and Pregnant Women . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Martin Meremikwu Indoor Residual Spraying and Insecticide-Treated Nets . . . . . . . . . . . . . . . . . . . 17 Christian Lengeler and Brian Sharp The Role of Artemisinin-based Combination Therapy in Malaria Management . . . . . . 25 Karen Barnes and Peter Folb Challenges in Monitoring the Impact of Interventions Against Malaria Using Diagnostics . . . . . 33 Imelda Bates, James Iboro and Guy Barnish Effective Delivery Methods for Malaria Treatment . . . . . . . . . . . . . . . . . . . . . . 39 Kamini Mendes, Andrea Bosman, Peter Olumese, Pascal Ringwald, Clive Ondari and Wilson Were Conclusion: Abuja and Beyond . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Mary Ettling Afterword: Malaria’s Unfinished Agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Nils Daulaire Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Acronyms and Abbreviations ACT - artemisinin-based combination therapy; or antimalarial combination therapy AM/LUM - artemether + lumefantrine (coartemether) AQ - amodiaquine ART - artesunate AS - artemisinin CHPS - community-based health planning and services

LLIN - long-lasting insecticidal nets MQ - mefloquine n - number NGO - non-governmental organization OR - odds ratio P. falciparum - Plasmodium falciparum P. malariae - Plasmodium malariae P. ovale - Plasmodium ovale

CI - confidence interval

P. vivax - Plasmodium vivax

CQ - chloroquine

PCR - polymerase chain reaction

DALY - disability-adjusted life year

PCV - packed cell volume

DDT - dichlorodiphenyltrichloroethane

PE - protective efficacy

EIR - entomological inoculation rate

PQ - primaquine

ELISA - enzyme-linked immunosorbent assay

PY - person-year

GFATM - Global Fund to Fight AIDS, Tuberculosis and Malaria

Q - quinine

HBM - home-based management

QT - quinine + tetracycline

HIV/AIDS - human immunodeficiency virus/acquired immunodeficiency syndrome

RBM - Roll Back Malaria

HMIS - health management information systems IEC - information education and communication IFA - indirect fluorescent antibody IHA - indirect haemagglutination antibody IMCI - Integrated Management of Childhood Illness

QD - quinidine + doxycycline

RCT - randomized controlled trial RDT - rapid diagnostic test RR - relative risk; rate ratio SMA - severe malaria anemia SP - sulfadoxine-pyrimethamine SWAps - sector-wide approaches UNICEF - United Nations Childrenâ&#x20AC;&#x2122;s Fund

IPT - intermittent preventive or presumptive treatment

USAID - United States Agency

IRS - indoor residual insecticide (house) spraying

WHO - World Health Organization

ITN - insecticide-treated (mosquito) nets

for International Development

Foreword JEFFREY D. SACHS THE EARTH INSTITUTE AT COLUMBIA UNIVERSITY The two most important tasks in restoring sustained economic growth in Africa are not economic policies but rather the control of AIDS and malaria. Without the control of these two diseases, there is little prospect of attracting foreign investment, upgrading technology, building a tourist sector, and raising educational attainments, not to mention saving productive lives. While the AIDS pandemic is new and disastrous, the burden of malaria is ancient. Malaria has arguably been the greatest shackle on Africa's economic development throughout modern history, and the same is true of other highly malarious regions. As this valuable Global Health Council technical report makes amply clear, we have the means to reduce the burden of malaria dramatically, through greatly scaled-up investments in both prevention and treatment.

Malaria control presents a paradox. On the one hand, the situation is worsening in many regions of Africa and some regions of Asia, as a result of rising drug resistance, economic disarray, conflict, and increasing impoverishment. On the other hand, several prevention and treatment interventions are both powerful and relatively inexpensive, and yet reach only a small proportion of the population in need. The paradox is explained, of course, by the fact that malaria itself has rendered the affected regions so impoverished that even low-cost interventions cannot be sustainably financed from national resources alone. Donor assistance, on a much larger scale than has been provided in recent years, will be necessary. Perhaps US$2–$3 billion per year will be needed for extensive malaria control throughout sub-Saharan Africa — a sum that is too large for impoverished African countries to bear, but a modest sum indeed for the rich world, equaling just US$2–$3 dollars per person per year in the donor countries. For such a modest sum, a substantial reduction in malaria morbidity and mortality could be achieved and sustained.

Reducing Malaria’s Burden: Evidence of Effectiveness for Decision Makers provides powerful guidance on how to proceed with a greatly scaled up effort to curtail the deadly impact of malaria. The report carefully documents the lessons on efficacy of a large number of interventions, including bed nets, indoor residual spraying, new combination drugs, intermittent presumptive treatment, and other protocols. With greater attention from the donor world, increased funding should become available in the coming years, through powerful new efforts such as the Global Fund to Fight AIDS, TB and Malaria. As malaria control is thereby scaled up, policy makers and practitioners throughout the world will find this report to be enormously useful in planning and implementing a new and bold attack against this ancient and costly scourge.

Malaria’s Challenge: Saving Lives By Applying Existing Knowledge 1

COLLEEN MURPHY , JIMMY VOLMINK , SARA WOLDEHANNA

GLOBAL HEALTH COUNCIL UNIVERSITY OF CAPE TOWN, SOUTH AFRICA 1

INTRODUCTION Malaria is a leading cause of mortality and morbidity worldwide, especially for pregnant women and children and particularly in sub-Saharan Africa where at least 90% of malaria deaths occur.1 Transmitted from person to person through the bite of a female Anopheles mosquito, malaria kills an estimated one to two million children each year and causes disease in a further 300 to 500 million individuals.2 These figures may significantly underestimate malaria’s true toll since the impact of malaria is greatest in areas where surveillance systems are weak. As a result of emerging drug resistance, climate and environmental change, collapsing health systems and the compounding effects of other infectious diseases, malaria remains a serious health concern for much of the world. Like many other diseases, malaria disproportionately affects people living in poverty — specifically those who are most marginalized.3 Although more people die from malaria today than 40 years ago,4 the last decade has seen a renewed commitment to basic as well as clinical and operational research to prevent and treat malaria. The mapping of the malaria genome is expected to accelerate vaccine development and contribute to the discovery of new drugs to replace those such as chloroquine, which have become ineffective.5,6 However promising, these developments are most likely to be years from materializing and interventions may be prohibitively expensive for countries most affected by the epidemic. Until such advances become a reality, it is important to identify and use existing therapies and strategies that are effective. This report draws attention to the evidence base for current approaches while recognizing knowledge gaps and practical challenges for those working to implement malaria programs in the field.

ASSESSING

THE EFFECTS OF INTERVENTIONS

The World Health Organization (WHO) identifies three key factors that collectively contribute to the burden of infectious diseases: insufficient knowledge of the disease, inadequate or non-existent tools, and the failure to use existing tools effectively.7 Effective anti-malarial drugs have been available for decades. There is a greater understanding 4

of how the disease is transmitted and a demonstrated ability to track epidemics. Yet, despite the effective means at our disposal, millions still face sickness and death from malaria, illustrating a failure to use existing tools and knowledge effectively. By fully implementing what we know today, more lives can be saved and the health of millions can be improved. As large-scale malaria control initiatives such as those established by the Roll Back Malaria partnership are expanded, it is crucial to implement interventions that are effective and safe in endemic areas. Evidence-based practices for controlling malaria rely on the consistent application of results from appropriate research. Randomized trials and, in particular, systematic reviews of randomized trials rank high in the evidence hierarchy for assessing effectiveness8 (see Figure 1) and, therefore, receive emphasis in this report where appropriate. These study designs are less prone to bias than other types of research and, therefore, provide reliable evidence on the effects of an intervention. Randomized trials are particularly important for detecting modest but important health benefits. Systematic reviews employ a strict and transparent scientific methodology to assemble, appraise and synthesize the results of all relevant studies that have addressed a particular research question. Since they look comprehensively at all relevant evidence that addresses a particular question, they are increasingly recognised as a useful decision-making tool in health care. The value of systematic reviews can be illustrated by the following example concerning amodiaquine use. Amodiaquine (AQ) has been widely used for malaria, most notably in Africa where resistance to chloroquine is high. However, nearly 20 years ago, fatal adverse drug reactions were reported among travellers using AQ as prophylaxis.10,11 As a result, the WHO discontinued using the drug in malaria control programs and removed it from its Essential Drugs List. The manufacturer withdrew prophylaxis as a drug indication.12 Subsequently, several countries banned AQ while some continued to use the drug for treatment. The ensuing confusion called for a careful analysis of the existing and available evidence. In the mid-1990s, a systematic review of published and unpublished data assessed the effects of AQ for treating malaria and found it to be safe and effective.13 As a result of this “new” evidence, WHO modified its

FIGURE 1. LEVELS OF EVIDENCE

Highest grade

Lowest grade

FOR

ASSESSING EFFECTIVENESS

■

I-1. Evidence obtained from systematic reviews/meta-analyses of all relevant randomized controlled trials.

■

I-2. Evidence obtained from at least one properly randomized controlled trial.

■

II-1. Evidence obtained from well-designed controlled trials without randomization.

■

II-2. Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

■

II-3. Evidence obtained from multiple time series with or without the intervention (including dramatic results in uncontrolled experiments).

■

III. Opinions of respected authorities, based on clinical experience, descriptive studies and case reports or reports of expert committees.

recommendations and reinstated AQ as a treatment option for falciparum malaria but deferred including it on its Essential Drugs List. A second systematic review concluded that AQ treatment was not associated with a greater risk of adverse events. These and other data provided the evidence to support reinstatement of AQ on the WHO’s core Essential Drugs List in 2003.14,15 With resistance to other first-line therapeutics on the rise, AQ in combination with other antimalarials can once again play a significant role as an inexpensive and effective treatment for uncomplicated malaria. The contributions in this report use the best available evidence to assess current guidelines, recommendations and practices in malaria control. In some cases the evidence base is still limited or unclear.Where there are knowledge gaps we would like to challenge researchers to focus future research endeavors where better evidence is needed in order to make better decisions possible.

THE CURRENT KNOWLEDGE BASE In this report, authors explore the current knowledge concerning malaria prevention, treatment, diagnostics and delivery programs and strategies. They also focus attention on vulnerable groups, particularly children and pregnant women who are at greater risk of malaria infection, illness and death. A chapter by Martin Meremikwu is devoted to this latter issue, highlighted in the Africa Malaria Day 2003 slogan, ‘Roll Back Malaria, Protect Women and Children!’ He focuses on WHO’s guidelines for treating young children and pregnant women and discusses the strength of evidence on the benefits and limitations of these recommendations. He also highlights the urgent operational challenges and research gaps that must be addressed.

As for most infectious diseases, primary prevention is a key component of worldwide malaria strategies. Both insecticide-treated bed nets (ITNs) and indoor residual spraying (IRS) prevent an infected mosquito from biting its human host and limit the lifecycle of the vector. Christian Lengeler and Brian Sharp examine the efficacy and impact of these two important interventions as well as the complex implementation issues of their wide-scale deployment in resourcepoor communities. While seeking to evaluate each approach

FIGURE 2. ROLLING BACK MALARIA — WORLD HEALTH ORGANIZATION’S 4 POINT STRATEGY Prompt access to treatment, especially for young children

■

Prevention and control in pregnant women

■ Vector ■

control

Prediction and containment of epidemics

in light of the evidence base, they underscore that an “either/or” approach to vector control may only be appropriate where local constraints hamper wide implementation of both strategies. Treatment regimens, already complex due to the existence of different strains of the parasite, are being severely challenged by the growing resistance to existing synthetic anti-malarials. Artemisinin, from the ancient Chinese herbal 5

remedy qinghaosum, and its derivatives, are today’s most promising treatment options. Artemisinin in combination with existing first line therapies is thought to ensure rapid cure, retard drug resistance, and reduce malaria incidence in low transmission areas. Karen Barnes and Peter Folb report on the status of artemisinin and related research. Well-designed studies provide critical scientific information for making informed decisions about which interventions are most effective. However, once programs are brought to scale, monitoring their effectiveness is often prohibitively expensive and difficult. Imelda Bates, James Iboro and Guy Barnish evaluate the benefits and limitations of commonly used malaria diagnostic methods (ranging from presumptive clinical diagnosis to rapid diagnostic tests) that can be used to assess the malaria status of individuals and thus monitor the effectiveness of interventions at the community, district/regional and central laboratory level. Importantly, this chapter does not aim to prescribe methods, but gives a balanced analysis of commonly used diagnostic procedures while keeping in mind the significant barriers faced within malaria-endemic communities.

Poverty snatched away my wife from me. When she got sick, I tried my best to cure her with tebel [holy water] and woukabi [spirits], for these were the only things a poor person could afford. However, God took her away. My son, too, was killed by malaria. Now I am alone. — An old man, Ethiopia from Dying for Change: Poor people's experience of health and ill health. WHO and the World Bank. 2002. ognize the context and realities of the disease: malaria’s toll is greatest among those who are least equipped to fight it, especially children and pregnant women in rural, peri-urban or displaced, poor communities. Treatment and prevention are only part of a comprehensive strategy that must include increased resource allocation and political commitment. This report cannot capture the human suffering associated with malaria. It does not focus on how poverty creates ill health, and how ill health contributes to poverty. Poverty disenfranchises individuals and communities, robbing them of voice and power to improve their situation. A chief concern among the many women and men interviewed for the World Bank’s poverty report series was their lack of involvement in decision-making about their own health care. “Poor people are angry and frustrated at their exclusion.They understand why they are ill and why they are poor, and often have ideas about what can be done. But the majority are ignored and marginalized by those with power, including health service authorities.”16

Drug efficacy is irrelevant to the millions of people at risk who do not have access to effective treatment and accurate knowledge of how best to use it. Kamini Mendis and her colleagues explore the channels (both private and public) available to ensure early and effective delivery of antimalarial treatment. Even communities that have access to formal health care services may be faced with a myriad of challenges, including limited uptake of services and poor disease management training. The Roll Back Malaria program works to integrate malaria treatment into other programs as well as to strengthen these health systems to improve diagnosis, disease management, drug procurement and referral services. The authors …Difficulties started in March, when their five-year-old also fittingly address the need for removing barriers, daughter, Grace, had a serious bout of malaria. Given lack of such as poor patient-provider communication, high money, their first recourse was with local herbs. Unfortunately, drug costs, complicated therapeutic regimens and the little girl’s condition did not improve. The family borrowed limited community involvement. For remote comsome money and bought a few tablets of chloroquine and munities with limited access to the formal health aspirin from the local shop. care sector, the evidence for other approaches such as “Home Management of Malaria” is discussed. After some improvement, the girl’s health sharply deteriorated Finally, Mary Ettling discusses the commitments made at the African Summit on Roll Back Malaria held in Abuja in 2000. At this meeting, 19 African heads of state,WHO, UNICEF, the World Bank and other partners set clear goals and objectives to reduce the toll of malaria by 2005 through appropriate and sustainable actions to strengthen country health systems.

MALARIA’S HUMAN FACE While this report emphasizes the importance of applying effective biomedical interventions, we rec6

two weeks later. By the beginning of May, Grace had become very weak. Her parents then sold some chickens for Shs. 2,500 and, with the help of neighbors, took her to Ngora Hospital where she was immediately admitted. She was seriously anemic and required urgent blood transfusion. However, the family was asked to pay Shs. 5,000 that they did not have. They went back home to try and look for money. It was too late. She died on 8 May and was buried the following day. — Uganda 1998 from Voices of the Poor: Can anyone hear us? World Bank 2000.

Among diseases, malaria especially is exacerbated by societal inequities and affects those that are already powerless. It causes grave physical suffering, retarded physical and cognitive development in children, loss of productivity, depression and increased vulnerability to other diseases. Thus malaria perpetuates the vicious cycle of illness and poverty. Likewise, the growing number of people who live in areas of conflict or natural disaster as refugees face the greatest threat of malaria with little or no access to medical facilities. Gender inequalities may lead to bed nets being used only by men, leaving children and women unprotected. Effective antimalarial drugs, while inexpensive by Western standards, are commonly not available or are beyond the reach of those who live on an equivalent of US$2 a day.

It is heartening that a considerable number of public-private partnerships have recently been formed to address the burden of malaria. International organizations, pharmaceutical companies, research centers, foundations, community-based groups and national governments are now working in greater concert. This technical report features authors from among these diverse stakeholders. As these groups may attest, the interpretation of research, the vital step in bringing knowledge to practice, is subject to differing viewpoints and may result in misunderstandings and misperceptions. Informed decision-making is a complex, delicate and fluid process that brings together a wealth of knowledge, expertise and interests. Moreover, decision-makers often have different constituencies, expertise, scope and interests.

It is imperative that actions address the entrenched health and social inequities that are pervasive worldwide.While mosquitoes may thrive in swamps and ponds, malaria finds fertile breeding grounds in poverty and inequity. Through adequate funding of scientifically sound programs and interventions, and investment in local research and development, the health advances experienced in developed countries can become a reality in communities currently afflicted by malaria.

Through Reducing Malaria’s Burden: Evidence of Effectiveness for Decision Makers our aim is to:

DECISION MAKERS’ VITAL ROLE Public health professionals in collaboration with concerned organizations and individuals can play a crucial role in the fight against malaria. While promoting the use of evidencebased policies and practices in malaria control, we can work towards a greater understanding of the complex set of factors that perpetuate the malaria epidemic as well as advocate for increased resources to address them. REFERENCES 1 World

Health Organization/UNICEF. The Africa malaria report 2003. WHO/CDS/MAL/2003. 2 The World

Bank. Malaria at a glance. 2001.

■

Build and diversify partnerships;

■

Understand and harness scientific and ideological friction;

■

Promote the role of science in decision-making;

■ Assist

policy makers in putting evidence into context.

Lastly, these chapters are designed to complement rather than replace existing knowledge and experience. People's needs and priorities, availability of resources and applicability of evidence are and should remain of paramount importance. Essentially, we hope that this technical report facilitates “globalizing the evidence and localizing the decision.”17

11 Hatton

C, Peto T, Bunch C, Pasvol G, Russel S, Singer C, et al. Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet 1986;1:411-3. 12 World Health Organization. Practical chemotherapy of malaria.WHO technical report series 1990;805.

3 Sachs J, Malaney P. The economic and social burden of malaria. Nature 2002; 415(6872):680-5.

13 Olliaro P, Mussano P.Amodiaquine for treating malaria (Cochrane Review). In:The Cochrane Library, Issue 3, 2003. Oxford: Update Software.

4 Guerin PJ, Olliaro P, Nosten F, Druilhe P, Laxminarayan R, Binka F, Kilama WL, Ford N,White NJ. Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development. Lancet Infect Dis 2002; 2(9):564-73.

14 MacLehose H, Klaes D, Garner P. Amodiaquine:A systematic review of adverse events.Available at www.who.int/medicines/organization/par/edl/ expcom13/Amodiaquine-adv-events.pdf.

Frankish H. Scientists reach milestone in malaria research. The Lancet 2002; 360 (9339), 1075. 6 Whitty

CJ, Rowland M, Sanderson F, Mutabingwa TK. Malaria. BMJ 2002; 325(7374):1221-4. 7 World Health Organization.Ad hoc committee on health research relating future intervention options. Investing in health research and development. TDR/Gen/96.1. 1996. Geneva, Switzerland. 8 Adapted from US Preventive Services Task Force. Guide to clinical preventive services, 2nd ed.Williams and Wilkins, Baltimore and National Health Medical Research Council. Guidelines for the development and implementation of clinical guidelines, 1st ed. Australian Government Publishing Service, Canberra. 9

Ibid.

10 Neftel K,Woodly W, Schmidt R, Frich P, Fehr J.Amodiaquine induced agranulocytosis and liver damage. British Medical Journal 1986;292:721-3.

15 World Health Organization.The 13th model list of essential medicines. 2003. 16 World Health Organization and the World Bank. Dying for change: Poor people's experience of health and ill health.The Voices of the poor study. Geneva:WHO. 2002. 17 Eisenberg JA. Globalize the evidence, localize the decision: Evidencebased medicine and international diversity. Health Affairs 2002; 21(3), 166-168.

CONTRIBUTORS: Colleen Murphy, Sr. Research Associate, Research and Analysis Department, Global Health Council; cmurphy@globalhealth.org Jimmy Volmink, Professor and Chair of Primary Health Care, Faculty of Health Sciences, University of Cape Town; jvolmink@cormack.uct.ac.za Sara Woldehanna, Sr. Research Associate, Research and Analysis Department, Global Health Council; swoldehanna@globalhealth.org Global Health Council Web site: www.globalhealth.org University of Cape Town Web site: www.uct.ac.za

Malaria in Children and Pregnant Women MARTIN MEREMIKWU UNIVERSITY OF CALABAR, NIGERIA

BACKGROUND Introduction Malaria kills an estimated one million people in Africa every year; nearly all deaths are attributable to Plasmodium falciparum infection, transmitted by the bite of an infected mosquito. More than 75% of these deaths occur in children under five.1 Malaria illness may be simple (uncomplicated) or severe (complicated), with severe malaria often leading to death or serious sequelae. In areas where malaria is endemic, those exposed acquire some immunity to malaria following several infections and subsequent episodes of the disease for these individuals are generally of the less severe form.

Severe illness and death from malaria in children Young children lack natural immunity to malaria and are, therefore, more likely to develop severe and complicated malaria. Cerebral malaria (malaria associated with repeated convulsions and unconsciousness) and severe malaria anaemia (SMA) are the most common complications of severe malaria and are the leading causes of malaria deaths in children. Cerebral malaria kills 10-50% of affected children even with treatment. Long-term neurological complications such as paralysis, impaired learning and epilepsy occur in 10-17% of survivors. One-quarter of these sequelae persist beyond six months and impair intellectual capability and development.2 Children with SMA who have respiratory distress are at high risk of dying and many do unless they receive prompt blood transfusion.3 Rural African communities frequently lack adequate blood transfusion services necessary to prevent otherwise avoidable deaths from malarial anaemia. Shortage of personnel and inadequate facilities for screening donor blood for infectious agents can also increase the risk of HIV and hepatitis B or C transmission. In this way, malaria may contribute indirectly to the epidemic of HIV/AIDS in African children.

