Causes, Epidemiology, Manifestations, and Diagnosis

Four species of the genus Plasmodium cause malarial infections in humans: P. falciparum, P. vivax, P. ovale, and P. malariae. Virtually all deaths are caused by falciparum malaria. Human infection begins when the malaria vector, a female anopheline mosquito, inoculates plasmodial sporozoites from its salivary gland into humans during a blood meal. The sporozoites mature in the liver and are released into the bloodstream as merozoites. These invade red blood cells, causing malaria fevers. Some forms of the parasites (gametocytes) are ingested by anopheline mosquitoes during feeding and develop into sporozoites, restarting the cycle.

P. falciparum predominates in Haiti, Papua New Guinea, and Sub-Saharan Africa, while P. vivax is more common in Central America and the Indian subcontinent and causes more than 80 million clinical episodes of illness yearly (Mendis and others 2001). The prevalence of these two species is approximately equal in the Indian subcontinent, eastern Asia, Oceania, and South America. P. malariae is found in most endemic areas, especially throughout Sub-Saharan Africa, but is much less common than the other species. P. ovale is unusual outside Africa, and where it is found accounts for less than 1 percent of isolates.

While more than 40 anophelines can transmit malaria, the most effective are those such as Anopheles gambiae, which are long-lived, occur in high densities in tropical climates, breed readily, and bite humans in preference to other animals. The entomological inoculation rate (EIR)—that is, the number of sporozoite-positive mosquito bites per person per year—is the most useful measure of malarial transmission and varies from less than 1 in some parts of Latin America and Southeast Asia to more than 300 in parts of tropical Africa.

The epidemiology of malaria may vary considerably within relatively small geographic areas. In tropical Africa or coastal Papua New Guinea, with P. falciparum transmission, more than one human bite per infected mosquito can occur per day and people are infected repeatedly throughout their lives. In such areas, morbidity and mortality during early childhood are considerable. For survivors, some immunity against disease develops in these areas, and by adulthood, most malarial infections are asymptomatic. This situation, with frequent, intense, year-round transmission, is termed stable malaria. In areas where transmission is low, erratic, or focal, full protective immunity is not acquired and symptomatic disease may occur at all ages. This situation is termed unstable malaria. An epidemic or complex emergency can develop when changes in environmental, economic, or social conditions occur, such as heavy rains following drought or migrations of refugees or workers from a nonmalarious to an endemic region. A breakdown in malaria control and prevention services intensifies epidemic conditions. Epidemics occur most often in areas with unstable malaria, such as Ethiopia, northern India, Madagascar, Sri Lanka, and southern Africa. Many other African countries situated in the Sahelian and Sub-Saharan areas are susceptible to epidemics (Djimdé and others 2004; Worrall, Rietveld, and Delacollette 2004). Public health specialists have only recently begun to appreciate the considerable contribution of urban malaria, with up to 28 percent of the burden in Africa occurring in rapidly growing urban centers (Keiser and others 2004).

The determinants of malaria and of risk factors for patients and communities relate to intrinsic (human, parasite, and vector) and extrinsic (environmental, control, and socioeconomic) factors (figure 21.1)(Breman 2001). Both humoral and cellular immunity are necessary for protection.

Figure 21.1

Determinants of the Malaria Burden: Intrinsic and Extrinsic Factors

Anemia may be quite common among young children living in areas with stable transmission, particularly where the parasite is resistant to chloroquine, sulfadoxine-pyrimethamine (SP), or other drugs. Correctly and promptly treated, uncomplicated falciparum malaria has a mortality rate of approximately 0.1 percent (Sudre and others 1992). Once vital organ dysfunction occurs or the proportion of erythrocytes infected increases to more than 3 percent, mortality rises steeply. Coma is a characteristic and ominous feature of falciparum malaria, and despite treatment it is associated with death rates of some 20 percent among adults and 15 percent among children. Convulsions, usually generalized and often repeated, occur in up to 50 percent of children with cerebral malaria (CM) (Mung'Ala-Odera, Snow, and Newton 2004). Whereas less than 3 percent of adults suffer neurological sequelae, roughly 10 to 15 percent of children surviving CM—especially those with hypoglycemia, severe malarial anemia (SMA), repeated seizures, and deep coma—have some residual neurological deficit when they regain consciousness. Protein-calorie under-nutrition and micronutrient deficiencies, particularly zinc and vitamin A, contribute substantially to the malaria burden (Caulfield, Richard, and Black 2004).

