Economic evaluation of a cluster randomized trial of interventions to improve health workers' practice in diagnosing and treating uncomplicated malaria in Cameroon.

BACKGROUND: Malaria rapid diagnostic tests (RDTs) are a valid alternative to malaria testing with microscopy and are recommended for the testing of febrile patients before prescribing an antimalarial. There is a need for interventions to support the uptake of RDTs by health workers. OBJECTIVE: To evaluate the cost-effectiveness of introducing RDTs with basic or enhanced training in health facilities in which microscopy was available, compared with current practice. METHODS: A three-arm cluster randomized trial was conducted in 46 facilities in central and northwest Cameroon. Basic training had a practical session on RDTs and lectures on malaria treatment guidelines. Enhanced training included small-group activities designed to change health workers' practice and reduce the consumption of antimalarials among test-negative patients. The primary outcome was the proportion of febrile patients correctly treated: febrile patients should be tested for malaria, artemisinin combination therapy should be prescribed for confirmed cases, and no antimalarial should be prescribed for patients who are test-negative. Individual patient data were obtained from facility records and an exit survey. Costs were estimated from a societal perspective using project reports and patient exit data. The analysis used bivariate multilevel modeling and adjusted for imbalance in baseline covariates. RESULTS: Incremental cost per febrile patient correctly treated was $8.40 for the basic arm and$3.71 for the enhanced arm. On scale-up, it was estimated that RDTs with enhanced training would save $0.75 per additional febrile patient correctly treated. CONCLUSIONS: Introducing RDTs with enhanced training was more cost-effective than RDTs with basic training when each was compared with current practice

Formulation of Functional Yogurt by Cofermentation of Milk and Papaya Fruit

This study was carried out to determine the potential of adding Fresh skinned papaya pulp (FSP) into yoghurt for the improvement of the functional properties of yoghurt and the resulting effects of adding PPF on the physicochemical and sensory properties of the product during a 30 days’ storage period at 6°C. Yoghurt samples A (Control), B, C, D and E were respectively produced at 0%, 5%, 10%, 15%, and 20% of milk incorporated with papaya fruit. Incorporation of PPF into the yogurt samples resulted in an increase in pH, proteins and carbohydrates and a reduction in titratable acidity as compared to the control. The microbial analysis showed no presence of coliform bacteria. The sensory evaluation result demonstrated significant differences in all the organoleptic attributes analyzed. Sample C with 10% incorporated papaya had the highest overall acceptability score

Predominance of N-acetyl transferase 2 slow acetylator alleles in children less than ten years experiencing adverse treatment events following artemisinin-based combination therapy in North and South West Regions of Cameroon

The human N-acetyltransferase II (NAT2) gene may vary between individuals resulting in variability in the incidence of adverse drug reactions. We set out in this adhoc analysis to determine the distribution of allele frequencies of NAT2 gene variants among children less than ten years treated with artemisinin-based combinations in Cameroon. Children with uncomplicated malaria were deparasitized with artemisinin based combination therapy (artesunate amodiaquine, dihydroartemisinin-piperaquine and artemether-lumefantrine) and followed up for 42 days and adverse events recorded. Blood was spotted on filter paper prior to drug administration for DNA extraction by chelex method. Standard nested PCR followed by restriction enzyme analysis with KpnI, TaqI, and BamHI for detection of polymorphisms in the NAT2 was performed. Allelic frequencies and acetylator phenotypes were compared between participants with or without adverse drug events. The prevalence of slow, intermediate and fast acetylators was 54, 34 and 12% respectively. Significant clustering of mutant alleles (NAT2*5, NAT2*6 and NAT2*7) occurred among those who experienced skin rash and tiredness (OR = 5.765, P = 0.046) (OR = 13.280, P = 0.020). No significant difference was observed between fast and slow acetylators with respect to the development of other recorded adverse events. Overall, producers of the slow acetylator alleles were more likely to develop any adverse events (OR = 8.286, P = 0.017) during the study period. Mutant alleles of the wild type NAT2*4 associated with the slow acetylator phenotype were the most predominant NAT2 allelic type and individuals with the phenotype were more likely to develop adverse events to ACTs.Keywords: N-Acetyltransferase 2, Artemisinin based combination therapy, adverse events, slow acetylators, allel

Performance of rapid subtyping tools used for the classification of HIV type 1 recombinants isolated from selected countries in west and central Africa

