Rationalizing artemisinin-based combination therapies use for treatment of uncomplicated malaria: A situation analysis in health facilities and private pharmacies of Douala 5e-Cameroon.

Artemisinin-based combination therapies (ACTs) represent one of the mainstays of malaria control. Despite evidence of the risk of ACTs resistant infections in resource-limited countries, studies on the rational use of ACTs to inform interventions and prevent their emergence and/or spread are limited. The aim of this study was designed to analyze practices toward ACTs use for treating the treatment of uncomplicated malaria (UM) in an urban community. Between November 2015 and April 2016, a cross-sectional and prospective study was conducted in the 6 health facilities and all pharmacies in the Douala 5e subdivision, Cameroon. Anonymous interviews including both open- and closed-ended questions were conducted with selected participants among drug prescribers, patients attending the health facilities, and customers visiting the pharmacies. Data analysis was performed using StataSE11 software (version 11 SE). A total of 41 prescribers were included in the study. All were aware of national treatment guidelines, but 37.7% reported not waiting for test results before prescribing an antimalarial drug, and the main reason being stock-outs at health facilities. Likewise, artemether+lumefantrine/AL (81%) and dihydroartemisinin+piperaquine (63.5%) were the most commonly used first- and second-line drugs respectively. Biological tests were requested in 99.2% (128/129) of patients in health facilities, 60.0% (74) were performed and 6.2% were rationally managed. Overall 266 (35%) of 760 customers purchased antimalarial drugs, of these, 261 (98.1%) agreed to participate and of these, 69.4% purchased antimalarial drugs without a prescription. ACTs accounted for 90.0% of antimalarials purchased from pharmacies, of which AL was the most commonly prescribed antimalarial drug (67.1%), and only 19.5% of patients were appropriately dispensed. The current data suggest a gap between the knowledge and practices of prescribers as well as patients and customers misconceptions regarding the use of ACTs in Douala 5e subdivision. Despite government efforts to increase public awareness regarding the use of ACTs as first-line treatment for UM, our findings point out a critical need for the development, implementation and scaling-up of control strategies and continuing health education for better use of ACTs (prescription and dispensing) in Cameroon.

Effectiveness of Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine in Pregnancy: Low Coverage and High Prevalence of Plasmodium falciparum dhfr-dhps Quintuple Mutants as Major Challenges in Douala, an Urban Setting in Cameroon.

Intermittent preventive treatment in pregnancy with sulfadoxine and pyrimethamine (IPTp-SP) is a key component in the malaria control strategy implemented in Africa. The aim of this study was to determine IPTp-SP adherence and coverage, and the impact on maternal infection and birth outcomes in the context of widespread SP resistance in the city of Douala, Cameroon. Clinical and demographic information were documented among 888 pregnant women attending 3 health facilities, from the antenatal care visit to delivery. Positive samples were genotyped for P. falciparum gene (dhfr, dhps, and k13) mutations. The overall IPTp-SP coverage (≥three doses) was 17.5%, and 5.1% received no dose. P. falciparum prevalence was 16%, with a predominance of submicroscopic infections (89.3%). Malaria infection was significantly associated with locality and history of malaria, and it was reduced among women using indoor residual spraying. Optimal doses of IPTp-SP were significantly associated with reduced infection among newborns and women (secundiparous and multiparous), but there was no impact of IPTp-SP on the newborn bodyweight. Pfdhfr-Pfdhps quintuple mutants were over-represented (IRNI-FGKAA, IRNI-AGKAA), and sextuple mutants (IRNI-AGKAS, IRNI-FGEAA, IRNI-AGKGS) were also reported. The Pfk13 gene mutations associated with artemisinin resistance were not detected. This study highlights the role of ANC in achieving optimal SP coverage in pregnant women, the mitigated impact of IPTp-SP on malaria outcomes, and the high prevalence of multiple SP-resistant P. falciparum parasites in the city of Douala that could compromise the efficacy of IPTp-SP.

Pathogenicity and non-opportunistic character of Blastocystis spp.: a hospital-based survey in Central Cameroon.

INTRODUCTION: Blastocystis spp. is a protist found in humans. Although usually the most frequent protozoa found in stool samples of both symptomatic and healthy subjects, its pathogenic or rather opportunistic role is yet to be clearly elucidated. To attempt to fill this gap, a cross-sectional study was conducted to compare the frequency of Blastocystis spp. in HIV positive (HIV+) versus HIV negative (HIV-) individuals in four health facilities of the Center Region of Cameroon. METHODOLOGY: Stool samples were collected from 283 HIV positive and 245 HIV negative subjects and analyzed using direct diagnostic tests. RESULTS: A total of 46 (8.7%) individuals were found infected with Blastocystis spp., including 6.7% HIV positive and 11.0% HIV negative. This species was more frequent in urban and semi-urban areas than in rural areas, but evenly distributed among genders and age groups as well as among all sectors of activity. The prevalence of Blastocystis spp. (11.3%) was higher in HIV+ patients with a CD4 count ≥ 500 cells / mm3, but no significant difference was found among HIV clinical stages. Likewise prevalence, the mean number of cysts per gram of stool was similar between HIV positive and HIV negative individuals. People infected with Blastocystis spp. showed diverse clinical signs, but only flatulence was significantly more prevalent. The frequencies of these clinical signs were not related to HIV status. CONCLUSION: No clear relationship links the infection with Blastocystis spp. to HIV, although its presence was associated with digestive disorder, suggesting that this parasite might not be opportunist.

Field evaluation of the 22 rapid diagnostic tests for community management of malaria with artemisinin combination therapy in Cameroon.

BACKGROUND: All suspected cases of malaria should receive a diagnostic test prior to treatment with artemisinin-based combinations based on the new WHO malaria treatment guidelines. This study compared the accuracy and some operational characteristics of 22 different immunochromatographic antigen capture point-of- malaria tests (RDTs) in Cameroon to inform test procurement prior to deployment of artemisinin-based combinations for malaria treatment. METHODS: One hundred human blood samples (50 positive and 50 negative) collected from consenting febrile patients in two health centres at Yaoundé were used for evaluation of the 22 RDTs categorized as "Pf Only" (9) or "Pf + PAN" (13) based on parasite antigen captured [histidine rich protein II (HRP2) or lactate dehydrogenase (pLDH) or aldolase]. RDTs were coded to blind technicians performing the tests. The sensitivity, specificity, and predictive values of the positive and negative tests (PPV and NPV) as well as the likelihood ratios were assessed. The reliability and some operational characteristics were determined as the mean values from two assessors, and the Cohen's kappa statistic was then used to compare agreement. Light microscopy was the referent. RESULTS: Of all RDTs tested, 94.2 % (21/22) had sensitivity values greater than 90% among which 14 (63.6%) were 'Pf + PAN' RDTs. The specificity was generally lower than the sensitivity for all RDTs and poorer for "Pf Only" RDTs. The predictive values and likelihood ratios were better for non-HRP2 analytes for "Pf + PAN" RDTs. The Kappa value for most of the tests obtained was around 67% (95% CI 50-69%), corresponding to a moderate agreement. CONCLUSION: Overall, 94.2% (21/22) of RDTs tested had accuracy within the range recommended by the WHO, while one performed poorly, below acceptable levels. Seven "Pf + PAN" and 3 "Pf Only" RDTs were selected for further assessment based on performance characteristics. Harmonizing RDT test presentation and procedures would prevent mistakes of test performance and interpretation.

Impaired T-cell-dependent protection against Leishmania major infection in HIV-positive patients is associated with worsened disease outcome.

Cutaneous leishmaniasis (CL) patients coinfected with HIV are known to show a more severe, prolonged course of disease; the immunological basis is not known. We now assessed clinical features, sera and skin biopsies of HIV(+) and HIV(-) patients with CL to identify drivers of increased susceptibility to Leishmania. CL lesion numbers, surface, and healing duration were significantly increased in HIV(+) as compared to HIV(-) patients (2.5, 14 and >4-fold, respectively). Patients with HIV infection exhibited lower serum Leishmania-specific IgG levels and decreased IL-6 and IL-8. Most importantly, dramatically decreased numbers of CD4(+) T cells (approximately eightfold), but not CD8(+) cells, together with fewer CXCR3(+) Th1 cells, fewer Foxp3(+) effector/regulatory T cells, and reduced levels of IFN-γ expression were found in lesional skin. Our findings suggest that compromised CD4(+) T-cell responses may be responsible for worsened disease outcome leading to defects in parasite elimination in the absence of sufficient numbers of IFN-γ-producing Th1 cells.

Multicentre study evaluating the non-inferiority of the new paediatric formulation of artesunate/amodiaquine versus artemether/lumefantrine for the management of uncomplicated Plasmodium falciparum malaria in children in Cameroon, Ivory Coast and Senegal.

BACKGROUND: This multicentre study was carried out in Cameroon, Ivory Coast and Senegal to evaluate the non-inferiority of the new paediatric formulation of artesunate/amodiaquine (AS+AQ)(Camoquin-Plus Paediatric®) in suspension form versus artemether/lumefantrine (AL)(Coartem®) in the management of African children with uncomplicated falciparum malaria. METHODS: It was an open randomized trial including children aged between 7 months and 7 years. The endpoints were Adequate Clinical and Parasitological Response (ACPR) at day 28, the clinical and biological tolerability. Statistical analyses were done in Intention To Treat (ITT) and in Per protocol (PP). RESULTS: At the end of the study 481 patients were enrolled in the three countries (249 in the AS+AQ arm and 232 in the AL arm). ACRP in ITT after PCR correction did not show any statistical difference between the two groups with 97.6% for AS+AQ versus 94.8% for AL. In the PP analysis, the corrected ACRP were respectively 98.7% and 96.9% for the two regimens. The clinical tolerance was good without significant difference. Anaemia was significantly higher at D7 in the two groups compared to D0. CONCLUSION: This study demonstrates the non-inferiority of AS+AQ versus AL, its efficacy and tolerance in the management of uncomplicated Plasmodium falciparum malaria in African children.

Clinical features and epidemiology of cutaneous leishmaniasis and Leishmania major/HIV co-infection in Cameroon: results of a large cross-sectional study.

Cutaneous leishmaniasis (CL) is endemic in Central Africa, including Cameroon. However, data on its prevalence and co-infection with HIV are scarce. Here we present the results of a large cross-sectional study reporting the prevalence, clinical features and species identification of CL and HIV co-infection in northern Cameroon. A total of 32 466 subjects were clinically screened for CL during a door-to-door survey, followed by parasitological diagnosis in the field laboratory. Amongst the subjects surveyed, 146 (0.4%) were diagnosed with active CL. Seven (4.8%) of these 146 CL patients tested positive for HIV-1 and/or HIV-2. The number of lesions per CL patient ranged from 1 to 20. Three of the five subjects with >10 active lesions were co-infected with HIV. In both CL and HIV co-infected subjects, three successful parasite isolates were identified as Leishmania major by PCR. This first report of L. major/HIV co-infection in Cameroon and Central Africa confirms the endemicity of CL in the region and highlights a worsened CL pathology in HIV co-infected individuals. These findings provide important data necessary for the development and implementation of successful control programmes against CL and HIV in this geographical area.

Comparative study of the efficacy and tolerability of dihydroartemisinin-piperaquine-trimethoprim versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Cameroon, Ivory Coast and Senegal.

