Antimalarial Policy Research Articles

The use of artemisinin-based combination therapies (ACTs) in public secondary health facilities in Lagos, Nigeria

The objectives of the study were to assess the prescription pattern of Artemisinin Combination Therapies (ACTs) in uncomplicated malaria and the knowledge, attitude and practice of physicians as regards use of ACTs in the outpatient clinics of public secondary health facilities in Lagos State. All the ten General Hospitals under the Lagos State Health Management Board were studied and classified as either rural or urban. 1878 retrospective antimalarial prescriptions of outpatients between March, 2005--March, 2006 were systematically sampled and questionnaires were distributed to prescribers in April--May, 2006. Prescription assessment was based on the recent Nigerian National Antimalarial Treatment Policy and WHO/INRUD drug use indicators. The percentage of prescriptions containing ACTs was found to be rather small (5.9%) inspite of the high proportion (59.2%) of prescribers who were favourably disposed to the National antimalarial policy change from Chloroquine to ACTs as first line. There was no statistically significant difference in frequency of ACTs prescription between the rural and urban health facilities. The prescription of Artemisinin derivatives as monotherapy was 18.2%. The prescription of Chloroquine was found to be more predominant, (48.8%) in all the health facilities. Despite the national policy change from Chloroquine to (ACTs) as the first line antimalarial, their use in the public secondary health facilities in Lagos State does not reflect this policy change and it appears that Chloroquine still remains the choice antimalarial drug.

Adding artesunate to sulphadoxine-pyrimethamine greatly improves the treatment efficacy in children with uncomplicated falciparum malaria on the coast of Benin, West Africa

BackgroundBenin has recently shifted its national antimalarial drug policy from monotherapies to combinations containing artemisinin derivatives. When this decision was taken, the available information on alternatives to chloroquine and sulphadoxine-pyrimethamine, the first- and second-line treatment, was sparse.MethodsIn 2003 – 2005, before the drug policy change, a randomized, open-label, clinical trial was carried out on the efficacy of chloroquine, and sulphadoxine-pyrimethamine alone or combined with artesunate, with the aim of providing policy makers with the information needed to formulate a new antimalarial drug policy. Children between six and 59 months of age, with uncomplicated malaria and living in the lagoon costal area in southern Benin, were randomly allocated to one of the three study arms and followed up for 28 days.ResultsTreatment failure (PCR corrected) was significantly lower in the artesunate + sulphadoxine-pyrimethamine group (4/77, 5.3%) than in chloroquine group(51/71, 71.8%) or the sulphadoxine-pyrimethamine alone group (30/70, 44.1%) (p < 0.001). Despite high sulphadoxine-pyrimethamine failure, its combination with artesunate greatly improved treatment efficacy.ConclusionIn Benin, artesunate + sulphadoxine-pyrimethamine is efficacious and could be used when the recommended artemisinin-based combinations (artemether-lumefantrine and amodiaquine-artesunate) are not available. However, because sulphadoxine-pyrimethamine is also used in pregnant women as intermittent preventive treatment, its combination with artesunate should not be widely employed in malaria patients as this may compromise the efficacy of intermittent preventive treatment.

Drug-resistant malaria parasites introduced into Madagascar from Comoros Islands.

To determine risk for drug-resistant malaria parasites entering Madagascar from Comoros Islands, we screened travelers. For the 141 Plasmodium falciparum isolates detected by real-time PCR, frequency of mutant alleles of genes associated with resistance to chloroquine and pyrimethamine was high. International-level antimalarial policy and a regional antimalarial forum are needed.

Evaluación de la eficacia de los medicamentos antimaláricos en Tarapacá, Amazonas colombiano

The current antimalarial drug policy in Colombia has been based on studies conducted in Antioquia and the Pacific Coast. However, the efficacy of antimalarial drugs in other endemic regions is unknown.The therapeutic efficacy of three monotherapies was assessed: amodiaquine and sulfadoxine/pyrimethamine for uncomplicated Plasmodium falciparum malaria, and chloroquine for Plasmodium vivax malaria in the municipality of Tarapacá, located in the Colombian province of Amazonas.Treatment was supervised and clinical/parasitological follow-up was undertaken through a 28-day period following to World Health Organization standard protocols for subjects with a single P. falciparum or P. vivax infection.Due to a decrease in malaria transmission at the time of the study, the sample size was very small. The treatment failed for two subjects who received amodiaquine, and treatment with sulfadoxine/pyrimethamine was discontinued due to a high frequency of therapeutic failures (7/8). Most subjects (18/20) with P. vivax infections showed an adequate therapeutic response.The use of sulfadoxine/pyrimethamine in Tarapacá, and possibly in the Amazon region of Colombia, needs to be reviewed. Therapeutic efficacy studies in other endemic areas in the Amazon and Orinoco regions in Colombia are desirable but not feasible. Alternative methods such as in vitro assays or detection of molecular markers for resistance in the parasite can provide a basis for decisions concerning antimalarial drug policy for the Amazon and Orinoco regions in Colombia.

Minority-Variant pfcrt K76T Mutations and Chloroquine Resistance, Malawi

Genotyping of the chloroquine-resistance biomarker pfcrt (Plasmodium falciparum chloroquine resistance transporter gene) suggests that, in the absence of chloroquine pressure, Plasmodium falciparum parasites in Malawi have reverted to chloroquine sensitivity. However, malaria infections in Africa are commonly polyclonal, and standard PCRs cannot detect minority genotypes if present in <20% of the parasites in an individual host. We have developed a multiple site-specific heteroduplex tracking assay (MSS-HTA) that can detect pfcrt 76T mutant parasites consisting of as little as 1% of the parasite population. In clinical samples, no pfcrt 76T was detected in 87 pregnant Malawian women by standard PCR. However, 22 (25%) contained minority-variant resistant genotypes detected by the MSS-HTA. These results were confirmed by subcloning and sequencing. This finding suggests that the chloroquine-resistant genotype remains common in Malawians and that PCR-undetectable drug-resistant genotypes may be present in disease-endemic populations. Surveillance for minority-variant drug resistant mutations may be useful in making antimalarial drug policy.

Assessment of the efficacy of antimalarial drugs in Tarapacá, in the Colombian Amazon basin

The current antimalarial drug policy in Colombia has been based on studies conducted in Antioquia and the Pacific Coast. However, the efficacy of antimalarial drugs in other endemic regions is unknown. The therapeutic efficacy of three monotherapies was assessed: amodiaquine and sulfadoxine/pyrimethamine for uncomplicated Plasmodium falciparum malaria, and chloroquine for Plasmodium vivax malaria in the municipality of Tarapacá, located in the Colombian province of Amazonas. Treatment was supervised and clinical/parasitological follow-up was undertaken through a 28-day period following to World Health Organization standard protocols for subjects with a single P. falciparum or P. vivax infection. Due to a decrease in malaria transmission at the time of the study, the sample size was very small. The treatment failed for two subjects who received amodiaquine, and treatment with sulfadoxine/pyrimethamine was discontinued due to a high frequency of therapeutic failures (7/8). Most subjects (18/20) with P. vivax infections showed an adequate therapeutic response. The use of sulfadoxine/pyrimethamine in Tarapacá, and possibly in the Amazon region of Colombia, needs to be reviewed. Therapeutic efficacy studies in other endemic areas in the Amazon and Orinoco regions in Colombia are desirable but not feasible. Alternative methods such as in vitro assays or detection of molecular markers for resistance in the parasite can provide a basis for decisions concerning antimalarial drug policy for the Amazon and Orinoco regions in Colombia.

The challenges of changing national malaria drug policy to artemisinin-based combinations in Kenya.

BackgoundSulphadoxine/sulphalene-pyrimethamine (SP) was adopted in Kenya as first line therapeutic for uncomplicated malaria in 1998. By the second half of 2003, there was convincing evidence that SP was failing and had to be replaced. Despite several descriptive investigations of policy change and implementation when countries moved from chloroquine to SP, the different constraints of moving to artemisinin-based combination therapy (ACT) in Africa are less well documented.MethodsA narrative description of the process of anti-malarial drug policy change, financing and implementation in Kenya is assembled from discussions with stakeholders, reports, newspaper articles, minutes of meetings and email correspondence between actors in the policy change process. The narrative has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy.ResultsFollowing a recognition that SP was failing there was a rapid technical appraisal of available data and replacement options resulting in a decision to adopt artemether-lumefantrine (AL) as the recommended first-line therapy in Kenya, announced in April 2004. Funding requirements were approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) and over 60 million US$ were agreed in principle in July 2004 to procure AL and implement the policy change. AL arrived in Kenya in May 2006, distribution to health facilities began in July 2006 coincidental with cascade in-service training in the revised national guidelines. Both training and drug distribution were almost complete by the end of 2006. The article examines why it took over 32 months from announcing a drug policy change to completing early implementation. Reasons included: lack of clarity on sustainable financing of an expensive therapeutic for a common disease, a delay in release of funding, a lack of comparative efficacy data between AL and amodiaquine-based alternatives, a poor dialogue with pharmaceutical companies with a national interest in antimalarial drug supply versus the single sourcing of AL and complex drug ordering, tendering and procurement procedures.ConclusionDecisions to abandon failing monotherapy in favour of ACT for the treatment of malaria can be achieved relatively quickly. Future policy changes in Africa should be carefully prepared for a myriad of financial, political and legislative issues that might limit the rapid translation of drug policy change into action.

Diagnosis and treatment of malaria in peripheral health facilities in Uganda: findings from an area of low transmission in south-western Uganda.

BackgroundEarly recognition of symptoms and signs perceived as malaria are important for effective case management, as few laboratories are available at peripheral health facilities. The validity and reliability of clinical signs and symptoms used by health workers to diagnose malaria were assessed in an area of low transmission in south-western Uganda.MethodsThe study had two components: 1) passive case detection where all patients attending the out patient clininc with a febrile illness were included and 2) a longitudinal active malaria case detection survey was conducted in selected villages. A malaria case was defined as any slide-confirmed parasitaemia in a person with an axillary temperature ≥ 37.5°C or a history of fever within the last 24 hrs and no signs suggestive of other diseases.ResultsCases of malaria were significantly more likely to report joint pains, headache, vomiting and abdominal pains. However, due to the low prevalence of malaria, the predictive values of these individual signs alone, or in combination, were poor. Only 24.8% of 1627 patients had malaria according to case definition and > 75% of patients were unnecessarily treated for malaria and few slide negative cases received alternative treatment.ConclusionIn low-transmission areas, more attention needs to be paid to differential diagnosis of febrile illnesses In view of suggested changes in anti-malarial drug policy, introducing costly artemisinin combination therapy accurate, rapid diagnostic tools are necessary to target treatment to people in need.

Artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Colombia

BackgroundArtemisinin-based combination therapy (ACT) is being widely promoted as a strategy to counteract the increase in Plasmodium falciparum antimalarial drug resistance.MethodsA randomized, double-blind, placebo-controlled, clinical trial of the efficacy, effect on gametocytes and safety of the addition of artesunate/placebo (4 mg/kg/day × 3 d) to amodiaquine (10 mg/kg/day × 3 d) was conducted in Choco department, a low intensity transmission area in northwest Colombia.ResultsFrom 2,137 screened subjects, 85 entered the study: 43 in the amodiaquine plus placebo and 42 in the amodiaquine plus artesunate groups. Potentially eligible cases failed to qualify mostly because they were not available for follow-up visits (73%). Based on a per protocol analysis, the therapeutic response to both treatments was high: amodiaquine/placebo 35/36, 97.2% (95% CI 85.5–99.9), and amodiaquine/artesunate 32/32, 100% (89.1–100) after PCR genotyping. The Kaplan-Meier survival estimates based on all eligible patients enrolled (amodiaquine/placebo: n = 42; amodiaquine/artesunate: n = 41) were similar in the two study groups (P = 0.3). The addition of artesunate significantly decreased gametocyte carriage on Day 4 (OR = 0.1 95% CI 0.02–0.6), Day 7 (OR = 0.2 95%CI 0.04–0.9), Day 14 (OR = 0.09 95% CI 0–0.8), and Day 21 (OR95%CI 0–0.9). Most subjects in both groups (81% in amodiaquine/placebo and 75.6% in amodiaquine/artesunate) reported at least one drug related adverse event. Symptoms were generally mild and self-limiting and there was no serious adverse event. Two patients on amodiaquine/artesunate voluntarily withdrew from study because they could not tolerate the medication.ConclusionBoth drug regimens were effective in this area of Colombia. The addition of artesunate reduced gametocyte carriage and did not adversely affect tolerability. In this set of patients, the rate of adverse events was higher than in other studies. Patients' follow-up is problematic in areas with dispersed population and affects the conduct of clinical studies and monitoring of treatment effects. The results are discussed in the light of concurrent increase resistance to amodiaquine in other endemic areas in Colombia and the factors that may influence a change in the national antimalarial drug policy.

Reconciling national treatment policies and drug regulation in Kenya

Malaria is the second largest public health challenge (after HIV/AIDS) in Kenya with an estimated 34 000 children dying from the direct effects of infection each year. It accounts for over a third of all consultations in government clinics. The typical Kenyan child will use antimalarial drugs at least four times in a year. Economic losses due to malaria are also large. As matters of public policy to reduce morbidity and mortality due to malaria the medicines to which communities resort must be safe and effective and efforts to control malaria must complement and not contradict each other. But currently neither of these areas is successfully addressed due to a clear disconnect between antimalarial drug registration in Kenya and the national antimalarial drug policy. Three examples illustrate this problem. The first example albeit now an historical one is the registration of sulfamethoxypyridazine products for human use in the late 1990s at a time when the national antimalarial policy statedthat only sulfadoxine-pyrimethamine or sulmethoxypyrazinepyrimethamine (SP) drugs should be used as first-line antimalarial policy. Sulfamethoxypyridazine has been considered unsuitable for human use for some years (WHO 1991) and is now generally restricted to veterinary use only. There were at least seven sulfamethoxypyridazinepyrimethamine products in the Kenyan market in 1998 though these were later withdrawn following a report from the National Quality Control Laboratory. (excerpt)

Quality of treatment for febrile illness among children at outpatient facilities in sub-Saharan Africa

For the prompt and effective management of malaria cases (a key strategy for reducing the enormous burden of the disease), healthworkers must prescribe antimalarial drugs according to evidence-based guidelines. In sub-Saharan Africa, the guidelines for use in outpatient settings generally recommend that febrile illness in children should be suspected to be malaria and be treated with an antimalarial drug. The quality of treatment offered to febrile children at outpatient facilities in this region has now been investigated in a literature review. The results of five methodologically comparable studies were also used to explore the determinants of malaria-treatment practices. The quality of treatment prescribed to febrile children was found to have been generally sub-optimal, with low levels of adherence to national guidelines, the frequent selection of non-recommended antimalarials, and the use of incorrect dosages. Several factors might be to responsible for these shortcomings. Although interventions such as the Integrated Management of Childhood Illness (IMCI) strategy can lead to improvements, a better understanding of the practices of the healthworkers responsible for treating febrile children will be needed before treatment is made much better. The failure to provide treatment of good quality will become an increasingly important problem as antimalarial policies involving drugs with more complex dosing regimens, such as artemisinin-based combination therapies (ACT), are implemented. If the malaria burden in Africa is to be greatly reduced, the deployment of ACT must be accompanied by interventions to ensure the correct treatment of children at the point of care. Some interventions, such as IMCI, can improve the treatment of not only malaria but also other potentially life-threatening illnesses.

Comparative efficacy of chloroquine and sulphadoxine – pyrimethamine in pregnant women and children: a meta‐analysis

To compare the efficacy of chloroquine and sulphadoxine-pyremethamine against Plasmodium falciparum infection in pregnant women and in children from the same endemic areas of Africa, with the aim of determining the level of correspondence in efficacy determinations in these two risk groups. Meta-analysis of nine published and unpublished in vivo antimalarial efficacy studies in pregnant women and in children across five African countries. Pregnant women (all gravidae) were more likely to be sensitive than children to both chloroquine (odds ratio: 2.07; 95% confidence interval: 1.5, 2.9) and sulphadoxine-pyrimethamine (odds ratio: 2.66; 95% confidence interval: 11.1, 6.7). Pregnant women demonstrated an almost uniform increased sensitivity for peripheral parasite clearance at day 14 compared with children. This finding was consistent across a wide range of drug sensitivities. Primigravidae at day 14 showed lower clearance to antimalarial drugs than multigravidae (P<0.05). There was no significant difference between parasite clearance in primigravidae and in children. The greater drug sensitivity in pregnant women probably indicates differences in host susceptibility rather than parasite resistance. Parasite sensitivity patterns in children may be a suitable guide to antimalarial policy in pregnant women.

Progressive Increase in Point Mutations Associated with Chloroquine Resistance inPlasmodium falciparumIsolates from India

Effective malaria control programs require continuous monitoring of drug pressure in the field, using molecular markers. We used sequence analysis to investigate the pfcrt and pfmdr1 mutations in Indian Plasmodium falciparum isolates. To evaluate the chloroquine drug pressure in the field, isolates were collected from 5 different areas at 2 time points, with an interval of 2 years. In 265 P. falciparum isolates, pfcrt mutations were observed at codons 72, 74, 75, 76, and 220, resulting in 8 different genotypes: SMNTS (61.89%), CIETS (12.08%), CMNKS (0.38%), CMNTA (2.64%), CMNTS (4.91%), SMNTA (0.38%), CIDTS (2.26%), and wild-type CMNKA (15.47%). During the 2-year period, there was a significant decrease in the number of isolates with the SMNTS genotype and an increase in the number of isolates with the highly chloroquine-resistant pfcrt genotype CIETS (P < .05). The N86Y mutation was less prevalent (30.13%) than the Y184F mutation (99.16%) in the pfmdr1 gene in 239 isolates, but the number of isolates with the N86Y mutation increased significantly during the 2-year period (P < .05). The number of isolates with higher total numbers of pfcrt and pfmdr1 2-loci mutations, therefore, increased significantly during this period. There was a regional bias in the mutation rate of these genes, because isolates from areas where chloroquine resistance was high had higher numbers of 2-loci mutations, and areas where chloroquine resistance was low had isolates with lower numbers of 2-loci mutations. There was a temporal increase in the number of pfcrt and pfmdr1 2-loci mutations, and this led to the higher level of chloroquine resistance. This is a cause for concern for the antimalarial drug policy in India.

Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug

IntroductionResearch is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited.ObjectivesTo describe the (a) role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b) challenges ahead before a new drug combination treatment policy is introduced in Tanzania.MethodsIn-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done.ResultsIn year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ – the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ). Research also indicated that since SP was also facing rising resistance trend, the need for a more effective drug was indispensable but for an interim 5–10 year period it was justifiable to recommend SP that was relatively more cost-effective than CQ and AQ. The government launched the policy change considering that studies (ethically approved by the Ministry of Health) on therapeutic efficacy and cost-effectiveness of artemisinin drug combination therapies were underway. Nevertheless, the process of communicating research results and recommendations to policy-making authorities involved critical debates between policy makers and researchers, among the researchers themselves and between the researchers and general practitioners, the speculative media reports on SP side-effects and reservations by the general public concerning the rationale for policy change, when to change, and to which drug of choice.ConclusionChanging national drug policy will remain a sensitive issue that cannot be done overnight. However, to ensure that research findings are recognised and the recommendations emanating from such findings are effectively utilized, a systematic involvement of all the key stakeholders (including policy-makers, drug manufacturers, media, practitioners and the general public) at all stages of research is crucial. It also matters how and when research information is communicated to the stakeholders. Professional organizations such as the East African Network on Malaria Treatment have potential to bring together malaria researchers, policy-makers and other stakeholders in the research-to-drug policy change interface.

THERAPEUTIC EFFICACY OF SULFADOXINE-PYRIMETHAMINE AND AMODIAQUINE AMONG CHILDREN WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA IN ZANZIBAR, TANZANIA

The efficacy of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) was assessed at Kivunge and Micheweni in Zanzibar, Tanzania, in 2001. The main objective was to obtain baseline data after observations of high levels of chloroquine treatment failures. Children (6-59 months) were randomized to receive either drug. At Kivunge, SP and AQ were given to 64 and 63 cases, while for Micheweni, 61 and 70 cases were treated. Main findings were overall high rates (> 90%) of adequate clinical response (ACR) with AQ. A lower ACR was seen in the SP group at Kivunge (87.1%) compared with Micheweni (94.8%). Furthermore, in the ACR group, 16.7% AQ parasitological resistance (RI-RIII) was encountered at Kivunge. Most of the cases of SP parasitological resistance (14.5%; RI/RII) were seen at Micheweni. Notwithstanding this, the overall treatment failure was only 9.2% with SP and 5.5% with AQ. The Zanzibar Ministry of Health has since reviewed its antimalarial drug policy.

Successful shift in antimalarial policy in Zambia

Successful shift in antimalarial policy in Zambia

Epidemiology of drug‐resistant malaria in Republic of Congo: using molecular evidence for monitoring antimalarial drug resistance combined with assessment of antimalarial drug use

In Congo, urgent efforts are needed to help with the revision of the national antimalarial drug policy. Despite its high resistance level, chloroquine (CQ) is still extensively used as the first-line treatment for uncomplicated Plasmodium falciparum malaria. The study was conducted in children under 5 years with uncomplicated malaria in Pointe-Noire and Brazzaville, the two largest cities that contain approximately 60% of the population of Congo. We investigated by polymerized chain reaction and sequencing methods the frequency distribution of molecular markers for antimalarial drug resistance, including mutations in P. falciparum chloroquine resistance transporter (pfcrt) gene associated with CQ resistance and mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes conferring resistance to sulphadoxine/pyrimethamine (SP) among pre-treatment P. falciparum isolates, as well as assessing antimalarial drug use in the community. pfcrt (K76T) mutation was present in most isolates (96.4%, n = 138) and high frequency (69.2%, n = 133) of triple-mutant dhfr-S108N, N51I, C59R was observed. The quintuple mutant (dhfr-S108N, N51I, C59R and dhps-A437G or S436A, K540E) considered as molecular marker for SP treatment failure was not found because dhps-K540E mutation was absent in isolates tested; this is a clear evidence for the excellent efficacy of SP that we previously described in the same population. The complete absence of the dhps-K540E mutation is a deterrent component for using this molecular marker as an early warning tool for SP resistance testing in that population. Poor compliance issues related to the antimalarial drug use including inappropriate manufacturing practices reported in this study require intensive attention and should be taken into account when implementing drug policy change. If Congo changes its treatment policy from CQ to SP monotherapy, this will not last long. The strategy of combining SP with other affordable and effective antimalarial drugs such as the artemisinin derivatives to improve efficacy and to delay the development of parasite resistance is essential.