HIV-1 genetic diversity in sub-Saharan Africa is broad and the AIDS epidemic is driven predominantly by recombinants in Central and West Africa. The classification of HIV-1 strains is therefore necessary to understand diagnostic efficiency, individual treatment responses as well as options for designing vaccines and antiretroviral (ARV) treatment guidelines. More so, accurate subtyping of a partial or full genome would represent the population dynamics of HIV and provide evidence for designing surveillance strategies within a geographic region. Evaluating the performance of rapid subtyping tools with options that incorporate phylogeny could be fast, more user-friendly and of high performance. A total of 570 HIV-1 partial sequences from Cameroon, Angola, Democratic Republic of Congo, Gabon and Senegal were obtained from the Los Alamos National Library (LANL) HIV Sequence Database. Phylogeny was performed using MEGA v6 and the results were used to evaluate the performance of eleven different rapid HIV-1 subtyping tools: REGA v2, REGA v3, NCBI, Stanford HIVDB, SUDI, Geno2Pheno, Euresist, STAR, jpHMM, COMET and SCUEAL. The performance of these subtyping tools differed among HIV-1 clades and across different viral genes. NCBI and SUDI showed the highest performance in subtyping. The discordance observed between the rapid subtyping tools and phylogeny implies that phylogenetic analysis is still the more suitable method for HIV-1 classification. However, the need to update the reference datasets of the subtyping tools, and validate algorithms for rapid subtyping and quality control is imperative as this information is relevant for clinical use and policymaking to the AIDS response.Keywords: HIV, phylogeny, performance, subtyping tools, algorith

Efficacy of amodiaquine, sulphadoxine-pyrimethamine and their combination for the treatment of uncomplicated Plasmodium falciparum malaria in children in Cameroon at the time of policy change to artemisinin-based combination therapy

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background The efficacy of amodiaquine (AQ), sulphadoxine-pyrimethamine (SP) and the combination of SP+AQ in the treatment of Cameroonian children with clinical malaria was investigated. The prevalence of molecular markers for resistance to these drugs was studied to set the baseline for surveillance of their evolution with time. Methods Seven hundred and sixty children aged 6-59 months with uncomplicated falciparum malaria were studied in three ecologically different regions of Cameroon - Mutengene (littoral equatorial forest), Yaoundé (forest-savannah mosaic) and Garoua (guinea-savannah). Study children were randomized to receive either AQ, SP or the combination AQ+SP. Clinical outcome was classified according to WHO criteria, as either early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF) or adequate clinical and parasitological response (ACPR). The occurrence of mutations in pfcrt, pfmdr1, dhfr and dhps genes was studied by either RFLP or dot blot techniques and the prevalence of these mutations related to parasitological and therapeutic failures. Results After correction for the occurrence of re-infection by PCR, ACPRs on day 28 for AQ, SP and AQ+SP were 71.2%, 70.1% and 80.9%, in Garoua, 79.2%, 62.5%, and 81.9% in Mutengene, and 80.3%, 67.5% and 76.2% in Yaoundé respectively. High levels of Pfcrt 76T (87.11%) and Pfmdr1 86Y mutations (73.83%) were associated with quinoline resistance in the south compared to the north, 31.67% (76T) and 22.08% (86Y). There was a significant variation (p < 0.001) of the prevalence of the SGK haplotype between Garoua in the north (8.33%), Yaoundé (36.29%) in the savannah-forest mosaic and Mutengene (66.41%) in the South of Cameroon and a weak relation between SGK haplotype and SP failure. The 540E mutation on the dhps gene was extremely rare (0.3%) and occurred only in Mutengene while the pfmdr1 1034K and 1040D mutations were not detected in any of the three sites. Conclusion In this study the prevalence of molecular markers for quinoline and anti-folate resistances showed high levels and differed between the south and north of Cameroon. AQ, SP and AQ+SP treatments were well tolerated but with low levels of efficacy that suggested alternative treatments were needed in Cameroon since 2005.Published versio

Patients with positive malaria tests not given artemisinin-based combination therapies: a research synthesis describing under-prescription of antimalarial medicines in Africa.

BACKGROUND: There has been a successful push towards parasitological diagnosis of malaria in Africa, mainly with rapid diagnostic tests (mRDTs), which has reduced over-prescribing of artemisinin-based combination therapies (ACT) to malaria test-negative patients. The effect on prescribing for test-positive patients has received much less attention. Malaria infection in endemic Africa is often most dangerous for young children and those in low-transmission settings. This study examined non-prescription of antimalarials for patients with malaria infection demonstrated by positive mRDT results, and in particular these groups who are most vulnerable to poor outcomes if antimalarials are not given. METHODS: Analysis of data from 562,762 patients in 8 studies co-designed as part of the ACT Consortium, conducted 2007-2013 in children and adults, in Cameroon, Ghana, Nigeria, Tanzania, and Uganda, in a variety of public and private health care sector settings, and across a range of malaria endemic zones. RESULTS: Of 106,039 patients with positive mRDT results (median age 6 years), 7426 (7.0%) were not prescribed an ACT antimalarial. The proportion of mRDT-positive patients not prescribed ACT ranged across sites from 1.3 to 37.1%. For patients under age 5 years, 3473/44,539 (7.8%) were not prescribed an ACT, compared with 3833/60,043 (6.4%) of those aged ≥ 5 years. The proportion of < 5-year-olds not prescribed ACT ranged up to 41.8% across sites. The odds of not being prescribed an ACT were 2-32 times higher for patients in settings with lower-transmission intensity (using test positivity as a proxy) compared to areas of higher transmission. mRDT-positive children in low-transmission settings were especially likely not to be prescribed ACT, with proportions untreated up to 70%. Of the 7426 mRDT-positive patients not prescribed an ACT, 4121 (55.5%) were prescribed other, non-recommended non-ACT antimalarial medications, and the remainder (44.5%) were prescribed no antimalarial. CONCLUSIONS: In eight studies of mRDT implementation in five African countries, substantial proportions of patients testing mRDT-positive were not prescribed an ACT antimalarial, and many were not prescribed an antimalarial at all. Patients most vulnerable to serious outcomes, children < 5 years and those in low-transmission settings, were most likely to not be prescribed antimalarials, and young children in low-transmission settings were least likely to be treated for malaria. This major public health risk must be addressed in training and practice. TRIAL REGISTRATION: Reported in individual primary studies