In areas with intense and stable transmission, falciparum malaria in primigravid and secundigravid women is associated with low birthweight (average reduction of about 170 grams) and consequently with increased infant and childhood mortality (Steketee and others 2001). HIV infection predisposes all pregnant women to more frequent and severe malaria, and the reverse may also be true (Ter Kuile and others 2004). P. vivax malaria in pregnancy is also associated with a reduction in birthweight (average reduction of some 100 grams), and this effect is greater in multigravid than in primigravid women (Nosten and others 1999).

The confirmatory diagnosis of clinical malaria rests on the microscopic demonstration of asexual forms of the parasite in stained peripheral blood smears. Newer diagnostic tests using antigen and nucleic acid detection methods are being evaluated. These tests are promising, but their limitations in relation to species sensitivity (except for P. falciparum), parasite quantitation, field feasibility, and costs necessitate further development and evaluation (Warhurst and Williams 2004).

Burden of Disease

In 2001, the World Health Organization (WHO) ranked malaria as the eighth-highest contributor to the global disease burden as reflected in disability-adjusted life years (DALYs), and the second highest in Africa (WHO 2002a). The DALYs attributable to malaria were estimated largely from the effects of P. falciparum infection as a direct 0000cause of death and the much smaller contributions of short-duration, self-limiting, or treated mild febrile events, including malaria-specific mild anemia and neurological disability following CM (Murray and Lopez 1996, 1997). The estimate assumes that each illness event or death can be attributed only to a single cause that can be measured reliably. Table 21.1 shows deaths and DALYs from deaths attributable to malaria and to all causes by WHO region (WHO 2002a). It does not include the considerable toll caused by the burden of malaria-related moderate and severe anemia, low birthweight, and comorbid events (Snow and others 2003). Sub-Saharan African children under four represent 82 percent of all malaria-related deaths and DALYs. Malaria accounts for 2.0 percent of global deaths and 2.9 percent of global DALYs. In the African region of WHO, 9.0 percent of deaths and 10.1 percent of DALYs are attributable to malaria.

Table 21.1

Deaths and DALYs from Deaths Attributable to All Causes and to Malaria by WHO Region, 2000.

Recent analysis of falciparum malaria morbidity concludes that 515 (interquartile range 298 to 659) million cases occur yearly (table 21.2). This figure is 92 percent higher than the 278 million malaria cases estimated by WHO for 1998, which also includes those attributable to P. vivax, and 200 percent higher than previous estimates for areas outside of Africa (Snow and others 2005). While the malaria incidence globally is 236 episodes per 1,000 persons per year in all endemic areas, it ranges from about 400 to 2,000 (median 830) episodes per 1,000 persons per year in areas with intense, stable (hyperendemic and holoendemic) transmission; these areas represent 38 percent of all falciparumendemic areas.

Table 21.2

Population at Risk for Falciparum Malaria, Cases and Attack Rates by World Health Organization Region, 2002*.

Direct Consequences of P. falciparum Infection

Two major syndromes, CM and moderate (hemoglobin less than 11 grams per deciliter) and severe (hemoglobin less than 8 grams per deciliter) malarial anemia, contribute directly and significantly to malaria mortality (tables 21.3 and 21.4). The differences in numbers derive from the different methods of calculating the burden. Children presenting with an acute febrile disease, peripheral parasitemia, and low hemoglobin concentrations account for the majority of inpatient admissions in areas with stable transmission. The arbitrary definition of 5 grams of hemoglobin per deciliter is prognostic for a fatal outcome and proves useful clinically as a criterion for transfusion. Lactic acidosis commonly coexists with hypoglycemia and is (with coma, repeated convulsions, shock, and hyperparasitemia) an important predictor of death from severe malaria (White and Breman 2005; WHO 2000b).

Table 21.3

Malaria-related Mortality and Morbidity, Africa, 2000.