Consequences of malaria in pregnant women Physiological changes that occur during pregnancy reduce the body’s defences against malaria. Consequently, malaria is a more severe disease in pregnant women than in non-pregnant adults living in endemic areas.4 Severe anaemia in pregnancy 8

is a major cause of maternal mortality in Africa. Although its causes include a multiplicity of factors including iron and folate deficiencies, hookworm infestation and HIV infections, malaria is the predominant cause of anaemia in pregnant women in endemic communities.5 It is estimated that in Africa, 400,000 pregnant women each year develop severe anaemia due to malaria, resulting in 10,000 maternal deaths.6 Plasmodium falciparum infection in pregnant women is also a leading contributor to babies being born with low birth weight.2

Interventions for malaria in children and pregnant women Malaria control programmes promote specific interventions that protect pregnant women and children from infection and minimise harm if they become ill with malaria. The Roll Back Malaria (RBM) initiative as well as other programs recommend the following interventions for treatment and prevention of malaria in these vulnerable groups: ■ Effective first-line drug treatment of uncomplicated malaria; ■ Intermittent preventive treatment (IPT) or chemoprophylaxis to reduce the consequences of malaria in pregnancy; ■ Insecticide-treated mosquito nets (ITNs). The scientific evidence for the effectiveness of these strategies is explored below.

ROLE

OF EVIDENCE

Effective first-line treatment of uncomplicated malaria The emergence and spread of Plasmodium falciparum resistance to common antimalarial drugs (particularly chloroquine (CQ) and sulfadoxine-pyrimethamine (SP)) pose a great threat to effective treatment of malaria in most parts of subSaharan Africa and southeast Asia where malaria is endemic. An informal consultation of the world’s leading malaria experts convened by the World Health Organization (WHO) produced guidelines for the best antimalarial drug use in various areas and situations.These recommendations take into account the varying availability of resources and patterns of parasite resistance to common antimalarial drugs in given scenarios.7

Scenarios A and B are representative of most endemic areas of tropical Africa, while Scenario D applies to countries in southeast Asia. (see Box 1) As these scenarios serve only as a general guide, policy decisions for malaria treatment should be informed by additional data on local malaria epidemiology and the therapeutic efficacy of antimalarial drugs.

BOX 1. WHO GUIDANCE ON SELECTION OF DRUGS FOR NATIONAL ANITMALARIAL TREATMENT POLICIES: SCENARIOS AND SETTINGS SCENARIO A: A country where chloroquine is the first-line treatment, but levels of resistance are high and resistance developed quickly to sulfadoxine-pyrimethamine (SP) in neighbouring countries when it was introduced as first-line treatment.

Drug options for treating malaria in young SCENARIO B: A country where data suggest that chloroquine children and pregnant women, based on the (CQ) and sulfadoxine-pyrimethamine (SP) are ineffective. recommendations of the WHO expert consultation, are presented for the four scenarios and are SCENARIO C: A new refugee camp where several non-governmental followed by a critical appraisal of the strength of organizations (NGOs) are operating. evidence on benefits and harms. The purpose of critical appraisal is to determine the validity of SCENARIO D: A country in Asia with multi-drug resistance to research taking into account the robustness of design, methods, analysis and interpretation of the Plasmodium falciparum. results. In the appraisal of research evidence on the effects of recommended treatment options, only trials that used randomised controlled designs or areas of sub-Saharan Africa where there is a high incidence systematic reviews of such trials have been selected. of parasite resistance to chloroquine and rising resistance to For appraisal of data on adverse drug effects, sulfadoxine-pyrimethamine. Combination therapies that case-control, cohort and other observational include artemisinin derivatives are preferred for being highly studies have also been considered. effective and also eliminating gametocytes (the sexual forms responsible for transmission of the parasite). However, given the economic constraints of malaria endemic communities Antimalarial drugs for treating in Africa, these communities will not be able to afford more costly artemisinin-based combinations without international young children aid.With these economic restrictions, cheaper and less effecTable 1 below shows the drugs recommended by the WHO tive options are recommended as interim measures pending expert consultation for treating malaria in children. the availability of adequate funds. Scenarios A and B represent the situation in many endemic

TABLE 1. WHO RECOMMENDED DRUG OPTIONS FOR TREATING UNCOMPLICATED MALARIA IN CHILDREN AGED < 5 YEARS SCENARIO

ANTIMALARIAL DRUG OPTIONS Under current constraints If increased funding is available

SCENARIO A

■ Chloroquine + sulfadoxinepyrimethamine

SCENARIO B

■ ■

■

SCENARIO C

■ ■ ■

SCENARIO D

Amodiaquine (where amodiaquine resistance < 5%) Amodiaquine + sulfadoxinepyrimethamine (where amodiaquine resistance > 5%) Amodiaquine + artesunate (where there is sulfadoxine-pyrimethamine resistance)

■

Artesunate + sulfadoxine-pyrimethamine Artesunate + amodiaquine With laboratory: treat P. vivax with chloroquine

■

Mefloquine + primaquine ■ Sulfadoxine-pyrimethamine + chloroquine ■ Chloroquine + primaquine ■

■

■ ■

Artesunate + sulfadoxine-pyrimethamine Amodiaquine + artemisinin derivative co-packed Sulfadoxine-pyrimethamine + artesunate co-packed Artemether + lumefantrine (coartemether)*

Amodiaquine + artemisinin derivative co-packed ■ Sulfadoxine-pyrimethamine + artesunate co-packed ■ Artemether + lumefantrine (coartemether)* ■ ■ ■

Artesunate + sulfadoxine-pyrimethamine Artesunate + mefloquine Artemether + lumefantrine (coartemether)*

*More data required on effectiveness of artemether + lumefantrine (coartemether) for treating uncomplicated malaria in young children.

Infections by P.vivax, the dominant parasite in Asia, remain highly sensitive to treatment with chloroquine despite widespread resistance of P.falciparum infections to the same drug. This explains why chloroquine is recommended in Scenario D.

Table 2 shows the available research evidence on the effectiveness and safety of various options for treating uncomplicated malaria in children. The reader should interpret each row of

options in the light of available evidence.While the best level of evidence of drug effectiveness is that supported by a systematic review of randomized controlled trials (RCTs), single RCTs also provide reliable evidence on effectiveness especially when the sample is of adequate size and most of the randomized participants (> 90%) have been accounted for in the analysis of the primary outcome measure of effectiveness. Absence of or inadequate evidence does not mean lack of effect but indicates the need for more research.

TABLE 2. APPRAISAL OF SCIENTIFIC EVIDENCE ON EFFECTS OF DRUGS RECOMMENDED FOR TREATING CHILDREN WITH UNCOMPLICATED MALARIA

Drug treatment options

Strength of scientific evidence

Amodiaquine alone

Benefit: One systematic review of 56 randomised controlled trials (RCTs) showed that amodiaquine is more effective than chloroquine.8 Harm: ■ Systematic review of RCTs and observational studies showed no severe adverse events for treating uncomplicated malaria with amodiaquine. ■

Chloroquine + sulfadoxine-pyrimethamine Amodiaquine + sulfadoxine-pyrimethamine

Quinine + sulfadoxine-pyrimethamine

Mefloquine + primaquine

Benefit: 9 ■ One systematic review of seven RCTs showed that these combinations are effective. Combination relieved symptoms faster than either component of the combination. Harm: ■ This systematic review did not detect increase in the risk of adverse events compared with single use of component drugs. Benefit: ■ No systematic review found. Two RCTs — one from Thailand and one from Brazil — showed good cure rates that were comparable to other regimens in use at the time in each country.10,11 Harm: ■ Only mild and transient adverse events were reported. No severe adverse events reported with this combination. Benefit: ■ No systematic review found on this combination. One RCT of Thai children showed that adding primaquine to mefloquine + sulfadoxine-pyrimethamine did not demonstrate an increased cure but reduced gametocyte carriage.12 Harm: ■ No severe adverse events were reported in this small Thai study. Comment: ■ Risk of intravascular haemolysis (which may lead to anaemia) with use of primaquine is known to be higher in people with G-6-PD enzyme deficiency, a condition common in tropical Africa. Treatment with primaquine should be avoided in places where this risk is high (i.e., West Africa).

Drug treatment options

Strength of scientific evidence

Artesunate + mefloquine

Benefit: ■ One systematic review including 41 RCTs evaluating artemisinin derivatives for treating uncomplicated malaria showed that artesunate + meflo quine achieved high cure rates and lower gametocyte carriage.13 ■ This systematic review included a small, inadequately-powered RCT on artesunate+sulfadoxine-pyrimethamine combination. ■ Published protocol for a large independent patient data (IPD) metaanalysis of artemisinin-based combinations found; results of complete review to be released shortly.14 ■ One large RCT of artesunate+ amodiaquine combination compared with amodiaquine alone showed better effectiveness and reduced gametocyte carriage.15 Harm: ■ Systematic review and RCTs above showed no increase in severe adverse events with any of these combination treatment options.

Artesunate + sulfadoxinepyrimethamine Artesunate + amodiaquine

Artemether + lumefantrine (coartemether)*

Benefit: ■ One systematic review of six RCTs showed that the 4-dose regimen was superior to chloroquine in areas with high chloroquine resistance, but inferior to other regimens tested. The 6-dose regimen has only been tested in two small studies in Thailand, one in adults, and one in children and adults combined.16 Harm: ■ No severe adverse events reported.

* More data are required on effectiveness of artemether + lumefantrine (coartemether) for treating uncomplicated malaria in young children.

Antimalarial drugs for treating pregnant women Table 3 illustrates drug treatment options recommended for malaria in pregnancy, while Table 4 outlines the available evidence on their effectiveness and safety.

Combination treatment options are recommended but there is very limited evidence available on the effectiveness of these drugs in pregnant women. Safety data from observational studies and a few RCTs reported no severe adverse drug effect in the mother or baby.

TABLE 3. WHO RECOMMENDED DRUG OPTIONS FOR TREATING MALARIA IN PREGNANT WOMEN

ANTIMALARIAL DRUG OPTIONS Scenario

Under current constraints

Scenario A

Chloroquine + sulfadoxinepyrimethamine

Scenario B

If increased funding is available

■

■ Quinine + sulfadoxinepyrimethamine after 1st trimester ■ Amodiaquine + sulfadoxinepyrimethamine (or artesunate + sulfadoxine-pyrimethamine where there is amodiaquine resistance)

■

Artesunate + sulfadoxine-pyrimethamine

First-line: quinine + sulfadoxine pyrimethamine ■ Second-line: sulfadoxine-pyrimethamine + artesunate

First-line: quinine + sulfadoxinepyrimethamine ■ Second-line: sulfadoxine-pyrimethamine + artesunate

Scenario C

■

Quinine + sulfadoxine-pyrimethamine after 1st trimester ■ Amodiaquine + sulfadoxinepyrimethamine (or artesunate + sulfadoxine-pyrimethamine where there is amodiaquine resistance)

■

Scenario D

■

Quinine + sulfadoxinepyrimethamine or mefloquine in 2nd and 3rd trimesters

■

Quinine + sulfadoxine-pyrimethamine or mefloquine in 2nd and 3rd trimesters

TABLE 4. APPRAISAL OF SCIENTIFIC EVIDENCE ON EFFECTS OF ANTIMALARIAL DRUGS RECOMMENDED FOR TREATING PREGNANT WOMEN

Drug treatment options Sulfadoxine-pyrimethamine + (chloroquine, amodiaquine or quinine)

Mefloquine

Artesunate + (amodiaquine, sulfadoxine-pyrimethamine or mefloquine)

Strength of scientific evidence Benefit: ■ No systematic review on treatment of malaria in pregnancy was found. ■ One RCT showed that artesunate + mefloquine in second or third trimester achieved higher day-63 cures rates (98%) than quinine (67%); and less gametocyte carriage.17 ■ No adequately powered RCT was found on the other drug combination options for treating uncomplicated malaria in pregnancy. Harm: First trimester: ■ Evidence on the safety of all recommended antimalarial drugs in the first trimester is lacking or, at best, still unclear. Second and third trimesters: ■ RCTs and observational studies showed no evidence that sulfadoxine-pyrimethamine and sulphonamides in the second and third trimesters increased the risk of kernicterus (high blood levels of the pigment bilirubin that is deposited in the brain resulting in damage).18 ■

Possible increase in risk of stillbirth with the use of mefloquine in pregnancy has been reported.19

A narrative overview that included studies of varied quality showed that the standard adult dose (not high dose) of antimalarial drugs recommended for pregnant women did not cause harm or congenital abnormalities.20

■

This overview reported that primaquine might increase the risk of intravascular haemolysis in fetus and infant.

■

Drugs given routinely for malaria in pregnancy Chloroquine, which is the most widely used drug for malaria prophylaxis for pregnant women, has become ineffective due to rising parasite resistance, poor compliance and the common occurance of pruritus (itching).21

The WHO recommends intermittent preventive treatment (IPT) as the most effective drug-based approach for preventing malaria in pregnancy.22 Sulfadoxine-pyrimethamine is currently the preferred antimalarial drug for IPT. Reliable evidence from a systematic review of RCTs (see Table 5) illustrates the effectiveness of this intervention.

TABLE 5. APPRAISAL OF SCIENTIFIC EVIDENCE ON EFFECTS OF DRUGS GIVEN ROUTINELY FOR MALARIA IN PREGNANCY

Drugs given routinely for malaria in pregnancy

Strength of scientific evidence

Intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine

Benefit: ■ One systematic review of 14 RCTs showed that giving drugs routinely in pregnancy — as prophylaxis or intermittent preventive therapy (administration of drug therapy in full treatment doses at predetermined intervals during pregnancy) — reduced the risk of the following consequences of malaria in the first two pregnancies:23 - Antenatal maternal severe anaemia - Antenatal maternal parasitaemia - Placental parasitaemia - Low birth weight - Perinatal mortality

Chemoprophylaxis

Harm: ■ No severe adverse events reported in systematic review. ■ No evidence that sulfadoxine-pyrimethamine or sulphonamides in the second and third trimesters increased the risk of kernicterus.24

Insecticide-treated nets for preventing malaria in children and pregnant women Insecticide-treated nets (ITNs) repel and kill mosquitoes. The World Health Organization recommends ITNs as the

key strategy for malaria control in young children and pregnant women. A systematic review of RCTs involving children (Table 6) showed that ITNs are effective. Limited data available on the use of ITNs in pregnancy also indicate that it is beneficial.

TABLE 6. APPRAISAL OF SCIENTIFIC EVIDENCE ON INSECTICIDE-TREATED NETS TO PREVENT MALARIA IN CHILDREN AND PREGNANT WOMEN

Target population

Strength of scientific evidence

Children:

Benefit: ■ One systematic review of RCTs showed that ITNs achieved a one-fifth reduction in death in three RCT involving 88,437 children under five.25 An estimated six lives were saved per 1,000 children protected with ITNs. ■ ITNs reduced incidence of mild malarial episodes by 48%. ■ The same systematic review showed that in one RCT including 23,035 participants the incidence of severe malaria morbidity was reduced by 45%. Harm: No evidence to show that ITNs cause any harm to users.

■

Pregnant women:

Benefit: ■ No systematic review of ITNs for malaria in pregnancy was found. A published protocol of a Cochrane systematic review was found.26 ■ One RCT (three study sites) showed that ITNs reduced the risk of maternal anaemia in all study sites, but reduced the incidence of malaria illness in pregnancy in only one of three study sites.27 ■ Another RCT showed no significant benefit of use of ITNs during pregnancy but reported low use of ITNs overall: 42% among women in their first pregnancy and 63% among those who had been pregnant more than once28 Harm: ■ No evidence in either trial that ITNs caused adverse effects during pregnancy or on infant development.

IMPLEMENTATION

AND

CHALLENGES

Monitoring parasite resistance to antimalarial drugs In many endemic communities, the emergence and spread of malaria parasites resistant to common antimalarial drugs like chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) pose a great problem to malaria control efforts.29 In such communities, treatment failures lead to high incidence of severe malaria and persistence of high death rates. There is a need to continually monitor drug efficacy and to build capacity for efficient monitoring of drug efficacy patterns in endemic areas. By doing so, new drug treatment policies based on the evidence could be implemented more quickly, thus preventing high treatment failure rates and deaths, especially among vulnerable groups such as pregnant women and young children.

Improving access to effective antimalarial drugs in resource-poor settings The recommended treatment options for uncomplicated malaria in children under five include primarily combination regimens (Table 1). Combination treatments are aimed at increasing cure rates and delaying development of parasite resistance to component drugs.30 For resourcepoor settings under scenarios representative of Africa, combinations of sulfadoxine-pyrimethamine (SP) with amodiaquine (AQ) and chloroquine (CQ) have been proposed. However, the spread of falciparum resistance to SP and CQ indicates that a combination of these two drugs would be ineffective in many African settings. Combination options that include artemisinin derivatives are more expensive and have been recommended for use

in situations where more funding is available. Scientific evidence on artemisinin-based combinations showed consistently high cure rates and low gametocyte carriage with potential for reducing transmission.31 However, high treatment costs of artemisinin-based combination regimens would make implementation very difficult in resource-poor settings such as in Africa. Many children who are at high risk of dying from malaria will not have access to these effective treatment regimens.

Safety of antimalarial drugs during pregnancy Lack of evidence on the safety of antimalarial drugs in early pregnancy makes treatment of malaria in pregnant women, especially with newer drugs, difficult. Spread of SP resistance in Africa means that its effectiveness in intermittent preventive treatment (IPT) in pregnant women would be compromised in some areas of Africa. The need to develop new drugs or evaluate existing drugs that could replace SP for intermittent preventive treatment in pregnancy in areas with high SP resistance must be considered a research priority.

Improving access and proper use of ITNs Delivering and maintaining use of ITNs by children and pregnant women has high operational and logistic costs. International aid should be effectively applied to provide subsidies for purchasing ITNs and to support effective delivery mechanisms. ITNs need to be periodically re-treated with insecticide. In addition to low coverage rate, low rates of re-treating ITNs pose a threat to effectiveness even in areas with high coverage (usage). Developing and sustaining strategies to increase re-treatment rates or increase availability of longer-lasting ITNs will increase the impact of ITNs in reducing mortality and morbidity among vulnerable groups.

R EFERENCES 1

Snow RW, Craig M, Deichmann U, Marsh K. Estimating mortality, morbidity, and disability due to malaria among Africaâ&#x20AC;&#x2122;s non-pregnant population. Bulletin of the World Health Organization 1999; 77: 624-640.

McGready R, Brockman A, Cho T, Cho D, van Vugt M, Luxemburger C, Chongsuphajaisiddhi T, White NJ, Nosten F. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multi-drug-resistant falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine & Hygiene 2000; 94(6): 689-93.

2 Murphy SC, Breman JG. Gaps in childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications in pregnancy. Am J Trop Med Hyg 2001; 64 (suppl. 1&2): 57-67.

18 Parise ME. Safety of sulfadoxine-pyrimethamine (SP) during pregnancy: what do the data show. MIM Conference Nov 20, 2002.

3 Marsh K, Forster D,Waruru C, et al. Indicators of life-threatening malaria in African children. New England Journal of Medicine 1995; 332: 13991404.

Steketee RW, Nahlen BL, Parise ME, Menendez C.The burden of malaria in pregnancy in malaria-endemic areas. Am J Trop Med Hyg 2001; 64(suppl. 1&2): 28-35. 5

Verhoeff FH, Brabin BJ, Chimsuku L, Kazembe P, Broadhead RL. An analysis of the determinants of anaemia in pregnant women in rural Malawi â&#x20AC;&#x201C; a basis for action. Ann Trop Med Parasitol 1999; 93: 119-133.

6 Guyatt HL, Snow RW. Epidemiology and burden of Plasmodium falciparum-related anemia among pregnant women in sub-Saharan Africa. Am J Trop Med Hyg 2001; 64 (Suppl. 1&2): 36-44. 7

World Health Organization. The use of antimalarial drugs. Report of a WHO informal consultation 13-17 November 2000. WHO/CDS/RBM/2001.33.

Op cit. 17.

Phillips-Howard PA, Wood D. The safety of antimalarial drugs in pregnancy. Drug Safety, 1996; 14(3): 131-145. 21 World Health Organization. Strategic framework for malaria control during pregnancy in the WHO Africa Region; November 2002; 1-35. 22 World Health Organization. WHO Expert Committee on Malaria, 20th Report.Technical Report Series No. 892 Geneva:WHO; 2000. 23

Garner P, Gulmezoglu AM. Drugs for preventing malaria-related illness in pregnant women and death in the newborn (Cochrane Review). In:The Cochrane Library, Issue 1, 2003. Oxford: Update Software.

Op cit. 18.

Lengeler C. Insecticide-treated bednets and curtains for preventing malaria (Cochrane Review). In: Cochrane Library, Issue 4, 2002. Oxford: Update Software. 26

Ekwaru JP, Preston C. Insecticide-treated nets for preventing malaria in pregnancy (Protocol for a Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software.

27 Dolan G, ter Kulie FO, Jacoutot V, White NJ, Luxemburger C, Malankiri L, Chongsuphajaisiddhi T, Nonsten F. Bed nets for the prevention of malaria and anaemia in pregnancy. Transactions of the Royal Society of Tropical Medicine & Hygiene 1993; 87(6): 620-6.

Olliaro P, Mussano P. Amodiaquine for treating malaria (Cochrane Review). In: The Cochrane Library, Issue 1, 2003. Oxford: Update Software. McIntosh HM. Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine for treating uncomplicated malaria (Cochrane Review). In The Cochrane Library, Issue 1, 2003. Oxford: Update Software. 10 de Souza JM, Sheth UK, de Oliveira RM, Roulet H, de Souza SD. An open, randomized, phase III clinical trial of mefloquine and of quinine plus sulfadoxine-pyrimethamine in the treatment of symptomatic falciparum malaria in Brazil. Bull World Health Organ. 1985;63(3):603-9. 11

Hall AP, Doberstyn EB, Karnchanachetanee C, et al. Sequential treatment with quinine and mefloquine or quinine and pyrimethamine-sulfadoxine for falciparum malaria. British Medical Journal 1977; 1: 1626-8. 12

28 Browne EN, Maude GH, Binka FN. The impact of insecticide-treated bednets on malaria and anaemia in pregnancy in Kassena-Nankana district, Ghana: a randomized controlled trial. Tropical Medicine & International Health 2001; 6(9): 667-76. 29 Bloland P, Ettling M. Making malaria-treatment policy in the face of drug resistance. Ann Trop Med Hyg 1999; 93: 5-23. 30

White NJ, Olliaro PL. Strategies for prevention of antimalarial drug resistance: rationale for combination chemotherapy for malaria. Parasitology Today 1996; 12: 399-401.

