Copayment mechanism in selected districts of Uganda: Availability, market share and price of quality assured artemisinin-based combination therapies in private drug outlets.

BACKGROUND: Malaria remains one of the leading causes of morbidity, and mortality in Uganda. A large proportion of malaria symptomatic patients seek healthcare in private sector. However, availability and affordability are major barriers to access to effective treatment. The private sector copayment mechanism in Uganda aims to increase availability and affordability of antimalarial agents. Our study assessed availability, price, and market share of quality assured artemisinin-based combination therapies (QAACTs) in private drug outlets in selected districts during the implementation of copayment mechanism. METHODS: This was a cross-sectional survey of anti-malarial agents in private drug outlets in in selected moderate-to-high (Tororo, and Apac districts) and low (Kabale and Mbarara districts) malaria transmission settings. Following the World Health Organization/Health Action International (WHO/HAI) criteria, an audit of the antimalarial agents was done using a checklist to determine availability, price, and market share of QAACTs. Data were entered in Epi-data and analyzed in STATA ver 14.0 at 95% confidence level. RESULTS: A total of twenty-eight (28) private drug outlets (pharmacies and drug shops) were included in the survey. One in seven (20/144: 95%CI: 9.1, 20.6) of the antimalarial agents in private drug outlets were quality assured artemisinin-based combination therapies (QAACT). Artemether-lumefantrine (AL), 8.9% (11/124) and Artesunate-Amodiaquine (AQ), 7.3% (9/124) were the only QAACTs present in the drug outlets at the time of the survey. The majority, 86.1%% (124/144) of antimalarial agents present in stock in the drug outlets were artemisinin based. The most common, 38.9% (56/144) ACT in the drug outlets was Dihydroartemisinin-Piperaquine (DHP). Most, 69.4% (100/144) of the antimalarial agents were in high malaria transmission settings. The cost of ACT antimalarial agents is high in the country, USD 1.4 (Artemether-Lumefantrine, AL), USD 2.4 (Dihydroartemisinin-Piperaquine, DP), the first line and second-line agents respectively for treatment of uncomplicated malaria in Uganda. There was a statistically significant difference between the dispensing price of 'Green leaf' ACTs (QAACT) and the recommended price (p<0.001). Predictors of availability of QAACT in private drug outlets include pharmacy drug outlet (aPR:0.4; 95%CI: 0.2, 0.9) and dispensing price more than 3000UGX (USD 0.83) (aPR: 0.4, 95%CI: 0.1, 0.51). CONCLUSION: Quality assured artemisinin-based combination therapies (QAACTs) are not common in private drug outlets in selected districts in Uganda. All the drug outlets had at least one ACT antimalarial agent present on the day of the survey. The dispensing price of QAACTs was significantly higher than the recommended markup price. There is need for awareness creation, surveillance, and monitoring of the implementation of Copayment mechanism in the country.

Cost of inappropriate prescriptions for uncomplicated malaria in Ghana.

BACKGROUND: Malaria remains a common course of morbidity in many sub-Saharan African countries. While treatment options have improved in recent times, inappropriate prescription seems conventional among providers, increasing the burden on patients and society. This study examined the cost of inappropriate prescriptions for uncomplicated malaria treatment in Ghana. METHODS: This study used retrospective data collected from January to December 2016 in 27 selected facilities, under different ownership in three regions of the country, mainly Volta, Upper East and Brong Ahafo. Stratified random sampling technique was used to extract 1625 outpatient folders of patients diagnosed and treated for malaria. Two physicians independently reviewed patient folders according to the stated diagnoses. Malaria prescriptions were described as inappropriate when they do not adhere to the standard treatment guidelines. The economic cost was mainly treatment cost which was sourced as medication cost. Total and average costs for country were calculated using sample estimates and the total number of uncomplicated malaria cases that received inappropriate prescriptions. RESULTS: The study revealed that patients received an average of two prescriptions per malaria episode. Artemether-lumefantrine (AL) was the major malaria medication (79.5%) prescribed to patients. Other medications usually antibiotics and vitamins and minerals were included in the prescription. More than 50% of prescribers did not follow the guidelines for prescribing medications to clients. By facility type, inappropriate prescription was high in the CHPS compounds (59.1%) and by ownership, government (58.3%), private (57.5%) and mission facilities (50.7%). Thus, about 55% of malaria prescriptions were evaluated as inappropriate during the review period, which translates into economic cost of approximately US$4.52 million for the entire country in 2016. The total cost of inappropriate prescription within the study sample was estimated at US$1,088.42 while the average cost was US$1.20. CONCLUSION: Inappropriate prescription for malaria is a major threat to malaria management in Ghana. It presents a huge economic burden to the health system. Training and strict enforcement of prescribers' adherence to the standard treatment guideline is highly recommended.