Basic or enhanced clinician training to improve adherence to malaria treatment guidelines: a cluster-randomised trial in two areas of Cameroon

Background The scale-up of malaria rapid diagnostic tests (RDTs) is intended to improve case management of fever and targeting of artemisinin-based combination therapy. Habitual presumptive treatment has hampered these intentions, suggesting a need for strategies to support behaviour change. We aimed to assess the introduction of RDTs when packaged with basic or enhanced clinician training interventions in Cameroon. Methods We did a three-arm, stratifi ed, cluster-randomised trial at 46 public and mission health facilities at two study sites in Cameroon to compare three approaches to malaria diagnosis. Facilities were randomly assigned by a computer program in a 9:19:19 ratio to current practice with microscopy (widely available, used as a control group); RDTs with a basic (1 day) clinician training intervention; or RDTs with an enhanced (3 days) clinician training intervention. Patients (or their carers) and fi eldworkers who administered surveys to obtain outcome data were masked to study group assignment. The primary outcome was the proportion of patients treated in accordance with WHO malaria treatment guidelines, which is a composite indicator of whether patients were tested for malaria and given appropriate treatment consistent with the test result. All analyses were by intention to treat. This study is registered at ClinicalTrials. gov, number NCT01350752. Findings The study took place between June 7 and Dec 14, 2011. The analysis included 681 patients from nine facilities in the control group, 1632 patients from 18 facilities in the basic-training group, and 1669 from 19 facilities in the enhanced-training group. The proportion of patients treated in accordance with malaria guidelines did not improve with either intervention; the adjusted risk ratio (RR) for basic training compared with control was 1·04 (95% CI 0·53–2·07; p=0·90), and for enhanced training compared with control was 1·17 (0·61–2·25; p=0·62). Inappropriate use of antimalarial drugs after a negative test was reduced from 84% (201/239) in the control group to 52% (413/796) in the basic-training group (unadjusted RR 0·63, 0·28–1·43; p=0·25) and to 31% (232/759) in the enhanced-training group (0·29, 0·11–0·77; p=0·02). Interpretation Enhanced clinician training, designed to translate knowledge into prescribing practice and improve quality of care, has the potential to halve overtreatment in public and mission health facilities in Cameroon. Basic training is unlikely to be suffi cient to support the behaviour change required for the introduction of RDTs

Designing and implementing interventions to change clinicians' practice in the management of uncomplicated malaria: lessons from Cameroon.

BACKGROUND: Effective case management of uncomplicated malaria is a fundamental pillar of malaria control. Little is known about the various steps in designing interventions to accompany the roll out of rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT). This study documents the process of designing and implementing interventions to change clinicians' practice in the management of uncomplicated malaria. METHODS: A literature review combined with formative quantitative and qualitative research were carried out to determine patterns of malaria diagnosis and treatment and to understand how malaria and its treatment are enacted by clinicians. These findings were used, alongside a comprehensive review of previous interventions, to identify possible strategies for changing the behaviour of clinicians when diagnosing and treating uncomplicated malaria. These strategies were discussed with ministry of health representatives and other stakeholders. Two intervention packages - a basic and an enhanced training were outlined, together with logic model to show how each was hypothesized to increase testing for malaria, improve adherence to test results and increase appropriate use of ACT. The basic training targeted clinicians' knowledge of malaria diagnosis, rapid diagnostic testing and malaria treatment. The enhanced training included additional modules on adapting to change, professionalism and communicating effectively. Modules were delivered using small-group work, card games, drama and role play. Interventions were piloted, adapted and trainers were trained before final implementation. RESULTS: Ninety-six clinicians from 37 health facilities in Bamenda and Yaounde sites attended either 1-day basic or 3-day enhanced training. The trained clinicians then trained 632 of their peers at their health facilities. Evaluation of the training revealed that 68% of participants receiving the basic and 92% of those receiving the enhanced training strongly agreed that it is not appropriate to prescribe anti-malarials to a patient if they have a negative RDT result. CONCLUSION: Formative research was an important first step, and it was valuable to engage stakeholders early in the process. A logic model and literature reviews were useful to identify key elements and mechanisms for behaviour change intervention. An iterative process with feedback loops allowed appropriate development and implementation of the intervention. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01350752

World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria

Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs