PART 1
A Response to the Current Crisis

Treatment of multi-drug resistant falciparum malaria on the North-Western border of Thailand. Photo credit: Dr. Francois Nosten.



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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance PART 1 A Response to the Current Crisis Treatment of multi-drug resistant falciparum malaria on the North-Western border of Thailand. Photo credit: Dr. Francois Nosten.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance 1 Malaria Today INTRODUCTION TO THE STUDY Chloroquine, after decades of use as the first-line drug for uncomplicated falciparum malaria, is failing. But it is still the most widely used antimalarial because a newer safe and effective alternative—artemisinin combination therapy (ACT) at a few dollars per course—has been considered unaffordable by national governments. As a result, illness and deaths from malaria are on the rise. Most fatalities occur among children in Africa, but failing drugs also account for a vast and largely unrecorded morbidity in people of other ages and demographics, not only in Africa, but in Asia and to some extent, everywhere that falciparum malaria (the most severe form) occurs. There also is evidence that drug resistance is leading to epidemics in fringe areas where malaria was previously well controlled when chloroquine was effective. The IOM Committee on the Economics of Antimalarial Drugs was constituted to study the economics of making effective antimalarials accessible to those who could benefit from them. The Committee had two main tasks: 1) to recommend global actions to ensure the broadest possible access to effective antimalarial drugs, thus halting the accelerating loss of life (and malaria’s attendant health and economic burdens) as quickly as possible; and 2) to consider some economic aspects of longer-term global malaria drug policy.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Genesis of the Project The U.S. Agency for International Development (USAID) has a strong history and current portfolio in bilateral and multilateral assistance projects in malaria. USAID represents the United States in the “Roll Back Malaria” (RBM) partnership, centered in the World Health Organization (WHO), and including malaria-endemic countries, their bilateral and multilateral development partners, the private sector, nongovernmental and community-based organizations, foundations, and research and academic institutions. It was largely in connection with its leadership role in RBM that USAID approached the Institute of Medicine for independent advice and economic recommendations to counter the current global crisis in antimalarial drug resistance. The Bill and Melinda Gates Foundation later joined as a study cosponsor. Charge to the Committee The charge to the committee from USAID was the following: The committee will recommend steps that could be taken to maximize the influence of both new and established antimalarial drugs while postponing the development of drug resistance. The immediate focus will be on the class of artemisinin derivatives and other drugs with which they are (or could be) coformulated or paired, but the methodology developed should be generally applicable to new agents still in the pipeline. The statement of task emphasized the fact that that influence would be maximized to the extent that: 1) new and established antimalarial drugs were affordable to the people who needed them; and 2) the antimalarial drugs were engineered and packaged, and delivered in ways that encouraged adherence to prescribed regimens. The Committee applied its energy mainly to the first point, while reviewing relevant information and making some recommendations on the second. About This Report The crisis of spreading resistance to antimalarial drugs has biomedical origins, but the inability of affected countries to respond by changing national treatment policies and making effective artemisinin-based drugs widely available is rooted in economics. The recommendations in this report were developed in light of the biomedical, social and cultural, and economic realities that define the burden of malaria and how it is addressed

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance BOX 1-1 Structure of This Report Part 1: A Response to the Current Crisis Chapter 1. Malaria Today Chapter 2. The Cost and Cost-Effectiveness of Antimalarial Drugs Chapter 3. The Case for a Global Subsidy of Antimalarial Drugs Chapter 4. An International System for Procuring Antimalarial Drugs Part 2: Malaria Basics Chapter 5. A Brief History of Malaria Chapter 6. The Parasite, the Mosquito, and the Disease Chapter 7. The Human and Economic Burden of Malaria Chapter 8. Malaria Control Chapter 9. Antimalarial Drugs and Drug Resistance Part 3: Advancing Toward Better Malaria Control Chapter 10. Research and Development for New Antimalarial Drugs Chapter 11. Maximizing the Effective Use of Antimalarial Drugs in endemic countries today. We attempt to draw together all these threads to present the reader with a complete and coherent set of facts from which to draw conclusions. The report is in three parts (Box 1-1). Part 1 focuses on the immediate financing problem and proposes a global solution. Part 2 gives a foundation for understanding malaria as a disease, the tools we have to control it, and the burden it imposes on affected populations. The chapters that make up Part 2 are intended as both background for the nonspecialist and updates for those with a basic knowledge of malaria. They lay groundwork for the policy discussions and recommendations, but the reader may choose to pass by some of this material. Part 3 stresses the need to make further inroads against malaria by investing in the development of better antimalarial drugs and finding ways to better use new and existing tools. The remainder of this chapter describes the extent of malaria in the world (with the greatest focus on Africa), how people deal with the disease on an individual level, how nations deal with it as a public health problem, and major global initiatives dealing with malaria control. It begins with a discussion of why this report focuses on artemisinin derivatives and artemisinin combination therapies (ACTs), and the roles of other antimalarial drugs.