Adoption of the new antimalarial drug policy in Tanzania – a cross‐sectional study in the community

To assess the diffusion of the change of first line antimalarial drug from chloroquine (CQ) to sulphadoxine/pyrimethamine (SP) at household level in a rural district of Tanzania less than a year after the policy implementation. Caretakers in 729 households were interviewed on knowledge of the new policy, home stocking of antimalarials, home-treatment practices of children younger than 5 years with fever, health-seeking behaviour and experience of SP. SP and CQ levels in blood were analysed from 328 children younger than 5 years in the households. Twelve focus group discussions (FGD) were performed with mothers, fathers and health workers. About 51% of the population knew that SP was the first line antimalarial. Only 8% of mothers stocked antimalarials, and only 4% stated self-treatment as the first action. We estimated that 84% of the children who had had fever during the last 4 weeks sought care at public health facilities. SP was detectable in 18% of the total child population and in 32% of those with reported fever, CQ in only 5% and 7%, respectively. The FGDs revealed negative perceptions of SP and fear of severe adverse reactions with mass media reported as key informant. The policy had diffused to the communities in the sense that CQ had been changed to SP, which was well known as first line treatment. Moreover, there was a reported dramatic change from self-treatment with CQ to seeking care at public health facilities where SP was given under observation.

Plasmodium falciparum: higher incidence of molecular resistance markers for sulphadoxine than for pyrimethamine in Kasangati, Uganda

In November of 2000, Uganda changed its anti-malarial policy to replace chloroquine (CQ) with a combination of CQ and sulphadoxine-pyrimethamine (SP) as the first line agents. Information was limited on the efficacy of either drug. The present study was designed to provide baseline information on the efficacy of SP and the prevalence of molecular markers that are associated with SP resistance. Blood samples were collected on filter paper from 169 consenting patients who were diagnosed with malaria. Patients were treated with SP and followed for 14 days using the WHO clinical guidelines. The samples were analysed for molecular resistance markers and correlation of the molecular markers with clinical findings was assessed. SP monotherapy was efficacious for 140 of 163 (85.9%) treated patients. We found a high level of mutations in alleles which have previously been reported to be associated with SP resistance, but there was no correlation between clinical outcomes and molecular markers. With the exception of codon S108 in dhfr (dhfr S108N was at 94.9%), frequencies of dihydropteroate synthase (dhps) mutant and mixed alleles combined (A437G 89% and K540E 83.9%) were higher than those of dihydrofolate reductase (dhfr) (N51I 58.4%, C59R 31.3%).

Evidence basis for antimalarial policy change in Sierra Leone: five in vivo efficacy studies of chloroquine, sulphadoxine–pyrimethamine and amodiaquine

To provide nationally relevant information on the antimalarial efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) in Sierra Leone, with a view to updating antimalarial policy in the country. Between October 2002 and May 2003, standard WHO methodology for in vivo efficacy assessment was used in five sites to study the therapeutic response of 6-59 months old uncomplicated Plasmodium falciparum malaria cases treated with CQ (n = 247), SP (n = 353) or AQ (n = 434). Follow-up was of 28 days, with polymerase chain reaction genotyping to distinguish late recrudescences from re-infections. Overall 85.3% of patients reached an analysable endpoint. CQ failure proportions were very high, ranging from 39.5% (95% CI: 25.0-55.6) in Kabala to 78.8% (65.3-88.9) in Kailahun. Early failures under CQ were frequent. SP efficacy was also disappointing, with failure from 23.2% (13.9-34.9) in Kabala to 46.1% (35.4-57.0) in Kailahun. AQ resistance was more moderate, ranging from 5.4% (1.8-12.1) in Makeni to 29.8% (20.3-40.8) in Kailahun, with almost no early failures. AQ also provided more rapid fever and parasite clearance. In a consensus meeting organized by the Ministry of Health and Sanitation, and based on these findings, artesunate (AS) + AQ and artemether-lumefantrine (Coartemtrade mark) were identified as the only options to rapidly replace CQ. The choice fell on AS + AQ because of expected high efficacy, lower cost in a blister presentation, and the absence of safety data on artemether-lumefantrine in pregnancy. Donor support is required to support this policy change. Throughout Africa, as SP resistance increases, these two regimens are probably the only options available while newer combinations are developed. Efficacy studies should focus on testing AQ and AS + AQ.