BACKGROUND: The ACT recommended by WHO is very effective and well-tolerated. However, these combinations need to be administered for three days, which may limit adherence to treatment.The combination of dihydroartemisinin-piperaquine phosphate-trimethoprim (Artecom®, Odypharm Ltd), which involves treatment over two days, appears to be a good alternative, particularly in malaria-endemic areas. This study intends to compare the efficacy and tolerability of the combination dihydroartemisinin-piperaquine phosphate-trimethoprim (DPT) versus artemether-lumefantrine (AL) in the treatment of uncomplicated Plasmodium falciparum malaria in Cameroon, Ivory Coast and Senegal. METHODS: This was a randomized, controlled, open-label clinical trial with a 28-day follow-up period comparing DPT to AL as the reference drug. The study involved patients of at least two years of age, suffering from acute, uncomplicated Plasmodium falciparum malaria with fever. The WHO 2003 protocol was used. RESULTS: A total of 418 patients were included in the study and divided into two treatment groups: 212 in the DPT group and 206 in the AL group. The data analysis involved the 403 subjects who correctly followed the protocol (per protocol analysis), i.e. 206 (51.1%) in the DPT group and 197 (48.9%) in the AL group. The recovery rate at D14 was 100% in both treatment groups. The recovery rate at D28 was 99% in the DPT and AL groups before and after PCR results with one-sided 97.5% Confidence Interval of the rates difference > -1.90%. More than 96% of patients who received DPT were apyrexial 48 hours after treatment compared to 83.5% in the AL group (p < 0.001). More than 95% of the people in the DPT group had a parasite clearance time of 48 hours or less compared to approximately 90% in the AL group (p = 0.023). Both drugs were well tolerated. No serious adverse events were reported during the follow-up period. All of the adverse events observed were minor and did not result in the treatment being stopped in either treatment group. The main minor adverse events reported were vomiting, abdominal pain and pruritus. CONCLUSION: The overall efficacy and tolerability of DPT are similar to those of AL. The ease of taking DPT and its short treatment course (two days) may help to improve adherence to treatment. Taken together, these findings make this medicinal product a treatment of choice for the effective management of malaria in Africa.

Multicentric assessment of the efficacy and tolerability of dihydroartemisinin-piperaquine compared to artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa.

BACKGROUND: The choice of appropriate artemisinin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate and simplicity of administration). To assess whether the combination dihydroartemisinin-piperaquine (DP) could be an alternative to artemether-lumefantrine (AL), the efficacy and the tolerability of the two products for the treatment of uncomplicated falciparum malaria in sub-Saharan Africa have been compared. METHODS: A multicentric open randomized controlled clinical trial of three-day treatment of DP against AL for the treatment of two parallel groups of patients aged two years and above and suffering from uncomplicated falciparum malaria was carried out in Cameroon, Côte d'Ivoire and Senegal. Within each group, patients were randomly assigned supervised treatment. DP was given once a day for three days and AL twice a day for three days. Follow-up visits were performed on day 1 to 4 and on day 7, 14, 21, 28 to evaluate clinical and parasitological results. The primary endpoint was the recovery rate by day 28. RESULTS: Of 384 patients enrolled, 197 were assigned DP and 187 AL. The recovery rates adjusted by genotyping, 99.5% in the DP group and 98.9% in the AL group, were not statistically different (p=0.538). No Early Therapeutic Failure (ETF) was observed. At day 28, two patients in the DP group and five in AL group had recurrent parasitaemia with Plasmodium falciparum. In the DP group, after PCR genotyping, one of the two recurrences was classified as a new infection and the other as recrudescence. In AL group, two recurrences were classified after correction by PCR as recrudescence. All cases of recrudescence were classified as Late Parasitological Failure (LPF). In each group, a rapid recovery from fever and parasitaemia was noticed. More than 90% of patients did no longer present fever or parasitaemia 48 hours after treatment. Both drugs were well tolerated. Indeed, no serious adverse events were reported during the follow-up period. Most of the adverse events which developed were moderate and did not result in the treatment being stopped in either treatment group. CONCLUSIONS: Dihydroartemisinin-piperaquine was as effective and well-tolerated as artemether-lumefantrine in the treatment of uncomplicated falciparum malaria. In addition, dihydroartemisinin-piperaquine, a single daily dose, could be an advantage over artemether-lumefantrine in Africa because of better treatment observance.

Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis.

BACKGROUND: Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. METHODS: An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. RESULTS: A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6-77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2-94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. CONCLUSION: AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.

Randomized, multicentre assessment of the efficacy and safety of ASAQ--a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine (ASAQ) was recently developed. To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted. METHODS: A multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response. RESULTS: Of 941 patients initially randomized and stratified into two age groups (<5 years, and >or=5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was >or=98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events. CONCLUSION: The non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process. TRIAL REGISTRATION: The protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.

Malaria vectors and transmission dynamics in Goulmoun, a rural city in south-western Chad.

BACKGROUND: Knowledge of some baseline entomological data such as Entomological Inoculation Rates (EIR) is crucially needed to assess the epidemiological impact of malaria control activities directed either against parasites or vectors. In Chad, most published surveys date back to the 1960's. In this study, anopheline species composition and their relation to malaria transmission were investigated in a dry Sudanian savannas area of Chad. METHODS: A 12-month longitudinal survey was conducted in the irrigated rice-fields area of Goulmoun in south western Chad. Human landing catches were performed each month from July 2006 to June 2007 in three compounds (indoors and outdoors) and pyrethrum spray collections were conducted in July, August and October 2006 in 10 randomly selected rooms. Mosquitoes belonging to the Anopheles gambiae complex and to the An. funestus group were identified by molecular diagnostic tools. Plasmodium falciparum infection and blood meal sources were detected by ELISA. RESULTS: Nine anopheline species were collected by the two sampling methods. The most aggressive species were An. arabiensis (51 bites/human/night), An. pharoensis (12.5 b/h/n), An. funestus (1.5 b/h/n) and An. ziemanni (1.3 b/h/n). The circumsporozoite protein rate was 1.4% for An. arabiensis, 1.4% for An. funestus, 0.8% for An. pharoensis and 0.5% for An. ziemanni. Malaria transmission is seasonal, lasting from April to December. However, more than 80% of the total EIR was concentrated in the period from August to October. The overall annual EIR was estimated at 311 bites of infected anophelines/human/year, contributed mostly by An. arabiensis (84.5%) and An. pharoensis (12.2%). Anopheles funestus and An. ziemanni played a minor role. Parasite inoculation occurred mostly after 22:00 hours but around 20% of bites of infected anophelines were distributed earlier in the evening. CONCLUSION: The present study revealed the implication of An. pharoensis in malaria transmission in the irrigated rice fields of Goulmoun, complementing the major role played by An. arabiensis. The transmission period did not depend upon irrigation. Correct use of insecticide treated nets in this area may be effective for vector control although additional protective measures are needed to prevent pre-bedtime exposure to the bites of infected anophelines.

Insecticide resistance in Anopheles gambiae from south-western Chad, Central Africa.

BACKGROUND: Indoor residual spraying and insecticide-treated nets (ITN) are essential components of malaria vector control in Africa. Pyrethroids are the only recommended compounds for nets treatment because they are fast-acting insecticides with low mammalian toxicity. However, there is growing concern that pyrethroid resistance may threaten the sustainability of ITN scaling-up programmes. Here, insecticide susceptibility was investigated in Anopheles gambiae sensu lato from an area of large scale ITN distribution programme in south-western Chad. METHODS: Susceptibility to 4% DDT, 0.05% deltamethrin, 0.75% permethrin, 0.1% bendiocarb and 5% malathion was assessed using the WHO standard procedures for adult mosquitoes. Tests were carried out with two to four days-old, non-engorged female mosquitoes. The An. gambiae Kisumu strain was used as a reference. Knockdown effect was recorded every 5 min and mortality scored 24 h after exposure. Mosquitoes were identified to species and molecular form by PCR-RFLP and genotypes at the kdr locus were determined in surviving specimens by Hot Oligonucleotide Ligation Assay (HOLA). RESULTS: During this survey, full susceptibility to malathion was recorded in all samples. Reduced susceptibility to bendiocarb (mortality rate of 96.1%) was found in one sample out of nine assayed. Increased tolerance to pyrethroids was detected in most samples (8/9) with mortality rates ranging from 70.2 to 96.6% for deltamethrin and from 26.7 to 96.3% for permethrin. Pyrethroid tolerance was not associated with a significant increase of knock-down times. Anopheles arabiensis was the predominant species of the An. gambiae complex in the study area, representing 75 to 100% of the samples. Screening for kdr mutations detected the L1014F mutation in 88.6% (N = 35) of surviving An. gambiae sensu stricto S form mosquitoes. All surviving An. arabiensis (N = 49) and M form An. gambiae s.s. (N = 1) carried the susceptible allele. CONCLUSION: This first investigation of malaria vector susceptibility to insecticides in Chad revealed variable levels of resistance to pyrethroid insecticides (permethrin and deltamethrin) in most An. gambiae s.l. populations. Resistance was associated with the L1014F kdr mutation in the S form of An. gambiae s.s.. Alternative mechanisms, probably of metabolic origin are involved in An. arabiensis. These results emphasize the crucial need for insecticide resistance monitoring and in-depth investigation of resistance mechanisms in malaria vectors in Chad. The impact of reduced susceptibility to pyrethroids on ITN efficacy should be further assessed.

Randomized, comparative study of the efficacy and safety of artesunate plus amodiaquine, administered as a single daily intake versus two daily intakes in the treatment of uncomplicated falciparum malaria.

BACKGROUND: Artesunate plus amodiaquine is a coblistered ACT, given as a single daily intake. It has been suggested that, in view of the number of tablets to be taken (particularly in adults), it may be possible to improve compliance by allowing patients to divide the daily dose. The objectives of this randomized, comparative, open-label, multicentre study, conducted in Senegal and in Cameroon in 2005, was to demonstrate the non-inferiority and to compare the safety of artesunate plus amodiaquine, as a single daily intake versus two daily intakes. METHODS: A three-day treatment period and 14-day follow-up period was performed in any subject weighting more than 10 kg, presenting with a malaria paroxysm confirmed by parasitaemia > or = 1,000/microl, after informed consent. Patients were randomly allocated into one of the two regimens, with dosage according to bodyweight range. All products were administered by an authorized person, blinded to both the investigating physician and the biologist. The primary endpoint was an adequate response to treatment on D14 (WHO definition). The two-sided 90% confidence interval of the difference was calculated on intent to treat (ITT) population; the acceptance limit for non-inferiority was 3%. The safety was evaluated by incidence of adverse events. RESULTS: Three-hundred and sixteen patients were included in the study. The two patient groups were strictly comparable on D0. The adequate responses to treatment were similar for the two treatment regimens on D14, PCR-corrected (99,4% in the one-daily intake group versus 99,3% in the comparative group). The statistical analyses demonstrated the non-inferiority of administering artesunate/amodiaquine as two intakes. The drug was well tolerated. The main adverse events were gastrointestinal disorders (2.5%) and pruritus (2.5%); safety profiles were similar in the two groups. CONCLUSION: This pilot study confirms the efficacy and good tolerability of artesunate plus amodiaquine, administrated either in one or in two daily intakes.

A preliminary test of the protective efficacy of permethrin-treated bed nets in an area of Anopheles gambiae metabolic resistance to pyrethroids in north Cameroon.

A trial of permethrin-treated nets (PTNs) versus untreated nets (UTNs) was conducted in Pitoa (north Cameroon), where the main malaria vectors, Anopheles gambiae s.l. and Anopheles arabiensis, show metabolic-based permethrin resistance. The deterrent effect of permethrin greatly reduced A. gambiae biting rate inside rooms where PTNs were installed. After 3 months of net use, malaria reinfection rate was significantly lower in children sleeping under a PTN, but no such effect was observed after 6 months. Parasitaemia was not significantly different between the two arms. These findings suggest good, although transitory, personal protection against malaria conferred by PTNs in an area of metabolic-based permethrin resistance.

Molecular epidemiology of malaria in Cameroon. XXI. Baseline therapeutic efficacy of chloroquine, amodiaquine, and sulfadoxine-pyrimethamine monotherapies in children before national drug policy change.

The availability of epidemiologic data on drug-resistant malaria based on a standardized clinical and parasitological protocol is a prerequisite for a rational therapeutic strategy to control malaria. As part of the surveillance program on the therapeutic efficacy of the first-line (chloroquine and amodiaquine) and second-line (sulfadoxine-pyrimethamine) drugs for the management of uncomplicated Plasmodium falciparum infections, non-randomized studies were conducted in symptomatic children aged less than 10 years according to the World Health Organization protocol (14-day follow-up period) at 12 sentinel sites in Cameroon between 1999 and 2004. Of 1,407 children enrolled in the studies, 460, 444, and 503 were treated with chloroquine, amodiaquine, or sulfadoxine-pyrimethamine, respectively. Chloroquine treatment resulted in high failure rates (proportion of early and late failures, 48.6%). Amodiaquine was effective at all study sites (proportion of failures, 7.3%). Sulfadoxine-pyrimethamine therapy was less effective than amodiaquine (P < 0.05), with failures observed in 9.9% of patients. Chloroquine is no longer a viable option and has been withdrawn from the official drug outlets in Cameroon. Amodiaquine and, to a lesser extent, sulfadoxine-pyrimethamine monotherapies are still effective in Cameroon, but further development of resistance to these drugs should be delayed by the novel strategy using artemisinin-based combination therapy. Our findings indicate that amodiaquine is the most rational partner for artesunate. Studies on the efficacy of artesunate-amodiaquine combination are currently being undertaken at several sites in the country.

Therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine and the sulfadoxine-pyrimethamine-amodiaquine combination against uncomplicated Plasmodium falciparum malaria in young children in Cameroon.

OBJECTIVE: To evaluate the therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine, and the sulfadoxine-pyrimethamine-amodiaquine combination for the treatment of uncomplicated Plasmodium falciparum malaria in young children in Cameroon. METHODS: In a randomized study we evaluated the effectiveness and tolerance of (i) sulfadoxine-pyrimethamine (SP) (25 mg/kg body weight of sulfadoxine and 1.25 mg/kg of pyrimethamine in a single oral dose), (ii) amodiaquine (AQ) (30 mg/kg body weight in three divided daily doses), and (iii) the sulfadoxine-pyrimethamine-amodiaquine combination (SP+AQ) (same doses as in the other two treatment groups, given simultaneously on day 0) in young children in southern Cameroon. The parasitological and clinical responses were studied until day 28 in accordance with the modified 1996 WHO protocol for the evaluation of the therapeutic efficacy of antimalarial drugs. FINDINGS: Of 191 enrolled patients, 6 and 8 were excluded or lost to follow-up before day 14 and between day 14 and day 28, respectively. For the AQ-treated patients, parasitological and clinical evaluation on day 14 showed late treatment failure in 2 of 61 (3.3%) and adequate clinical response with parasitological failure in one (1.6%). There was an adequate clinical response in all patients treated with SP or SP+AQ. Therapeutic failure rates on day 28 were 13.6%, 10.2% and 0% in the SP, AQ, and SP+AQ groups, respectively. Anaemia improved in all three regimens. AQ produced faster fever clearance but was associated with more transient minor side-effects than SP. SP+AQ reduced the risk of recrudescence between day 14 and day 28 but increased the incidence of minor side-effects. CONCLUSION: SP+AQ can be recommended as a temporary means of slowing the spread of multidrug resistance in Plasmodium falciparum in Africa while the introduction of other combinations, including artemisinin derivatives, is awaited.