Singhasivanon V, Chongsuphajaisiddhi T, Sabchareon A, Attanath P, Webster HK, Edstein MD, Lika ID. Pharmacokinetic study of mefloquine in Thai children aged 5-12 years suffering from uncomplicated falciparum malaria treated with MSP or MSP plus primaquine. Eur J Drug Metab Pharmacokinet 1994; 19(1):27-32.

13 McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria (Cochrane Review). In:The Cochrane Library, Issue 4, 2002. Oxford: Update Software.

C ONTRIBUTOR

Martin Meremikwu, Department of Paediatrics, University of Calabar, Cross River State, Nigeria; meremiku@skannet.com

International Artemisinin Study Group. Artesunate combinations for uncomplicated malaria: a prospective individual patient data meta-analysis (Protocol for a Cochrane Review). In:The Cochrane Library, Issue 4, 2002. Oxford: Update Software.

15 Adjuik M, Agnamey P, Babiker A, Borrmann S, Brasseur P, Cisse M, Cobelens F, Diallo S, Faucher JF, Garner P, Gikunda S, Kremsner PG, Krishna S, Lell B, Loolpapit M, Matsiegui PB, Missnou MA, Mwanza J, Ntoumi F, Olliaro P, Rezbach P, Some E, Taylor WR. Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomized, multicentre trial. Lancet 2002; 359: 1365-72. 16 Omari AAA, Preston C, Garner P. Artemether-lumefantrine for treating uncomplicated falciparum malaria (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software.

Price RN, Nosten F, Luxemburger C, ter Kuile FO, Paiphun L, Chongsuphajaisiddhi T, White NJ.1: Effects of artemisinin derivatives on malaria transmissibility. Lancet. 1996 15;347(9016):1654-8.

ACKNOWLEDGEMENTS Paul Garner of the Liverpool School of Tropical Medicine advised on the manuscript. The author (MM) is supported by the Effective Health Care Alliance through a Department for International Development (UK) Programme Grant, and PREMA-EU (a Concerted Action European Union grant; Contract No. ICA4-CT-2001-10012)

P OTENTIAL None

CONFLICT OF INTEREST

Indoor Residual Spraying and Insecticide-Treated Nets CHRISTIAN LENGELER,1 BRIAN SHARP2 1 SWISS TROPICAL INSTITUTE 2 MEDICAL RESEARCH COUNCIL, SOUTH AFRICA

INTRODUCTION Background Primary prevention of malaria on a large scale is essentially achieved through controlling the vectors (mosquitoes) that cause malaria. Currently the two main vector control interventions are 1) Indoor Residual Insecticide (house) Spraying (IRS), and 2) Insecticide-Treated (mosquito) Nets (ITNs). A much more modest role is played by larval control (mostly carried out in selected urban settings) and personal protection measures including insect repellents and improved housing. IRS has a long and distinguished history in malaria control. Using mainly dichlorophenyltrichlorethane (DDT), malaria was eliminated as a public health problem in large parts of the world (viz. in Asia, Russia, Europe and Latin America). In Southern Africa, over 13 million people in seven countries are currently protected by IRS.1 However, virtually no IRS programmes operate in the remaining highly endemic countries of sub-Saharan Africa. The main reasons are that IRS requires highly structured government-supported programmes and a sustainable high level of financing, which are not available in many of these countries. For these reasons many countries were not included in the eradication campaigns following the Kampala Malaria Conference of 1950. Epidemiological evidence collected since 1950 suggests that IRS can be effective in all types of endemic areas, although the expected impact may vary.2 Using mosquito nets as a protection against nuisance insects was already practised in historical times and it was one of the main control methods recommended by Ronald Ross following his discovery of the malaria-mosquito link nearly 100 years ago.3 As a malaria intervention, the insecticide treatment of mosquito netting was simultaneously developed by different armies operating in tropical regions during World War II.4 Properly utilised, even an untreated mosquito net provides a good physical barrier against mosquitoes. However, mosquitoes can easily find and bite any part of the body that comes in contact with the net during the night. If the net has holes, mosquitoes can enter it. In order to address these problems and improve the protective effect of nets, it is essential to treat mosquito nets with (pyrethroid) insecti-

cides. In addition to providing personal protection, treated nets kill mosquitoes in the vicinity, and hence, like spraying, reduce overall transmission levels. ITNs provide an effective vector control tool that is simple enough to be used even in poor countries such as in highly endemic sub-Saharan Africa.This has enabled dramatically improved malaria control efforts in such settings.

Reasons/rationale for the intervention/program/project Both IRS and ITNs aim at the primary protection of individuals against the bite of infected Anopheles mosquitoes. IRS operates both through repelling mosquitoes from entering houses and by killing female mosquitoes who are resting inside houses after having taken a blood meal. This implies that IRS is most effective against mosquito species that are indoor-resting (‘endophillic mosquitoes’). ITNs can be likened to a trap, in which the sleeper acts as bait. While ITNs have a certain repellent effect (largely depending on the insecticide used), their main mode of action is to prevent mosquitoes from biting and to kill them if they attempt to do so. This process is well documented by a large body of entomological evidence.5 For both interventions, the main effect is to reduce the average longevity of the vectors and hence to dramatically reduce the proportion of mosquitoes living long enough for the parasite cycle to be completed within them. As a result, overall transmission levels decrease. Both interventions are especially effective when applied on a large scale, since this maximizes the impact to shorten the life of the mosquitoes and hence reduces overall transmission, - the so-called "mass effect". For IRS this is well documented in a number of trials6, while for ITNs a similar phenomenon has been demonstrated in several different study sites. This includes a significant effect on improving survival among unprotected children living among or near many ITNs.7,8 As a result, even unprotected individuals — often the poorer members of the community who cannot afford a net — benefit from ITNs. In the following sections, the evidence for a health impact of both IRS and ITNs are reviewed. The sections are divided into impact under trial conditions ("efficacy" — see ROLE OF EVIDENCE) and impact under programmatic conditions ("effectiveness" — see I MPACT OF INTERVEN TION / PROGRAM / PROJECT ). 17

ROLE

OF EVIDENCE

Efficacy of IRS Evidence regarding the health impact of IRS is largely based on long-term observational data documenting the decline in malaria following large-scale programmes conducted in many parts of the world. This evidence is reviewed in a subsequent section (see Impact of Intervention/program/project). Additional evidence comes from non-randomised and often non-controlled trials carried out in the 1950s and 1960s. In sub-Saharan Africa, early small-scale IRS trials without proper control groups were conducted in the 1950s in Liberia, Cameroon, Nigeria, Senegal, Burkina Faso, Benin, Togo, Rwanda, Burundi and Uganda. These trials consistently documented a substantial impact of IRS on transmission of malaria but only rarely its interruption.2,9 On the basis of these observational studies, three large pilot projects documented the beneficial health impacts of IRS on the African continent. In an observational study in the Pare-Taveta Malaria Scheme in Tanzania, the introduction of IRS with the insecticide dieldrin led to a substantial reduction in malaria transmission from an annual entomological inoculation rate (EIR, the number of infective mosquito bites per person) of 10 - 50 to less than 1. There was also a decrease in the crude mortality rate from 24 per 1,000 in 1955 to 16 per 1,000 in 1958, and in the infant mortality rate from 165 to 132 per 1,000.10,11 After spraying programs ceased, the transmission and mortality rates increased slowly again, but without returning to their original level. In Kisumu, Kenya, a controlled trial evaluating IRS with fenitrothion reduced malaria transmission by 96% compared to baseline in two years. As a result, the crude death rate in the intervention areas was reduced by 43% and the infant mortality rate by 41%, while no changes were observed in an adjacent control area.12

In northern Nigeria (Garki Project), IRS with propoxur also substantially decreased transmission and improved infant and child mortality. The addition of mass drug administration resulted in even better impact results.13 Finally, a recent randomised controlled trial (RCT) at village level in Pakistan showed that IRS with alphacypermethrin had a marked impact on mosquitoes and reduced the number of P. falciparum episodes by 95% and the number of P. vivax episodes by 80%.14 A number of recent trials compared the health impact and cost of IRS and ITNs and the results are presented in a section below.

Efficacy of ITNs During the last 15 years, a large body of evidence has been compiled on key technical and managerial aspects of ITNs as well as on their efficacy and effectiveness. This section is based on a Cochrane systematic review of the impact of ITNs.15 From a total of 77 ITN trials found, 22 RCTs and 25 â&#x20AC;&#x2DC;high qualityâ&#x20AC;&#x2122; controlled trials were eligible for inclusion in the review. Twenty trials examined the impact of treated bed nets, while two examined the impact of treated curtains. In some trials the intervention consisted of treating existing nets with an insecticide while the control group used largely untreated nets. In other trials, the investigators provided treated mosquito nets or curtains to the population. Findings relating to the various outcomes assessed are shown below:

Childhood mortality Five cluster-randomised controlled trials, all conducted in Africa, examined impact of ITNs on childhood mortality. Both the relative and the absolute impact were analysed. The key results are summarised in Table 1.

TABLE 1. CHILDHOOD MORTALITY RESULTS FROM ITN TRIALS Country

Bites/person (EIR)

Intervention rate

Control rate

Protective efficacy

Rate Difference

(95% CI)

Comparison 1: Control group=no nets Kenya17

10-30

9.4

13.2

33% (7 – 51%)

3.8 (1.1 – 6.6)

Ghana18

100-300

28.2

34.2

18% (1 – 30%)

6.0 (1.4 – 10.6)

Burkina Faso19

300-500

41.8

48.7

14% (-8 – 30%)

6.9 (-2.5 – 16.2)

Kenya20

200-300

43.9

51.9

16% (6 – 25%)

8.0 (3 – 13)

1-10

18.7

24.3

23% (1 – 41%)

5.6 (0.4 – 10.7)

Comparison 2: Control group=untreated nets Gambia21

Note: Rates in the intervention and control groups and for the rate difference are expressed as deaths/1000/year in children aged 1-59 months. 95% confidence intervals are corrected for cluster randomisation16 EIR=entomological inoculation rate; CI=confidence interval; NA=not available

When treated nets were compared with no nets, (4 trials) the summary rate ratio (RR) was 0.84 (95% confidence interval 0.77-0.89), giving a protective efficacy (PE — mortality rate reduction achieved by ITNs) of 16 percent (95% CI 11 – 23%). The summary risk difference (expressing how many lives can be saved for every 1,000 children protected) was six per 1,000 protected children per year. In the one study in which the control group had untreated nets, the PE was 23% (95% CI 1-41%) and the risk difference was 5.6 deaths per 1,000 protected children per year. When the five included trials were pooled (regardless of the type of control group), the summary RR was 0.83 (95% CI 0.77 - 0.88) giving a summary PE of 17 percent (95% CI 12 – 23 percent). The summary risk difference was 5.5 deaths averted per 1,000 children protected with ITNs per year.

Severe malaria disease Only one RCT examined severe malarial disease as an outcome.17 A reduction of 45% (95% CI 20-63) in the frequency of severe malaria episodes was observed following the introduction of ITNs.These findings highlight the potential for ITNs to significantly reduce malaria hospital caseloads in endemic areas.

Mild disease episodes Because of the large number of subgroups that were analysed, a summary of the main findings for protective efficacies is given in Table 2. Summary estimates are given for RCTs only. ITNs showed a consistently high impact in preventing malaria disease episodes. The measured impact was substantially, but not significantly, higher when the control group had no nets at all. In areas of unstable malaria transmission (where levels of infective mosquitoes change from year to year), the impact against P. falciparum episodes appeared to be higher than the impact against P. vivax episodes. 19

TABLE 2. IMPACT

OF INSECTICIDE-TREATED

NETS

FOR THE

Level of stratification

N trials

Stable malaria (EIR > 1) Control group=no nets Control group=untreated nets

4 3

Unstable malaria (EIR < 1) P. falciparum results Control group=no nets Control group=untreated nets

PREVENTION

MILD MALARIA EPISODES Protective efficacy (95% CI)

50% (44-55) 39% (27-48)

1 2

62% (48-72) 43% (20-60)

P. vivax results Control group=no nets Control group=untreated nets

2 2

52% (45-59) 25% (-8-48)

Mixed infections and P. vivax >30% of all infections Control group=no nets Control group=untreated nets

1 7

48% (40-55) 16% (11-21)

Note: For each level, the number of trials contributing to the analysis is indicated. Protective efficacy defined as (1-RR)x100, or the percentage reduction in malaria episodes.

Anaemia (deficiency of red blood cells) The packed cell volume (PCV, a marker for anaemia) of children in the ITN group was higher by 1.7 absolute PCV% (or approximately 0.6 g/dl) compared to children not using nets at all (n=9 trials). When the control group used untreated nets, the difference was smaller (0.4 absolute PCV%; or 0.13 g/dl).

Anthropometric measures Three ITNs studies have demonstrated a positive impact on anthropometrical measurements. In The Gambia21 mean z-scores of weight-for-age and weight-for-height were higher in children from treated villages (-1.36 and -0.98, respectively) than in those from untreated villages (-1.46 and -1.13)(p=0.008 and p=0.001, respectively). In the trial carried out in Kenya,17 infants sleeping under insecticide-treated nets in the intervention areas had significantly higher z-scores for weight-for-age than control (F=21.63, p=0.03).22 In a study carried out in Tanzania, children aged 6-40 months and protected by treated nets grew 286 grams more (95% CI 171-402 g) in a five-month period than children not having any net.23

Comparing the impact of IRS and ITNs In recent years, a number of trials have been conducted to compare the health impact of IRS and ITNs. The main aim of these trials was to provide an indication of which vector 20

control approach was the most cost-effective. The main trials are listed below. However, a meta-analysis to synthesize the results of these trials was not possible given the heterogeneity in the methodologies and outcomes. For the same reason, the cost data are difficult to compare between sites. A randomised comparison of 12 villages (control vs. IRS vs. ITNs) using the insecticide lambdacyhalothrin24 documented the clear impact of IRS and ITNs in children aged 1 - 6 years on the EIR (9.4 vs. 0.08 vs. 0.06 infective bites per person per night), as well as on haemoglobin levels (a marker for anaemia): 9.3 vs. 10.2 vs. 10.2 g/dl (p<0.05 for both comparisons vs. control). Compared to the control group, both IRS and ITNs lowered malaria parasite prevalence and densities in the blood as well as the number of reported disease episodes. As for cost, ITNs were significantly cheaper than IRS to implement (US$1.3 vs. US$4.6 per protected person per year). In India, a randomised comparison of ITN and IRS in 126 villages clearly demonstrated a lower malaria incidence rate in the ITN villages (28.1 cases per 1,000 person years (PY)) versus IRS treatment with deltamethrin (43.3 cases per 1,000 PY). Control villages had 61.5 cases per 1000 PY, yielding a PE of 54 percent for ITNs and a PE of 30% for IRS.25 In South Africa a recent cluster-randomised comparison of IRS with deltamethrin against ITNs treated with permethrin or deltamethrin showed that ITNs gave a significantly better protection against P. falciparum episodes, with an adjusted PE of 33% (95% CI 28 to 39%).26 The cost of ITNs (US$3.7 per protected person per year) was higher

than that of a single round of IRS (US$2.3), although this difference would have been reduced if nets had been bought at world market prices – which were roughly a third of what was paid for ITNs in that trial.27 Observational evidence from China indicated that IRS with DDT was comparable to ITNs treated with deltamethrin in reducing the number of P. vivax cases (Yuyi County Anti-Epidemic Station4). A comparative field trial from the Solomon Islands indicated that ITNs were more effective in improving entomological parameters than IRS with DDT.28 A non-randomised comparison between IRS with malathion and permethrin-treated nets in Afghan refugee camps in Pakistan showed that they had a comparable PE in preventing malaria episodes due to P. vivax (44% vs 42% protection for ITNs) and P. falciparum (49% vs 61 % protection for ITNs).29 In a community-allocated but non-randomised trial in Thailand ITNs were found to be more cost-effective than IRS with DDT (US$1.5 vs. US$ 1.9 per case averted).30 Finally, recent work from a non-randomised comparative study in the Kenyan highlands showed good PE for both IRS with lambdacyhalothrin and nets treated with deltamethrin in reducing the prevalence of infection in all ages compared to untreated areas: PE 75% (95% CI 7376%) for IRS vs. PE 63% (95% CI 58–68%) for ITNs. The economic cost of protecting one person for one year was US$0.88 for IRS (single round) vs. US$2.3 for ITNs.31

What can be concluded from these trials? Both IRS and ITNs have been found to be efficacious across a large number of settings. Overall, the health impact of ITNs was slightly better than IRS, although the differences were not striking in most settings and cannot be used to justify one approach over the other. The difference in costs of IRS and ITN was usually not large. However, it is important to emphasize that all the studies above included the cost of providing the nets. If the cost of the nets was borne by the users (a situation found in virtually all settings so far, including China and Vietnam), ITNs would be more expensive to the end-user and less expensive than IRS for a government provider. This is also confirmed by economic modelling.32 Treating nets only had a median cost of US$1 per year vs. a median cost of US$8 for single round IRS and US$15.9 for two-round IRS. Providing both the nets and the insecticide had a median cost of US$7.2 per year and was therefore comparable to a single round of IRS. Choosing between IRS and ITNs is, therefore, largely a matter of operational feasibility and availability of local resources, rather than one of malaria epidemiology or costeffectiveness.

IMPLEMENTATION

ISSUES

IRS Past and current implementation models for IRS are clearly based on the provision of all services by the public health system. As a result, successful implementation of IRS has relied almost entirely on governments having adequate funding and a well-organized structure of sprayers and logistical support. There are no examples of IRS programmes being directly organized or paid for by consumers. There are, however, recent examples of successful IRS activities funded by commercial companies for the benefit of local communities and employees, including examples from Zambia33 and Mozambique.34 In the absence of sufficient government funding to meet IRS needs, this model offers hope that the private sector will recognize a net benefit in helping local residents avoid malaria. A cost-benefit analysis of this approach would be useful.

ITNs In contrast with IRS, many ITN implementation models exist,35,36 even though only a few have been attempted to date on a large scale. One successful model has involved the purchase of mosquito nets by consumers through ordinary commercial channels while government public health services ensure their regular re-treatment (primarily in China, Vietnam and a few Latin American countries).35 Another approach has been the provision of free ITNs in the context of complex emergencies, for example in refugee camps. A third model involves donor-funded social marketing with various mechanisms of distribution, usually through the existing commercial channels (for example in Kenya or Tanzania) or through health clinics (Malawi) – see also www.psi.org/our_programs/products/itn.html. Using this approach, the largest number of ITNs in sub-Saharan Africa (about 3 million ITNs with 4 million treatment kits sold in 10 countries) have been distributed at a cost per person-year protection of less than US$2. A fourth model is a supported commercial sector approach, largely implemented through the USAIDsupported Netmark Plus partnership program (www.netmarkafrica.org/). This project encourages private sector initiatives to broaden access to ITNs. Thus far there is very limited experience with large-scale distribution of free ITNs through the public health service except during complex emergencies. In the only non-crisis example to date, ITNs were distributed free to pregnant women during African Malaria Day in Kenya in 2001. Accounting for losses of nets during distribution, the public sector cost to deliver an ITN to a pregnant woman was US$5.3.37 A global strategic framework for ITNs was developed in 2002 by the Roll Back Malaria (RBM) partnership38

(see also http://mosquito.who.int/). The strategy includes: (1) The development and support of a commercial market for ITNs within a public-private partnership. For the public sector this requires creating an "enabling environment" including adequate legislation, removal of taxes and tariffs on nets and public health insecticide, and a vigorous demand creation campaign.

The impact of ITN programmes have been clearly demonstrated in China,47 Vietnam,48 and Tanzania.49,50 In Tanzania the regular use of treated nets was associated with a 27% improvement in child survival and a 63% reduction in the level of anaemia in children.

(2) Strictly targeted subsidies for vulnerable groups (primarily pregnant women and infants), either through the direct subsidy of the products or through a voucher which enables targeted groups to purchase subsidised ITNs from local commercial retailers.39

CHALLENGES/NEXT STEPS

The global strategy also calls for a high level of national coordination between all ITN stakeholders within the country (commercial sector, government ministries, non-governmental organisations, researchers, donors, multilateral organisations). Such a coordinated action led to a highly successful national upscaling of ITNs in Tanzania.40 More operational experience needs to be gathered in order to inform efforts to scale up national ITN initiatives.

IMPACT

OF INTERVENTION / PROGRAM / PROJECT

IRS The elimination of malaria transmission through IRS in southern Europe and the Mediterranean, Russia and large parts of Asia and Latin America during the eradication era in the 1950s and 1960s illustrates its programmatic effectiveness. For example, DDT was used on a large scale to rid Italy of malaria after World War II. In Sri Lanka child mortality was cut in half between 1946 - 1956,41 and in Guyana malaria-specific mortality was virtually eliminated between 1945 and 1952.42 Similar results were shown in 12 other Latin American countries between 1955 and 1968.43 In India malaria declined to the point that it was no longer considered a public health problem â&#x20AC;&#x201C; from 75 million cases in 1947 to 100,000 cases in 1965.4 In South Africa where IRS has been used for over 50 years, malaria has been eliminated in many areas. The most endemic areas in Kwa-Zulu Natal now have only approximately 5,000 cases of malaria per year.44 Of all these countries, the size of the mortality reductions and their temporal coincidence with the eradication programmes largely based on IRS gives plausibility to a causal link. Conversely, ending DDT spraying in Latin America,45 Sao Tome or in Madagascar had a demonstrable detrimental effect on the malaria situation. In Madagascar, after IRS was discontinued, over 10,000 deaths were recorded in a single epidemic period in 1987 - 1988.46

ITNs

Both IRS and ITNs are proven interventions that are highly cost-effective in preventing and reducing malaria transmission. Choosing between IRS and ITNs is largely a matter of operational feasibility and availability of local resources. Given the enormous human costs of malaria, the large-scale deployment of IRS and ITNs needs to be considered an urgent priority in all endemic areas in the world. Many challenges remain in the large-scale deployment of both IRS and ITNs.