Table 21.4

Deaths from Malaria in Children Under Five, Africa, 2001.

The vast majority of deaths in developing countries occur outside the formal health service, and in Africa, most government civil registration systems are incomplete (Breman 2001; Greenberg and others 1989). Newer demographic and disease-tracking systems are being used globally and should help rectify the woefully inadequate vital statistics available for malaria and other diseases (INDEPTH 2002).

Health personnel usually attribute causes of death during demographic surveillance system surveys through a verbal autopsy interview with relatives of the deceased about the symptoms and signs associated with the terminal illness. Both the specificity and the sensitivity of verbal autopsy vary considerably depending on the background spectrum of other common diseases, such as acute respiratory infection, gastroenteritis, and meningitis, which share common clinical features with malaria (Korenromp and others 2003).

In malarious Africa, some 30 to 60 percent of outpatients with fever may have parasitemia. Monthly surveillance of households will detect a quarter of the medical events that are detected through weekly surveillance, and weekly contacts with cohorts identify approximately 75 percent of events detected through daily surveillance (Snow, Menon, and Greenwood 1989). Given the predominance of fevers, malaria case management in Africa and other endemic areas usually centers on presumptive diagnosis.

Estimates of the frequency of fever among children suggest one episode every 40 days. If we assume that the perceived frequency of fever in Africa is similar across all transmission areas (and possibly all ages), African countries would witness approximately 4.9 billion febrile events each year. Estimates indicate that in areas of stable malaria risk, a minimum of 2.7 billion exposures to antimalarial treatment will occur each year for parasitemic persons, or 4.93 per person per year (Snow and others 2003). While these diagnostic, patient management, and drug delivery assumptions are debatable, they indicate the magnitude of the challenges malaria presents.

The case-fatality rates of CM are high, even with optimal management. Murphy and Breman (2001) report a mean case-fatality rate of 19.2 percent and Snow and others (2003) cite a figure of 17.5 percent. Those who succumb at home without optimal treatment will have higher case-fatality rates.

Studies of neurological sequelae after severe malaria indicated that 3 to 28 percent of survivors suffered from such sequelae, including prolonged coma and seizures (MungAla-Odera, Snow, and Newton 2004). CM is associated with hemiparesis, quadriparesis, hearing and visual impairments, speech and language difficulties, behavioral problems, epilepsy, and other problems (table 21.3). The incidence of neurocognitive sequelae following severe malaria is only a fraction of the true residual burden, and the impact of milder illness is unknown.

Studies of children presenting to hospital with malaria and hemoglobin of less than or equal to 5 grams per deciliter indicate a median transfusion rate of 80.1 percent. Thus, 275,400 to 442,290 surviving SMA admissions, newborn through 14 years, will be exposed to blood transfusion each year in Sub-Saharan Africa. As a result, each year 5,300 to 8,500 children, age birth through 14 years, living in stable endemic areas of Africa are likely to acquire HIV infection because of exposure to blood transfusion to manage SMA (Colebunders and others 1991; Savarit and others 1992).

Interventions and Their Effectiveness

Malaria will be conquered only by full coverage, access to, and use of antimalarial services by priority groups; rapid, accurate diagnosis; prompt and effective patient management (diagnosis, treatment, counseling and education, referral); judicious use of insecticides to kill and repel the mosquito vector, including the use of ITNs; and control of epidemics. Eliminating malaria from most endemic areas remains a distant, huge, but surmountable challenge because of the widespread Anopheles breeding sites; the large number of infected people; the use of ineffective antimalarial drugs; and the inadequacies of resources, infrastructure, and control programs. The Roll Back Malaria Partnership, which began in 1998, aims to halve the burden of malaria by 2010 and has developed strategies and targets for 2005 (box 21.1). While ambitious, the initiative is making substantial progress by means of effective and efficient deployment of currently available interventions (WHO 2003, 2005). Indeed, Brazil, Eritrea, India, and Vietnam are reporting recent successes in reducing the malaria burden (Barat 2005). Despite the enormous investment in developing a malaria vaccine administered by means of a simple schedule and recent promising results in the laboratory and in field trials in Africa, no effective, long-lasting vaccine is likely to be available for general use in the near future (Alonso and others 2004; Ballou and others 2004).

