Drug dispensing practices during implementation of artemisinin-based combination therapy at health facilities in rural Tanzania, 2002-2005.

OBJECTIVE: To assess the degree to which policy changes to artemisinin-based combination therapies (ACTs) as first-line treatment for uncomplicated malaria translate into effective ACT delivery. METHODS: Prospective observational study of drug dispensing practices at baseline and during the 3 years following introduction of ACT with sulfadoxine-pyrimethamine (SP) plus artesunate (AS) in Rufiji District, compared with two neighbouring districts where SP monotherapy remained the first-line treatment, was carried out. Demographic and dispensing data were collected from all patients at the dispensing units of selected facilities for 1 month per quarter, documenting a total of 271, 953 patient encounters in the three districts. RESULTS: In Rufiji, the proportion of patients who received a clinical diagnosis of malaria increased from 47.6% to 57.0%. A majority (75.9%) of these received SP + AS during the intervention period. Of patients who received SP + AS, 94.6% received the correct dose of both. Among patients in Rufiji who received SP, 14.2% received SP monotherapy, and among patients who received AS, 0.3% received AS monotherapy. CONCLUSIONS: The uptake of SP + AS in Rufiji was rapid and sustained. Although some SP monotherapy occurred, AS monotherapy was rare, and most received the correct dose of both drugs. These results suggest that implementation of an artemisinin combination therapy, accompanied by training, job aids and assistance in stock management, can rapidly increase access to effective antimalarial treatment.

Trends in antimalarial drug deployment in sub-Saharan Africa.

Antimalarial drug resistance is forcing newly developed pharmaceuticals into widespread use at an accelerating pace. To have the greatest public health impact, new pharmaceuticals will need to be deployed effectively in sub-Saharan Africa. Achieving effective antimalarial drug deployment over the short- to medium-term will require an appreciation of how drugs are currently used in Africa and the development of innovative approaches to optimize that use. Over the long-term, fundamental changes in the way that drugs are deployed will probably be required. There are many new strategies and initiatives that, to a greater or lesser degree, will influence how drugs are used. These influences may have a positive or negative effect on reducing malaria morbidity and mortality. The concept of analyzing and monitoring programmatic effectiveness allows for a more holistic understanding of these influences and allows for more unbiased, evidence-based decision making related to drug policy and deployment.

Traitements antipaludiques associés en Afrique: faut-il y croire?: résumé

La pharmacore ́ sistance constitue l'une des plus graves menaces pour la lutte antipaludique. En Afrique, l'efficacite ́desantipaludiques e ́ conomiquement abordables s'amenuise tre` s vite alors que les me ́ dicaments hautement efficaces onttendance a` couˆ ter trop cher. Or des strate ́ gies d'un bon rapport cout-efficacite ́ s'imposent pour prolonger la dure ́edevie utile des antipaludiques. Des observations faites en Asie du Sud-Est sur un traitement associant des dérivés del'arte ́ misinine a`delame ́ floquine indiquent un ralentissement du phe ́ nome` ne de pharmacore ́ sistance a` l'e ́ gard de cesdeux substances. D'ou` la possibilite ́ de trouver une solution au proble` me de la pharmacore ́ sistance en Afrique ou`denombreux obstacles s'opposent toutefois a` la mise en place efficace d'un traitement associe ́ . En effet, les taux detransmission sont relativement e ́ leve ́ s, une forte proportion d'infections asymptomatiques se produit chez des sujetssemi-immuns, les me ́ dicaments sont souvent utilise ́ s de fac ̧ on inopportune et sans informations suffisantes, les diagnostics de laboratoire font souvent de ́ faut et les services de sante ́ publique sont, en general, insuffisants en Afrique subsaharienne. En outre, le traitement associé coute relativement cher. Les auteurs examinent ici le traitement associe ́tel qu'il est applique ́ en Asie du Sud-Est, en relevant au passage les problèmes à résoudre si l'on veut l'adopter avecsucce` s en Afrique subsaharienne

Increased carriage of trimethoprim/sulfamethoxazole-resistant Streptococcus pneumoniae in Malawian children after treatment for malaria with sulfadoxine/pyrimethamine.

Treatment of malaria with sulfadoxine/pyrimethamine and of presumed bacterial infections with trimethoprim/sulfamethoxazole (cotrimoxazole) was assessed to see if either increases the carriage of cotrimoxazole-resistant Streptococcus pneumoniae in Malawian children. Children <5 years old treated with sulfadoxine/pyrimethamine, cotrimoxazole, or no antimicrobial agent were enrolled in a prospective observational study. Nasopharyngeal swabs were taken before treatment and 1 and 4 weeks later. Pneumococci were tested for antibiotic susceptibility by broth microdilution. In sulfadoxine/pyrimethamine-treated children, the proportion colonized with cotrimoxazole-nonsusceptible pneumococci increased from 38.1% at the initial visit to 44.1% at the 4-week follow-up visit (P=.048). For cotrimoxazole-treated children, the proportion colonized with cotrimoxazole-nonsusceptible pneumococci increased from 41.5% at the initial visit to 52% at the 1-week follow-up visit (P=.0017) and returned to 41.7% at the 4-week follow-up. Expanding use of sulfadoxine/pyrimethamine to treat chloroquine-resistant malaria may have implications for national pneumonia programs in developing countries where cotrimoxazole is widely used.

Effect of Plasmodium falciparum parasitemia density on hemoglobin concentrations among full-term, normal birth weight children in western Kenya, IV. The Asembo Bay Cohort Project.

The relative importance of acute high-density versus persistent low-density Plasmodium falciparum parasitemia in contributing to the public health problem of malarial anemia remains unclear. The Asembo Bay Cohort Project in western Kenya collected monthly hemoglobin (Hb) and parasitologic measurements and biweekly assessments of antimalarial drug use among 942 singleton live births between 1992 and 1996. A mixed-model analysis appropriate for repeated measures data was used to study how time-varying parasitemia and antimalarial drug exposures influenced mean Hb profiles. Incidence of World Health Organization-defined severe malarial anemia was 28.1 per 1,000 person-years. Among children aged less than 24 months, concurrent parasitemia was significantly associated with lower mean Hb, especially when compared to children with no concurrent parasitemia. Increased densities of the 90-day history of parasitemia preceding Hb measurement was more strongly associated with mean Hb levels than concurrent parasitemia density. While the highest quartile of 90-day parasitemia history was associated with lowest mean Hb levels, children in the lowest 90-day exposure quartile still experienced significantly lower Hb levels when compared to children who remained parasitemia-free for the same 90-day period. The results highlight the importance of collecting and analyzing longitudinal Hb and parasitologic data when studying the natural history of malarial anemia.

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.

Longitudinal cohort study of the epidemiology of malaria infections in an area of intense malaria transmission I. Description of study site, general methodology, and study population.

A large-scale longitudinal cohort project was initiated in western Kenya in June 1992. The primary purpose of the project was to study Plasmodium falciparum malaria in a highly endemic area using a comprehensive and multidisciplinary approach, which included epidemiology, entomology, and immunology. Between June 1992 and July 1994, pregnant women living in 15 rural villages were identified during a monthly census and 1,164 were enrolled. The women were followed-up throughout their pregnancy and they, along with their newborn infants and direct siblings of the infants' less than 15 years of age, were monitored over time. As of May 1995, 1,017 infants had been born to these women. This paper presents the design and general methodology used in this study and describes the initial experience with intense monitoring of a large population over a prolonged period.

Longitudinal cohort study of the epidemiology of malaria infections in an area of intense malaria transmission II. Descriptive epidemiology of malaria infection and disease among children.

A large-scale longitudinal cohort project was initiated in western Kenya in June 1992. Between June 1992 and July 1994, 1,848 children less than 15 years of age were monitored prospectively for a mean of 236 days. During this period, 12,035 blood smears were examined for malaria and only 34% were found to be negative. Parasite prevalence (all species) decreased with age (from a high of 83% among children 1-4 years old to 60% among children 10-14 years old). Even more dramatic decreases were noted in the prevalence of high density falciparum infection (from 37% among children 12-23 months old to < 1% among 10-14-year-old children) and in clinical malaria (20% to 0.3% in the same age groups). Children < 1 year of age accounted for 55% of all cases of anemia detected. Anemia was consistently associated with high density infection in children < 10 years of age (20% to 210% increased risk relative to aparasitemic children). These results demonstrate the relationship between high-density malaria infection and two clinical manifestations of malarial illness.

Malaria surveillance--United States, 1995.

PROBLEM/CONDITION: Malaria is caused by four species of Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, or P. malariae), which are transmitted by the bite of an infective female Anopheles sp. mosquito. Most malaria infections in the United States occur among persons who have traveled to areas with ongoing transmission. Occasionally, cases occur in the United States through exposure to infected blood products, by congenital transmission, or by local mosquito-borne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. REPORTING PERIOD: Cases with onset of illness during 1995. DESCRIPTION OF SYSTEM: Malaria cases confirmed by blood smears are reported to local and/or state health departments by health-care providers and/or laboratory staff. Case investigations are conducted by local and/or state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS). Data from NMSS serve as the basis for this report. RESULTS: CDC received reports of 1,167 cases of malaria with onset of symptoms during 1995 among persons in the United States or one of its territories. This number represents an increase of 15% from the 1,014 cases reported for 1994. P. vivax, P. falciparum, P. malariae, and P. ovale were identified in 48.2%, 38.6%, 3.9%, and 2.2% of cases, respectively. More than one species was present in three patients (0.3% of total). The infecting species was not determined in 80 (6.9%) cases. The number of reported malaria cases acquired in Africa (n=519) remained approximately the same as in 1994 (n=517); cases acquired in Asia increased by 32.4% (n=335); and cases acquired in the Americas increased by 37.4 % (n=246). Of 591 U.S. civilians who acquired malaria abroad, 15.6% had followed a chemoprophylactic drug regimen recommended by CDC for the area where they had traveled. Nine patients became infected in the United States. Of these nine cases, five were congenitally acquired; one was acquired by organ transplantation; and one was acquired by a blood transfusion. For two of the nine cases, the source of infection was unknown. Six deaths were attributed to malaria. INTERPRETATION: The 15% increase in malaria cases in 1995 compared with 1994 resulted primarily from increases in cases acquired in Asia and the Americas, most notably a 100% increase in the number of cases reported from South America. This change could have resulted from local changes in disease transmission, travel patterns, reporting errors, or a decreased use of effective antimalarial chemoprophylaxis. In most reported cases, U.S. civilians who acquired infection abroad were not on an appropriate chemoprophylaxis regimen for the country where they acquired malaria. ACTIONS TAKEN: Additional information was obtained concerning the six fatal cases and the nine infections acquired in the United States. Malaria prevention guidelines were updated and distributed to health-care providers. Persons traveling to a malarious area should take the recommended chemoprophylaxis regimen and use personal protection measures to prevent mosquito bites. Any person who has been to a malarious area and who subsequently develops a fever or influenza-like symptoms should seek medical care; investigation should include a blood smear for malaria. Malaria infections can be fatal if not diagnosed and treated promptly. Recommendations concerning prevention and treatment of malaria can be obtained from CDC.

Analysis of repeated hemoglobin measures in full-term, normal birth weight Kenyan children between birth and four years of age. III. The Asemobo Bay Cohort Project.

Anemia is an important public health problem. During very early childhood numerous factors affect hemoglobin (Hb) concentration over time, making single cross-sectional measurements difficult to interpret when studying the natural history of anemia or evaluating anemia control strategies. We analyzed repeated Hb measures contributed by 942 Kenyan children between birth and 48 months of life using a mixed effects model, with a regression spline used to describe the population mean Hb profile, and random intercepts and slopes and first-order autoregressive correlation structure to accommodate the within-individual correlation among the repeated Hb measures. The approach facilitates the study of time-stationary and time-varying covariates that influence Hb in early life. The fitted mean Hb profile obtained from the analytic model is consistent with the observed mean Hb of the study population. Village of residence was associated with greatest difference in mean Hb at time of birth (16 versus 19 g/dL; P < 0.0001). Monthly weight-for-age was also associated with mean Hb after 3 months of age. This is the first description of an analysis strategy specifically for repeated Hb measures collected in a longitudinal field study in Africa. The strategy will facilitate improved study of time-varying covariates thought to influence pediatric anemia.

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.

Chloroquine in Africa: critical assessment and recommendations for monitoring and evaluating chloroquine therapy efficacy in sub-Saharan Africa.

Chloroquine-resistant malaria is a major public health threat in sub-Saharan Africa. While a few countries have already replaced chloroquine as the first-line therapy for uncomplicated malaria or are in the process of doing so, other countries are faced with the complicated task of assessing the current status of drug resistance, making national policy-level decisions about whether to replace chloroquine or not, and initiating a monitoring system to track changes in the efficacy of malaria therapy. There is currently no standardized approach for collecting and interpreting data on therapy efficacy. There is also no agreement as to how much chloroquine resistance or treatment failure is acceptable and how much warrants a change in treatment policy. Using data collected in 10 sites in eastern and southern Africa between 1990 and 1996, we have assessed the therapeutic response to chloroquine and investigated predictors of clinical success or failure. Based on these experiences and analyses, a standardized protocol for in vivo studies of the efficacy of malaria therapy and for approaches to designing monitoring systems are proposed. The process of making policy-level decisions based on data collected by these systems is also discussed.

A longitudinal investigation of IgG and IgM antibody responses to the merozoite surface protein-1 19-kiloDalton domain of Plasmodium falciparum in pregnant women and infants: associations with febrile illness, parasitemia, and anemia.

This study was aimed at delineating characteristics of naturally acquired immunity against the merozoite surface antigen-1 (MSP-1) of Plasmodium falciparum, a candidate malaria vaccine antigen. A case/control study was performed on 75 case/control pairs of infants with febrile illness at the time of the first detected infection indicating a clinical case. The presence and level of antibodies at one month prior to the first infection and at the time of the first infection in the afebrile group was significantly higher than in the febrile group. Decreased parasite density and decreased infection-related loss of hemoglobin was seen in infants with anti-MSP-1(19kD) IgG antibodies. In addition, mothers who were positive for the presence of these antibodies conferred protection against placental infection and infection in their infants. In this study, development of anti-MSP-1(19kD) antibody responses in 24 infants were studied longitudinally using monthly serum samples collected from birth until approximately one year of age. In addition, umbilical cord blood sera and respective mothers' sera were analyzed. Longitudinal studies of antibody responses revealed several short-lived IgG and IgM peaks throughout an infant's first year that correlated with detection of parasitemia. The protection against parasitemia and febrile illness was observed in infants when anti-MSP-1(19kD) antibodies were present; when infants were negative for IgG, they had a 10-times greater risk of becoming parasitemic. These data from a longitudinal and prospective study of malaria suggest a protective role for anti-MSP-1(19kD) antibodies in infants and pregnant women.

Prevalence of malaria parasitemia and accuracy of microscopic diagnosis in Haiti, October 1995.

In October 1995 the Ministry of Public Health and Population in Haiti surveyed 42 health facilities for the prevalence and distribution of malaria infection. They examined 1,803 peripheral blood smears from patients with suspected malaria; the overall slide positivity rate was 4.0% (range, 0.0% to 14.3%). The rate was lowest among 1- to 4-year-old children (1.6%) and highest among persons aged 15 and older (5.5%). Clinical and microscopic diagnoses of malaria were unreliable; the overall sensitivity of microscopic diagnosis was 83.6%, specificity was 88.6%, and the predictive value of a positive slide was 22.2%. Microscopic diagnoses need to be improved, and adequate surveillance must be reestablished to identify areas where transmission is most intense. The generally low level of malaria is encouraging and suggests that intensified control efforts targeted to the areas of highest prevalence could further diminish the effect of malaria in Haiti.

Malarone-donation programme in Africa.

PIP: Glaxo Wellcome announced in November 1996 its intent to donate up to 1 million treatment courses per year of its new antimalarial drug, Malarone, to countries in Africa, Southeast Asia, and South America, where malaria is endemic. Because the effectiveness of the small number of available antimalarial drugs is threatened by the emergence of drug resistance, the advantages of introduction of this new drug to a given area should be given careful consideration. Chloroquine, for example, is nearing the end of its effectiveness as a first-line drug for the treatment of uncomplicated falciparum malaria in many areas of East and Central Africa. The lifespan of its replacement, sulfadoxine-pyrimethamine, is likely to be even shorter given its long half-life and the ease with which resistance-conferring mutations occur. In Southeast Asia and the Amazon basin of South America, where multidrug-resistant Plasmodium falciparum malaria is a serious problem, the advantages of Malarone introduction clearly outweigh any disadvantages. In sub-Saharan Africa, the premature distribution and increasing use of artemisinins may jeopardize their long-term effectiveness, however. Another factor complicating decisions to introduce Malarone is its required 3-day course of treatment, necessitating hospitalization if compliance is to be ensured. The donation project gives patients in developing countries access to an expensive drug that would otherwise be unavailable. Time must be taken, however, to fully debate the project's pros and cons, resolve inherent logistic problems, and establish guidelines for Malarone use in sub-Saharan Africa.^ieng

Drug resistance among malaria and other parasites.

Recent decades have witnessed the emergence and spread of parasites resistant to standard drug therapies, particularly malaria. Chloroquine-resistant Plasmodium falciparum has now spread to most malarial areas, and resistance to other antimalarial drugs, including mefloquine and sulfadoxine-pyrimethamine, have become significant problems in some parts of Southeast Asia and South America. Chloroquine-resistant P. vivax is well established in Papua New Guinea and Indonesia and has been reported in other areas. Trichomonas and Giardia infections resistant to metronidazole have also been documented. This article reviews the current status of drug resistance among parasites, particularly malaria, and offers strategies for managing patients with these infections.

PIP: Reviewed in this article is the research literature on issues related to the development, spread, and impact of drug resistant malaria and current recommendations on chemoprophylaxis for the prevention of malaria. Also examined is metronidazole resistance in both Giardia and Trichomonas and the possibility of ivermectin resistance in human filariasis. Consistent themes in the literature on drug resistance include widespread and uncontrolled use of drugs, heavy reliance on a small number of drugs, use of single drug therapy, poor compliance with recommended treatment regimens, and slow development of new therapeutic alternatives. The way existing drugs are administered must be improved so their usefulness can be sustained. New drugs should not be introduced before they are needed to delay selection of resistant parasite strains. Mass drug administration should be used cautiously. Where possible, treatment should be based on a specific diagnosis. Efforts are needed to improve patient compliance with multiple-dose treatments. Although multidrug therapy has been proposed as an effective way to limit resistance, it poses problems in terms of increased cost and complexity. Finally, vaccines, appropriate and sustainable vector avoidance or elimination strategies, environmental control, and human behavior modification are important to reduce the need for drug therapy.

Identification of T-cell determinants in natural immune responses to the Plasmodium falciparum apical membrane antigen (AMA-1) in an adult population exposed to malaria.

AMA-1 of Plasmodium falciparum is a promising candidate antigen in malaria vaccine development. In this study, we have mapped the immunodominant T-cell determinants in this antigen by using synthetic peptides. From the amphipathic scores, 17 putative T-cell determinants were identified. Nine of the 17 peptides complementary to the putative T-cell determinants induced proliferation of peripheral blood mononuclear cells (PBMC) from Kenyan residents who had lifelong exposure to malaria; none of these peptides induced proliferation of PBMC from donors who were not previously exposed to malaria. This indicates that AMA-1 peptides were stimulating T cells that were previously primed by prior exposure to P. falciparum. Many positive responders showed reactivity to more than one peptide, and some of the potent proliferative T epitopes were found to be localized in the highly conserved regions of AMA-1, suggesting that it may be possible to induce T-cell memory that can recognize different variant forms of the parasite. This information on the natural immune responses against the AMA-1 vaccine antigen in clinically immune adults will be helpful in the development of an AMA-1 antigen-based malaria vaccine and may also guide testing of AMA-1-based vaccine formulations.