Combination therapy for malaria in Africa: hype or hope?

The development of resistance to drugs poses one of the greatest threats to malaria control. In Africa, the efficacy of readily affordable antimalarial drugs is declining rapidly, while highly efficacious drugs tend to be too expensive. Cost-effective strategies are needed to extend the useful life spans of antimalarial drugs. Observations in South-East Asia on combination therapy with artemisinin derivatives and mefloquine indicate that the development of resistance to both components is slowed down. This suggests the possibility of a solution to the problem of drug resistance in Africa, where, however, there are major obstacles in the way of deploying combination therapy effectively. The rates of transmission are relatively high, a large proportion of asymptomatic infection occurs in semi-immune persons, the use of drugs is frequently inappropriate and ill-informed, there is a general lack of laboratory diagnoses, and public health systems in sub-Saharan Africa are generally weak. Furthermore, the cost of combination therapy is comparatively high. We review combination therapy as used in South-East Asia and outline the problems that have to be overcome in order to adopt it successfully in sub-Saharan Africa.

Making malaria-treatment policy in the face of drug resistance.

The threat, development, spread, and intensification of antimalarial drug resistance are posing tremendous challenges to malaria-control activities throughout the world. Fundamental aspects of these activities are the identification and promotion of safe and effective therapy for acute malarial illness. A major tool in providing guidance on appropriate therapy is the national malaria-therapy policy, which describes antimalarial drugs available for use in a given country, their relative efficacy, and how best to use them in a variety of settings, from the community to the referral hospital. This review describes some of the factors that need to be considered in the development of a national, antimalarial drug policy as well as those that have impeded timely development of national policies, especially in sub-Saharan Africa.

A systematic approach to the development of a rational malaria treatment policy in Zambia.

Despite the spread of chloroquine-resistant Plasmodium falciparum throughout sub-Saharan Africa, chloroquine (CQ) remains the first-line treatment for uncomplicated infection in most countries. To assess the efficacy of CQ and sulphadoxine-pyrimethamine (SP) in Zambia, studies using a standardized 14-day in vivo test were conducted at 6 geographically representative sites. Febrile children < or = 5 years of age were treated with standard doses of CQ or SP and monitored for parasitological failure (using modified WHO criteria) and clinical failure (fever with parasitaemia after completion of therapy). RII/RIII (high to moderate level) parasitological failures were identified in 34% to 70% of CQ-treated children (total N = 300) at the 6 sites and clinical failures in 31% to 48%. SP testing at 2 sites identified RII/RIII failures in 3% and 17% of children and only 1 clinical failure at each site. Because of the high levels of CQ resistance identified in these trials, the Ministry of Health of Zambia convened a national consensus meeting which recommended that Zambia's national malaria treatment policy be modified to make SP available at all health facilities for use in persons who fail initial therapy with CQ. In addition, selected sites, staff, and the methodology from these studies were used to implement a sentinel surveillance system for antimalarial drug efficacy. This systematic approach to antimalarial drug efficacy testing could be easily replicated in other countries seeking to reassess their malaria treatment policies.

An effectiveness and cost analysis of presumptive treatment for Mycobacterium tuberculosis.

BACKGROUND: Delay in treatment of tuberculosis has contributed to both the spread of tuberculosis and its case fatality rate. METHODS: Decision analysis was used to examine the effectiveness and cost of presumptive treatment in patients evaluated for tuberculosis. RESULTS: Over a range of assumptions, empiric antituberculous therapy for acid-fast bacillus smear-positive persons lowers mortality and cost per person evaluated when available rapid diagnostic laboratory methods for tuberculosis are used. In contrast, the average cost per life saved by giving presumptive treatment to all acid-fast bacillus smear- and HIV-negative patients exceeds. $1 million. Empiric treatment for HIV-infected patients with acid-fast bacillus-negative smears decreases average mortality by 2% at an additional cost of $8000 per life saved. When the prevalence of multiple-drug resistance exceeds 9.6%, presumptive drug-resistant therapy for acid-fast bacillus smear-positive patients, rather than the initial four-drug regimen recommended for much of the United States, minimizes both mortality and costs. CONCLUSIONS: Empiric antituberculous therapy often minimizes average mortality and cost for patients evaluated for tuberculosis when rapid diagnostic methods are used.