IRS For IRS the key issue remains the securing of long-term human and financial resources for regular spraying campaigns. This is especially the case in resource-poor countries (for example, Madagascar or Ethiopia) and in countries where the level of transmission is so low that it becomes increasingly difficult to justify large outlays of public money for this purpose. However, dramatic lessons from the past show what negative consequences such cost-saving exercises may have in recurrent epidemics. Secondly, insecticide resistance remains a constant threat to the effectiveness of IRS, as demonstrated recently in South Africa with the emergence of pyrethroidresistant Anopheles funestus.51 There is currently a large choice of products to address this problem, even though the cost may increase with the use of newer compounds, which are progressively replacing DDT.36 Finally, behavioural issues have been increasingly documented in recent years, with people either refusing to have their homes sprayed, or re-plastering walls soon after spraying.26

ITNs For ITNs, current challenges include the creation of an enabling environment (see above), an improved supply of ITNs affordable to the majority of rural African populations, and mechanisms to provide targeted subsidies to high-risk groups. An important practical problem is that nets need to be regularly re-treated (every 6 - 12 months) and this has proven to be a major challenge for all current programmes. The development and commercialisation of long-lasting insecticidal nets (LLIN) offer considerable promise to solve this problem. There are already two good LLIN options on the market and a few more products are close to commercialisation.

Pyrethroid-resistant mosquitoes are mainly found in Western Africa,52 where selection is considered to be a direct result of intense agricultural insecticide use, and more recently in South Africa51 and southern Mozambique. Fortunately, from studies in West Africa, it does not seem that this has reduced the effectiveness of ITNs for protecting against malaria transmission.53

Some researchers have hypothesised that where malaria transmission is particularly high, the benefits of vector control will be transitory, shifting morbidity and mortality to an older age.54,55 The serious implications of this hypothesis for decision-making have been discussed and challenged.56,57,58 Recently, evidence from long-term followup studies (DA Diallo pers. comm.) has shown that such an age-shift is highly unlikely.59,60

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20 Phillips-Howard PA, Nahlen BL, Kolczak MS, Hightower AW, ter Kuile FO, Alaii JA, Gimnig JE, Arudo J, Vulule JM, Odhacha A, Kachur SP, Schoute E, Rosen DH, Sexton JD, Oloo AJ, Hawley WA. Efficacy of permethrin-treated bed nets in the prevention of mortality in young children in an area of high perennial malaria transmission in western Kenya. Am J Trop Med Hyg. 2003 Apr; 68(4 Suppl):23-9.

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7 Binka FN, Indome F, Smith T. Impact of spatial distribution of permethrin-impregnated bed nets on child mortality in rural northern Ghana. Am J Trop Med Hyg 1998; 59(1):80-85.

8 Hightower A, Phillips-Howard P, terKuile F, Terlouw D,Vulule J, Ombok M et al. To what extent do your neighbors' bed nets protect you? Arusha, Tanzania:Third MIM Pan-African Malaria Conference; 2002.

23 Shiff C, Checkley W, Winch P, Premji Z, Minjas J, Lubega P. Changes in weight gain and anaemia attributable to malaria in Tanzanian children living under holoendemic conditions. Trans.R.Soc.Trop.Med.Hyg. 90, 262265. 1996.

9 Bruce-Chwatt LJ. Lessons learned from applied field research activities in Africa during the malaria eradication era. Bull World Health Organ 1984; 62 Suppl:19-29. 10 Pringle G. Experimental malaria control and demography in a rural East African community: a retrospect.Trans R Soc Trop Med Hyg 1969; 63:2-18. 11 Bradley

DJ. Morbidity and Mortality at Pare-Taveta, Kenya and Tanzania, 1954-66: the effects of a period of malaria control. In: Feachem RG, Jamison D, editors. Disease and mortality in Sub-Saharan Africa. Oxford: Oxford University Press; 1991. 248-262.

12 Payne D, Grab B, Fontaine RE, Hempel JH. Impact of control measures on malaria transmission and general mortality. Bull World Health Organ 1976; 54(4):369-377. 13

Molineaux L. The impact of parasitic diseases and their control, with an emphasis on malaria and Africa. In:Vallin J, Lopez AD, editors. Health policy, social policy and mortality prospects. Paris: IUSSP; 1985. 13-44. 14 Rowland M, Mahmood P, Iqbal J, Carneiro I, Chavasse D. Indoor residual spraying with alphacypermethrin controls malaria in Pakistan: a community-randomised trial.Trop Med Int Health 2000; 5(7):472-481. 15 Lengeler C. Insecticide-treated bednets and curtains for preventing malaria. Cochrane Database of Systematic Reviews. 2003. 16

Bennett S, Parpia T, Hayes R, Cousens S. Methods for the analysis of incidence rates in cluster randomized trials. Int J Epidemiol 2002; 31(4):839-846. 17

Nevill CG, Some ES, Mung'ala VO, Mutemi W, New L, Marsh K et al. Insecticide-treated bednets reduce mortality and severe morbidity from malaria among children on the Kenyan coast. Trop Med Int Health 1996; 1(2):139-146.

Snow RW, Molyneux CS, Njeru EK, Omumbo J, Nevill CG, Munui E et al. The effects of malaria control on nutritional status in infancy. Acta Tropica 65, 1-10. 1997.

24 Curtis CF, Maxwell CA, Finch RJ, Njunwa KJ. A comparison of use of a pyrethroid either for house spraying or for bednet treatment against malaria vectors.Trop Med Int Health 1998; 3(8):619-63. 25 Misra SP,Webber R, Lines J, Jaffar S, Bradley DJ. Malaria control: bednets or spraying? Spray versus treated nets using deltamethrin--a community randomized trial in India. Trans R Soc Trop Med Hyg 1999; 93(5):456457. 26 Mnzava AE, Sharp BL, Mthembu DJ, le Sueur D, Dlamini SS, Gumede JK et al. Malaria control - two years' use of insecticide-treated bednets compared with insecticide house spraying in KwaZulu-Natal. S Afr Med J 2001; 91(11):978-983. 27 Goodman CA, Mnzava AE, Dlamini SS, Sharp BL, Mthembu DJ, Gumede JK. Comparison of the cost and cost-effectiveness of insecticidetreated bednets and residual house-spraying in KwaZulu-Natal, South Africa.Trop Med Int Health 2001; 6(4):280-295. 28

Kere NK, Arabola A, Bakote'e B, Qalo O, Burkot TR,Webber RH et al. Permethrin-impregnated bednets are more effective than DDT housespraying to control malaria in Solomon Islands. Med Vet Entomol 1996; 10(2):145-148.

Rowland M. Malaria control: bednets or spraying? Malaria control in the Afghan refugee camps of western Pakistan.Trans R Soc Trop Med Hyg 1999; 93(5):458-459.

Kamolratanakul P, Butraporn P, Prasittisuk M, Prasittisuk C, Indaratna K. Cost-effectiveness and sustainability of lambdacyhalothrin-treated mosquito nets in comparison to DDT spraying for malaria control in western Thailand. Am J Trop Med Hyg 2001; 65(4):279-284.

Guyatt HL, Corlett SK, Robinson TP, Ochola SA, Snow RW. Malaria prevention in highland Kenya: indoor residual house-spraying vs.

insecticide-treated bednets.Trop Med Int Health 2002; 7(4):298-303. 32

Goodman CA, Coleman PG, Mills AJ. Cost-effectiveness of malaria control in sub-Saharan Africa. Lancet 1999; 354(9176):378-385.

Sharp B, van Wyk P, Sikasote JB, Banda P, Kleinschmidt I. Malaria control by residual insecticide spraying in Chingola and Chililabombwe, Copperbelt Province, Zambia.Trop Med Int Health 2002; 7(9):732-736.

treated nets on child survival in rural Tanzania. Lancet 2001; 357:12411247. 50

Abdulla S, Schellenberg JA, Nathan R, Mukasa O, Marchant T, Smith T et al. Impact on malaria morbidity of a programme supplying insecticide treated nets in children aged under 2 years in Tanzania: community cross sectional study. BMJ 2001; 322:270-273.

51 34

LSDI. Annual Report 2001, Lubombo Special Development Initiative Malaria Control. Durban. 2002. Unpublished Medical Research Council Report.

Feilden RM. Experiences of implementation. In: Lengeler C, Cattani J, deSavigny DH, editors. Net Gain - a new method to prevent malaria deaths. Ottawa: IDRC and WHO; 1996. 55-110.

Hargreaves K, Koekemoer LL, Brooke BD, Hunt RH, Mthembu J, Coetzee M. Anopheles funestus resistant to pyrethroid insecticides in South Africa. Med Vet Entomol 2000; 14(2):181-189.

52 Chandre F, Darrier F, Manga L, Akogbeto M, Faye O, Mouchet J et al. Status of pyrethroid resistance in Anopheles gambiae sensu lato. Bull World Health Organ 1999; 77(3):230-234. 53

36 Hanson K, Goodman C, Lines J, Meek S, Bradley D, Mills A. The economics of malaria control. Unpublished report. London, U.K.; Health Economics and Financing Programme, London School of Hygiene and Tropical Medicine; 2002. (for pdf version see also http://mosquito.who.int/). 37

Guyatt HL, Gotink MH, Ochola SA, Snow RW. Free bednets to pregnant women through antenatal clinics in Kenya: a cheap, simple and equitable approach to delivery.Trop Med Int Health 2002; 7(5):409-420.

RBM. Scaling up insecticide-treated netting programmes in Africa; a strategic framework for coordinated national action. Geneva, Switzerland; RBM,Technical Support Network for Insecticide-Treated Materials; 2002.

39 Mushi AK, Armstrong

Schellenberg JR, Mponda H, Lengeler C.Targeted subsidy for malaria control with treated nets using a discount voucher system in southern Tanzania. Health Policy and Planning 2003; In press.

Magesa SM, deSavigny DH, Njau RJ, Miller JE, Jamu L, Lengeler C et al. Creating an enabling environment for going to scale with insecticide treated net interventions: experience from Tanzania. Submitted.

41 Newman P. Malaria eradication and population growth, with special reference to Ceylon and British Guiana. Ann Harbor, USA: Ann Harbor School of Public Health, the University of Michigan, Bureau of Public Health Economics; 1965. 42 Giglioli G. Changes in the pattern of mortality following the eradication of hyperendemic malaria from a highly susceptible community. Bull World Health Organ 1972; 46(2):181-202. 43

Gramiccia G, Hempel J. Mortality and morbidity from malaria in countries where malaria eradication is not making satisfactory progress. J Trop Med Hyg 1972; 75(10):187-192.

Sharp BL, le Sueur D. Malaria in South Africa - the past, the present and selected implications for the future. S Afr Med J 1996; 86(1):83-89.

Henry MC, Doannio JM, Darriet F, Nzeyimana I, Carnevale P. Efficacy of permethrin-impregnated Olyset mosquito nets in a zone with pyrethroid resistance vectors. II. Parasitic and clinical evaluation. Med Trop (Mars ) 1999; 59(4):355-357.

54 Trape JF, Rogier C. Combatting malaria morbidity and mortality by reducing transmission. Parasitology Today 1996; 12(6):236-240. 55 Snow RW, Omumbo JA, Lowe B, Molyneux CS, Obiero JO, Palmer A et al. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 1997; 349:16501654. 56 Lengeler C, Smith,TA, Armstrong Schellenberg,J.R. Focus on the effect of bednets on malaria morbidity and mortality. Parasitology Today 1997; 13(3): 123-124. 57 Molineaux L. Nature's experiment: what implications for malaria prevention? Lancet 1997; 349:1636-1637. 58 Lines J. Severe malaria in children and transmission intensity. Lancet 1997; 350:813. 59

Smith TA, Leuenberger R, Lengeler C. Child mortality and malaria transmission intensity in Africa.Trends Parasitol 2001; 17(3):145-149.

Binka FN, Hodgson A, Adjuik M, Smith T. Mortality in a seven-and-ahalf-year follow-up of a trial of insecticide-treated mosquito nets in Ghana.Trans R Soc Trop Med Hyg. 2002, 96(6): 597-599.

C ONTRIBUTORS Christian Lengeler, Project Leader, Swiss Tropical Institute, Switzerland; christian.lengeler@unibas.ch Brian Sharp, Director, Malaria Research Programme, Medical Research Council, South Africa; sharpb@mrc.ac.za Swiss Tropical Institute Web site: www.sti.ch

Roberts DR, Manguin S, Mouchet J. DDT house spraying and reemerging malaria. Lancet 2000; 356:330-332.

Medical Research Council of South Africa Web site: www.mrc.ac.za/ malaria/malaria.htm

Mouchet J, Laventure S, Blanchy S, Fioramonti R, Rakotonjanabelo A, Rabarison P et al. La reconquete des hauts plateaux de Madagascar par la malaria. Bull Soc Pathol Exot 1997; 90(3):162-168.

47 Tang L. Progress in malaria control in China. Chin Med J 113(1):89-92.

2000;

Hung lQ, Vries PJ, Giao PT, Nam NV, Binh TQ, Chong MT et al. Control of malaria: a successful experience from Viet Nam. Bull World Health Organ 2002; 80(8):660-666.

49 Armstrong Schellenberg JR, Abdulla S, Nathan R, Mukasa O, Marchant TJ, Kikumbih N et al. Effect of large-scale social marketing of insecticide-

ACKNOWLEDGEMENTS The authors are grateful to their institutions for the support received during the preparation of this document.

P OTENTIAL None.

CONFLICT OF INTEREST

The Role of Artemisinin-based Combination Therapy in Malaria Management KAREN BARNES, PETER FOLB UNIVERSITY OF CAPE TOWN , SOUTH AFRICA

INTRODUCTION Background Malaria morbidity and mortality in Africa is rising, and this is principally a result of increasing chloroquine and sulfadoxine-pyrimethamine (SP) resistance and delays in access to effective therapy.1,2 Antimalarial resistance results in an increase in treatment failure, prolonged illness, hospitalisation and death as well as increased malaria transmission, particularly of resistant parasites. Drug resistance is generally underestimated and policy change is complex, slow and costly, resulting in significant delays in ensuring an effective malaria treatment policy in many malaria-endemic countries. In addition to resistance to therapies, the other important reason for the high mortality from malaria is delay in receiving effective medication. Rural health workers and even parents can be taught to identify the symptoms and signs of lifethreatening malaria.3 However, many patients with more severe malaria are not able to take medicines orally because they are confused, unconscious or vomiting. Conventional therapy for severe malaria, in addition to the highest level of supportive care available, is injectable (parenteral) quinine. A considerable proportion of people living in malaria-endemic areas do not have ready access to health facilities able to provide parenteral treatment. For patients unable to take oral medication, delay in access to prompt parenteral therapy can be fatal. Progression from being unable to take oral treatment to severe malaria can occur within hours.4 Once the opportunity for early therapeutic intervention is lost and organ failure has developed, the prognosis worsens considerably and survival depends a great deal on access to a healthcare facility with resources to manage malaria complications.5 Such facilities are scarce in malaria-endemic countries.

Rationale for use of artemisinin-based combination therapy

used for centuries in China as a traditional treatment for fever and malaria. In recent years, artemisinin derivatives have become the focus of worldwide attention in the light of emerging resistance of Plasmodium falciparum to firstline drugs; to date resistance to artemisinin has not been demonstrated in malaria parasites.While artemisinin derivatives require at least seven days of treatment when administered alone, when combined with other first-line drugs, artemisinin-based combination therapies (ACTs) can eradicate parasites quickly and protect against the development of resistance to both drugs. Improved cure rates and decreased gametocyte carriage have been confirmed in limited African field trials.6,7 Artemisinin derivatives are the only first-line malaria treatments to act on gametocytes (the stage of the malaria parasiteâ&#x20AC;&#x2122;s life cycle responsible for ongoing malaria transmission) thereby potentially reducing malaria transmission and particularly the transmission of resistant strains of malaria.The principle of using combination therapy to delay the emergence and spread of resistance is established in the management of tuberculosis and HIV, and is expected to apply equally to malaria.8 This chapter will explore the role of artemisinin-based combinations in addressing the increasing morbidity and mortality in malaria-endemic countries, either when administered orally for uncomplicated malaria or as a suppository in more severe malaria.

ROLE

OF EVIDENCE

Selection of malaria treatment occurs at two levels, that of policy makers and that of individual health care providers (both formal and informal). Policy makers require evidence to determine when malaria treatment policy should be changed and to select which antimalarial(s) should replace the current treatment. Health care providers are influenced by availability of antimalarial treatments (which in the public sector is often guided by malaria treatment policy and the essential drugs programme) and by perceived effectiveness, safety and affordability.

Artemisinin is the active antimalarial component isolated from the medicinal herb Artemisia annua, which has been

The efficacy and safety of artesunate in combination with sulfadoxine-pyrimethamine (SP) has been evaluated in randomised controlled trials involving 2865 patients in sub-Saharan Africa (Taylor W, personal communication, 2003). Results from the first study published from The Gambia,11 where the cure rate with SP monotherapy is 93%, showed that both cure rate and parasite clearance were significantly higher in patients who received 3 days of artesunate plus a single dose of SP compared with those who received SP alone. Gametocyte carriage was 68% following SP treatment in comparison to 21% following combination treatment (p = 0.001).

BOX 1. ARTEMISININ

DERIVATIVES CURRENTLY WIDELY AVAILABLE

■

ARTEMETHER

■

ARTEMISININ

■

ARTESUNATE

■

CO-ARTEMETHER (artemether plus lumefantrine)

■

DIHYDROARTEMISININ

The largest series of therapeutic efficacy studies with artesunate plus mefloquine demonstrate a sustained increased cure rate (almost 100% from 1998 onwards), despite the established resistance pattern seen for high-dose mefloquine alone between 1990-94, prior to deployment of artesunate plus mefloquine (Figure 1).12

Artemisinin-based Combination Therapy

Cured (%)

With the possible exception of artemisinin derivatives, resistance of P falciparum to all available alternatives has been frequently documented.9 FIGURE 1. CUMULATIVE CURE RATES (95% CI), ASSESSED Artemisinin derivatives used alone are associated AT DAY 28 FOR DIFFERENT REGIMENS FROM PROSPECTIVE STUDIES with high treatment failure rates unless administered for seven days, which is not often achieved 100 as symptoms are generally relieved within two three days. Thus, artemisinin derivatives should MAS3 90 only be used in combination with a second effective antimalarial; poor efficacy of this component 80 significantly compromises the efficacy of the M25 combination. Results presented below focus on 70 M15 currently available combinations that are either packaged together or manufactured as a fixed 60 dose combination. There are a number of artemisinin-based combinations currently under 50 development, with dihydro-artemisinin plus 6 0 4 8 6 3 7 1 2 9 5 -8 99 99 99 99 99 99 99 99 99 99 piperaquine and artesunate plus chlorproguanil5 1 1 1 1 1 1 1 1 1 1 8 dapsone most likely to be widely available in the Year 19 medium term. M15 = mefloquine (15 mg/kg)

A considerable clinical evidence base has been M25 = mefloquine (25mg/kg) established through the largest randomised con- MAS3= artesunate (4 mg/kg for 3 days) with mefloquine (25 mg/kg split dose) trolled trials ever conducted on antimalarials, demonstrating that artemisinin-based combinaArtemether-lumefantrine is the first fixed-dose combination tions improve cure rates, decrease gametocyte carriage and of two antimalarials that was not widely used prior to being are well tolerated with few serious adverse effects (Taylor W, marketed. A Cochrane systematic review of randomised and personal communication, 2003). In the first of these multiquasi-randomised trials comparing artemether-lumefantrine centre trials to be published, 941 children who had uncomadministered orally with standard treatment regimens (e.g., plicated P falciparum malaria were randomly assigned three chloroquine, sulfadoxine-pyrimethamine or mefloquine) days treatment with amodiaquine plus artesunate or amodifound only two trials where participants received the aquine plus placebo. Both regimens were well tolerated.The recommended full six doses of artemether-lumefantrine. combination of artesunate and amodiaquine significantly These showed no difference in cure rates from artesunate improved treatment efficacy in Gabon 85% vs. 71%, plus mefloquine.13 Six trials with 1698 participants tested a (p=0.02) and Kenya 68% vs. 41% (p<0.0001), although these two were equivalent in Sénégal where the day-28 cure four-dose regimen. Failure rates for a four-dose regime of rates for amodiaquine-artesunate versus amodiaquine were artemether-lumefantrine were higher than standard 82% vs. 79% (p=0.5).10 treatment regimes. While artemether-lumefantrine was 26

better than chloroquine in two studies, the failure rate for chloroquine at the trial sites was over 50%.

Artesunate Artesunate can be administered as a tablet, an injection, or as a rectal suppository. A comparison of intravenous artesunate and quinine in 113 adults with severe malaria reported mortality of 12% with artesunate and 22% with quinine (p=0.22).14 In patients with hyperparasitaemia who had no other features of severe malaria but were at an increased risk of developing severe malaria, oral artesunate was found to be superior to intravenous quinine in reducing both clinical symptoms and parasites.15 Rectally-administered artesunate has been shown to be safe and highly effective in children and adults with uncomplicated or moderately severe falciparum malaria.16,17 A number of recent randomised controlled and open label studies of rectal artesunate in Africa and Asia have demonstrated the rapid antimalarial efficacy of a single dose of rectal artesunate (10 mg/kg) in moderately severe falciparum malaria in both children and adults prior to referral for definitive treatment. All patients had evidence of adequate absorption of the drug. Clearance of malaria parasites from the peripheral blood was consistently more rapid with rectal artesunate than with quinine injection. These clinical and parasitological responses suggest that rectal artesunate could provide useful initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment may not be available. There are also a number of small open label studies, some of which were randomised, demonstrating the clinical and parasitological efficacy of rectal artesunate in adults with severe P falciparum infections18 where rectal artesunate was administered repeatedly and was combined sequentially with a second oral antimalarial to prevent recrudescence (reappearance) of malaria.

Safety of artemisinin derivatives Artemisinin and its derivatives have been used extensively, especially in Southeast Asia, for the treatment of P falciparum malaria with very little evidence of toxicity. Most of the concerns regarding the safety of artemisinin derivatives are based on animal studies or on mild to moderate adverse events that have been reported from clinical studies.19,20 However, only a few studies have included young children in Africa.21 Concerns about potential neurotoxicity stem from animal studies that showed an unusual pattern of damage to the brainstem induced by high dose (>15mg/kg/day for 14 days) parenteral artemether and arteether.22 Although prolonged coma time was observed in two of three randomised controlled trials comparing artemether with quinine in the treatment of cerebral malaria, a meta-analysis

found no increased risk of prolonged coma in the artemisinin derivative-treated patients.23 Autopsy of fatal severe malaria cases exposed to artemisinin derivatives found no evidence of neurotoxicity. There have been sporadic case reports of impaired balance, nystagmus, fine motor coordination, paraesthesia and seizures following treatment of severe falciparum malaria with an artemisinin derivative. However, concomitant administration of mefloquine and malaria itself may have caused these neurological abnormalities. Clinical studies have reported pruritus and mild skin rash in 1-4% of patients receiving artemisinin-based combination therapy, with a higher incidence observed with the concurrent administration of sulfadoxine-pyrimethamine24,25,26,27 Two cases of severe allergic reactions to artesunate have been reported in Thailand.28 Of 153 children with malaria enrolled in a randomised controlled trial comparing artesunate plus amodiaquine with amodiaquine alone, nine children (6% [95% CI 3-11]) developed a significant decrease in their neutrophil count. Three were on amodiaquine-artesunate and six on amodiaquine alone; all had normal neutrophil counts before treatment.29 A decrease in the number of neutrophil cells in the blood (neutropenia) is associated with increased risk of severe infections. Infants born to 287 women inadvertently exposed during pregnancy to a mass administration of a single dose of artesunate plus SP, had higher birth weights than those not exposed, and there were no differences in the proportion of congenital abnormalities, stillbirths, abortions or neonatal deaths between exposed and unexposed women.30 In a prospective open-label study of pregnant women treated with artemisinin derivatives (mostly artesunate) for 539 multidrug-resistant falciparum malaria episodes, there was no evidence of adverse effects. Birth outcomes did not differ significantly from community rates for abortion, stillbirth, or congenital abnormality.31 Although these studies suggest that artemisinins may have a relatively good safety profile during pregnancy, only 80 of the women studied were exposed to the drug during the first trimester.

Implementation Issues The gaps between scientific knowledge and health policy as well as between theoretical health policy and practice continue to widen.32 Although local efficacy data is recognised as a necessary pre-requisite for an appropriate and evidence-based malaria policy, efficacy data alone are not sufficient to ensure effective policy-making or implementation. Even with adequate data on the status of antimalarial drug resistance, enormous challenges face those attempting to use research results to determine policy and/or influence practice.33

Effectiveness vs. efficacy

Curtailing resistance and transmission

Effectiveness of treatment may be lower than the efficacy reported in clinical trials as a result of poor adherence to therapy, sub-therapeutic dosing (usually done to limit cost to the patient), poor quality medication or greater disease severity than the group studied. For example, artemetherlumefantrine needs to be administered with a food or drink containing fat to ensure adequate absorption, a particular challenge for patients suffering from nausea or who cannot afford or access such foods. Studies are usually conducted in well-equipped facilities that also provide further supportive care, which is generally scarce in malaria endemic countries.

As clinical trials may overestimate the value of ACT in the real world, research is needed to determine the net benefit of wide-scale deployment of these drugs. A prospective study of malaria incidence and treatment was conducted on the northwest border of Thailand to assess the incidence of P. falciparum malaria and the therapeutic responses to mefloquine treatment over 13 years. During this time, mefloquine resistance was decreased following the widespread deployment of artesunate plus mefloquine, and there has been a sustained decline of at least six-fold in the incidence of P. falciparum malaria in the study area. Laboratory studies confirmed that the susceptibility of falciparum malaria parasites to mefloquine improved significantly following the addition of artesunate to mefloquine (p=0.003).35 Although such a study would take years to replicate, the significantly decreased malaria case load observed in Vietnam and KwaZulu-Natal, South Africa following the large-scale implementation of ACTs is encouraging (Figure 2).

Diagnostic challenges

6000

B. Introduction of IRS in southern Mozambique in October 2000

5000

C. Implementation of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria in KZN in January 2001

4000 3000 2000 1000

Source: KwaZulu-Natal Department of Health, South Africa

Jan-03

Jul-02

Jan-02

Jul-01

Jan-01

Jul-00

Jan-00

Jul-99

Jan-99

Jul-98

Jan-98

0 Jul-97

Rare serious adverse effects of treatment are unlikely to be detected in randomised trials involving hundreds of patients. However, a systematic review of over 10,000 patients reported no instances of severe adverse events or toxicity.34 It is important to note that those at highest risk, including pregnant women, infants and the immunocompromised (as a result of HIV-AIDS or malnutrition) may be systematically excluded from therapeutic efficacy studies.This is particularly important for potentially lifethreatening adverse effects that are not clinically apparent, such as neutropenia or hepatotoxicity. Both require routine laboratory monitoring for early detection, which is not achievable in most health care facilities situated in the tropics.

A. Reintroduction of DDT for Indoor Residual Spraying (IRS) of traditional structures in KZN in March 2000

7000

Jan-97

Adverse events

Number of notified malaria cases

Malaria diagnosis is usually based on clinical symptoms, often resulting in misdiagnosis in patients presenting with a disease caused by another pathogen that will not respond to malaria treatment. In areas with higher intensity malaria transmission, even the introduction of definitive diagnosis would not fully address this problem, as many malaria FIGURE 2. NUMBER OF NOTIFIED MALARIA CASES infections are asymptomatic. Thus the IN KWAZULU-NATAL, SOUTH AFRICA BY MONTH IN RELATION TO presence of parasites does not necesTIMING OF SIGNIFICANT MALARIA CONTROL INTERVENTIONS sarily imply that malaria is the cause of the presenting disease.

Treatment-seeking behaviour The beneficial effects on antimalarial resistance and transmission depend on ensuring that the majority of falciparum infections are treated with artemisinin-based combinations and that the use of either component alone is curtailed.This is influenced by the treatment-seeking behaviour of patients and their adherence to completing malaria treatment, as well as by the intensity of malaria transmission. In areas of high intensity malaria transmission, individuals carrying malaria parasites are frequently asymptomatic and are thus less likely to seek treatment, potentially resulting in lower ACT coverage. It is encouraging to note that despite having to carry the cost themselves, the majority (88.5%) of symptomatic patients in a Myanmar study preferred artesunate plus mefloquine over the drugs they had used before; perception of higher drug efficacy was the reason given for the preference by most.36

Costs Despite growing international evidence that ACT is one of the few effective measures available to “Roll Back Malaria”, the costs of ACTs are an important obstacle to widespread implementation. This reflects the poor documentation of the high societal and economic costs associated with antimalarial resistance, and the perceptions of healthcare providers and governments that ACT would not be affordable or sustainable in their resource-constrained environments. However, decreasing malaria transmission would result in a decrease in malaria cases and hospital admissions. Delaying the development of resistance should prolong the effective life of these antimalarials, resulting in fewer treatment failures and therefore fewer deaths and potentially lower future costs. Economic evaluations are underway to measure the cost and cost-effectiveness of implementing an ACT malaria treatment policy. Biological and economic modelling are also being used to explore how to optimise the deployment of antimalarials as well as to assess their effectiveness and impact on direct and indirect costs of malaria.37,38

Rectal artesunate Rectal administration of artesunate as initial treatment prior to referral makes it possible to provide a rapidly acting and effective drug to patients with acute malaria who are unable to take oral medication and have no access to healthcare facilities where parenteral antimalarial therapy is available. Suppositories can be safely administered in minimally-equipped health care facilities and even at home. Provided that early administration of rectal artesunate does not deter patients from reaching a health care facility able to provide further malaria treatment and appropriate supportive care, this intervention has the potential to reduce malaria-related morbidity and mortality in rural areas in

the tropics. Among the artemisinin derivatives, artesunate was selected on the basis of its rapid and broad spectrum of antimalarial activity, reliable absorption and reassuring safety and efficacy profiles in comparison to other available treatments.39,40 A thermostable suppository formulation of artesunate was chosen because unrefrigerated storage and ease of administration are essential where facilities are rudimentary. Many patients with potentially life-threatening malaria have more severe disease than those enrolled in clinical studies, with deeper levels of coma, severe acidosis, severe anaemia and impairment of pulmonary and renal function. Although minimally trained personnel can administer artesunate suppositories safely, staff (and parents) should be informed of the need to observe for the expulsion of suppositories. The time to clear a fever has sometimes been reported to be shorter with artemisinin derivatives than quinine. Although rapid fever clearance is an important clinical benefit, it does not necessarily reflect cure and may create a false sense of security; additional definitive curative treatment remains essential even if symptoms are relieved. Health care providers need to ensure that patients or caregivers understand the need for further curative treatment at a referral centre.

Scaling up ACT The scaling up of artemisinin-based combination therapy as first-line treatment policy has followed the improved cure rates, decreased malaria transmission and delayed resistance documented on the western border of Thailand.41 There is now growing international consensus that wide-scale systematic implementation of ACT is one of few effective measures that will enable malaria-endemic countries to achieve the ambitious goals set in Abuja to Roll Back Malaria, particularly the goal of cutting malaria morbidity and mortality in half by 2010.42 A statement from the World Health Organisation (WHO) released on 20 February 2002, recommended that:

“Governments…rapidly adopt more effective treatments. The aim is to provide effective treatment against malaria and to slow the spread of drug resistance... In particular, WHO recommends the use of artemisinin-based combination therapy.”43 The widespread use of ACTs was initially adopted in Southeast Asia, in Thailand and Vietnam and more recently in Cambodia, Bhutan and Myanmar. ACTs are increasingly being recommended elsewhere as first-line treatment for uncomplicated malaria in South America (western Peru, Surinam, Bolivia, Guyana and French Guyana) and in Africa (South Africa, Zambia, Gabon, Burundi and Zanzibar). Funding by the Global Fund to Fight AIDS, Tuberculosis and Malaria has largely facilitated these policy changes. 29

Policy Implementation The successful translation of policy into practice is challenging, and improvements to the public health care infrastructure required for facilitating this are beyond the scope of this chapter. However, the most important aspects include: the proactive guarantee of supplies through the early involvement of pharmaceutical services, intensive training in small groups, on-site structured monitoring visits, and the physical removal from each facility of the antimalarial drug being withdrawn and its replacement with the new treatment. The implementation of changes in malaria treatment policy has been compromised in countries without the staff and resources to do this on the scale needed to insure a complete switch in drugs (Williams HA, unpublished data 2002). Thus, implementation plans should be drafted well in advance of the date of implementation, so that adequate funds are identified to assist with additional demands on already limited health care resources.

CHALLENGES/NEXT STEPS There has been a welcome increase recently in funding for both the wide-scale public sector implementation of effective case management and for the comprehensive evaluations of such interventions within the normal context of use. Consensus is growing regarding the important role of artemisinins in malaria case management, particularly for the use of ACT as first-line treatment of uncomplicated malaria and for the rectal administration of artesunate to patients who are unable to tolerate oral treatment and do not have access to injectable treatment. There are, however, a number of questions that need to be resolved to optimise the public health benefits of these strategies. Despite the evidence available to date, concern has been expressed that the purported benefits of ACT have not yet been proven in Africa.44,45 This has motivated large-scale comprehensive evaluations of the staged introduction of ACT that are currently underway in the public sector in Southern and East Africa.46 These studies aim to establish whether ACT is cost effective (or even cost-saving) as well as whether ACT improves treatment cure rates, reduces malaria transmission, decreases morbidity and mortality and delays the emergence of resistance to affordable firstline anti-malarial therapy within the normal context of use in Africa. These studies also hope to establish how treatment-seeking behaviour and patient adherence influence the public health impact of ACTs. Tools for monitoring drug safety and adherence with treatment need strengthening, particularly in resource-poor

settings. Although more safety data is available regarding artemisinin derivatives than other antimalarials, concerns regarding safety in high-risk groups, specifically pregnant women and infants, require further monitoring. As these special risk groups carry the highest burden of malaria, addressing this need is urgent. The efficacy and safety of ACT for routine intermittent treatment through antenatal and vaccination programmes are currently being studied. Rectal artesunate has been shown to clear parasites more rapidly than parenteral quinine, although this does not necessarily lead to a clinical advantage or a decrease in mortality. Large randomised placebo-controlled studies are underway in Africa and Asia to establish whether the administration of rectal artesunate to patients unable to tolerate oral treatment in basic health care facilities where parenteral treatment is not available, decreases malariarelated hospital admissions and deaths. These studies are being conducted without other interventions, so they will reflect benefits within the normal context of use where health care providers face numerous challenges. These include the use of presumptive or clinical rather than definitive diagnosis of malaria, the high prevalence of HIV/AIDS and malnutrition, dual infections at presentation (e.g., meningitis), and the widespread use of concomitant medication (traditional and Western medicines). Concern that the rectal administration of artesunate may delay seeking definitive treatment and supportive care if needed, or that rectal artesunate may be less reliably absorbed in patients with more severe malaria, should also be answered through these studies. Changing national malaria treatment policy could be the single intervention that is most likely to enhance access to ACT, whether administered orally for uncomplicated malaria or rectally for more severe malaria. However, what is not known is how much evidence is required to change existing national treatment policy. In countries that have different transmission profiles, evidence from one or two local studies may not be sufficient to convince policy makers of the need for a national level change of policy. The guidelines most widely used are those of the WHO, which recommends implementing a malaria treatment policy change when first-line treatment fails in 25% of patients; this recommendation is considered to contribute to the prolonged use of ineffective malaria treatment, particularly since the recommended 14-day follow-up underestimates resistance.47 Up-to-date international guidelines on what constitutes adequate sentinel surveillance for determining malaria treatment efficacy and the levels of resistance at which the change process should be initiated, would facilitate rational antimalarial drug policy making. Global agencies tasked with malaria control should take a lead in preparing such guidelines. Once a minimum standard of surveillance is agreed upon, adequate resources will need to be earmarked to support this pivotal activity.

The most frequently cited obstacle to enhancing access to ACT has been its substantially higher cost per treatment course when compared to chloroquine or SP. Economic and societal costs of ineffective treatment policies need to be defined so that these can be compared with the costs of an ACT policy change. However, it is likely that the cost of such a policy change will not be affordable to many malaria endemic countries, and international funding to support this change is needed. It is of concern that the Global Fund to Fight AIDS,Tuberculosis and Malaria (GFATM) is currently spending more in the procurement of chloroquine than of ACTs in Africa, despite established widespread chloroquine resistance and an associated increase in mortality.48 This funding should rather be targeted to ensure that communities suffering from malaria are

provided with effective malaria treatment.This will require revision of the procedure for technical review of funding applications so that the mechanisms currently in place within the GFATM to ensure rational funding of secondline tuberculosis treatment can also be applied to malaria treatment.

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Snow W, Trape J, Marsh K. The past, present and future of childhood malaria mortality in Africa.Trends in Parasitology. 2001-17, 593-597.

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NJ.Antimalarial drug resistance and mortality in falciparum malaria. Trop Med Int Health 1999-4: 469-470. 5 White

NJ.The pathophysiology of malaria.Adv Parasitol 1992-31: 83-173.

von Seidlein L, Milligan P, Pinder M et al. Efficacy of artesunate plus pyrimethamine – sulfadoxine for uncomplicated malaria in Gambian children: a double blind, randomized, controlled trial. Lancet 2000-355: 352 – 57. 7

Adjuik M, P Agnamey, A Babiker, et al. Amodiaquine and artesunate versus amodiaquine for uncomplicated falciparum malaria in African children: a randomized multi-centre trial. Lancet. 2002-359 (9315): 1365-72. 8 White

NJ. Preventing antimalarial drug resistance through combinations. Drug Resistance Updates. 1998-1:3-9.

Op cit 4.

Op cit. 7.

Op cit. 6.

Through dedicated partnership between malaria endemic countries and international research and funding organisations, the ambitious goals set in Abuja to roll back malaria are achievable. The widespread use of ACT is one of the few tools currently available that can reduce morbidity and mortality from malaria and make malaria a preventable and treatable condition.

Karunajeewa HA, Kemiki A, Alpers MP, Lorry K, Batty KT, Ilett KF, Davis TM. Safety and therapeutic efficacy of artesunate suppositories for treatment of malaria in children in Papua New Guinea. Pediatr Infect Dis J. 2003-22(3): 251-6.

17 Sabchareon A, Attanath P, Chanthavanich P, Phanuaksook P, Prarinyanupharb V, Poonpanich Y, Mookmanee D, Teja-Isavadharm P, Heppner DG, Brewer TG, Chongsuphajaisiddhi T. Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria. Am J Trop Med Hyg. 1998- 58: 11-16. 18 Awad MI, Alkadru AMY, Behrens RH, Baraka OZ, Eltayeb IB. Descriptive study of the efficacy and safety of artesunate suppository in combination with other antimalarials in the treatment of severe malaria in Sudan. Am J Trop Med Hyg. 2003-68(2): 153-8. 19

Ribeiro IR, Olliaro P. Safety of artemisinin and its derivatives: A systematic review of published and unpublished clinical trials. Med Trop (Mars) 1998-58, 50 – 53.

Price R, van Vugt M, Phaipun L, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg. 1999-60, 547-555.

21 Newton P, Proux S, Green M. Fake artesunate in southeast Asia. Lancet. 2001-357 (9272): 1948-50. 22

Brewer T.G., Grate S.J., Peggins J.O., Weina P.J., Petras J.M., Levine B.S., Heiffer M.H., Schuster B.G. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 1994-51: 251-259.

McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria. In The Cochrane Library (2003), Issue 3: 1-25; Oxford: Update Software.

12 Nosten F, van Vugt M, Price R, Luxemburger C, Thway KL, Brockman A, McGready R, ter Kuile F, Looareesuwan S, White NJ. Effects of artesunate mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in Western Thailand: a prospective study. Lancet 2000-356, 297-302.

24 Bakshi R, Hermeling-Fritz I, Gathmann I, Alteri E. An integrated assessment of the clinical safety of artemether-lumefantrine: a new oral fixeddose combination antimalarial drug. Trans R Soc Trop Med Hyg 200094(4): 419-424.

Omari AAA, Preston C, Garner P. Artemether-lumefantrine for treating uncomplicated falciparum malaria (Cochrane Review). In: The Cochrane Library (2003), Issue 4. Chichester, UK: John Wiley & Sons, Ltd.

Newton PN, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. Randomised comparison of artesunate and quinine in the treatment of severe malaria. Clin Infect Dis. 2003-37(1): 7-16.

15 Luxemborger C,Thwai KL, Raimond SD, Chongsuphajaisiddhi T,White NJ. Oral artesunate in the treatment of uncomplicated hyperparasitaemic falciparum malaria. Am J Trop Med Hyg. 1995-53: 522-525.

Price R, van Vugt M, Phaipun L, Luxemburger C, Simpson J, McGready R, ter Kuile F, Kham A, Chongsuphajaisiddhi T, White NJ, Nosten F. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 1999-60, 547-555.

26 Tjitra E, Suprianto S, Currie BJ, Tjitra E, Suprianto S, Currie BJ, Morris PS, Saunders JR, Anstey NM.Therapy of uncomplicated falciparum malaria: a randomised trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia. Am J Trop Med Hyg 2001-65(4): 309-317.

van Vugt M, Looareesuwan S, Wilairatana P, McGready R, Villegas L, Gathmann I, Mull R, Brockman A, White NJ, Nosten F. Artemather lumefantrine for the treatment of multidrug resistant falciparum malaria. Trans R Soc Trop Med Hyg 2000-94: 545-548.

Leonardi E, Gilvary G, White NJ, Nosten F. Severe allergic reactions to oral artesunate: a report of two cases. Trans R Soc Trop Med Hyg. 200195(2): 182-183.

Op cit. 19.

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Yamay G. African heads of state promise action against malaria. BMJ. 2000-320: 1228.

Ibid.

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Op cit. 7. 45

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Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, Staedke SG, Gasasira A, Rosenthal PJ. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial. Lancet. 2002-360, 2031-2038.

McGready R, Cho T, Keo NK, Thwai KL, Villegas L, Looareesuwan S, White NJ, Nosten F. Artemisinin antimalarials during pregnancy: a prospective treatment study of 539 episodes of multidrug resistant Plasmodium falciparum. Clin Infect Dis. 2001-33(12): 2009-2016.

Kachur SP, Abdulla S, Barnes KI, Mshinda H, Durrheim DN, Kitua A & Bloland P. Complex, and large, trials of pragmatic malaria interventions. Tropical Medicine and International Health. 2001-6, 324-325.

47 32 Kitua AY. Antimalarial drug policy: making systemic change. Lancet. 2000-354, 32.

White NJ. The assessment of antimalarial drug efficacy. Trends Parasitol. 2002-18(10), 458-64.

48 33

Bloland PB. A contrarian view of malaria therapy policy in Africa. American Journal of Tropical Medicine and Hygiene 2003-68, 125-126. 34

Op cit. 19.

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Op cit. 1.

C ONTRIBUTORS Karen Barnes, Division of Pharmacology, University of Cape Town, South Africa; kbarnes@uctgsh1.uct.ac.za Peter Folb, Division of Pharmacology, University of Cape Town, South Africa; pfolb@uctgsh1.uct.ac.za

Hastings IM. Modelling parasite drug resistance: lessons for management and control strategies.Trop Med Int Health 2001-6(11):883-90. 38

Goodman CA, Coleman PG, Mills AJ. Changing the first line drug for malaria treatment--cost-effectiveness analysis with highly uncertain intertemporal trade-offs. Health Econ. 2001-10(8):731-49.

White NJ. Clinical Pharmacokinetics and phramacodynamics of artemisinin and derivatives. Trans. R. Soc. Trop. Med. Hyg. 1994-88 (Suppl 1): S41 â&#x20AC;&#x201C; S43.

University of Cape Town Web site: www.uct.ac.za

P OTENTIAL None.

CONFLICT OF INTEREST

Challenges in Monitoring the Impact of Interventions Against Malaria Using Diagnostics IMELDA BATES,1 JAMES IBORO,2 GUY BARNISH1 1 LIVERPOOL SCHOOL OF TROPICAL MEDICINE, UNITED KINGDOM 2 MOUNT HAGEN GENERAL HOSPITAL, PAPUA NEW GUINEA

INTRODUCTION Background Monitoring the efficacy of malaria interventions on study populations is an integral part of any well-designed research project. However, monitoring the effectiveness of these interventions once they are scaled up is much more difficult. The rigorous and comprehensive monitoring systems used in a research setting often utilise tools that are specially designed for the task and are generally independent of the local health system processes. These monitoring tools may be too cumbersome and expensive to be used long-term for monitoring interventions once they expand outside of the research setting. During initial research studies, little attention is often paid to identifying mechanisms that are practical, feasible and affordable for monitoring whether interventions are successful in a real life context. Monitoring at this level relies on local systems, which are often of variable and unknown quality.

Reasons for studying malaria monitoring tools The tools that are most commonly used to provide information about malaria status of individuals, communities and populations are clinical algorithms, rapid diagnostic tests and direct visualisation of malaria parasites by microscopy of peripheral blood samples. Large-scale epidemiological studies have also utilised serological and molecular techniques that lend themselves to rapid processing of large numbers of samples. This chapter will provide an overview of malaria-specific diagnostic tools that are commonly used at different levels within a country â&#x20AC;&#x201D; from villages and peripheral health facilities to national and research institutions. It will also consider local capacity to apply these tools to provide accurate data. Monitoring the impact of interventions for improved malaria control relies on appropriate use of good quality diagnostic tools.

ROLE

OF EVIDENCE

The following sections will consider the range of different approaches that can be used to monitor the impact of interventions on malaria and highlight some of the benefits and drawbacks of each. This topic does not easily lend itself to study by large randomised trials and the majority of studies cited have been field-based and conducted on relatively small samples. Much of the research in this area concentrates on the assessment of the usefulness of various types of rapid diagnostic tests for malaria. These tests have generally been compared to light microscopy or polymerase chain reaction or to results from a combination of both techniques. Studies aimed at identifying individual or groups of diagnostic features, or refining algorithms for clinical diagnosis of malaria have generally used direct visualisation of malaria parasites by microscopy as the â&#x20AC;&#x2DC;gold standardâ&#x20AC;&#x2122; for diagnosis. However it is widely recognised that microscopy has significant limitations when used in this way for the case definition of malaria. Microscopy depends on sophisticated technical skills and even in the best hands, low-level parasitaemia and parasites sequestered in deep tissues may be missed. Furthermore, visualisation of parasites does not necessarily indicate that malaria is responsible for symptoms, especially in immune populations that may have asymptomatic infections.

Evaluation of tools for monitoring implementation i) Monitoring in communities and peripheral health facilities Presumptive diagnosis and clinical algorithms The main malaria-specific methods for monitoring interventions at the community level are presumptive diagnosis and clinical algorithms. In practice, presumptive diagnosis usually means that all cases of fever in endemic areas are treated as malaria. Clinical algorithms have been developed to improve the accuracy of malaria diagnosis. They are more complex than presumptive diagnosis because they rely on a combination of signs and symptoms. For example, in Papua New Guinea, the 33

presence of fever, anaemia and splenomegaly (enlargement of the spleen) in the absence of other obvious causes of fever was highly predictive of malaria.1 Despite the lack of a ‘gold standard’ for clinical case definition,2 most cases of malaria in rural clinics in endemic countries are diagnosed on clinical features alone.1 The accuracy of presumptive diagnosis based on fever as recommended by the World Health Organization (WHO)3 depends on knowledge of the local prevalence of malaria. This is influenced by many factors including seasonal and climate variations. Attempts have been made to improve the sensitivity and specificity of clinical diagnosis by incorporating fever with other indicators (e.g., level of temperature, lack of cough) and developing these into algorithms that can be followed by field workers. The increasing prevalence of HIV/AIDS, which is associated with non-malaria fever, has made the accuracy of clinical diagnosis alone doubtful in some areas.4 It is difficult to extrapolate from one area to the next because clinical criteria with the best predictive value for malaria are site specific (depending on prevalence and local patterns of drug resistance), and vary with the expertise of the health worker. Presumptive diagnosis or clinical algorithms may therefore only be useful in specific, restricted localities. They are not sensitive enough to accurately detect the changes from baseline levels of malaria that will occur when a new intervention is scaled up to a large population. Furthermore they need to be backed up by accurate, locally relevant sentinel surveys for malaria or by using laboratory-based technologies to monitor at static sites.

Rapid Diagnostic Tests To be appropriate for monitoring malaria interventions in individuals in large populations, the ideal rapid test for malaria needs to be robust, cheap, and simple to perform and interpret. Much progress has been made in the development of rapid diagnostic tests to make them applicable for use in communities by non-technical field workers. Although there are many different types of rapid diagnostic kits available for malaria, most have a similar format. They are designed for use with blood samples obtained from a finger prick. The sample is applied to a ‘stick’ that contains malaria-specific reagents. When additional chemicals, which are supplied with the test kit, are added, a reaction takes place and a coloured band appears on the stick if the patient has malaria. Rapid diagnostic tests are simple to perform and interpret, do not require electricity or special equipment and can be shipped and stored under ambient conditions. Health workers with minimal skills can be trained to use them in three hours to one day with good retention of skills over a one-year period.5,6 Rapid diagnostic tests are based on the detection of the malaria parasite antigens HRP-2 or pLDH and their sensi34

tivity and specificity is gradually improving with new generations of tests. They perform well for malaria detection both in immune and non-immune populations.7 Rapid diagnostic tests generally achieve a sensitivity of >90% in detecting P. falciparum at densities of above 100 parasites per µl blood. Below this level sensitivities decrease markedly. At the present time there are no commercial rapid tests that are able to differentiate reliably between P. vivax, P. ovale and P. malariae. Since rapid diagnostic tests detect circulating antigens, they can identify P. falciparum infection in peripheral blood even when the parasites are sequestered in tissues.This may be particularly useful in monitoring the impact of interventions in pregnant women as HRP-2 from P. falciparum sequestered in the placenta can be detected even though blood smears are negative.8 One of the major drawbacks of tests based on the HRP-2 antigen is that the antigen may persist in the blood for 1-2 weeks after treatment and the tests are unable to differentiate between new and treated infections.This is not the case with pLDH-based tests, which detect only viable parasites and become negative as parasites disappear from the blood. Consequently pLDH-based tests are useful for monitoring interventions such as responses to drug therapy and for detecting early reappearance of drug-resistant parasites. pLDH detection provides better discrimination between P. falciparum and P. vivax than HRP-2 based tests9 but the correlation in the results of these tests and microscopy is weaker at very low parasite densities. Because rapid diagnostic tests are not quantitative, they cannot provide prognostic information based on parasite densities. Rapid diagnostic tests have been evaluated extensively in diverse clinical situations, in both endemic and nonendemic countries.The utility of some of these assessments has been compromised by variations in methodologies and small sample sizes. In specific situations where microscopy is not available such as war zones, refugee camps, and during other complex emergencies and epidemics,10,11 rapid tests may be particularly useful for monitoring the impact of malaria interventions. Rapid diagnostic tests were found to have unacceptably high rates of false-negative results when used by travellers for self-diagnosis of malaria. This suggests that in their present form, rapid diagnostics are unlikely to be suitable for self-monitoring of malaria interventions.12, 13,14 Although rapid diagnostic tests have several advantages over microscopy (Table 1), they are generally too expensive for widespread use in monitoring the impact of interventions. The kits currently available are more expensive than microscopy, with cost per test varying from US$ 0.60 to US$ 2.50.15

TABLE 1. COMPARISON OF THE REQUIREMENTS, PERFORMANCE, DIRECT COSTS AND TECHNICAL SPECIFICATIONS OF MICROSCOPY AND RAPID DIAGNOSTIC TESTS15 Microscopy

RDTs

Training

Microscope Preferred, not necessary Blood collection,staining reagents and supplies, water Trained microscopist

None None Blood collection (supplied in some kits) Only minimal training required

PERFORMANCE Test duration Labour-intensiveness Subjectivity Robustness

Usual minimum 60 minutes High High Average

15-20 minutes Low Low High

DIRECT COST Cost per test

US$ 0.12 - 0.40

US$ 0.60 - 2.50

5 - 10 parasites/µL Yes Possible Possible

40 - 100 parasites/µL Some RDTs Not possible Not possible

Possible

Not possible

Yes

Not applicable

Some RDTs

REQUIREMENTS Equipment Electricity Supplies

TECHNICAL SPECIFICATIONS Detection threshold Detection of all species Quantification Differentiation between P. vivax, P. malariae and P. ovale Differentiation between sexual and asexual stages Detection of (P. falciparum) sequestered parasites Antigen persistence

ii) Monitoring by district and regional health facilities with a laboratory Direct visualisation of malaria parasites in peripheral blood Microscopy of stained blood films: In addition to its use in clinical management and public health, microscopy of stained blood films is the ‘gold standard’ for monitoring the impact of malaria interventions in research studies. A small drop of blood is spread on a glass slide and allowed to dry before being stained. When examined by light microscopy using high power, malaria parasites can be seen as small dark dots inside red blood cells. Microscopy allows quantification of parasites and identification of different

species and is an essential tool for all surveillance and diagnostic health laboratories. It is cheap, varying from US$ 0.40 - 0.70 per slide16 and is sensitive and specific. A skilled microscopist is able to detect parasitaemia as low as 0.01-0.001%.5,17 However, provision of an accurate microscopy service depends on sophisticated technical skills, supervisory and training networks, constant supplies of high quality reagents, electricity and regular maintenance of microscopes. These requirements, combined with the time it takes to do each test, mean that microscopy is not usually suitable for evaluation of malaria interventions at the community level where fast processing and user-friendliness are essential.

Microscopy of fluorescent parasites in blood: Acridine orange can be added to blood samples to improve the speed and sensitivity of detection of malaria parasites. Acridine orange is a fluorescent marker that causes the parasites to fluoresce.They can be visualised with a specially adapted microscope and this principal has been used as the basis of the QBCÂŽ method. This involves centrifuging blood in a special capillary tube containing a float and coated with acridine orange. The upper layer of red cells, which contains the parasites, is visualised using fluorescence microscopy in the space between the float and the capillary tube. The disadvantages of techniques based on inducing parasite fluorescence, such as the need for special microscope filters and its lesser ability to quantify and speciate parasites, mean that it may not be a better alternative than routine microscopy for large-scale monitoring.18-21

Malaria antibody detection Malaria antibodies are detectable in the blood a few days after infection and may persist for many years.22 Tests based on the detection of malaria antibodies are therefore of little value for monitoring the impact of interventions on acute malaria illness. There are various techniques for detecting malaria antibodies in blood samples such as indirect fluorescent antibody (IFA) test, enzyme-linked immunosorbent assay (ELISA) and indirect haemagglutination antibody (IHA) that enable large numbers of samples to be processed quickly. Serological techniques for antibody detection (unlike microscopy, PCR and antigen detection) are an important tool for epidemiological monitoring because they permit evaluation of past exposure to malaria. Examples of the use of serological techniques in epidemiological studies include detection of altitude boundaries of transmission in Africa, identification of residual transmission foci in Tunisia after control activities, confirmation of malaria eradication from Mauritius and Greece and the validation of chemoprophylactic malaria control in Panama.22 iii) Monitoring by central reference or research laboratories Malaria antigen detection by ELISA Detection of malaria antigens using ELISA is highly specific and sensitive for P. falciparum malaria infections and, unlike antibody detection methods, it does not remain positive for long periods after the initial infection. However, it may be positive for a few days after parasites have disappeared from the peripheral blood and are no longer detectable by microscopy.23 This technique lends itself to screening of large batches of samples and can be used on specimens that have been frozen and thawed.

PCR-based molecular detection methods Polymerase chain reaction (PCR)-based techniques are being increasingly used at both the individual and popula-

tion level to supplement information obtained from microscopy or rapid diagnostic tests. These methods rely on detecting very small amounts of malarial DNA and can be used on many different types of tissues including blood samples. It is now possible to adapt PCR techniques so that they are able to quantify a vast range of levels of parasitaemia from 50â&#x20AC;&#x201C;108 parasites/ml of blood making the method 20-50 times more sensitive than conventional microscopy. PCR-based techniques are also highly speciesspecific making them particularly useful for demonstrating mixed infections that are often missed by microscopy.24 PCR techniques are playing an increasingly important role in wide-scale monitoring of malaria interventions. It is now possible to collect dried blood spots on filter paper in the field and to obtain satisfactory sensitivity results for PCR detection of P. falciparum up to six months after collection.25 The ability of PCR techniques to provide information about the epidemiology and geographical distribution of different Plasmodia species in insect and human hosts makes it an important technique for expanding knowledge about parasite biology and disease pathogenesis in the population.26 PCR techniques are also able to discriminate drugresistant P. falciparum strains from drug-sensitive ones by identifying point mutations and PCR may thus have an important role in demonstrating the effect of interventions on changes in the epidemiology of drug-resistance.27 Stringent and expensive precautions are required to minimise the rate of contamination of PCR with irrelevant DNA fragments28 and the cost of equipment, supplies and expertise means that the technique is only available in specialised laboratories, mainly in industrialized, malaria-free countries.

Implementation of malaria monitoring strategies Clinical diagnosis alone is not sufficiently accurate to be used as a monitoring tool for assessing the impact of malaria interventions in malaria-endemic regions. It can be reasonably accurate if the algorithm is specifically designed for use within a well-defined area. For example, two different studies in The Gambia showed that a sensitivity of 70-88% and specificity of 63-82% for malaria diagnosis could be achieved using a weighting and scoring system for clinical signs and symptoms.29,30 These methods may be too complicated to implement and supervise and many of the key symptoms and signs of malaria in one area may not be applicable elsewhere. For instance, shivering and chills are associated with clinical malaria in Ethiopia31 but not in India.32 Reduced feeding is more likely to indicate malaria in The Gambia than in India and Ethiopia.29,30 The inaccuracy of presumptive diagnosis, the complexity of clinical algorithms and the lack of transferability mean that a monitoring system based solely on clinical findings is not likely to be useful for widespread monitoring of malaria interventions.

The simplicity and accuracy of rapid diagnostic tests, particularly those that do not remain positive once the acute malaria infection has subsided, make them well-suited for use in monitoring the impact of malaria interventions by non-technical staff. Their major drawback for use in endemic areas is their inability to provide information about parasite density. This information is needed because the same level of parasitaemia has different clinical implications depending on the context. For example, a young child with low-level parasitaemia may have serious malarial disease and require urgent treatment whereas the same parasite density in an immune adult may indicate asymptomatic parasitaemia, yet both will have the same positive rapid test result. The inability of rapid tests to clearly differentiate between different malaria species will also limit their usefulness in areas where mixed infections are common.These difficulties mean that the use of rapid diagnostic tests for monitoring malaria interventions will need to be carefully supervised and the results interpreted with caution. Despite this there have been several studies from high transmission areas, for example in Tanzania,6 Uganda33 and India,34 which show that rapid diagnostic tests are an effective tool for malaria monitoring when used in field situations by rural health workers with minimal training. Techniques such as ELISA can be used for large-scale epidemiological studies where hundreds of stored samples need to be screened for malaria. These methods can be adapted to detect either malaria antibodies or soluble antigens depending on whether information about past or present malaria exposure is needed for monitoring purposes. Molecular malaria detection methods can be extremely sensitive and have an increasingly important role to play in studies of the distribution, biology and drug resistance patterns of Plasmodia species. For example PCR was able to identify and unexpectedly high incidence of P. malariae and P. ovale infections in villagers in Guinea Bissau that were missed by conventional light microscopy.35 However, in highly endemic areas, where the whole population has frequent exposure to malaria, the ability of molecular methods to detect minute traces of malarial material may limit its usefulness as a general screening tool for malaria. Other major drawbacks of the use of PCR as a malaria monitoring tool are contamination, lack of expertise and facilities in resource-poor countries, and cost.

CHALLENGES/NEXT

STEPS

The way forward Clinical diagnosis when used alone results in considerable over-diagnosis. If expensive combination therapy for malaria is introduced widely, clinical diagnosis may not be cost-effective as either a diagnostic or monitoring tool. This will have significant impact on malaria management particularly within programmes such as Integrated Management of Childhood Illnesses (IMCI), that rely on a syndromic approach. Further studies are urgently needed to determine whether this approach to monitoring malaria has a role in specific settings and to clearly define the situations where it may be useful. The high prevalence of HIV/AIDS in many countries where malaria co-exists further complicates efforts to refine the clinical diagnosis of malaria. More research is needed to clarify the exact nature of the interaction between malaria and HIV/AIDS and the clinical implications of this interaction. Rapid diagnostic tests which detect pLDH can be used reliably in field conditions by rural health workers with minimal training. Evidence is accumulating to show that these tests appear to be better than clinical diagnosis alone for monitoring malaria infections and can be used in situations such as mobile surveys, where microscopy is not possible. Further work is needed to enable these tests to be able to measure parasite quantity and to reliably identify different species. Unless the cost of rapid tests can be reduced, they are unlikely to be used by poorer countries on a large scale in malaria monitoring programmes. For monitoring large-scale malaria interventions, when samples can be batched and hundreds screened at a time at a central laboratory, methods such as ELISA are more appropriate than individual test kits. A central facility in each country which has malaria serological and PCR capability would be able to track regional, national and sub-national trends in malaria epidemiological patterns and provide high-quality data to guide decisions about important malaria-related issues such as setting appropriate drug policy.

R EFERENCES 1 Genton B, Smith T, Baea K, Narara A, Al-Yaman F, Beck PH, Hii H, Alpers M: Malaria: how useful are clinical criteria for improving the diagnosis in a highly endemic area? Trans Roy Soc Trop Med Hyg 1994, 88:537-541.

21 Petersen E, Marbiah NT: QBC ® and thick blood films for malaria diagnosis under field conditions.Trans Roy Soc Trop Med Hyg 1994, 88: 4116417. 22

Voller A:The immunodiagnosis of malaria. In Malaria. Principles and practice of malariology, vol.1.Wernsdorfer WH, McGregor I, eds. Edinburgh, Churchill Livingstone, 1988, 815-825.

World Health Organization. A standard protocol for assessing the proportion of children presenting with febrile disease who suffer from malarial disease. Geneva, World Health Organization, 1994 [unpublished document WHO/MAL/94.1069; available on request from Division of Control of Tropical Diseases (CTD)].

World Health Organisation: The overlap in the clinical presentation and treatment of malaria and pneumonia in children: report of a meeting, Geneva, 8 April 1991. Geneva: World Health Organisation, mimeographed document no.WHO/MAL/92.1065:1992.

Nwanyanwu OC, Kumwenda N, Kazembe PN, Jemu S, Ziba C, Nkhoma WC, Redd SC: Malaria and human immunodeficiency virus infection among male employees of a sugar estate in Malawi. Trans Roy Soc Trop Med Hyg 1997, 91:567-9.

World Health Organisation. Malaria diagnosis. Memorandum from a WHO meeting. Bull Wld Hlth Org 1988, 66:575.

Premji Z, Minjas JN, Shiff CJ: Laboratory diagnosis of malaria by village health workers using the rapid manual ParaSight ®-F test. Trans Roy Soc Trop Med Hyg 1994, 88: 418.

7 World Health Organization: A rapid antigen capture assay for the diagnosis of falciparum malaria. Bull Wld Hlth Org 1996, 74:47-54. 8 Leke RFG, Djokam RR, Mbu R, Leke RJ, Fogako J, Megnekou R, Metenou S, Sama G, Zhou Y, Cadigan T, Parra M,Taylor DW: Detection of the Plasmodium falciparum antigen histidine-rich protein 2 in blood of pregnant women: Implications for diagnosing placental malaria. J Clin Microbiol 1999, 37:2992-6.

Voller A, Bidwell DE, Chiodini PL: Evaluation of malaria antigen ELISA.Trans Roy Soc Trop Med Hyg 1994, 88:188.

Brown A, Kain KC, Pipithkul J, Webster HK: Demonstration by the polymerase chain reaction of mixed Plasmodium falciparum and P. vivax infections undetected by conventional microscopy. Trans Roy Soc Trop Med Hyg 1992, 86:609-612.

25 Long GW, Fries L, Watt GH, Hoffman SL: Polymerase chain reaction amplification from Plasmodium falciparum on dried blood spots. Am J Trop Med Hyg 1995, 52: 344-6133. 26

Viariyakasol S, Siripoon N, Petcharapirat C, Petcharapirat C, Jarra W, Thaithong S, Brown KN, Snounou G: Genotyping of Plasmodium falciparum isolates by the polymerase chain reaction and potential uses in epidemiological studies. Bull Wld Hlth Org 1995, 73:85-95.

27 Peterson DS, Di Santi SM, Povoa M, Calvosa VS, Do Rosario VE, Wellems TE: Prevalence of the dihydrofolate reductase Asn-108 mutation as the basis for pyrimethamine-resistant falciparum malaria in the Brazilian Amazonas. Am J Trop Med Hyg 1991, 49: 364-9. 28

Wilson SM: Applications of nucleic acid based technologies to the diagnosis and detection of disease.Trans Roy Soc Trop Med Hyg 1993, 87:609611.

29 Bojang KA, Obaro S, Morison LA: A prospective evaluation of a clinical algorithm for the diagnosis of malaria in Gambian children. Trop Med Int Health 2000, 5(4):231-6.

Lee MA, Aw LT, Singh M: A comparison of antigen dipstick assays with polymerase chain reaction (PCR) technique and blood film examination in the rapid diagnosis of malaria. Ann Acad Med Singapore 1999, 28:498-501.