Box 21.1

Roll Back Malaria Partnerships Strategy and Goals for 2005. The goal of Roll Back Malaria Partnership is to halve the burden of malaria by 2010. The following targets for specific intervention strategies were established at the Abuja Malaria Summit in (more...)

Drug Use

Proper use of drugs is essential. Early diagnosis and effective treatment of patients lends credibility to the malaria program, strengthens confidence in the health care system by families and communities, and raises the esprit of clinicians and public health workers.

Early Diagnosis and Treatment

Early diagnosis and effective treatment can cure infection, prevent further morbidity and progression to severe disease and death, and arrest transmission. This intervention requires timely and accurate diagnosis; use of efficacious drugs; education of patients and their families about the disease, home management, and prevention; and referral to higher levels of the health system. The following are critical to the effectiveness of this intervention:

• Timeliness. A febrile malaria attack warrants early treatment. If left untreated, a proportion of P. falciparum malaria infections, perhaps 1 in 250 (and to a far lesser extent infections with other malaria species) will progress to severe disease within a few hours to a few days (Greenwood and others 2005). The globally agreed goal is that diagnosis and effective treatment should be provided within 24 hours of the onset of symptoms and signs.
• Diagnosis and effective drug treatment. An accurate diagnosis of malaria is based on detection of the parasite and, if laboratory diagnosis is not feasible, on clinical grounds. Health workers must monitor the therapeutic efficacy of drugs closely and change treatment policies when parasite resistance to chloroquine (figure 21.2), SP, and other drugs emerges (Baird 2005; Laxminarayan and others 2006; WHO 2002a). Concerns include unreliable and inaccurate microscopy and the disadvantages of alternative tests plus the widespread distribution and use of substandard and counterfeit drugs. The recommended treatments for malaria in areas with resistance to single drugs are combination treatments, preferably artemisinin combination therapy (ACT) (WHO 2001a, 2001b, 2003a, 2005). While ACT is a welcome, life-saving approach, more information on the cost-effectiveness of this new strategy is needed (Arrow, Panosian, and Gellband 2004; Yeung and others 2004). Baird (2005) reports that ACT costs range from US$2.00 (artesunate-amodiaquine, three doses in 48 hours) to US$9.12 (artemether-lumefantrine, six doses in 48 hours) per adult treatment; WHO has obtained the latter drug for US$2.40 per adult treatment for qualified purchasers, meaning those from low-income malarious countries.
• Location of clinical management. Effective management of patients requires skilled and well-equipped personnel at all levels of the health system. The two strategies for delivering antimalarials effectively are through health facilities and in or near the home when access to health facilities is limited. Given the pervasiveness of malaria infections, more information on the most effective and efficient ways to promote home treatment is urgently needed.

Figure 21.2

Chloroquine Treatment Failure in Africa, 1997–2002

Evidence for the effectiveness of early diagnosis and treatment is available from two different epidemiological conditions and health systems. In areas of low to moderate transmission, for example, southern Africa, the Americas, and Southeast Asia, where health care systems are relatively effective, the two major consequences of prompt and effective intervention are reduction of the period of infectivity of infected persons, and thus reduced transmission and incidence, and a lowered case-fatality rate and overall mortality. In Vietnam and the KwaZulu-Natal province of South Africa, P. falciparum malaria incidence and mortality rates fell when effective treatment policies (artesunate and ACT) replaced failing monotherapies (Hung and others 2002). The effective drug policies were implemented in conjunction with enhanced vector control; thus, effective treatment alone does not account for the fall in malaria incidence and mortality.

In areas with stable, high transmission of P. falciparum malaria—for instance, Papua New Guinea and Sub-Saharan Africa—where access to treatment is poor, little is known about the impact of early and effective treatment on malaria transmission. With a high EIR (10 to 1,000), a reduction in transmission intensity is unlikely to affect the incidence of disease until low EIRs (less than 10) are reached.

IPT in Pregnancy and Infancy

IPT is recommended in pregnancy in areas with high and stable transmission of P. falciparum malaria; IPT usually consists of two curative doses of antimalarial treatment. The recommended drug is SP given during the second and third trimesters of pregnancy during prenatal care visits. IPT in infancy involves giving infants treatment doses during vaccination or well-baby visits to health clinics.

In primigravid and secundigravid women, the incidence of severe maternal anemia, the incidence and density of placental parasitemia, and the incidence of low birthweight were 25 to 95 percent lower when mothers were given IPT than when they were not (Kayentao and others 2005; Steketee and others 2001). While initial studies indicate that IPT in infancy reduces anemia and febrile episodes, more research is needed. SP is becoming ineffective for IPT, and health experts are suggesting ACT as a replacement (White 2005).

Chemoprophylaxis

Chemoprophylaxis is advised by travel medicine specialists for nonresidents of endemic areas who are exposed to malaria for short periods. WHO does not recommend chemoprophylaxis for permanent residents of endemic areas because of low feasibility and compliance and high costs relative to the public health benefits (WHO 1996, 2000a, 2000b). The choice of chemoprophylaxis will depend on the drug-sensitivity profile, tolerance, side effects, costs, regimen, and compliance by patients (Baird 2005; Kain, Shanks, and Keystone 2001; White and Breman 2005). The effectiveness of chemoprophylaxis will depend mainly on patient compliance and parasite susceptibility.

Supervision and Policy Change

In relation to drug use, all control activities must be supervised and evaluated rigorously to ensure high-quality care for patients and program effectiveness and efficiency (Bryce and others 1994; Jha, Bangoura, and Ranson 1998). Studies in 37 countries indicate the need for a treatment policy change to ACT (WHO 2002a). Several countries in Africa, Asia, and South America are now implementing ACT as the first-line treatment for uncomplicated malaria (WHO 2005). Many countries are also trying to improve the time lag before treatment. More than 83 percent of the population in the three malarious provinces in South Africa is within 10 kilometers of a health facility (Sharp and le Sueur 1996). In Burkina Faso, Ethiopia, and Uganda, where access to clinics was poor and difficult, mothers and community health workers were empowered to dispense treatment, which resulted in major reductions in mortality and morbidity in children (Kidane and Morrow 2000; Pagnoni and others 1997; Sirima and others 2003).

Economics of Malaria Control Interventions

Goodman, Coleman, and Mills's (2000) study represents the most thorough attempt to compare the cost-effectiveness of a wide range of malaria control interventions. They find that in a very low-income country, the cost-effectiveness range per DALY averted was US$19 to US$85 for ITNs (nets plus insecticide), US$32 to US$58 for residual spraying (two rounds per year), US$3 to US$12 for chemoprophylaxis for children (assuming an existing delivery system), US$4 to US$29 for IPT for pregnant women, and US$1 to US$8 for case-management improvements. Goodman, Coleman, and Mills (2000) find that even though some interventions are relatively cheap, achieving high coverage may require a level of expenditure currently out of reach for many African countries and that overcoming operational barriers to achieving widespread coverage is likely to require substantial assistance from external donors.

Analysis

The following analysis incorporates new knowledge on the effects of interventions and on their costs for a low-income, Sub-Saharan African population living in an area of high, stable transmission. The modeling draws on a wide range of sources on the costs and effects of each intervention, extrapolated across settings and operational conditions. The approach allows for changing cost-effectiveness over time, for example, as resistance to antimalarial drugs or insecticides increases. To address problems of uncertainty in relation to many of the parameters, we used probabilistic sensitivity analysis, which allows for multivariate uncertainty by assigning ranges rather than point estimates to input variables. We assumed that cost and effectiveness input variables follow uniform triangular or normal continuous probability distributions (Mulligan, Morel, and Mills 2005).

We consider the cost-effectiveness of a limited subset of interventions: ITNs, IRS, IPT during pregnancy, and patient management with a change of the first-line drug. We include costs to the provider and the community and incremental out-of-pocket expenses for households, but because of major valuation and measurement problems, we do not include the indirect costs of patients' time to seek care and of the lost productivity resulting from morbidity. We consider only gross costs for all interventions except patient management, given the uncertainty inherent in estimating savings.