Effectiveness and cost of rapid and conventional laboratory methods for Mycobacterium tuberculosis screening.

OBJECTIVE: Because delay in the diagnosis of tuberculosis (TB) contributes to the spread of disease and the associated mortality risk, the authors examined the effectiveness and cost of recent advances in methods of diagnosing TB and testing for drug susceptibility, comparing these rapid methods to traditional approaches. METHODS: Decision analysis was used to compare newer rapid and older nonrapid methods for diagnosing TB and testing for drug susceptibility. The average time to diagnosis, average time to treatment, average mortality, and cost of caring for patients evaluated for TB were compared. RESULTS: Using a combination of solid medium and broth cultures, nucleic acid probes for identification, and radiometric broth drug susceptibility testing would lead to diagnosis on average 15 days faster and to appropriate therapy on average five days sooner than methods currently employed by many U.S. laboratories. The average mortality would drop by five patients per 1000 patients evaluated (31%) and the average cost per patient would drop by $272 (18%). CONCLUSIONS: In this era of cost containment, it is important to incorporate test sensitivity and specificity when evaluating technologies. Tests with higher unit costs may lead to lower medical expenditures when diagnostic accuracy and speed are improved. U.S. laboratories should employ available rapid techniques for the diagnosis of TB.

A nation-wide malaria knowledge, attitudes and practices survey in Malawi: objectives and methodology.

A malaria knowledge, attitudes and practices survey was conducted in Malawi during April and May, 1992, to provide policy makers and program managers with information needed to design or improve malaria control programs, to establish epidemiologic and behavioral baselines, and to identify indicators for monitoring program effectiveness. Using cluster-sample survey methodology, 1531 households, in 30 clusters of 51-52 households each, were identified and members interviewed. Interviews were conducted by trained survey teams composed of young Malawian women with secondary level education. Heads of households were asked about malaria prevention methods used and about household economics; caretakers of children were asked about treatment and health seeking behavior in a recent malaria episode in a child; and women who had been pregnant in the past 5 years were asked about their antenatal clinic utilization and malaria during pregnancy. Survey results will be used to make programmatic decisions, including developing health education messages and establishing monitoring and evaluation of malaria control activities and outcomes in Malawi.

PIP: A malaria knowledge, attitudes and practices survey was conducted in Malawi in the late rainy season, April 1-May 16, 1992, corresponding to the season of peak malaria transmission to provide policy makers and program managers with information needed to design or improve malaria control programs, to establish epidemiologic and behavioral baselines, and to identify indicators for monitoring program effectiveness. A cluster-sample survey methodology, modified from the Expanded Program for Immunization cluster-sampling methodology was used to identify and interview members of a total sample of 1531 households, in 30 clusters of 51 to 52 households each. Heads of households were asked about malaria prevention methods used and about household economic; caretakers of children were asked about treatment and health seeking behavior in a recent malaria episode in a child; and women who had been pregnant in the past 5 years were asked about their antenatal clinic utilization and malaria during pregnancy. A total of 7025 persons in 1531 households were included in the survey: 1178 adults with recent fever illness and caretakers of 724 children with recent fever illness were interviewed; 1395 households included at least one woman who had ever been pregnant, with 809 women having completed a pregnancy within the last 5 years. Preventive measures used in the households and household income were ascertained for 1531 households. In several articles, detailed results will be described for each part of the survey. These results will be used to be guide policy makers and program managers in making decisions based on current data in designing and improving malaria control programs and health education messages. Baseline epidemiologic and behavioral indicators will be identified for monitoring program impact to help focus intervention efforts on high risk groups, through channels that will most effectively reach the greatest number of people.

Malaria knowledge, attitudes and practices in Malawi: survey population characteristics.

A national knowledge, attitudes and practices (KAP) survey was conducted in March-April 1992 to examine malaria illness and the people's response to illness and malaria prevention. Fifty-one households in each of 30 randomly selected communities were sampled and information was recorded from 1,531 households and 7,025 individuals. The population is characterized by low income (average household and per capita income were US $490 and $122, respectively) and low education levels (among adult women, 45% had no formal education and only 3.9% completed more than 8 years of schooling). Characteristics of the population were similar to those found in the 1987 national census, suggesting that the survey population was representative of the larger population of Malawi. Children under 5 years of age made up 15.8% of the population and had the highest rates of fever illness; these children experienced an estimated 9.7 cases/year of fever illness consistent with malaria. Although adults reported fever less frequently, women of reproductive age experienced an estimated 6.9 episodes of fever annually. The burden of malaria morbidity in this population is extremely high and occurs in all age groups.