30 Olaleye BO, Williams LA, D’Alessandro U, Weber MM, Mulholland K, Okorie C, Langerock P, Bennett S, Greenwood BM: Clinical predictors of malaria in Gambian children with fever or a history of fever.Trans Roy Soc Trop Med Hyg 1998, 92:300-4.

Allan R, Nam S, DoullL: MERLIN and malaria epidemic in northeast Kenya. Lancet 1998, 351:1966-7.

Muhe L, Oljira B, Degefu H, Enquesellassie F, Weber WM: Clinical algorithm for malaria during low and high transmission seasons. Arch Dis Child 1999, 81:216-220.

World Health Organisation: A global Strategy for malaria control. Geneva:World Health Organisation, 1993.

Bassett MT,Taylor P, Bvirakare J, Chiteka F, Govere E: Clinical diagnosis of malaria: can we improve? J Trop med Hyg 1991, 94:65-9.

Jelinek T, Amsler L, Grobusch MP, Nothdurft HD: Self-use of rapid tests for malaria diagnosis by tourists. Lancet 1999, 354:1609.

Kilian AHD, Mughusu EB, Kabagambe G, von Sonnenburg F: Comparison of two rapid, HRP2-based diagnostic tests for Plasmodium falciparum.Trans Roy Soc Trop Med Hyg 1997, 91:666-667.

34 Singh N,Valecha N: Evaluation of a rapid diagnostic test ‘DetermineTM malaria pf ’ in epidemic-prone forest villages of central India (Madhya Pradesh). Ann Trop Med Parasit 2000, 94(5):421-7.

Funk M, Schlagenhauf P, Tschopp A, Steffen R: MalaQuick versus ParaSight-F as a diagnostic aid in traveller’s malaria. Trans Roy Soc Trop Med Hyg 1999, 93:268-272. Trachsler M, Schlagenhauf P, Steffen R: Feasibility of a rapid dipstick antigen-capture assay for self-testing of travellers’ malaria. Trop Med Int Health 1999, 4:442-7.

Snounou G, L Pinheiro, A Goncalves, L Fonseca, F Dias, K. Niel Brown, K.V. do Rosario. The importance of sensitive detection of malaria parasites in the human and insect hosts in epidemiological studies, as shown by analysis of field samples from Guinea Bissau. . Trans Roy Soc Trop Med Hyg 1993, 87:649-653.

16 Essential Medical Laboratory Services project. Malawi 1998-2002. Ministry of Health and Population, Malawi and Liverpool School of Tropical Medicine, UK.

C ONTRIBUTORS

World Health Organization. Malaria Diagnosis: New Perspectives. Report of a joint WHO/USAID Informal Consultation, 25-27 October 1999.WHO/CDS/RBM/2000.14 WHO/MAL/2000.109.

Imelda Bates, Malaria Knowledge Programme, Liverpool School of Tropical Medicine, UK; ibates@liverpool.ac.uk.

James Iboro, Mount Hagen General Hospital, Highlands Province, Papua New Guinea; jiboro@yahoo.com.au.

World Health Organisation: Severe and complicated malaria. Second edition.Trans Roy Soc Trop Med Hyg 1990, 84 (Suppl.2): 23-5. Baird JK, Purnomo, Jones TR: Diagnosis of malaria in the field by fluorescence microscopy of QBC ® capillary tubes. Trans Roy Soc Trop Med Hyg 1992, 86: 3-5.

19 20

Anonymous: QBC ® malaria diagnosis. Lancet 1992, 339: 1022-3.

Bawden M, Malone J, Slaten D: QBC ® malaria diagnosis: easily learned and effectively applied in a temporary military field laboratory. Trans Roy Soc Trop Med Hyg 1994, 88: 302.

Guy Barnish, Malaria Knowledge Programme, Liverpool School of Tropical Medicine, UK; gbarnish@liv.ac.uk. Liverpool School of Tropical Medicine Web site: www.liv.ac.uk/lstm/lstm.html.

P OTENTIAL None

CONFLICT OF INTEREST

Effective Delivery Methods for Malaria Treatment KAMINI MENDES, ANDREA BOSMAN, PETER OLUMESE, PASCAL RINGWALD, CLIVE ONDARI, WILSON WERE WORLD HEALTH ORGANIZATION

INTRODUCTION Effective drugs to treat malaria combined with insecticides and other mosquito vector control strategies constitute the principal tools for combating malaria today. While the tools used for malaria control have changed very little in the past 50 years, strategies and approaches for delivering them have developed significantly. Malaria eradication campaigns of the 1950s and 1960s approached the delivery of interventions through highly regimented ‘vertical’ programmes. This approach achieved high degrees of coverage in a short space of time, which is essential for an eradication strategy.1-3 However, following this period of intense effort, eradication campaigns failed in their ultimate goal of completely eliminating malaria in all but a few countries. As a result, the morale of campaign managers crumbled, global commitment waned, and systems put into place for the delivery of antimalarial interventions gradually collapsed. Under these circumstances, the vertical channels for delivering interventions were difficult to sustain. This, together with growing drug and insecticide resistance, led to a global resurgence of malaria. Moreover, serious efforts to achieve adequate intervention coverage in a number of sub-Saharan African countries, apart from those in time-limited projects and studies, were never undertaken. Roll Back Malaria (RBM), the most recent globally co-ordinated effort against malaria, bases its concepts on the understanding that ‘eradication-type’, disease-specific efforts are generally unsustainable.2,4,5 RBM is a partnership between the World Health Organization (WHO), the United Nations Development Programme (UNDP), the United Nations Children's Fund (UNICEF) and the World Bank with the goal of halving the world's malaria burden by 2010.The RBM partnership also includes national governments, civil society and non-governmental organizations, research institutions, professional associations, development agencies and banks, the private sector and the media. In the case of malaria, eradication is too lofty a goal for much of the world given the nature of the tools we have today. Instead, RBM proposes to deliver malaria interventions through integrated health systems, and in doing so, strengthen their capacity to deliver care for other diseases as well.4-6

Background Why treat effectively and early? The aim of treating malaria is to eliminate blood parasites in the infected person and thus bring about a clinical cure. Doing so will shorten the duration of illness and reduce morbidity. If P.falciparum malaria infection is left to its own course, it will, in a proportion of non-immune persons, progress to a severe and complicated form that could be fatal. Appropriate and effective treatment, if given early enough, will substantially reduce the risk of death by arresting the progression of the disease. Whilst the benefits of early and effective treatment of malaria may appear to be obvious, it has nevertheless been the subject of controversy. There has, in particular, been debate about whether the million or so child deaths from malaria in Africa could in fact be prevented by improving access to effective treatment. Due to very high rates of transmission of malaria in subSaharan Africa, it is the very young (children under five) who have not yet developed protective immunity that are most vulnerable to the illness. In some of these children, the disease will progress rapidly to severe malaria and death. Child deaths often occur where health systems are weak and communities are dispersed over vast areas of land and poorly served by transport and communication facilities. In such situations, access to antimalarial treatment is limited and is thought to contribute to the high burden of malaria mortality. Nonetheless, given the rapid clinical course of malaria in young children it is unclear whether there is sufficient time to intervene with treatment to be able to save lives, and if improving access to treatment will reduce malaria mortality in Africa. A recent controlled study in Ethiopia illustrates that training and availability of antimalarial treatment near the home and in the community lead to significant reductions in malaria mortality in children (Figure 1).7 These results were achieved by empowering mothers to recognize malarial episodes and promptly dispense treatment. In addition, uncontrolled studies in Burkina Faso8,9 where health workers and caregivers were trained in dispensing antimalarial treatment led to a reduction in the incidence of severe malaria (Figure 1). Other descriptive studies10,11 also indicate that 39

improving access to treatment through enhancing the performance of health facilities to offer treatment for malaria leads to better malaria outcomes. Cost effectiveness of treating malaria In addition to the impact on disease progression, early and effective treatment has been found to be one of the most cost-effective interventions for malaria.12,13 Even with more expensive artemisinin- based combination therapies (ACTs), the cost of treating malaria14 is estimated to be well below

achieve this under the often harsh and difficult circumstances in which malaria prevails is discussed in the remainder of the chapter. The targets of malaria treatment are primarily the poor (often the very poor) who are usually left behind by market forces, under-served by health services, have little access to health information and may not be able to utilise the services available. Recognizing these challenges, we propose an approach that is guided by the principles governing health care delivery today: Delivery of malaria treatment must be fully integrated into the rest of the health system; vertical approaches are to be avoided.

■

FIGURE 1. IMPACT OF IMPROVING ACCESS TO ANTIMALARIAL TREATMENT: SUMMARY FINDINGS FROM A CONTROLLED CLINICAL TRIAL IN ETHIOPIA7 AND AN UNCONTROLLED STUDY IN BURKINA FASO9

Prompt recognition of malaria symptoms and treatment with chloroquine reduces under-5 mortality by 40% in 2 districts with hyper-and holoendemic malaria in Ethiopia

■ The private sector, which can play an important role in delivering health care, should be engaged.

no intervention

IMPLEMENTATION ISSUES

intervention

Integrated delivery of malaria treatment through the health care system 0

% overall <5 mortality per 1000 child-years

Early treatment of fevers in children under 6 years of age with pre-packaged anitmalarial drugs in the home reduces morbidity from malaria in rural malaria-endemic Burkina Faso no intervention intervention 0 4 8 12 % children progressing to severe malaria Reprinted from WHO/RBM Africa Malaria Day Report 2003 (courtesy of A. Reinisch)

the Gross Domestic Product (GDP) per capita of malaria endemic countries per Disability Adjusted Life Year (DALY) saved, the threshold below which interventions are deemed highly cost effective for poor countries.6 Providing effective treatment is a challenge; however an even more difficult yet critical element, particularly for children in Africa, is how to deliver treatment early and fast enough to save lives. How and what is being done to

■ Institution-based health systems alone cannot effectively meet the demands of malaria treatment; communities themselves have to be empowered to deliver antimalarial treatment nearer the home.

Current public sector health care delivery systems are organised on the basis of integration of services and decentralisation of the health system.15 Financing of health care is often through sector-wide approaches (SWAps),16 which seek to avoid verticality or ‘ear-marking’ of funds. Malaria at the heart of health systems strengthening For several reasons that are linked to the nature of the disease, malaria calls loudly for a response from the health system. Where the disease is endemic, it is often responsible for high disease burden accounting for as much as 40% of out-patient attendances; absorbing 30% of hospital beds and a significant proportion of national public health budgets. It is a disease with a high turnover – i.e., a short duration of illness and a high incidence. Malaria manifests acutely in a manner that compels the patient to seek treatment. Moreover, malaria engages almost all levels of the system. At the most peripheral level, malaria treatment entails diagnosis and treatment of fever and, when appropriate, referral; at the secondary and tertiary levels, it calls for the treatment of severe and complicated illness that requires institution-based intensive care.Thus the need for a response to malaria makes a compelling case for strengthening health systems in endemic countries. Delivering effective treatment for malaria within a health system entails addressing multiple issues including:

Efficient drug procurement, supply and distribution systems;

■

Quality-controlled laboratory services for diagnosis;

■

Health staff trained in disease management;

■

Systems to monitor drug efficacy and quality;

■ Facilities for referral of severe malaria patients to higher levels of care.

However, these services are often far from satisfactory in areas where malaria’s burden is greatest. For most people living under the threat of malaria, health facilities are beyond reach in less than 24 hours, antimalarial drug stockouts are frequent, diagnosis is often based on clinical judgement and referral facilities such as ambulances are rarely available. It is therefore not surprising that public sector health services are under-utilised and bypassed as a source of malaria treatment even by people living in poverty. Addressing malaria through Integrated Management of Childhood Illness Integrated delivery of health care entails incorporating malaria diagnosis, treatment and referral into the general health services. Where malaria is primarily a childhood illness such as it is in Africa, clinical management of malaria forms an essential part of the Integrated Management of Childhood Illness (IMCI), a strategy that aims to strengthen the quality of care in health facilities.17-19 Malaria diagnosis, treatment and referral at facility level constitute important components of the clinical management algorithms of IMCI. By strengthening quality assurance and quality control for malaria commodities and services, as well as by enhancing national and regional drug procurement services in settings where a major proportion of facilities cater for malaria, health service capacity for other diseases will be improved.

Community and Home Management of Malaria The rationale for treatment near the home Even the most effective health facilities are unlikely to meet all treatment needs as the worst malaria situations occur in remote and rural areas and among marginalised populations, ethnic minorities and forest dwellers in Africa, Asia and Latin America. As transport facilities are also scant in these settings, the likelihood of reaching a functional health facility in time is very low. Recognizing these constraints, programmes have sought to make treatment available as near the home as possible, whether in the community or in the home itself. This strategy is referred to as “Home Management of

Malaria”.7,20,21 The time element in accessing effective treatment – now generally acknowledged to be within 24 hours of the onset of illness in the case of a non-immune person – is critical to saving child lives in Africa and reducing child and adult mortality in other endemic regions of the world.22,23 Therefore, one of the most important strategies to reduce childhood malaria deaths is home management of malaria. This strategy entails educating community health workers, volunteers and/or mothers to recognise symptoms suggestive of malaria and deliver appropriate antimalarial drugs. There is already considerable experience with community and home management of malaria within smallscale projects in African countries,21,24 and efforts are currently under way to scale up such programmes on a nation-wide basis in Uganda, Ghana and Ethiopia. The principles of home management are very much embodied in West Africa’s community health programmes. The Indian sub-continent also has a wealth of experience with community-based health interventions, which is being drawn upon for malaria. The multiple demands of Home Management The implementation of home management of malaria places heavy demands on resources, planning and management. It involves engaging communities, training cadres of community health workers, pre-packaging drugs and putting in place supervisory and simple monitoring systems. It requires intensive support from public health services, particularly from the peripheral health facilities. But perhaps the most valuable, and also the most vulnerable component of these programmes, is the human resource element — community health workers or their equivalents, whether community volunteers, shop keepers or mother co-ordinators who frequently function on a voluntary basis. In many Asian countries, the backbone of effective public health programmes has been cadres of village level workers (i.e., midwives and public health inspectors in Sri Lanka (Personal Communication, Ministry of Health, Sri Lanka) and multipurpose workers in India (Personal Communication, Ministry of Health, India)) who are on a government payroll. In Africa, experiences with community health nurses in Ghana (Personal Communication, Ministry of Health, Ghana) show the importance of an investment in the community level of health care. Governments need to consider how these persons can be remunerated to prevent the currently high and unaffordable loss of trained personnel within these programmes.

The role of the private sector in delivering treatment for malaria The private sector represents both a solution and a problem. In nearly all situations where malaria is a major health problem today, the private sector plays a significant role in deliv-

ering antimalarial treatment, and in some affected communities it may be the sole provider of life-saving medicines. As a network of small-scale traders and peddlers, the private sector sells a variety of goods from food to household items and drugs. While its motive is profit, the private sector may offer the best option for making treatment accessible to those in remote communities who would otherwise have to travel long distances to reach health facilities. Once having reached the facility, it is all too frequent to find them functioning poorly, out-of-stock of antimalarial drugs and offering no more than a clinical diagnostic service and referral back to the drug sellers for purchasing treatment. It is therefore imperative to engage and train local drug vendors in the basics of disease recognition as well as in proper prescription and referral practices, which form an integral component of home management of malaria in Africa today.20 Although it is an important channel of delivering antimalarial drugs, the informal private sector is also a source of some major challenges in malaria treatment delivery. As it usually comprises a large number of unregulated and unregistered drug sellers, investment in their training may be costly and would need to be continued when new traders enter the market. More importantly, control over drug quality and price is quite difficult to impose.The result is that in all but those countries with highly regulated and efficient health systems, the private sector antimalarial drug market is chaotic. An unregulated variety of antimalarial drugs is usually available to the buyer in gross contravention of national treatment policy. The quality of these drugs is questionable, and some may even be counterfeit.25,26 When governments have been slow to review national treatment policy and replace failing drugs with effective ones, populations have turned to this poorly regulated private sector market in order to buy newer drugs that are perceived to be effective. Thus, where health systems are weak, the ‘private sector’ is both a part of the solution and the problem.The ultimate responsibility for ensuring quality in the private sector service lies with the public sector health system. The public sector’s stewardship role is critically important to ensure the quality of drugs sold and the services delivered in the informal private sector.

Partnership with the private not-for-profit sector for delivery of antimalarial treatment It is widely accepted that government cannot be the sole provider of health care. In many malaria endemic situations, non-governmental organizations (NGOs) are governments’ most reliable partners in the delivery of health care. Outsourcing of health care delivery for malaria to these organisations by national and district level health administrations is common practice and is actively encouraged by principal financing sources such as bilateral agencies and the

Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM). NGOs bring expertise and a committed workforce and are able to function efficiently without the bureaucracy of governments. Most NGOs also employ local people from the endemic communities and thus build national capacity in the process.

IMPACT OF DELIVERING ANTIMALARIAL TREATMENT The foregoing discussion illustrates the importance of effective delivery of antimalarial treatment for reducing the morbidity and mortality associated with malaria. As treatment removes the infected person from the reservoir of infection, early and effective treatment may also have an impact on malaria transmission, especially in situations where malaria is unstable and its transmission intensities are low. In such situations malaria incidence can decline dramatically after a treatment centre is established and people begin to be treated effectively and early. Furthermore, as the anaemia associated with malaria ‘weakens’ the individual, more prompt treatment reduces debilitation and the number of days of work or school missed. Early and effective treatment of the disease, therefore, leads to increased productivity and hence economic growth, which is otherwise hampered by malaria in endemic countries.

CHALLENGES/NEXT

STEPS

A strong public sector health system is fundamental to improving the utilisation and delivery of antimalarial treatment. Providing safe and effective malaria treatment demands that the public sector health system 1) maintains up-to-date malaria treatment policies, 2) develops a strong and well functioning network of health care facilities and institutions that can deliver treatment efficiently, 3) extends itself beyond the facility level to the community through home management programmes and 4) plays a stewardship role within the partnership with NGOs and the private sector. Above all, the drive against malaria will only be successful if the resources of the global community as a whole, together with those of the endemic countries themselves, are adequately engaged to achieving this end.

Formulations, presentation and packaging of drugs Compliance with the dosage and duration of treatment is essential for both the outcome of the disease and to prolong the useful therapeutic life of antimalarial drugs by delaying the onset of parasite resistance. A growing body of evidence indicates that compliance improves significantly when drugs are packaged in ‘units-of-therapy’.27 In the future there will be

Increasingly complex drug regimens

Q/T

Q/D

ART + MQ25

AM / LUM

ART + AQ

ART + SP

MQ - 25

MQ - 15

AQ +SP

CQ +SP

The affordabillity gap

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

For the future, WHO-recommended antimalarial treatment is combinations of drugs containing artemisinin derivatives (artemisininbased combination therapies, ACTs) as opposed to single drugs. Since most drug combination therapies for malaria do not yet exist as co-formulated products, blister co-packaging, which places drugs in 'unit-dose' and 'course-of-therapy' packages, has become a necessity to ensure adherence to drug regimens. The development of special pediatric formulations of antimalarial drugs that facilitate administration of treatment to young children is also being encouraged.

FIGURE 2. AVERAGE COST OF AN ADULT TREATMENT FOR MALARIA, FROM CURRENT MONOTHERAPIES TO THE NEWER COMBINATION THERAPIES28

Average cost per adult Rx (US$)

drug formulations that become unstable when the blister pack is opened in order to discourage the practice of keeping the drugs for a subsequent episode of illness.

(SP = sulfadoxine-pyrimethamine; CQ = chloroquine; AQ = amodiaquine; MQ = mefloquine (at 15 or 25 mgs per kg body weight); ART = artesunate; AM/LUM = artemether + lumefantrine (coartemether); Q = quinine; QD = quinidine + doxycycline; QT = quinine + tetracycline. Adapted from WHO28

The affordability of ACT Given that those affected by malaria are generally the poorest, cost is a major barrier to accessing treatment. The fact that most individuals seek treatment from private drug sellers does not imply that such treatment is more affordable. For the poor, it is often a matter of choosing between risking death or spending a major part of their income to avert such risk. The cost of antimalarial treatment is likely to increase significantly with the adoption of the newer recommended treatments. ACTs will cost over one US$ per treatment compared to previous mono-therapies available at a price of only a few US cents (Figure 2). Affordability will, therefore, become an even greater barrier, and one that must be addressed by the global community and national governments.28 A few options can be considered: governments can adopt the same policy for malaria treatment as they have done for some other health interventions, such as treatment for tuberculosis, childhood vaccines and antenatal services – i.e., making antimalarial treatment a public good and providing drugs free-of-charge to the patient. Alternatively, governments can introduce large subsidies to lower the price of antimalarial drugs to affordable levels. However both options will have implications for engagement of the private sector: If cost recovery of these drugs is not an option, how can the private sector, which functions on the

basis of profit, be engaged in the delivery of malaria drugs? The answer may lie in new approaches such as franchising pre-packaged drugs to reliable private sellers.

Communication for behaviour change Malaria treatment delivery systems should incorporate effective communication of information to the consumer. Key components of the message should include the need for early recognition of illness and treatment, how and where to access quality drugs, the need for full compliance with treatment, recognition of treatment failure or severe disease and action to be taken in this event. Poor adherence to treatment reported from many malaria-endemic countries reflects more on the failure of providers to communicate effectively than on the practices of the consumer – mostly poor people on whom the blame is often placed. Current Roll Back Malaria efforts in African countries comprise major Information Education and Communication (IEC) components. For example, Ghana has mounted a multimedia campaign on effective treatment termed the ‘HealthyHappy-Homes’ (Personal Communication: Ministry of Health, Ghana), and in Uganda, a medical drama series appears on television. Multi-country initiatives that are now underway to support IEC for malaria (Personal Communication: P Smith, RBM, WHO) need to be enhanced and sustained.

Feedback from communities to providers is as important as providing information to the communities at risk. A community radio programme in Malawi became so popular as a means of voicing the communities’ concerns to the government (with health issues prominently on the list) that the national broadcasting station began to provide airtime to hear from communities. This in turn led to community concerns being better heard and addressed (Personal Communication: J. Greenshields, Radio for Development, UK).

Monitoring of services Two of the five Global Indicators for Roll Back Malaria relate to the delivery of early and effective treatment.29 They are: 1) the proportion of people able to access effective treatment within 24 hours of the onset of illness and 2) the proportion of health institutions with stock-outs of antimalarial treatment within the past three months. If this information is to be used for improving access to treatment, monitoring systems will have to be sustainable and integrated with existing Health Management Information Systems (HMIS). In many countries these systems routinely monitor the availability of antimalarial drugs in health facilities. Home management programmes will likewise benefit from strengthening the village-based community monitoring systems that exist in a few countries in Africa.

Quality assurance and control Regulation, quality assurance and quality control of both drugs and diagnostic/clinical services are an important but often neglected component of the delivery of treatment in countries today. Recent surveys of the quality of antimalarial drugs in the African market showed that the content and dissolution index of even the conventional drugs chloroquine and sulfadoxine-pyrimethamine were significantly below acceptable standards.30

Organisation of the public sector health services A strong public sector health system is vital and indispensable in order for a country to deliver treatment for malaria. Its role however should not be one of being the sole provider of health care but of stewardship. It must be involved in formulating policy, co-ordinating and outsourcing tasks to implementing partners, financing the delivery of malaria interventions through SWAps, regulating the quality of care, and extending the reach of the health system through community or home management of malaria. Financial resources and managerial competence needed for

such functions are limiting factors in many countries and are both tasks of government. Whilst the former is widely acknowledged the latter is too often overlooked.

Research and development Product research and development must be designed to be relevant to public health needs. Product profiles that will improve malaria outcomes include: ■ Ease of delivery and use by poor people in hard-to-access situations;

Co-formulated combination drugs with simple treatment regimens;

■

■ Drugs that are effective against both major types of malaria (P.falciparum and P.vivax) with transmission blocking properties;

Non-invasive diagnostic procedures which will aid the targeting of treatment;

■

Treatments for the severely ill or those who are likely to become sick, that can be administered at the peripheral levels of the health system (i.e., by non parenteral routes) e.g., rectal artesunates.

■

In addition, new and more effective ways are needed to communicate to populations at risk.

Bridging the resource gap For general health systems to adequately address the challenge of malaria, particularly in African countries, they will need a much greater financial investment than what presently exists. The per capita resource gaps of African countries that have planned for rolling back malaria lie in the range of US$ 0.20 to more than US$ 2 per capita.31 Although funding has not reached the billions of dollars mandated,32 international financial support for malaria control programmes in endemic countries has begun to increase through initiatives such as the GFATM,33-35 bilateral and multilateral sources, philanthropic endowments and charities. Many of these increased resources are explicitly for the purpose of “goingto-scale” with the delivery of interventions. Great challenges still remain however. First, countries must allow for additional funding created by these new resources through elevating national allocations for health expenditure. Unless this is secured, these external resources could be used as valuable foreign exchange for other non-health exigencies of poor countries. Second, these additional funds should be invested through sector-wide approaches rather than as expenditures earmarked specifically for malaria.

R EFERENCES 1

Gramiccia, G. and Beales, P.F. (1988) The recent history of malaria control and its eradication. In Malaria, Principles and Practice of Malariology (Wernsdorfer, W. and McGregor, I., eds.), pp. 1335-1378, Churchill Livingstone.

2 Najera, A.J. (2001) Malaria Control: achievements, problems and strategies. Parassitologia 43(1-2). 3

Carter, R. and Mendis, K. (2002) Evolutionary and historical aspects of the burden of malaria. Clinical Microbiological Reviews 15 (4), 564 - 594.

Nabarro, D.N. and Mendis , K.N. (2000) Roll Back Malaria is unarguably both necessary and possible. Bulletin of the World Health Organisation 78, 1454-1455.

Nabarro, D.N. and Taylor, E.M. (1998) The Roll Back Malaria campaign. Science 280, 2067 - 2062-2068. 6 WHO. (2002) World Health Report, 2002 World Health Organisation, Geneva. 7 Kidane, G. and Morrow, R.H. (2000) Teaching mothers to provide home treatment of malaria in Tigray, Ethiopia: a randomised trial. Lancet 356 (9229), 550-555. 8

Pagnoni, F. et al. (1997) A community-based programme to provide prompt and adequate treatment of presumptive malaria in children.Trans R Soc Trop Med Hyg 91, 512-517. 9

Sirima, S.B. et al. (2003) Early treatment of childhood fevers with prepackaged antimalarial drugs in the home reduces severe malaria morbidity in Burkina Faso.Tropical Medicine and International Health 8 (2), 1-7.

10 Rooth, I. and Bjorkman, A. (1992) Fever episodes in a holoendemic malaria area of Tanzania: parasitological and clinical findings and diagnostic aspects related to malaria.Trans R Soc Trop Med Hyg 86 (5), 479-482. 11

Lepers, J. (1989) Malaria in 1988 in a village of the Malagasy Highland Plateaux: Epidemiological findings. Archives of the Insitut Pasteur, Madagascar 56 (1), 97-130.

Newton, C. and Krishna, S. (1998) Severe falciparum malaria in children: Current understanding of pathophysiology and supportive treatment. Pharmacology and Therapy 79 (1), 1-53.

24 WHO. (1999) The community-based malaria control programme in Tigray, Ethiopia, northern Ethiopia. A review of programme set up, activities, outcomes and impact. (WHO/CDS/RBM/99.12, 1999) World Health Organisation, Geneva. 25

WHO. (1999) Counterfeit Drugs. Guidelines for the Development of Measures to Combat Counterfeit Drugs. (WHO/EDM/QSM/99.1) World Health Organisation, Geneva.

26 WHO. (1999) Counterfeit and substandard drugs in Myanmar and Vietnam. (WHO/EDM/QSM/99.3) World Health Organisation, Geneva. 27 Ansah, E.K. et al. (2001) Improving adherence to malaria treatment for children: the use of pre-packed chloroquine tablets vs. chloroquine syrup. Tropical Medicine & International Health 6 (7), 496-504. 28 WHO. (2003) Access to antimalarial medicines: Improving the affordability and financing of artemisinin-based combination therapies (WHO/CDS/MAL/2003.1095 (ed. H Haak)) World Health Organisation, Geneva. 29 WHO. (2000) Framework for monitoring progress and evaluating outcomes and impact. (WHO/CDS/RBM/2000.25) World Health Organisation, Geneva. 30 WHO. (2003) Report on the Study on Quality of Antimalarials. (WHO/EDM/PAR (in press)) World Health Organisation, Geneva. 31 WHO. (2001) Country strategies and resource requirements. (WHO/CDS/RBM/2001.34) World Health Organisation, Geneva. 32

WHO. (2001) Macroeconomics and health: Investing in health for economic development,World Health Organisation, Geneva.

33 Nordstrom, A. (2002) Global fund for AIDS, tuberculosis and malaria. Lancet 359 (9317), 1621-1622. 34

Ellman, T. et al. (2002) First round of payments from the Global Fund. Lancet 360 (9328), 262.

Goodman, C. et al. (1999) Cost -effectiveness of malaria control in subsaharan Africa. Lancet 354 (9176), 378-385.

35 Teklehaimanot, A. and Snow, R.W. (2002) Will the Global Fund help roll back malaria in Africa? Lancet 360 (9337), 888-889.

Goodman, C. et al. (2000) Economic analysis of malaria control in subsaharan Africa. Strategic research series. Global Forum for Health Research, Geneva.

14 WHO. (2001) Antimalarial drug combination therapy. Report of a WHO technical consultation 4-5 April, 2001. (WHO/CDS/RBM/2001.35) World Health Organisation, Geneva. 15

Collins, C. (1996) Decentralization. In Health Policy and Systems Development: An Agenda for Research (Janovsky, K., ed.) World Health Organisation, Geneva.

C ONTRIBUTORS Kamini Mendis, Roll Back Malaria Department, World Health Organisation; mendisk@who.int Andrea Bosman, Roll Back Malaria Department, World Health Organisation; bosmana@who.int Peter Olumese, Roll Back Malaria Department, World Health Organisation; olumesep@who.int

16 WHO. (1997) A guide to sector wide approaches for health development: Concepts, issues and working arrangements, (WHO/ARA/97.12) World Health Organisation, Geneva.

Pascal Ringwald, Roll Back Malaria Department, World Health Organisation; ringwald@who.int

Clive Ondari, Essential Drugs and Medicines Department, World Health Organisation; ondaric@who.int

Wilson Were, Roll Back Malaria Department, World Health Organisation; werew@who.int

WHO. (1995) The Integrated Management of Childhood Illness strategy., (WHO/CDR/95.14) World Health Organisation, Geneva. Kolstad, P.R. et al. (1997) The integrated management of childhood illness in western Uganda. Bull World Health Organisation 75 (Suppl 1), 77-85.

19 Winch

P.J. et al. (2002) An implementation framework for household and community integrated management of childhood illness.Tropical Medicine & International Health 17(4), 345-353. 20 Marsh,V.M. et al. (1999) Changing home treatment of childhood fevers by training shop keepers in rural Kenya. Trop Med Int Health 4 (5), 383389. 21

WHO. (2003) Scaling Up Home Management of Malaria: From Research to Implementation (In Press) World Health Organisation, Geneva.

Roll Back Malaria Web site: www.rbm.who.int WHO Essential Drugs www.who.int/medicines

and

Medicines

Department Web

site:

ACKNOWLEDGEMENTS The authors would for valuable assistance.

P OTENTIAL

acknowledge

Ms Victoria

Reyes

CONFLICT OF INTEREST

Alles, H. et al. (1998) Malaria mortality rates in South Asia and in Africa: Implications for malaria control. Parasitology Today 14 (9), 369-375.

None

Conclusion: Abuja and Beyond MARY ETTLING UNITED STATES AGENCY FOR INTERNATIONAL DEVELOPMENT

THE AFRICAN SUMMIT ON ROLL BACK MALARIA As this technical report has demonstrated, malaria takes its greatest toll on the poor and most vulnerable, particularly young children and pregnant women. It is now known that at least one-fifth of all child deaths in Africa are due to malaria. Developing strategies and commitments to reduce this toll formed the impetus for the African Summit on Roll Back Malaria (RBM), held in Abuja, Nigeria on April 25, 2000. Here, African leaders including 19 Heads of State recommitted themselves to intensified action across the continent in the fight against malaria. African leaders were joined at the Summit by senior officials from key development partners, including WHO, UNICEF and the World Bank, all of whom also committed themselves to that fight. The Abuja Summit provided clear goals and intensified momentum for scaling-up at country level. Delegates resolved to initiate appropriate and sustainable action to strengthen health systems to ensure that by the year 2005: At least 60% of those suffering from malaria have prompt access to and are able to use correct, affordable and appropriate treatment within eight hours of the onset of symptoms.

■

■ At least 60% of those at risk of malaria, particularly pregnant women and children under five years of age, benefit from the most suitable combination of personal and community protective measures such as insecticide treated mosquito nets and other materials to prevent infection and suffering.

At least 60% of all pregnant women who are at risk of malaria, especially those in their first pregnancies, have access to chemoprophylaxis or presumptive intermittent treatment.

■

Moreover, representatives committed themselves to: Halve the malaria mortality for Africa's people by 2010, through implementing the strategies and actions for Roll Back Malaria, agreed upon at the summit.

■

■ Initiate actions at country level to provide resources to facilitate realization of RBM objectives.

■ Work with our partners in malaria-affected countries towards stated targets, ensuring the allocation of necessary resources from private and public sectors and from nongovernmental organizations.

Create an enabling environment in our countries, which will permit increased participation of international partners in our malaria control actions.

■

Attainment of these goals requires substantial increases in economic resources for malaria control, strengthened capacity at country level for delivery of effective programs, a better coordinated global partnership to support scale-up in countries, and intensified research to provide new tools for the fight against malaria. Since Abuja, financial resources for malaria have increased with the creation of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) as well as other developments. Also following Abuja, the Roll Back Malaria Partnership reformed itself to become better-coordinated and more responsive to country needs.

ROLLING BACK MALARIA Expanded Response to the Global Malaria Epidemic Since the global Roll Back Malaria (RBM) initiative began in late 1998, spending to fight malaria has more than doubled to about US$ 200 million. The Abuja Summit estimated that the need is about five times as great, and that the estimated US$ 1 billion should be raised through increased domestic spending by governments and through international assistance. Presently, most of the cost of preventing and treating malaria in Africa is borne by those who can least afford it – the disadvantaged and marginalized people most afflicted. For its part, USAID is providing assistance to 22 national malaria programs and three regional initiatives. Significant support has been invested in “going to scale” efforts in national malaria control programs in Africa and to crossborder initiatives addressing the problem of drug resistance. The response focuses on seven key areas:

■

Preventing malaria infection and illness;

Promoting effective treatment of malaria illness, including a response to drug resistance;

■

Protecting pregnant women from malaria;

■ Developing new tools and approaches for malaria prevention and control; ■

Malaria vaccine development;

■ Addressing the needs of populations in complex humanitarian emergencies; ■ Strengthened partnership within Roll Back Malaria for scaling up effective action.

Preventing malaria infection and illness. Access and use of insecticide-treated nets is one of the key intervention strategies for Roll Back Malaria. Proper use of insecticide-treated bednets (ITNs) can reduce overall child mortality by up to 30% and significantly reduce morbidity in children and pregnant women. However, less than 10% of African children are covered by an ITN. Promoting effective treatment of malaria illness. Recognition of malaria symptoms and prompt, effective treatment are critical to saving the lives of children infected with malaria. The aim is to increase the proportion of children with fever who receive prompt treatment with an effective drug within 24 hours. This approach involves improving symptom recognition and treatment-seeking behaviors at the household level, improving case management at health facilities, and developing national capacity to set appropriate policies and monitor antimalarial drug efficacy. Growing antimalarial drug resistance is challenging malaria control. New drugs exist but are significantly more costly than current therapies. An Institute of Medicine panel is developing guidance for the RBM partnership on the most efficient means of financing these newer, more effective treatments. Operations research is studying issues affecting the introduction of combination drug therapies in Africa. In recent years, 13 countries in Africa have changed their national policies to require the use of more effective antimalarial treatments. Protecting pregnant women from malaria. Each year, 22 million pregnancies in Africa are at risk of malaria. Placental malaria infection increases the risk of low birth-weight and other adverse birth outcomes. RBM notes that the impact of malaria on pregnant women and their newborns can be substantially reduced by the use of "intermittent preventive treatment" (IPT), providing at least two treatment doses of an effective antimalarial at routine antenatal clinics to all pregnant women living in areas at risk of endemic malaria in Africa. This strategy has the potential to reach the two-

thirds of pregnant women in sub-Saharan Africa who attend clinics for antenatal care. Six countries have now adopted IPT as policy and most other countries in the region are considering changes in their policies in the light of the new recommendation. Developing new tools and approaches for malaria prevention and control. Malaria control in the future will be strengthened by new tools and approaches which are being developed by the U.S. Centers for Disease Control and Prevention (CDC), the WHO Special Programme for Tropical Disease Research and Training (TDR) and the Multinational Initiative on Malaria (MIM). Malaria vaccine development. Several vaccine candidates are in or nearing clinical field trials. One prime objective is to develop a vaccine to protect the most vulnerable residents in malaria-endemic areas, primarily children and pregnant women. The strategy to meet this objective is to create and maintain a pipeline of the most promising approaches and vaccines that are tested in field trials as soon as possible. Addressing the needs of populations in complex humanitarian emergencies. There is a growing recognition that African populations in areas of war and conflict are at particular and increased risk of malaria. RBM has estimated that countries affected by complex emergencies account for more than 30% of the world’s annual malaria mortality. The World Health Organization has launched a five-year effort to roll back malaria in complex emergency situations, with particular focus on Sudan, Angola, the Democratic Republic of Congo, and Liberia. Strengthening partnership with RBM for scaling up effective action. The members of the RBM partnership represent the full spectrum of actors needed to work in concert with communities and those afflicted to bring effective initiatives to national and regional scale. In the reformed RBM partnership, working groups have been established as the forum for the identification of best practices and implementation models as well as the development of consensus among partners on strategies for scaling up key interventions.

DEVELOPING STRATEGIES In publishing and disseminating Reducing Malaria’s Burden: Evidence of Effectiveness for Decision Makers, the Global Health Council and its contributing authors add to the analysis and thinking around priority interventions of the RBM partnership. The review of evidence and strategies presented in this report can help to guide the coordinated RBM partnership in its support to countries. Together, using evidence-based approaches, real and lasting progress can be achieved in the fight against malaria.

Afterword: Malariaâ&#x20AC;&#x2122;s Unfinished Agenda NILS DAULAIRE GLOBAL HEALTH COUNCIL

What happens when a disease in the industrialized world consistently ranks among the top 20 killers of the affluent and is responsible for economic losses in the tens of billions of dollars? It gets put on the top of the research and action agenda of organizations such as the National Institutes of Health (NIH) and major foundations. Congressional hearings and blue ribbon panels explore the dynamics of the disease and develop master strategies for its control. It is the subject of enormous quantities and a wide range of research, from basic to highly applied. Vast sums, both public and private, are dedicated to addressing the disease, its contributors, and its consequences. It is made a priority: consider the â&#x20AC;&#x153;warsâ&#x20AC;? on cancer, heart disease, and diabetes.

ities and, ideally, without the need for blood sampling; and new drugs with high effectiveness, simple regimens, and low toxicity to counteract the rapid spread of drug-resistant strains of malaria.

What happens when such a disease instead targets the poor and most severely affected communities off the beaten path? We know the answer; we have seen the sorry history of malaria and its global resurgence.

And finally, the essential element of any effective strategy to reduce the intolerable toll of malaria is in the use of this knowledge and the delivery of effective services to those who are in greatest need. Applied research is needed to better understand what works in the field, on each step of the processes needed to prevent clinical infection, mitigate exposure to mosquitoes, detect and diagnose cases early in the course of the disease, and treat effectively. In particular, experience has shown that we need to better understand and apply fundamental approaches to engaging communities and families throughout every part of this continuum if the promise is to be fulfilled of a world in which malaria does not dictate the lives of millions.

Around the world, US$73 billion a year1 is devoted to health research. Malaria, which according to the World Health Organization (WHO) is the thirteenth leading cause of death and of disability-adjusted years of life lost globally,2 accounts for a scant US$100 million,3 or barely one-tenth of one percent of global research spending. This report has laid out many of the key issues confronting the control of malaria. It highlights just how much is still needed in each of the essential areas: new and improved tools, better understanding of the disease and its processes, and the effective and widespread application of existing technologies to effective control. The need for better tools is marked in four areas: effective vaccines that can be used for those at highest risk of severe adverse consequences from malaria (notably young children and pregnant women); highly efficacious environmental control mechanisms aimed at the mosquito vector; rapid and reliable diagnostic tests that can be used among populations with limited access to higher level health facil-

While malaria has been known and extensively studied as a disease process over the past century, new technologies in genetics and biochemical engineering offer new and potentially crucial windows into understanding the dynamics and potential weak links in the complex interactive cycle of the malaria parasite and its vectors. Exploiting these new opportunities for knowledge about the disease may be one of the most significant scientific challenges of the early 21st century.

This agenda cannot be achieved on barely one-tenth of one percent of the global health research budget. It is time for the world to put its resources where it claims its values lie.

1 Global Forum for Health Research. 2002. The 10/90 Report on Health Research 2000-2001. Geneva. 2

World Health Organization. 2002. Global Burden of Disease. Geneva.

Macroeconomics and health: Investing in health for economic development. Report of the Commission on Macroeconomics and Health. WHO 2001. Geneva.

Glossary Anopheles: Genus of mosquito comprising nearly numerous species that transmit malaria through the bite of its female.

Antigen: Substance recognized by the body as being foreign and which stimulates it to produce antibodies.

Chemoprophylaxis: Treatment involving the use of a drug to prevent infection/disease.

Cerebral malaria: Condition in which the brain is infected by the malaria parasite. Seizures are a common complication of cerebral malaria and are associated with an increased risk of death and neurological complications.

Complicated (severe) malaria: Malaria infection that is serious and life threatening, especially in children. Condition usually occurs as a result of delay in treating an uncomplicated attack of malaria, yet may develop very rapidly in children. Symptoms in children include coma, acute kidney failure, circulatory collapse and repeated convulsions. Adult symptoms include respiratory distress, severe anemia, generalized convulsions, and shock.

Effectiveness: The extent to which an intervention achieves its intended effect in a â&#x20AC;&#x2DC;real worldâ&#x20AC;&#x2122; setting.

Efficacy: The extent to which an intervention achieves its intended effect under ideal circumstances.

Endemic: Continual, sometimes low-level presence of disease in a defined geographical area.

Epidemic: Occurrence of disease within a specific geographical area or population that is well in excess of the normal level, either within a specified geographical area or widespread among a population.

Gametocyte: Precursor of the sexual forms of the malaria parasite, which releases either male or female gametes within the stomach of the mosquito.

Gametocyte carriage: human blood.

Carrying the infective form of the parasite in

Parasitemia: Circulation of parasites in the bloodstream.

Plasmodium: Genus of the parasite that causes malaria.The genus includes four species that infect humans: Plasmodium falciparum (causes the most serious form of the disease), Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale.

Randomized controlled trial: A study in which participants are randomly assigned to one of two or more intervention/treatment arms. Randomization minimizes the differences among groups by equally distributing people with particular characteristics among each study group.

Recrudescence: Reappearance of disease in a host whose infection has been dormant/inactive. Malaria recrudescence (short term relapse or delayed) is due to the survival of malaria parasites in red blood cells.

Sequella: A pathological condition or abnormality resulting from a disease, injury or treatment.

Systematic review: A review in which bias has been reduced by the systematic identification, appraisal and synthesis of all relevant studies according to a predetermined and explicit method (a.k.a. research synthesis, meta-analysis).

Uncomplicated (simple) malaria: Malaria infection in which symptoms include fever, headaches, chills and sweats, muscular and abdominal pain, vomiting and diarrhea. Presentation is highly variable and mimics that of many other diseases. Without prompt and effective treatment, infection could lead to more serious, life threatening condition.

Vector: An organism, typically an insect, which transmits an infectious agent from one host to another.

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