Insecticide-treated Nets

We based our analysis of ITNs on the delivery mechanism used in the WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR) trials, where householders, community health workers, and program staff worked together to treat the nets. In relation to insecticide, we considered permethrin and deltamethrin. Deltamethrin is effective for a year; thus, re-treatment is annual. Permethrin lasts for six months; thus, we assumed two treatments per year if the transmission season is longer than six months. The activities undertaken were the training of staff and community health workers, a campaign to inform the community about the intervention, the procurement and transport of the insecticide and nets, and the initial treatment and the re-treatment of the nets. We calculated cost-effectiveness for each intervention for two scenarios: one whereby nets were distributed to households and the second whereby treatment was arranged for existing nets. We drew estimates of the effectiveness of ITNS from a recent meta-analysis of WHO/TDR-sponsored trials conducted in Sub-Saharan Africa (Lengeler 2004). We adjusted the key parameter and effectiveness estimates to account for the proportion of children sleeping and not sleeping under a recently treated net.

With one treatment per year using deltamethrin, the mean cost per DALY averted was US$11 (90 percent range of US$5 to US$21). With one treatment of permethrin per year the cost-effectiveness ratio (CER) increased slightly to a mean of US$12 (90 percent range of US$6 to US$20). Two treatments of permethrin per year increased the mean CER to US$17 (90 percent range of US$9 to US$31). Even if net coverage is low and nets have to be distributed and treated, the intervention remains an extremely attractive use of resources. Moreover, the model includes health benefits only for children under five. If we included benefits for other household members, the CERs would be lower.

Insecticide Residual Spraying

We considered four insecticides for our analysis of the cost-effectiveness of IRS: DDT; malathion; and two pyrethroids, deltamethrin and lambda-cyhalothrin. We used the results of the Cochrane Review meta-analysis of ITN trials conducted in Africa to approximate the results of spraying on morbidity and mortality and adjusted effectiveness estimates to account for noncompliance (Lengeler 2004).

We found little difference between the CERs for the four insecticides when one round of spraying was done per year: they ranged from US$5 to US$18. With two rounds per year, costs increased, but we assumed that effectiveness remained the same, so all the CERs approximately doubled to US$11 to US$34. These results should be interpreted with caution because of uncertainty in relation to the estimates of effectiveness in children under five. The model was based on one round of spraying per year in areas of seasonal transmission and two rounds per year in areas of high, intense (perennial) transmission. Effectiveness will depend on the length of the transmission seasons and on the insecticide. DDT lasts for six months or more, lambda-cyhalothrin for three to six months, and malathion and deltamethrin for only two to three months (Lengeler 2004; Lengeler and Sharp 2003).

IPT during Pregnancy

We analyzed the cost-effectiveness of IPT assuming that primigravid women are given two or three doses of SP at a prenatal clinic. We analyzed benefits to the child by decreased mortality and benefits to the mother resulting from changes in the incidence of severe anemia. We estimated the effect of IPT on the neonatal mortality rate as a function of increased birthweight based on the Cochrane meta-analysis of malaria prevention in pregnancy (Gülmezoglu and Garner 1998). The model allowed for level of drug resistance, probability of initial attendance at a prenatal clinic, probability of returning for a second visit, probability of returning for a third visit, and compliance with the drug regimen. We estimated both incremental and average costs.

The incremental CER for IPT in pregnancy using SP had a 90 percent range from US$9 to US$21 with a mean of US$13. Average total cost-effectiveness had a mean of US$24 (90 percent range of US$16 to US$35).

Change in First-Line Drug

We analyzed the cost-effectiveness of changing first-line therapies to SP and to ACT using a patient-management model with a decision-tree framework in which a patient presents with uncomplicated malaria at an out-patient facility and progresses to full recovery, recovery with neurological sequelae, or death. Three potential drug policy changes were considered (see table 21.5). For current drug policies we assumed either chloroquine or SP as the first-line drug, with SP or amodiaquine as a second-line drug and quinine as the third-line drug. We then examined the cost-effectiveness of policy switches to either SP or ACT as first-line drug (with amodiaquine as second line and quinine as third line).

Table 21.5

Change in First-Line Drug.

Amodiaquine was chosen as the second-line drug in the new drug policy because, like chloroquine and SP, it is relatively cheap. Low compliance, adverse effects, and potential cross-resistance between amodiaquine and chloroquine excluded it from first-line selection. We omitted other potential drugs to limit the scope of analysis.

We used commonly found levels of drug resistance to create likely ranges. When used as second-line treatment, we assumed that a drug faced half the level of resistance than when it was used as a first-line drug. We estimated the growth rate of resistance to each drug based on its expected current location along a sigmoid growth curve. We assessed compliance with each drug based on the length and complexity of each regimen. We gave the widest range (20 to 70 percent) to compliance with ACT, which usually requires a three-day treatment, to account for the different lengths of regimen and variety of formulations.

Figure 21.3 shows that a switch from chloroquine to SP is cost-effective (less than $150 per DALY averted) when chloroquine resistance is above 35 percent. Switching from chloroquine to ACT becomes cost-effective as chloroquine resistance reaches around 37 percent. Switching from SP to ACT becomes cost-effective as SP resistance reaches 12 percent. This low threshold is due to the high growth rate of resistance to SP when it is used as a first-line therapy.

Figure 21.3

Cost-Effectiveness of Switching the First-Line Drug

Results and Interpretation

Table 21.6 presents the average CERs for the interventions reviewed. All interventions can be considered attractive using a cutoff of US$150 per DALY averted. For the childhood preventive interventions, the level of existing infrastructure is a key factor in influencing cost-effectiveness. ITNs are an even better use of resources if net coverage is already high, and IPT is even more cost-effective if prenatal care coverage is good. However, even if levels of infrastructure are poor, these interventions are still attractive based on cost-effectiveness criteria.

Table 21.6

CERs for ITNs, IRS, and IPT (2001 US$).

Curtis and Mnzava's (2000) review comparing worldwide trials of ITNs and IRS for malaria control suggests that they were of equivalent effectiveness. Lengeler and Sharp (2003 21,) also conclude that choosing between IRS and ITNs is "largely a matter of operational feasibility and availability of local resources, rather than one of malaria epidemiology or cost-effectiveness." DDT is the cheapest insecticide but is seldom used because of concerns about its environmental impact. An updated systematic review of the health effects of IRS as well as a full economic comparison between spraying with DDT and other insecticides and ITNs is urgently required. Such reviews should include the environmental benefits of reducing DDT levels and the costs of alternative interventions.

As effective patient management, IPT, and other approaches toward drug use become more widespread, drug resistance will increase, which will affect cost-effectiveness. In terms of first-line treatment, while a switch from chloroquine to SP is unlikely to be costly, cost-effectiveness depends on the initial level of severe resistance to each drug. A switch from chloroquine to ACT is likely to be costly but more effective, given that resistance to ACT is essentially nonexistent and the growth rate of resistance to ACT is likely to be low (Yeung and others 2004). Given the high growth rate of resistance to SP, switching to ACT becomes cost-effective when SP resistance surpasses 12 percent, a relatively low threshold. A switch from chloroquine to ACT appears to be highly cost-effective at all initial levels of chloroquine resistance above 37 percent. Recent studies indicate the remarkable effectiveness of the ACT artemether-lumefantrine in East African areas of chloroquine, amodiaquine, and SP resistance (Mutabingwa and others 2005; Piola and others 2005); it is expected that the availability of ACTs will increase and the costs will decrease in the near future.

Research Priorities

Current interventions to combat malaria remain inadequate for achieving the increased levels of successful patient management and prevention to which all malarious countries aspire and for which ambitious targets have been set (box 21.1). Greatly increased support for malaria research and for developing institutional capacity must occur to make advances and to bring them to populations in need. The WHO Scientific Working Group on Malaria and others have identified four major areas of research as follows (Remme and others 2002; WHO 1996; WHO 2003c).

Conclusion

Given the heavy burden of malaria, the need to use existing strategies and interventions in scaled-up programs more effectively and to deploy them more widely is urgent and merits the highest priority, especially in Africa. While existing tools can be improved, newer tools are required. The history of malaria research and control shows that they are synergistic. Integrating research and control activities has resulted in success in several areas of the world, and will result in vanquishing malaria early in the 21st century.

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