PIP: A national knowledge, attitudes and practices (KAP) survey was conducted in March-April 1992 to examine malaria illness and the people's response to illness and malaria prevention. 51 households in each of 30 randomly selected communities were sampled and information was recorded from 1531 households and 7025 individuals. The average annual income per household was US $490 and the average per capita income was $122. Female-headed households are most commonly in the "very low" income grouping. Among adult women, 45% had no formal education and only 3.9% had completed more than 8 years of schooling. 23% of male households and 58% of female households reported no normal education. Children under 5 years of age made up 15.8% of the population and had the highest rates of fever illness. Seasonally adjusted estimates of fever episodes by age group and gender for adults showed that these children experienced the highest reported rates: an estimated 9.7 cases/year of fever illness consistent with malaria. Infants and children under 5 years of age had the highest reported rates of fever (45.6% and 49.0%, respectively). Although adults reported fever less frequently, women of reproductive age experienced an estimated 6.9 episodes of fever annually. Reported malaria-like fever in the previous 14 days was recorded for each household member; overall, 33% of the population reported fever in this interval. Data from the National Health Information System indicate that in 1989 approximately 10% of the more than 3.7 million total outpatient cases of malaria for the year were reported in the mid-April to mid-May time interval. The burden of malaria morbidity in this population is extremely high and occurs in all age groups.

Malaria and childbearing women in Malawi: knowledge, attitudes and practices.

Information on women's use of antenatal clinic (ANC) service, including malaria prevention and treatment during pregnancy, was collected during a national malaria knowledge, attitudes, and practices survey in Malawi. Among 1531 households, 809 (53%) included a woman who had carried a pregnancy past the second trimester within the past 5 years. Of these, 756 (93%) women reported at least one ANC visit during pregnancy (median = 4); 336 (42%) attended 5 or more times. Approximately half (51%) reported delivering in a hospital; 5% delivered in a clinic; 13% delivered at home with a trained birth attendant; and 28% delivered at home with only family attending. Women at increased risk for delivery complications (e.g. primigravidas and grand multigravidas) were no more likely to attend ANC or deliver in hospital than women without increased risk. The woman's level of education was the only significant predictor of initiating ANC care, continued ANC attendance, and delivery in hospital. In a setting where 43% of women pregnant within the past 5 years had received no formal education and 70% had completed less than 5 years, this survey identified a critical need for targeting health messages towards poorly educated women to ensure proper utilization of antenatal care services, including coverage with malaria prevention throughout pregnancy.

PIP: Information on women's use of antenatal clinic (ANC) service, including malaria prevention and treatment during pregnancy, was collected during a national malaria knowledge, attitudes, and practices survey in Malawi. Among 1531 households, 809 (53%) included a woman who had carried a pregnancy past the second trimester within the past 5 years. Of these, 756 (93%) women reported at least one ANC visit during pregnancy (median = 4); 336 (42%) attended 5 or more times. Among ANC attenders, 723 (96%) reported receiving an ANC card, but only 210 (26%) could produce the card for examination by the interviewer. Delivery occurred at home with a family member attending among 225 (28%) women; 103 (13%) reported home delivery with a TBA present; 421 (51%) delivered in hospital; and 43 (5%) in a clinic. Women at an increased risk for delivery complications (e.g. primigravidas and grand multigravidas) were no more likely to attend ANC or deliver in hospital than women without increased risk. Tetanus toxoid immunization was reported by 689 (91%) ANC attenders, and 576 (76%) reported receiving iron. Women who attended ANC were significantly more likely to deliver at a hospital or clinic (452/756, 60%) than women who had never attended ANC (3/53, 6%) (p .001). For those delivering at a health care facility, 309 (68%) walked to the facility; most of the women were accompanied by a female relative (274, 60%). Most women (80%) reported waiting until the onset of labor to travel to the facility. The woman's level of education was the only significant predictor of initiating ANC care, continued ANC attendance, and delivery in hospital. In a setting where 43% of women pregnant within the past 5 years had received no formal education and 70% had completed less than 5 years, this survey identified a critical need for targeting health messages towards poorly educated women to ensure proper utilization of antenatal care services, including coverage with malaria prevention throughout pregnancy.

Economic impact of malaria in Malawian households.

Household heads were questioned about household income and household expenditures on the treatment or prevention of malaria in a nationwide malaria knowledge, attitudes, and practices (KAP) survey conducted in Malawi in 1992. Very low income households with an average annual income of $68 constituted 52% of the sampled households. The primary income source for these households was farm production (92%), with the majority of goods produced consumed by the household and not available as discretionary income. Expenditure on malaria prevention varied with household income level. Only 4% of very low income households spent resources on malaria preventive measures compared to 16% of other households. In contrast, over 40% of all households, independent of income level, reported expenditures on malaria treatment. Almost half of the reported malaria cases sought treatment at a health facility at a cost of $0.21 per child case and $0.63 per adult case. The overall direct expenditure on treatment of malaria illness in household members was $19.13 per year (28% of annual income) among very low income households and $19.84 per year (2% of annual income) among low to high income households. The indirect cost of malaria, calculated on the basis of days of work lost, was $2.13 per year (3.1% of annual income) among very low income households and $20.61 per year (2.2% of annual income) among low to high income households. Very low income households carried a disproportionate share of the economic burden of malaria, with total direct and indirect cost of malaria among these households consuming 32% of annual household income compared to 4.2% among households in the low to high income categories.

Malaria knowledge, attitudes and practices in Malawi: policy implications for the National Malaria Control Program.

PIP: Following data analysis and the presentation of the summary report to Ministry of Health officials, a group of Ministry of Health staff examined results for implications for national policy development, those elements which were relevant to 1) health education messages; 2) the development of programmatic indicators; 3) constraints on the use of services and access to treatment and prevention; and 4) direct and indirect costs of malaria in Malawi. Despite years of chloroquine use, less than 30% of children were reported to receive an appropriate dose, thereby limiting effective therapy. Plans to implement a new first line drug for therapy for use of sulfadoxine-pyrimethamine must be clearly spelled out. 10% of children attending government clinics and 43% of those attending private facilities receive an injection for malaria, a gross overuse of injectable drugs. With 83% of women perceiving malaria as a problem during pregnancy and 68% thinking that antimalarials can prevent it, there is a need for increased management of malaria in pregnancy. Use of malaria preventive measures is very low and income-dependent. Educational messages must include teaching that mosquitoes transmit malaria, as only 55% of household heads reported this as the cause of malaria fevers. In certain locally based public health projects, use of bed nets could be much higher. There is an imbalance between the average household expenditure on treatment (US $13.33) compared to prevention ($2.47). In addition, 40% of households have an annual income of less than US $110 and expenditure on treatment exceeds 10% of these family incomes. The use of malaria prevention measures was closely linked to household income and, estimated annual expenditure on sprays, coils and bed nets was high ($42.60, $12.56, and $12.42, respectively). This underscores that 1) households that do spend money on prevention tend to spend substantial amounts; and 2) the money spent might be more effective if it were spent on bed nets rather than sprays.^ieng

The economic cost of malaria in Africa.

Although malaria is the major health problem in Africa, there is little research on its economic impact. This study adapts a framework for assessing the economic costs of illness to available data on malaria. Direct costs of illness are the costs of treatment and control activities, and indirect costs are the value of lost time due to morbidity and premature mortality. Direct costs were estimated by applying the average estimated health systems costs per case to the number of cases. Indirect costs were assessed by multiplying adult output per day times the estimated productive time lost through both adult and childhood cases. As data are not available to assess the economic impact of malaria in Africa as a whole, four case studies were performed on countries or regions for which needed data could be found. The four sites (Rwanda, Solenzo medical district of Burkina Faso, Mayo-Kebbi district, Chad, and Brazzaville, Congo) were chosen to illustrate the diversity in kinds of data which can be used (aggregate national health statistics versus household surveys) and in locations (urban versus rural). Costs were calculated for the recent past and were projected to 1995 based on recent epidemiological trends. Estimates for all sub-Saharan Africa were derived from the averages of these sites. In 1987, a case of malaria cost $9.84 (in 1987 US dollars)--$1.83 in direct costs and $ 8.01 in indirect costs. As the average value of goods and services produced per day in Africa was $0.82, this cost is equivalent to 12 days of output.(ABSTRACT TRUNCATED AT 250 WORDS)

Economic cost of malaria in Rwanda.

Although malaria is widely recognized as a major public health problem in much of Africa, its impact on a specific national or regional economy has proved difficult to assess. This paper demonstrates the kind of analysis possible given available national aggregate statistics on epidemiology and economic indicators, the type of data most readily available. An economic model which applies the average cost of malaria per case to the known number of cases in Rwanda for 1989 estimated the total cost to be $ 2.88 per capita (in 1987 US dollars). Of this cost, $0.63 per capita represents the direct cost of treatment, including care of outpatients and hospitalized cases in both government and private facilities, as well as self-treatment. The other $ 2.25 per capita represents the indirect costs of productive time lost to malaria morbidity in adults and to care for sick children, and the cost of lifetime earnings lost through premature malaria mortality. The average output per day of the Rwandan economy was $0.83 in 1989. Thus, the per capita malaria cost equals 3.5 days of production or 1% of GDP. The average cost of each of the 1,722,271 reported malaria cases in 1989 was $11.82: $2.58 in direct and $9.24 in indirect cost. The direct cost per case is equal to 160% of the per capita budget of the Ministry of Health. Economic and epidemiological projections to 1995 yield an increase in malaria cases to over 4 million at a cost of $7.11 per capita. Direct costs are projected to rise over 200% due to increasing costs of drugs and supplies to treat increasingly drug-resistant cases. Indirect costs, which are tied to a declining economy, are projected to rise by just over 100%. By 1995, malaria is projected to cost 2.4% of the Rwandan GDP, exacerbating an already serious impact.

Estimating the direct and indirect economic costs of malaria in a rural district of Burkina Faso.

Comprehensive estimates of the direct economic costs of malaria should include not only the costs of care at established health facilities, but also other expenditures, such as travel and out-of-pocket costs of drugs. They should include all episodes of illness, whether or not the patient attended a health facility. Also, the indirect economic costs, which are based on the value of time lost due to illness, consider seasonal variations in the marginal product of labor according to the agricultural season. A 1985 representative survey of 626 households in Solenzo medical district, Burkina Faso, provided household data on health service utilization, expenditures, and agricultural production with which to implement these refinements. Numbers of malaria deaths and cases were estimated by adjusting survey totals according to monthly patterns of reported malaria deaths. The marginal product of labor was valued according to typical activities in each of three agricultural seasons: brewing millet beer during the maintenance period (January-February), growing cotton during the cash crop season (March-April), and growing millet and sorghum during the food crop season (May-December). The resulting values were $0.28, $1.09, and $0.55 per day, respectively. Cost per case averaged $5.96 and cost per capita $1.15. Indirect cost due to mortality was the largest cost component ($0.79 per capita), followed by direct costs incurred by the user (e.g. transportation costs and drug purchases, $0.22 per capita). Direct costs paid by providers were small, only $0.04 per capita. A household survey provides the necessary data for more comprehensive population-based estimates of costs of malaria.

Economic analysis of several types of malaria clinics in Thailand.

The costs of three types of malaria clinics in Maesot District, north-west Thailand, for a one-year period in 1985-86 were compared from the institutional, community and social (institutional plus community) perspectives. The greatest number of patients at the lowest average institutional cost per smear and per positive case diagnosed (US$ 0.82) were seen at the large central clinic in Maesot town. The peripheral clinic in Popphra, a subdistrict town, had moderate institutional costs per smear and per positive case (US$ 1.58). The periodic mobile clinic, which served five villages on a fixed weekly schedule, had low average institutional costs per smear, but the highest cost per positive case (US$ 3.53). Community costs (those paid by patients and their families) were lowest in the periodic clinic. Addition of a periodic clinic to a system of central and peripheral clinics increased the number of malaria cases treated, particularly those involving women and under-16-year-olds. Although the periodic clinic entailed a modest increase in institutional costs, it minimized social costs. The results of the study suggest that use of a combination of central, peripheral, and periodic clinics, which maximizes access to malaria treatment, minimizes the social costs of malaria.

PIP: The costs of 3 types of malaria clinics in Maesot District, northwest Thailand, for a 1 year period in 1985-86 were compared from the institutional, community, and social (institutional + community) perspectives. The greatest number of patients at the lowest average institutional cost/smear and per positive case diagnosed (US $0.82) were seen at the large central clinic in Maesot town. The peripheral clinic in Popphra, a subdistrict town, had moderate institutional costs/smear and per positive case (US $1.58). The periodic mobile clinic which served 5 villages on a fixed weekly schedule had low average institutional costs/smear, but the highest cost/positive case (US $3.53). Community costs (those paid by patients and their families) were lowest in the periodic clinic. The addition of a periodic clinic to a system of central and peripheral clinics increased the number of malaria cases treated, particularly those involving women and under-16 year olds. Although the periodic clinic entailed a modest increase in institutional costs, it minimized social costs. The results of the study suggest that the use of a combination of central, peripheral, and periodic clinics, which maximizes access to malaria treatment, minimizes the social costs of the disease. (author's modified)

Malaria clinics in Mae Sot, Thailand: factors affecting clinic attendance.

Clinics of the Anti-Malaria Program of Thailand play an important part in the control of malaria morbidity and mortality, treating over 60% of reported cases yearly. Interviews were conducted both with attenders at three clinics in Mae Sot District and among those reporting malaria illness but not attending. Distance travelled to the clinic, costs of travel and frequency of other treatment prior to clinic attendance were all highest among patients at the large centralized clinic, moderate in a peripheral fixed clinic, and lowest in a village-based mobile clinic. Reported length of illness prior to attendance was similar for all three clinics. As many as 91% of villagers interviewed chose not to treat their illness in a malaria clinic. These non-attenders reported longer illness time and higher expenditures on treatment than clinic patients. Provision of village-based clinics can improve access. However, the widespread reliance on non-Program treatment of malaria suggests the need for policies to address these alternative therapeutic modes.

Evaluation of malaria clinics in Maesot, Thailand: use of serology to assess coverage.

The clinics of the anti-malaria programme in Thailand serve an increasingly important role in the strategy for control of malaria within a context of multi-drug resistant falciparum malaria. Figures from clinics in Maesot District show a predominance of young males among positive cases treated (56% of all cases). In contrast, sero-epidemiological findings from a random sample of over 500 villagers in the area show similar exposure rates among males and females of equal age. There were no statistically significant differences between males and females 0-15 and 16-30 years old in percentages positive by indirect fluorescent antibody tests or enzyme-linked immunosorbent assays (ELISA), mean level of ELISA positivity, or rate of sero-conversion. Differences in level of positivity did occur between males and females over 30. An index constructed from the serological findings indicated under-representation of children and women of all ages in clinics but suggested that coverage of children could be improved by the provision of a community-based, fixed-schedule mobile clinic.

Cost-effectiveness research in malaria control and the need for health behaviour and socio-economic research in malaria control in Thailand.

The complexity of the malaria situation in Thailand requires behavioural and socio-economic research in wide variety of areas including; migration, illness behaviour, motivation of staff and communities and the relationship of institutional and community expenditure to reduction in morbidity. The research ideally should be constructed in such a way as to maximize the availability of methods for incorporation into routine monitoring, evaluation, and policy making activities of the Anti-Malaria Programme.

Development of two indices of postoperative morbidity.

Two indices of postoperative morbidity, Nursing Assessment Index and Observed Treatment Index, are described and evaluated in this study of 4,182 consecutive anesthetics. The use of these indices in studies of the quality and effectiveness of surgical and anesthetic care should increase the economy and precision with which the causes of unsatisfactory outcome are identified. Specific illustrations of the relationship of the preanesthetic status of patients to their postoperative morbidity as measured by these indices and mortality rates are given. In addition these two indices of morbidity measured on the seventh postoperative day are shown to be strongly co-related with subsequent in-hospital deaths. Thus, of the 100 patients with a Nursing Assessment Index worse than 3, 19 percent died; only 0.4 percent of the 550 patients who had no morbidity as measured by this index died. Although they ultimately survive, about an equal number of patients become seriously ill as die follow operations.