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance THE ROLE OF THE ARTEMISININS IN MALARIA CONTROL Artemisinins are the focus of international attention, and the centerpiece of the recommendations in this report. Their full story—from discovery onward—is recounted in Chapter 9, as are the properties, advantages, and disadvantages of other currently effective antimalarials, and those of historic importance. Because the artemisinins figure so prominently, a few lines of explanation are in order to justify the primacy given to this family of compounds in the current circumstances. It already has been said that chloroquine—after a remarkable period of effectiveness—no longer works against falciparum malaria in much of the world. The only other drug that has had relatively widespread use in Africa—sulfadoxine-pyrimethamine (SP)—worked as first-line therapy for a much shorter period than chloroquine before being evaded by resistant malaria organisms in many places. Continued use of SP would foster additional resistant strains and the drug would become largely ineffective, probably within several years. This should not be allowed to happen because SP has a very specific and important role, at least for the time being. It is the agent of choice for intermittent preventive therapy (IPT) for pregnant women. Next to children, they are the individuals most vulnerable to malaria, particularly in Africa. One further idea must be introduced, and this is the global shift in strategy toward simultaneous treatment with two different antimalarials, adopted as a means to delay the development and spread of drug-resistant malaria. Combination treatment is not specific to artemisnin combinations but will become the standard henceforth, involving other drugs in the future. The question remains as to why artemisinins are considered essential components of combinations, over the other currently effective antimalarials with which they would be paired: amodiaquine, mefloquine, and the most recent addition, Lapdap.1 In fact, other combinations of drugs from different classes could be developed, but they are unlikely to be better than ACTs and would lack some of the benefits of a combination with an artemisinin. The main reasons for endorsing artemisinin-containing combinations are: the artemisinins represent a new family of compounds, with a novel mode of action, and faster antimalarial activity than any of the other drugs; they have proven themselves robust over at least a decade of consistent use in Asia, both in terms of effectiveness and safety and in the lack of any documented drug resistance (at least in part because they have a re- 1   SP and Lapdap both are made up of two drugs but are not considered combinations in the sense of ACTs because the mechanisms of action of the two drugs are linked, and the individual drugs are not fully effective antimalarials.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance markably short half-life, so subtherapeutic levels in the body, which promote resistance, are fleeting); in places where the level of transmission is low, they may play a role in reducing transmission because they act against the gametocyte (sexual) stage of the malaria parasite, as well as the asexual forms responsible for malaria symptoms; and finally, they have proven effective at the individual level in every transmission zone in Africa and elsewhere. In contrast, the “companion” drugs are all related to earlier drugs, and there is either already documented resistance to them in some places, or the presumption that cross-resistance to the related drugs could compromise them. (The choice of which companion drug should be used in a given area will depend largely on the existing or potential resistance to each one.) In addition, any cautions applied to ACTs because of the lack of widespread use in Africa apply equally to these drugs, since none of them has been used extensively in high-transmission settings. Can we be absolutely sure that widespread use of ACTs will halt the rising malaria mortality in Africa now resulting from the use of ineffective drugs? Not by direct evidence, although current evidence points in that direction. The truth is that they have not been deployed on a large scale in the highly endemic parts of Africa. Determining their overall impact will require years of surveillance, which should be carried out as conscientiously as possible. But there is no rationale for delaying actions to move ACTs into the hands of the greatest number of consumers, as quickly as possible, to replace the failing drugs now being used. MALARIA TODAY The Extent and Effects of Malaria There is no time in memory when malaria was not a global health problem. It was common in many parts of the world until well into the 20th century. It was eliminated in Europe, North America, and parts of other continents through deliberate programs of mosquito control and clinical treatment, as well as through generally improved social and living conditions. The muscle behind eradication efforts elsewhere was never applied in Africa’s highly endemic areas, however (Breman, et al., 2001). Today, sub-Saharan Africa remains the area of greatest malaria concentration, but significant problems exist in Asia, in Latin America, and focally in other areas. At least 85 percent of deaths from malaria occur in Africa, 8 percent in Southeast Asia, 5 percent in the Eastern Mediterranean region, 1 percent in the Western Pacific, and 0.1 percent in the Americas.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Now, at the beginning of the 21st century, there is good reason to believe that inroads against malaria can be made in Africa and elsewhere, using the control measures described in this report, if effective combination antimalarials are made widely available. Malaria in Africa The extent of the challenge is illustrated by the map of Africa (Figure 1-1), showing a vast swath between the northern coastal countries and the most southerly ones (excluding most of the horn of Africa) where malaria transmission is intense and malaria is ever-present. This area is ringed by a region prone to seasonal malaria transmission or periodic epidemics—with often devastatingly high mortality rates. More than half a billion people—more than two-thirds of the African population—live with malaria year in, year out, most of them where transmission is intense. The vast majority of the million or so deaths from malaria occur in Africa, mostly among children who have yet to acquire sufficient immunity to protect them from heavy malaria infections. The prevalence of malaria varies with levels of endemicity, but it averages to at least one acute clinical episode per year for which some treatment is sought, or on the order of half a billion treated episodes. It is worth remembering that the malaria map would have looked very different half a century ago, and that control measures are largely responsible for shrinking the highly-endemic zone. The low- and no-transmission areas of southern Africa (including Namibia, Swaziland, South Africa, Botswana, and Zimbabwe) were previously highly endemic—and could become so again, if control measures fail. The map lays out the boundaries of a very large problem, but does not tell the whole story. Who becomes sick and who dies is what is important. Once the discussion moves beyond acknowledging that malaria is a “big” problem, however, estimates of the relevant numbers—malaria cases, deaths from malaria—and the distribution among the population, geographically and by age, vary so widely that they can appear unusable for policy and planning. This lack of specificity is at least part of what makes tackling the problem so unsettling. Malaria in Asia There are about 27 million cases and 30,000 deaths from falciparum malaria in Southeast Asia each year, with no perceptible decline over the last decade (WHO Regional Office for South-East Asia,). Unlike Africa, where acquired semi-immunity protects most adults from severe clinical disease and death, intermittent infections in Asian endemic areas are usu-

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance FIGURE 1-1 Distribution of Endemic Malaria in Africa. SOURCE: Reprinted with permission from MARA/ARMA, Copyright 2001. Taken from Craig, MH, Snow RW, le Sueur D. 1999. A Climate-Based Distribution Model of Malaria Transmission in Sub-Saharan Africa. Parasitology Today 15(3):105-111. ally symptomatic, not uncommonly with very high parasitemias (parasite numbers in the blood) and a risk of death. Apart from the sheer numbers—not approaching African levels, but substantial—Southeast Asia has been the epicenter of drug-resistant malaria precisely because of this pattern of infection and treatment of nonimmune individuals with heavy parasite loads. Some of the most difficult problems arise in border areas, where refugees have gathered after political conflicts. Isolated tribal groups in various countries, with little or no access to health care, also suffer disproportionately from malaria.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Malaria in the New World North America and most of the Caribbean are free from malaria transmission, a result of eradication efforts that began in earnest in the 1950s. But 200 million people live where there is still some risk of transmission, in 21 countries of Central and South America, and the Caribbean, about 20 percent of them in areas considered “high risk” for the region. About one million cases and 200 deaths were recorded in 2001. Drug resistance is becoming widespread, and changes in drug policy have already been made in some places. And the same factors that can disrupt control in Africa and Asia—migration, civil unrest, poor economic conditions—occur in the Americas. The Varied and Far-Reaching Effects of Malaria2 Malaria is not simply a matter of episodes of illness and deaths, as enormous as those burdens are. Effects vary from place to place, but nearly all people living in endemic areas will at some stage in their lives become infected with malaria through the bite of a mosquito, and after the parasite has multiplied in numbers, they will suffer an attack of fever and other symptoms when large numbers of parasites are released into the bloodstream. Untreated, these episodes may progress in severity and naturally resolve, or the person may become overwhelmed and die. Or antimalarial drugs may be used to quell the infection. Functional immunity develops in those who survive the early episodes, if they are continually exposed to malaria from birth, preventing most symptomatic recurrences at older ages. But that is not the whole story. There are less obvious, but equally serious, consequences of the chronic infections and repeated reinfections that characterize life in high-transmission areas, including most of sub-Saharan Africa. Chronic, subclinical infections can cause anemia and pre-dispose to undernutrition. These processes may further increase the chances of severe malaria developing with a subsequent infection, and possibly of more severe outcomes of infections with other pathogens. Unlike other adults in endemic areas, pregnant women are themselves more susceptible to malaria’s most severe effects—including death—and asymptomatic infection of the placenta significantly reduces the weights of their newborn children, reducing their chances of surviving infancy. Some proportion of those who survive severe malaria—with or without effective treatment—are left with permanent, serious effects, including epi- 2   Chapter 6 gives a detailed account of the disease and its effects, which are summarized briefly here.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance lepsy and spasticity. More subtle consequences have also been described and include behavioral disturbances and cognitive impairment. Currently, it is not possible to do much more than mention this spectrum of effects. They cannot yet be quantified, which is not surprising when even the most concrete of end points—the number of deaths from malaria—is only roughly estimated (see Chapter 7). What People Do When They Suspect Malaria Where malaria is common, a child may have four or five bouts of fever, and an adult one or two each year, all presumed to be malaria. People live with malaria in their midst in a variety of ways, but not infrequently with a compromised quality of life. Families do make efforts and spend precious resources to prevent malaria (in part, by eliminating nuisance insects), but most of the readily accessible methods, such as burning mosquito coils or leaves, are only partially effective. Insecticide-treated bednets—the most effective single preventive intervention—are still relatively rare, though coverage is increasing (see Chapter 8). In the absence of effective prevention, treatment of symptomatic cases is the most common form of malaria control. Decisions about whether and what kind of treatment to seek depend, first, on whether the patient or caregiver thinks that malaria is the cause of the illness. A host of considerations—specific symptoms, personal and family history, season of the year—factor into this judgment. Unfortunately, the symptoms of severe malaria—convulsions, loss of consciousness—often are ascribed to other causes, so malaria treatment is not sought, at least initially. When a decision is made to seek treatment for what is presumed to be malaria, what actually happens reflects both the demand side—what people want—and the supply side—what is available to them. It is, in many ways, more complex than a parallel decision to seek treatment for a febrile illness in the United States or Europe, where there would be no need to worry, for instance, about whether a clinic or hospital actually has the drug needed to treat the disease. The costs of treatment in money, time, travel, and otherwise, in general, are more onerous for a poor rural African, Asian, or South American family than for their poor counterparts in richer countries. Decisions may be delayed while options are weighed, funds gathered, and arrangements made. People know that children die of malaria, but they also know from experience that most episodes resolve uneventfully. An unfortunate reality is that in the cases when children do die from malaria, it can happen very quickly, especially for the very young: one day the child has a mild fever and then one of a number of serious symptoms appear, and the child is dead. In those cases, the consequences of waiting are severe and irreversible.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance TABLE 1-4 The Abuja Summit Targets, April 2002 RBM strategy Abuja target (by 2005) Prompt access to effective treatment   60% of those suffering with malaria should have access to and be able to use correct, affordable, and appropriate treatment within 24 hours of the onset of symptoms Insecticide-treated nets (ITNs)   60% of those at risk for malaria, particularly children under 5 years of age and pregnant women, will benefit from a suitable combination of personal and community protective measures, such as ITNs Prevention and control of malaria in pregnant women   60% of pregnant women at risk of malaria will be covered with suitable combinations of personal and community protective measures, such as ITNs 60% of pregnant women at risk of malaria will have access to intermittent preventive treatment Malaria epidemic and emergency response   60% of epidemics are detected within 2 weeks of onset 60% of epidemics are responded to within 2 weeks of detection Note: The original Abuja declaration included the recommendation for chemoprophylaxis as well, but current WHO and RBM policy strongly recommends IPT—and not chemoprophylaxis—for prevention of malaria during pregnancy. SOURCE: WHO/UNICEF (2003) Major Reforms Reorganization of the RBM Secretariat Creation of an independent governance board Reconstitution of the Technical Support Network Tactical Changes Selection of 8 to 12 focus countries that show a high degree of commitment and can make rapid progress in the next 3 years Appointment of Country Champions to provide dynamic leadership in these focus countries

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Even before the final report was issued in August 2002, RBM was reorganized along the lines recommended. It is too soon to know whether these changes will lead to the success envisioned by the evaluation team, but major efforts are being made toward that end. If the recommendations in this report are implemented, RBM’s ability to make rapid progress will get a large boost, particularly in increasing access to effective drugs. The United Nations Millennium Development Goals At the United Nations Millennium Summit in September 2000, world leaders agreed to a set of goals and targets to combat the world’s ills: poverty, hunger, disease, illiteracy, environmental degradation, and discrimination against women. All 189 Member States of the United Nations adopted the eight broad “Millennium Development Goals” (MDGs), with timetables for achieving them by 2015. One of the goals names malaria specifically, and two others are directly relevant. These MDGs are: Reverse the spread of diseases, especially HIV/AIDS and malaria. Reduce under-5 mortality by two-thirds. Reduce maternal mortality by three-quarters. The UN secretary general and the administrator of the UN Development Programme created the Millennium Project to recommend the best strategies for achieving the MDGs. Ten task forces of global experts were established to identify operational priorities, organizational means of implementation, and financing structures necessary to achieve the MDGs. Task Force 5 is focused on HIV/AIDS, malaria, TB, other major diseases and access to essential medicines, and a subgroup focused specifically on malaria. Each task force is to complete its report by the end of 2004, and a final synthesis of recommendations will be presented to the UN secretary general and the chair of the UN Development Group by June 30, 2005. The issues addressed by the IOM Committee on the Economics of Antimalarial Drugs are directly relevant to the MDGs, and should complement the work of the malaria subgroup of Task Force 5. The Global Fund The Global Fund to Fight AIDS, Tuberculosis and Malaria (the “Global Fund”) began operation just 2 years ago, in 2002. The idea of a centralized fund to help combat the three most devastating infectious diseases in countries without the resources to do so was first raised at a meeting in July 2000 of the Group of Eight (G8) leading industrialized countries. It gained currency through further discussions and meetings, and was solidified by

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance United Nations Secretary-General Kofi Annan at the African Summit on HIV/AIDS in Abuja, Nigeria, in April 2001, who called for the creation of a global trust fund for the three diseases. As of July 2003, total pledges by donors to the Fund amounted to US$4.7 billion. Forty governments have pledged 98 percent of the funds, and 2 percent come from the private sector. By February 2004, a total of US$245 million in Global Fund resources had been disbursed to about 120 countries. In the first two rounds of grants, 21 percent went for malaria programs (59 percent for HIV/AIDS, 19 percent for tuberculosis). Over the first three rounds, a minority of funding was destined for purchase of ACTs—less than US$20 million, and less than the amount allocated for purchases of chloroquine and SP (Attaran et al., 2004). This reflects the requests of countries to the Global Fund, which does not dictate how countries should approach malaria control. However, the international health financing community—of which the Global Fund is a major part—has significant influence on what countries plan by way of disease control and what they ask for. Given the level of funding of the Global Fund itself, countries have made realistic requests, which may not include large quantitites of ACTs, because the price would make such requests nonviable. Countries also are concerned about how sustainable a system built on ACTs would be after Global Fund grants run out (if not renewed). A principle by which the Global Fund operates is that their grants are not fungible: they must augment existing funding for the three diseases and not supplant them. Evidence that allocations for malaria from other sources are being reduced is grounds for the Global Fund to terminate a malaria grant. This principle acknowledges the historic underinvestment in malaria and the other diseases. Strictly speaking, it also can be seen as limiting the endemic countries’ ability to freely allocate resources according to their own priorities, while signalling the global acceptance—of both donor and recipient countries—that only with greater resources is there hope of making progress against these diseases. With continued and increasing donor contributions, the Global Fund has the potential to be a major positive force for malaria control. REFERENCES Ahorlu CK, Dunyo SK, Afari EA, Koram KA, Nkrumah FK. 1997. Malaria-related beliefs and behaviour in Southern Ghana: Implications for treatment, prevention and control. Tropical Medicine and International Health 2(5):488-499. Attaran A, Barnes KI, Curtis C, d’Alessandro U, Fanello CI, Galinski MR, Kokwaro G, Looareesuwan S, Makanga M, Mutabingwa TK, Talisuna A, Trape JF, Watkins WM. 2004. WHO, the Global Fund, and medical malpractice in malaria treatment. Lancet 363(9404):237-240.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance SEAM. 2001. Strategies for Enhancing Access to Medicines. Country Assessment: Cambodia. Arlington, VA: Management Sciences for Health. Shakoor O, Taylor RB, Behrens RH. 1997. Assessment of the incidence of substandard drugs in developing countries. Tropical Medicine and International Health 2(9):839-845. Shretta R, Guimier J-M. 2003. Flow of antimalarial drugs in the public and private sector, affordability and discussions of potential strategies to improve financial access. Paper commissioned by the Institute of Medicine. Silva T, Russell S, Rakodi C. 1997. The opinions of health and water service users in Sri Lanka. Working paper. International Development Department, University of Birmingham, Birmingham, UK. [Online]. Available: http://www.idd.bham.ac.uk/research/Projects/Role_of_gov/workingpapers/paper25.htm. Smithson P, Asamoa-Baah A, Mills A. 1997. The case of the health sector in Ghana. Working paper. International Development Department, University of Birmingham, Birmingham, UK. [Online]. Available: http://www.idd.bham.ac.uk/research/Projects/Role_of_gov/workingpapers/paper26.htm. Snow RW, Peshu N, Forster D, Mwenesi H, Marsh K. 1992. The role of shops in the treatment and prevention of childhood malaria on the coast of Kenya. Transactions of the Royal Society of Tropical Medicine and Hygiene 86(3):237-239. Stein CM, Gelfand M. 1985. The clinical features and laboratory findings in acute Plasmodium falciparum malaria in Harare, Zimbabwe. Central African Journal of Medicine 31(9):166-170. United States Embassy. 2003. [Online]. Available: http://usembassy.state.gov/Cambodia [accessed 2003]. WHO (World Health Organization). 2003. More equitable pricing for essential drugs: What do we mean and what are the issues? In: WHO Commission on Macroeconomics and Health, Norway. Background paper for the WHO-WTO secretariat workshop on differential pricing and financing of essential drugs, Høsbjør, Norway, April 8-11, 2001. World Health Organization. [Online]. Available: www.who.int/medicines/library/edm_general/who-wto-hosbjor/equitable_pricing.doc. WHO Regional Office for South-East Asia. Malaria: Issues and Challenges. [Online]. Available: http://w3.whosea.org/mal/issues.htm [accessed April 7, 2004]. WHO/UNICEF. 2003. The Africa Malaria Report 2003. Geneva: World Health Organization. Wilkinson D, Holloway J, Fallavier P. 2000. Findings from the Evaluation of User Fees, Categorized by Evaluation Objectives. Draft study to evaluate the impact of user fees on access, equity and health providers’ practices. Phnom Penh, November 2000. Winch PJ, Makemba AM, Kamazima SR, Lurie M, Lwihula GK, Premji Z, Minjas JN, Shiff CJ. 1996. Local terminology for febrile illnesses in Bagamoyo district, Tanzania and its impact on the design of a community-based malaria control programme. Social Science and Medicine 42(7):1057-1067. World Bank. 1999. Volume Two: Main Report. Poverty Reduction and Economic Management Sector Unit, East Asia and Pacific Region. Cambodia: Public Expenditure Review. Washington, DC: The World Bank. World Bank. 2002. World Development Indicators. Washington, DC: The World Bank. World Bank. 2003. World Development Indicators. Washington, DC: The World Bank.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance APPENDIX 1A THE TEHIP STUDY Why Do They Die? An Inquiry into Treatments Preceding Deaths from Malaria5 A child in rural Tanzania dies from malaria. One can hardly help but envision the cascade of events—what might have happened or not happened—that led to such a sorrowful ending. But guesswork is not an adequate substitute for knowing. The solutions that will keep such children alive and malaria-free depend on understanding why and where the fatal failures of social transactions occurred. The Research Area TEHIP studied the circumstances leading to deaths from malaria in the stable, perennial malaria-transmission belt that runs along the coast of Tanzania and up the Rufiji and Kilombero River basins. The transmission risk there is typical of the majority (75 percent) of Tanzania and of sub-Saharan Africa in general (MARA Collaboration, 2003). The population of Rufiji District is 203,000, divided among several ethnic groups. The district occupies 14,500 km2 and is entirely rural, with 94 registered villages. There are 57 formal health facilities: two hospitals (one government and one NGO), five health centers with inpatient facilities (all government), and 50 dispensaries (46 government). Over-the-counter drugs are available from many private shops and kiosks in the villages. People also consult traditional healers and traditional birth attendants. Integrated management of childhood illness (IMCI) services, intermittent presumptive treatment (IPT) of malaria in pregnancy, and 1st, 2nd, and 3rd line antimalarial services are available at all formal health services. Within the District, insecticide treated nets (ITNs) are distributed through social marketing. The Rufiji Demographic Surveillance Site (DSS) covers part of Rufiji District, including 1,800 km2 north of the Rufiji River and west of the Rufiji Delta, with a population of 85,000 in 17,000 households in 31 villages. The DSS registers all births, deaths, in-migrations, out-migrations, pregnancies, and other vital events. Events are detected by 150 village “key informants,” and verified by DSS staff. Twenty-eight full-time enumerators update the population register every 4 months, based on household surveys. 5   Based on an analysis prepared for this study (de Savigny et al., 2003).

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Verbal Autopsies The information available for each death is gathered during the process of “verbal autopsy” (VA). Once a key informant documents a death in the study area, a DSS VA supervisor, who is also a trained clinical officer or health officer, conducts the VA interview using standard questionnaires that are designed specifically for deaths of: a) children under 31 days of age; b) children under 5 years but 31 days and older; and c) population aged 5 years and above. The questionnaires and responses are in Kiswahili, the common language of the area. Open-ended and closed questions are asked on the history of events leading to death, as well as about previously diagnosed medical conditions, and signs and symptoms before death. Use of health facilities prior to death, reasons for using or not using a particular health facility, and confirmatory evidence of cause of death (if available) are asked about and recorded. A typical bereavement interview for a VA takes 45 to 60 minutes. The VA supervisor establishes a tentative cause of death from signs, symptoms, sequence, and severity, as well as any confirmatory evidence. A physician reviews the material and makes the final determination of cause of death that is subsequently entered in the database. Malaria-Related Deaths This study covered the period January 1999 through the end of December 2001, during which 3,023 deaths occurred and 2,953 (97.7 percent) verbal autopsies were conducted in the DSS. Of these deaths, 722 which fell under the following codings were suspected to be directly or indirectly due to malaria: acute febrile illness 1-4 weeks acute febrile illness ≤7days acute febrile illness including malaria acute febrile illness with seizures acute febrile illness with anemia cerebral malaria fever plus malnutrition malaria malaria confirmed unspecified acute febrile illness Among these 722, 45.8 percent were male, 54.2 percent female; 44.3 percent were under 5 years of age, 55.7 percent were 5 years or older; 39 (5.4 percent) had convulsions and possible cerebral malaria, while 94.6 percent reported no convulsions.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance As a cautionary note, VA methods have distinct limitations. Specifically, not all the cases identified as “malaria” in this series truly represent malaria, especially those with unspecified acute febrile illness at an older age. And undoubtedly, some malaria deaths were coded as nonmalaria. For example, life-threatening anemia, likely due to malaria, is prevalent in young children over 6 months of age in the study area, yet VA coded deaths due to anemia with malaria are infrequent among recorded malaria deaths. Types of Care Sought The term modern care describes what conventionally includes biomedical, Western, pharmaceutical, professional, official, or formal health care. Traditional care describes what conventionally includes traditional medicine, traditional healers, traditional providers, lay providers, traditional practices, or folk care. From the VAs, 13 possible sources of treatment were collapsed into six subcategories of provider type: Government Home/Shops Non-Government Traditional Medicine at Home Traditional Medicine at Practitioner No Care and into three broader subcategories: Modern Care Traditional Care No Care Of the 722 individuals whose deaths were ascribed to malaria, 626 (87 percent) sought care at least once before death, while 96 (13 percent) did not, or could not, seek care. Treatment usually starts at home using antipyretics and antimalarials from local shops or left over from previous episodes. Malaria is perceived by adult caregivers as a mild disease, and if it becomes serious or life threatening, the presumptive diagnosis changes from malaria to something that is more often treated with traditional medicine or practices. Yet these beliefs are not rigid. Every case is subject to a process of continuing debate and reevaluation within the family. As a result, modern pharmaceuticals also are sought, albeit with delay, when convulsions fail to resolve, or recur after traditional medicine (Oberlander and Elverdan, 2000). Significant switching from one provider to another occurs over time; this phenomenon is most apparent when comparing treatment of malaria without convulsions to malaria with convulsions.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Key Observations Cases with convulsions were significantly (p<0.05) more likely to receive care. Of the group that did not have convulsions, 91 percent used modern care first, and by the second treatment, more than 99 percent used modern care. Hence traditional care delayed modern care for 9 percent of cases. Of the group that had convulsions, 90 percent used modern care first, but only 63 percent continued with modern care for a second treatment. Government health facilities and shopkeepers were the main source of antimalarial drugs. This pattern held up over broad age groups, sex, and socioeconomic status. (At the time of the study, all government providers had adequate drug supplies, which could be a factor in their popularity. The first-line drug was chloroquine, however, at a time when drug resistance was already widespread in this area.) Other Relevant Factors In this study, modern care was more popular than previous reports would suggest. But some part of that modern care involved self-treatment and a variety of private providers. Knowledge of appropriate treatment regimens is lacking on the part of the public as well as the private providers (Brugha et al., 1999; Marsh et al., 1999), and under-dosing in home-based care is common. These may account for at least some treatment failures. The only other study of health-seeking patterns in a large series of VAs is from the mid-1980s from the Bagamoyo District of Tanzania, another district in the Coast Region (Mtango et al., 1992). In that series, malaria deaths were not analyzed separately, but government providers were the choice in only 45 percent of all deaths. A preference for traditional healers was cited by 41 percent of mothers as the reason for not using government services. At that time, it was also true that government providers were often without adequate drug supply. Why Did They Die? The study results to date cannot answer that question, but they begin to narrow the possibilities. Some form of care was sought in the majority of malaria deaths (88 percent). No care was sought for 12 percent of child deaths. Included among these were sudden deaths following apparently mild illness, which may have been impossible to prevent under the circumstances. This pattern is considerably better than was seen in the mid-1980s in Bagamoyo, when 55 percent of children who died had not utilized any

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance modern care (Mtango et al., 1992), and better than for all deaths in the same area during the same period when 20 percent of all-cause deaths had no prior health-seeking events (Tanzania Essential Health Interventions Project and Ministry of Health of Tanzania, 2002). With belief systems for malaria treatment-seeking now firmly on the side of modern care, there is obviously something still failing in the transaction to obtain this care, or in the quality of the care and referral once it is accessed. TEHIP is continuing to refine the information from this study, and will be analyzing the narrative portion of the verbal autopsy questionnaires to look at some specific aspects of the health care received, including: delay in seeking modern care (e.g., tried to treat at home without antimalarials, no transport, beliefs, poor recognition of severity, lack of confidence in modern care, no power to decide, insufficient finances); delay in receiving modern care (e.g., after working hours, weekends, long queues, satisfaction); and ineffective modern care (e.g., poor communication, no referral, drugs not available, abusive health worker, non-compliant providers, poor adherence of patients). All of these factors could have contributed to failed treatment. The study, as yet, can provide no direct information on the possible contribution of drug resistant malaria to these deaths. The current results suggest that policies and efforts aimed at improving early recognition of symptoms and danger signs at home, prompt treatment or treatment-seeking, compliance with the full course of treatment, and the quality of the antimalarial available are highly justified. REFERENCES De Savigny D, Mwageni E, Mayombana C, Masanja H, Minhaj A, Momburi D, Mkilindi Y, Mbuya C, Kasale H, and Reid G. 2003. Care seeking patterns in fatal malaria: Evidence from Tanzania. Paper commissioned by the Institute of Medicine. MARA Collaboration. 2003. MARA LITe for Africa CD version 3.0.0. South Africa: Medical Research Council of South Africa. Mtango FDE, Neuvians D, Broome CV, Hightower AW, Pio A. 1992. Risk factors for deaths in children under 5 years old in Bagamoyo District, Tanzania. Tropical Medicine and Parasitology 43(4):229-233. Oberlander L, Elverdan B. 2000. Malaria in the United Republic of Tanzania: Cultural considerations and health-seeking behaviour. Bulletin of the World Health Organization 78(11):1352-1357. Tanzania Essential Health Interventions Project, Ministry of Health of Tanzania. 2002. Burden of Disease Profile 2001—Coastal Zone. Dar es Salaam: Ministry of Health of Tanzania.