Impact assessment of Intensified Malaria Control Project in transitioning a high malaria-endemic district to a low-endemic district: an epidemiological aspect.

Intensified Malaria Control Project (IMCP) was implemented in 2005 to control malaria in all North-Eastern and Odisha states of India. The present study aimed to investigate the impact of IMCP in reducing the malaria burden in Udalguri district, Assam state of North-East India. Malaria epidemiological data were obtained for IMCP intervention (Udalguri) and nonintervention district (West Singhbhumi, Jharkhand state). IMCP activities include introducing bi-valent rapid diagnostic kits (RDTs), Artemether-Lumefantrine drug in North-East India, long-lasting insecticidal nets (LLINs) distribution, and creating awareness programs about malaria in an intensified mode. The data revealed a significant decline in annual parasite incidence (API) from 14.94 (2005) to 2.61 (2018), -37% (95%CI: -57%, -19%, p = 001) after using LLINs in 2009 and -64% (95%CI: -116%, -14%, p = 013) after the introduction of RDTs in district Udalguri. Whereas control district showed a -28% (95%CI: -63%, 6.3%, p = 0.051) decrease in API using LLINs and a 10% (95%CI: -7.6%, 28%, p = 0.122) increase after the introduction of RDTs. Plasmodium falciparum (Pf) and P. vivax (Pv) were the major malarial parasites in Udalguri. Pv-malaria was much higher (71%) than Pf-malaria (29%) during the study period. An increasing trend of Pf cases was observed in Udalguri. Udalguri and Khoirabari BPHCs showed an overall reduction of 94% (95%CI: -143%, -45%, p = 0.001) and 84% (95%CI: -126%, -39%, p = 0.003), respectively; however, only a 10% (95%CI: -65%, -41%, p = 0.360) reduction in API was observed in Orang BPHC. An overall decrease in malaria indicates the effective implementation of vector and disease control strategies in the Udalguri district.

Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana.

BACKGROUND: Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria in Ghana. Artemisinin (ART) tolerance in Plasmodium falciparum has arisen in Southeast Asia and recently, in parts of East Africa. This is ascribed to the survival of ring-stage parasites post treatment. The present study sought to assess and characterize correlates of potential ART tolerance based on post-treatment parasite clearance, ex vivo and in vitro drug sensitivity, and molecular markers of drug resistance in P. falciparum isolates from children with uncomplicated malaria in Ghana. METHODS: Six months to fourteen years old children presenting with acute uncomplicated malaria (n = 115) were enrolled in two hospitals and a Health Centre in Ghana's Greater Accra region and treated with artemether-lumefantrine (AL) according to body weight. Pre- and post-treatment parasitaemia (day 0 and day 3) was confirmed by microscopy. The ex vivo ring-stage survival assay (RSA) was used to detect percent ring survival while the 72 h SYBR Green I assay was used to measure the 50% inhibition concentration (IC50s) of ART and its derivatives and partner drugs. Genetic markers of drug tolerance /resistance were evaluated using selective whole genome sequencing. RESULTS: Of the total of 115 participants, 85 were successfully followed up on day 3 post-treatment and 2/85 (2.4%) had parasitaemia. The IC50 values of ART, artesunate (AS), artemether (AM), dihydroartemisinin (DHA), amodiaquine (AQ), and lumefantrine (LUM) were not indicative of drug tolerance. However, 7/90 (7.8%) pre-treatment isolates had > 10% ring survival rates against DHA. Of the four isolates (2 RSA positive and 2 RSA negative) with high genomic coverage, P. falciparum (Pf) kelch 13 K188* and Pfcoronin V424I mutations were only present in the two RSA positive isolates with > 10% ring survival rates. CONCLUSIONS: The observed low proportion of participants with day-3 post-treatment parasitaemia is consistent with rapid ART clearance. However, the increased rates of survival observed in the ex vivo RSA against DHA, maybe a pointer of an early start of ART tolerance. Furthermore, the role of two novel mutations in PfK13 and Pfcoronin genes, harboured by the two RSA positive isolates that had high ring survival in the present study, remains to be elucidated.

Cost-Utility Analysis of Community Case Management for Malaria Control in Burundi.

BACKGROUND: The community case management (CCM) program for malaria control is a community-based strategy implemented to regulate malaria in children in Burundi. This study compared the cost and utility of implementing the CCM program combined with health facility management (HFM) versus HFM alone for malaria control in children under five in Burundi. METHODS: This study constructed a five-year Markov model with one-week cycles to estimate cost-utility and budget impact analysis (BIA). The model defined 10 health states, simulating the progression of the disease and the risk of recurrent malaria in children under five years of age. Cost data were empirically collected and presented for 2019. Incremental cost per disability-adjusted life year (DALY) averted, and a five-year budget was estimated. One-way and probabilistic sensitivity analyses (PSAs) were then performed. RESULTS: From provider and societal perspectives, combining the CCM program with HFM for malaria control in Burundi was more cost-effective than implementing HFM alone. The addition of CCM, using artesunate amodiaquine (ASAQ) as the first-line treatment, increased by US$1.70, and US$ 1.67 per DALY averted from the provider and societal perspectives, respectively. Using Artemether Lumefantrine (AL) as the first-line treatment, adding the CCM program to HFM increased by US$ 1.92, and US$ 1.87 per DALY averted from the provider and societal perspectives. At a willingness-to-pay of one GDP/capita, the CCM program remained a 100% chance of being cost-effective. In addition, implementing the program for five years requires a budget of US$ 15 800 486-19 765 117. CONCLUSION: Implementing the CCM program and HFM is value for money for malaria control in Burundi. The findings can support decision-makers in Burundi in deciding on resource allocation, especially during the program's scale up.

Prevalence of malaria among febrile patients and assessment of efficacy of artemether-lumefantrine and artesunate-amodiaquine for uncomplicated malaria in Dolisie, Republic of the Congo.

BACKGROUND: In the Republic of the Congo, malaria represents a major public health problem affecting all age groups. A regular surveillance of the current efficacy of first-line anti-malarial drugs is required in the face of possible emergence and spread of artemisinin-resistant Plasmodium falciparum strains in Africa. The purpose of this study was to determine the prevalence of malaria among febrile patients of all ages and assess the efficacy of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) in Congolese children. METHODS: Febrile patients of all ages were initially screened for malaria by both rapid diagnostic test (RDT) and microscopy. Patients less than 12 years of age, with parasitaemia ≥ 1000 asexual parasites of P. falciparum/µL of blood, without any signs of severity, were enrolled in a therapeutic efficacy study and treated after obtaining their parents' (or legal guardian's) informed consent in two health centres in Dolisie. The patients were followed for 28 days in accordance with the 2009 World Health Organization standard protocol. If parasitaemia reappeared on or after day 7, the genetic profiles (genes expressing merozoite surface protein-1 [msp1], merozoite surface protein-2 [msp2], and glutamine-rich protein [glurp]) of pre-treatment and post-treatment isolates were compared by nested polymerase chain reaction (PCR) followed by capillary electrophoresis to make a distinction between recrudescence and re-infection. The clinical and parasitological outcome was analysed by the per-protocol method and Kaplan-Meier survival curves. RESULTS: A total of 994 febrile patients of all ages were screened by RDT and microscopy. Of 994 patients, 323 (32.5%) presented a positive RDT, and 266 (26.8%) were microscopy-positive. Based on microscopy as the reference diagnostic method, the sensitivity and the specificity of the RDT were 98.9 and 91.8%, respectively. The Cohen's kappa coefficient was 0.86. A total of 121 children aged less than 12 years (61 in AL treatment group and 60 in ASAQ treatment group) were included in therapeutic efficacy study. Before PCR correction, the proportions of adequate clinical and parasitological response were 96.6% for AL and 86.0% for ASAQ in the per-protocol population (P < 0.05). The PCR-corrected efficacy rates were 98.2% and 94.2% for AL and ASAQ, respectively (P > 0.05). Both treatments were well tolerated. CONCLUSIONS: AL and ASAQ remain highly effective for the first-line treatment of uncomplicated P. falciparum malaria in Dolisie. Despite high efficacy of first- and second-line treatment, there is a continuing need to scale up effective malaria preventive interventions and vector control strategies in the country. TRIAL REGISTRATION NUMBER: ACTRN12616001422415.

An assessment of the knowledge, practices and resources during the delivery of malaria health care services among private health care practitioners: a cross section study in the Mid-Western Region of Uganda.

BACKGROUND: Approximately 50 % of the population in Uganda seeks health care from private facilities but there is limited data on the quality of care for malaria in these facilities. This study aimed to document the knowledge, practices and resources during the delivery of malaria care services, among private health practitioners in the Mid-Western region of Uganda, an area of moderate malaria transmission. METHODS: This was a cross sectional study in which purposive sampling was used to select fifteen private-for-profit facilities from each district. An interviewer-administered questionnaire that contained both quantitative and open-ended questions was used. Information was collected on availability of treatment aides, knowledge on malaria, malaria case management, laboratory practices, malaria drugs stock and data management. We determined the proportion of health workers that adequately provided malaria case management according to national standards. RESULTS: Of the 135 health facilities staff interviewed, 61.48 % (52.91-69.40) had access to malaria treatment protocols while 48.89 % (40.19-57.63) received malaria training. The majority of facilities, 98.52 % (94.75-99.82) had malaria diagnostic services and the most commonly available anti-malarial drug was artemether-lumefantrine, 85.19 % (78-91), followed by Quinine, 74.81 % (67-82) and intravenous artesunate, 72.59 % (64-80). Only 14.07 % (8.69-21.10) responded adequately to the acceptable cascade of malaria case management practice. Specifically, 33.33 % (25.46-41.96) responded correctly to management of a patient with a fever, 40.00 % (31.67-48.79) responded correctly to the first line treatment for uncomplicated malaria, whereas 85.19 % (78.05-90.71) responded correctly to severe malaria treatment. Only 28.83 % submitted monthly reports, where malaria data was recorded, to the national database. CONCLUSIONS: This study revealed sub-optimal malaria case management knowledge and practices at private health facilities with approximately 14 % of health care workers demonstrating correct malaria case management cascade practices. To strengthen the quality of malaria case management, it is recommended that the NMCD distributes current guidelines and tools, coupled with training; continuous mentorship and supportive supervision; provision of adequate stock of essential anti-malarials and RDTs; reinforcing communication and behavior change; and increasing support for data management at private health facilities.

Assessment of Plasmodium falciparum anti-malarial drug resistance markers in pfk13-propeller, pfcrt and pfmdr1 genes in isolates from treatment failure patients in Democratic Republic of Congo, 2018-2019.

BACKGROUND: The national policy for malaria treatment of the Democratic Republic of Congo recommends two first-line artemisinin-based combinations for the treatment of uncomplicated malaria: artesunate-amodiaquine and artemether-lumefantrine. This study investigated the presence of markers associated with resistance to the current first-line artemisinin-based combination therapy (ACT) in isolates of Plasmodium falciparum from treatment failure patients in the Democratic Republic of Congo. METHODS: From November 2018 to November 2019, dried blood spots were taken from patients returning to health centres for fever within 28 days after an initial malaria treatment in six sentinel sites of the National Malaria Control Programme across Democratic Republic of Congo. The new episode of malaria was first detected by a rapid diagnostic test and then confirmed by a real-time PCR assay to define treatment failure. Fragments of interest in pfk13 and pfcrt genes were amplified by conventional PCR before sequencing and the Pfmdr1 gene copy number was determined by a TaqMan real-time PCR assay. RESULTS: Out of 474 enrolled patients, 364 (76.8%) were confirmed positive by PCR for a new episode of P. falciparum malaria, thus considered as treatment failure. Of the 325 P. falciparum isolates obtained from 364 P. falciparum-positive patients and successfully sequenced in the pfk13-propeller gene, 7 (2.2%) isolates carried non-synonymous mutations, among which 3 have been previously reported (N498I, N554K and A557S) and 4 had not yet been reported (F506L, E507V, D516E and G538S). Of the 335 isolates successfully sequenced in the pfcrt gene, 139 (41.5%) harboured the K76T mutation known to be associated with chloroquine resistance. The SVMNT haplotype associated with resistance to amodiaquine was not found. None of the isolates carried an increased copy number of the pfmdr1 gene among the 322 P. falciparum isolates successfully analysed. CONCLUSION: No molecular markers currently known to be associated with resistance to the first-line ACT in use were detected in isolates of P. falciparum from treatment failure patients. Regular monitoring through in vivo drug efficacy and molecular studies must continue to ensure the effectiveness of malaria treatment in Democratic Republic of Congo.

Protocol for a quasi-experimental study to assess the feasibility, acceptability and costs of multiple first-lines artemisinin-based combination therapies for uncomplicated malaria in the Kaya health district, Burkina Faso.

INTRODUCTION: As demonstrated in mathematical models, the simultaneous deployment of multiple first-line therapies (MFT) for uncomplicated malaria, using artemisinin-based combination therapies (ACTs), may extend the useful therapeutic life of the current ACTs. This is possible by reducing drug pressure and slowing the spread of resistance without putting patients' life at risk. We hypothesised that a simultaneous deployment of three different ACTs is feasible, acceptable and can achieve high coverage rate if potential barriers are properly identified and addressed. METHODS AND ANALYSIS: We plan to conduct a quasi-experimental study in the Kaya health district in Burkina Faso. We will investigate a simultaneous deployment of three ACTs, artemether-lumefantrine, pyronaridine-artesunate, dihydroartesinin-piperaquine, targeting three segments of the population: pregnant women, children under five and individuals aged five years and above. The study will include four overlapping phases: the formative phase, the MFT deployment phase, the monitoring and evaluation phase and the post-evaluation phase. The formative phase will help generate baseline information and develop MFT deployment tools. It will be followed by the MFT deployment phase in the study area. The monitoring and evaluation phase will be conducted as the deployment of MFT progresses. Cross-sectional surveys including desk reviews as well as qualitative and quantitative research methods will be used to assess the study outcomes. Quantitatives study outcomes will be measured using univariate, bivariate and multivariate analysis, including logistic regression and interrupted time series analysis approach. Content analysis will be performed on the qualitative data. ETHICS AND DISSEMINATION: The Health Research Ethics Committee in Burkina Faso approved the study (Clearance no. 2018-8-113). Study findings will be disseminated through feedback meetings with local communities, national workshops, oral presentations at congresses, seminars and publications in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT04265573.

Green Analytical Methods of Antimalarial Artemether-Lumefantrine Analysis for Falsification Detection Using a Low-Cost Handled NIR Spectrometer with DD-SIMCA and Drug Quantification by HPLC.

Two green analytical approaches have been developed for the analysis of antimalarial fixed dose tablets of artemether and lumefantrine for quality control. The first approach consisted of investigating the qualitative performance of a low-cost handheld near-infrared spectrometer in combination with the principal component analysis as an exploratory tool to identify trends, similarities, and differences between pharmaceutical samples, before applying the data driven soft independent modeling of class analogy (DD-SIMCA) as a one-class classifier for proper drug falsification detection with 100% of both sensitivity and specificity in the studied cases. Despite its limited spectral range and low resolution, the handheld device allowed detecting falsified drugs with no active pharmaceutical ingredient and identifying specifically a pharmaceutical tablet brand name. The second approach was the quantitative analysis based on the green and fast RP-HPLC technique using ethanol as a green organic solvent and acetic acid as a green pH modifier. The optimal separation was achieved in 7 min using a mobile phase composed of ethanol 96% and 10 mM of acetic acid pH 3.35 (63:37, v/v). The developed method was validated according to the total error approach based on an accuracy profile, was applied to the analysis of tablets, and allowed confirming falsified drugs detected by spectroscopy.

An Individual Participant Data Population Pharmacokinetic Meta-analysis of Drug-Drug Interactions between Lumefantrine and Commonly Used Antiretroviral Treatment.

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.

Vivax malaria in pregnancy and lactation: a long way to health equity.

BACKGROUND: The Sustainable Development Goals (SDG) call for increased gender equity and reduction in malaria-related mortality and morbidity. Plasmodium vivax infections in pregnancy are associated with maternal anaemia and increased adverse perinatal outcomes. Providing radical cure for women with 8-aminoquinolines (e.g., primaquine) is hindered by gender-specific complexities. CASE PRESENTATION: A symptomatic episode of vivax malaria at 18 weeks of gestation in a primigravid woman was associated with maternal anaemia, a recurrent asymptomatic P. vivax episode, severe intra-uterine growth restriction with no other identifiable cause and induction to reduce the risk of stillbirth. At 5 months postpartum a qualitative glucose-6-phosphate dehydrogenase (G6PD) point-of-care test was normal and radical cure with primaquine was prescribed to the mother. A 33% fractional decrease in haematocrit on day 7 of primaquine led to further testing which showed intermediate phenotypic G6PD activity; the G6PD genotype could not be identified. Her infant daughter was well throughout maternal treatment and found to be heterozygous for Mahidol variant. CONCLUSION: Adverse effects of vivax malaria in pregnancy, ineligibility of radical cure for pregnant and postpartum women, and difficulties in diagnosing intermediate levels of G6PD activity multiplied morbidity in this woman. Steps towards meeting the SDG include prevention of malaria in pregnancy, reducing unnecessary exclusion of women from radical cure, and accessible quantitative G6PD screening in P. vivax-endemic settings.

Adherence to antimalarial drug policy among doctors in Delta State, Nigeria: implications for malaria control.

BACKGROUND: Malaria is a public health problem compounded with a widespread emergence of drug-resistant Plasmodium falciparum which necessitated the formulation of a new antimalarial drug policy (AMP). OBJECTIVE: This study was designed to assess adherence to the policy among physicians in health facilities in Delta state, Nigeria. DESIGN: Cross-sectional, analytic study. Data were collected with a semi-structured questionnaire. SETTING: Two secondary and one tertiary health facilities in Delta State, Nigeria. PARTICIPANTS: Physicians selected with a simple random technique from the facilities. MAIN OUTCOME MEASURES: Prescribing pattern of antimalarial drugs and adherence to WHO treatment guideline among doctors. RESULTS: Majority (90.8%) of respondents believed the antimalarial policy (AMP) should be strictly adhered to, although three-fifth (61.0%) of them rated its performance as poor. The level of adherence to the national antimalarial drug policy was high (78.5%) as most doctors prescribed Arthemeter-Lumefantrine, AL for uncomplicated malaria however barely two-fifth (35.4%) adhered to prescribing injectable Artesunate for complicated malaria. AL, (71.9%) was the most prescribed antimalarial drug for uncomplicated malaria The most prescribed antimalarial drugs for complicated malaria was artesunate (40.0%) followed by quinine (27.6%) and artemether (26.7%); although, chloroquine was also prescribed. CONCLUSION: The level of adherence to AMP among doctors was sub-optimal. Continuous education of doctors on the new AMP is needed to achieve malarial control. FUNDING: No funding was received for this study.

Cost-effectiveness of artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of uncomplicated malaria in Papua New Guinean children.

BACKGROUND: A recent randomized trial showed that artemisinin-naphthoquine (AN) was non-inferior to artemether-lumefantrine (AL) for falciparum malaria and superior for vivax malaria in young Papua New Guinean children. The aim of this study was to compare the cost-effectiveness of these two regimens. METHODS: An incremental cost-effectiveness analysis was performed using data from 231 children with Plasmodium falciparum and/or Plasmodium vivax infections in an open-label, randomized, parallel-group trial. Recruited children were randomized 1:1 to receive once daily AN for 3 days with water or twice daily AL for 3 days given with fat. World Health Organisation (WHO) definitions were used to determine clinical/parasitological outcomes. The cost of transport between the home and clinic, plus direct health-care costs, served as a basis for determining each regimen's incremental cost per incremental treatment success relative to AL by Day 42 and its cost per life year saved. RESULTS: In the usual care setting, AN was more effective for the treatment of uncomplicated malaria in children aged 0.5-5.9 years. AL and AN were equally efficacious for the treatment of falciparum malaria, however AN had increased anti-malarial treatment costs per patient of $10.46, compared with AL. AN was the most effective regimen for treatment of vivax malaria, but had increased treatment costs of $14.83 per treatment success compared with AL. CONCLUSIONS: Whilst AN has superior overall efficacy for the treatment of uncomplicated malaria in PNG children, AL was the less costly regimen. An indicative extrapolation estimated the cost per life year saved by using AN instead of AL to treat uncomplicated malaria to be $12,165 for girls and $12,469 for boys (discounted), which means AN may not be cost-effective and affordable for PNG at current cost. However, AN may become acceptable should it become WHO prequalified and/or should donated/subsidized drug supply become available.

Assessment of Efficacy and Safety of Arterolane Maleate-Piperaquine Phosphate Dispersible Tablets in Comparison With Artemether-Lumefantrine Dispersible Tablets in Pediatric Patients With Acute Uncomplicated Plasmodium falciparum Malaria: A Phase 3, Randomized, Multicenter Trial in India and Africa.

BACKGROUND: Administration of artemisinin-based combination therapy (ACT) to infant and young children can be challenging. A formulation with accurate dose and ease of administration will improve adherence and compliance in children. The fixed-dose combination dispersible tablet of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg can make dosing convenient in children. METHODS: This multicenter (India and Africa), comparative, parallel-group trial enrolled 859 patients aged 6 months to 12 years with Plasmodium falciparum malaria. Patients were randomized in a ratio of 2:1 to AM-PQP (571 patients) once daily and artemether-lumefantrine (AL) (288 patients) twice daily for 3 days and followed for 42 days. RESULTS: The cure rate (ie, polymerase chain reaction-corrected adequate clinical and parasitological response) in the per-protocol population at day 28 was 100.0% and 98.5% (difference, 1.48% [95% confidence interval {CI}, .04%-2.91%]) in the AM-PQP and AL arms, respectively, and 96.0% and 95.8% (difference, 0.14% [95% CI, -2.68% to 2.95%]) in the intention-to-treat (ITT) population. The cure rate was comparable at day 42 in the ITT population (AM-PQP, 94.4% vs AL, 93.1%). The median parasite clearance time was 24 hours in both the arms. The median fever clearance time was 6 hours in AM-PQP and 12 hours in the AL arm. Both the treatments were found to be safe and well tolerated. Overall, safety profile of both the treatments was similar. CONCLUSIONS: The efficacy and safety of fixed-dose combination of AM and PQP was comparable to AL for the treatment of uncomplicated P. falciparum malaria in pediatric patients. CLINICAL TRIALS REGISTRATION: CTRI/2014/07/004764.

Safety Profile of Artemether-Lumefantrine: A Cohort Event Monitoring Study in Public Health Facilities in Tanzania.

BACKGROUND AND OBJECTIVE: Artemisinin combination therapies such as artemether-lumefantrine (AL) are effective for first-line treatment of uncomplicated acute Plasmodium falciparum malaria. However, the safety profile of AL in large populations has not been fully assessed. The objective of this study was to establish the safety of AL in public health facilities in Tanzania using the Cohort Event Monitoring (CEM) method. METHODOLOGY: Patients who presented to public health facilities in four regions of Tanzania who were prescribed AL were enrolled in a CEM study, a prospective, observational cohort study to establish a profile of adverse events (AEs) for the medicine when used in routine clinical practice. Pre- and post-treatment forms were used to record baseline information and new health events before and 7 days after treatment. RESULTS: A total of 8040 patients were enrolled in the study, of whom 6147 were included in the analysis. Following treatment initiation, a total of 530 AEs were reported in 6% (383) of the patients. The most frequent post-treatment AEs were in alimentary system (42%), including vomiting, nausea, diarrhoea, abdominal pain and anorexia, followed by AEs in the neurological system (25%). Causality assessment of the events showed that 51.9% (275/530) were possibly related to AL. There was a significant difference in the frequency of AEs by age-group with an increase in the number of AEs as age increased (P < 0.001). There was no statistically significant difference in the frequency of the events between males and females (P = 0.504). The AE profile was consistent with the AEs reported in the product information and in other studies; no new adverse drug reactions were identified. The majority of the reported AEs were the same as the symptoms of malaria and therefore indistinguishable from the underlying disease. CONCLUSIONS: The safety profile of AL for treatment of malaria continues to be favourable. CEM as a pharmacovigilance tool has proven to provide reliable safety data in a short period.

Assessment of the effectiveness of the CD3+ tool to detect counterfeit and substandard anti-malarials.

BACKGROUND: The US FDA recently developed CD3+, a counterfeit detection tool that is based on sample illumination at specific wavelengths of light and visual comparison of suspect sample and packaging materials to an authentic sample. To test performance of the CD3+ in field conditions, a study was conducted in Ghana which compared the CD3+ side-by-side with two existing medicine quality screening technologies-TruScan™ Portable Raman spectrometer and GPHF Minilab(®). METHODS: A total of 84 anti-malarial test samples comprising artemether-lumefantrine tablets and artesunate-amodiaquine tablets were used. The technologies were evaluated for sensitivity in determining counterfeit/substandard (The term counterfeit or falsified is used in this article to refer to medicines that carry a false representation of identity or source or both. The term substandard is used to refer to medicines that do not meet the quality specifications given in the accepted pharmacopeia.) medicines, specificity in determining authentic products, and reliability of the results. Authentic samples obtained from manufacturers were used as reference standards. HPLC analysis data was used as the "gold standard" for decisions regarding a sample being authentic or substandard/counterfeit. RESULTS: CD3+ had a sensitivity of 1.00 in detecting counterfeit/substandard products compared to Minilab (0.79) and TruScan (0.79). CD3+ had a lower specificity (0.53) in determining authentic products compared to the specificities reached by Minilab (0.99) and TruScan (1.00). High sensitivity in this context means that the technology is effective in identifying substandard/counterfeit products whereas the low specificity means that the technique can sometimes mischaracterize good products as substandard/counterfeit. Examination of dosage units only (and not packaging) using CD3+ yielded improved specificity 0.64. When only assessment of sample identification was done, the TruScan provided sensitivity (1.00) and specificity (0.99); and the Minilab provided sensitivity (1.00) and specificity (1.00). All three technologies demonstrated 100 % reliability when used to analyse the same set of samples over 3 days by a single analyst and also when used to determine the same set of samples by three different analysts. Eight of the field samples were confirmed to be counterfeits with no active pharmaceutical ingredient content. All three technologies identified these samples as counterfeits. CONCLUSIONS: The study revealed the relative effectiveness of the technologies as quality control tools. Using a combination of CD3+, with either the Minilab or TruScan, to screen for medicine quality will allow for complete examination of both the dosage units and the packaging to decide whether it is authentic or counterfeit.

Budget Impact Analysis of Using Dihydroartemisinin-Piperaquine to Treat Uncomplicated Malaria in Children in Tanzania.

BACKGROUND AND OBJECTIVE: Dihydroartemisinin-piperaquine (DhP) is a very cost effective anti-malarial drug. The aim of this study was to predict the budget impact of using DhP as a first- or second-line drug to treat uncomplicated malaria in children in Tanzania. METHODS: A dynamic Markov decision model was developed based on clinical and epidemiological data to estimate annual cases of malaria in children aged under 5 years. The model was used to predict the budget impact of introducing DhP as the first- or second-line anti-malarial drug, from the perspective of the National Malaria Control Program in 2014; thus, only the cost of drugs and diagnostics were considered. Probabilistic sensitivity analysis was performed to explore overall uncertainties in input parameters. RESULTS: The model predicts that the policy that uses artemether-lumefantrine (AL) and DhP as the first- and second-line drugs (AL + DhP), respectively, will save about $US64,423 per year, while achieving a 3% reduction in the number of malaria cases, compared with that of AL + quinine. However, the policy that uses DhP as the first-line drug (DhP + AL) will consume an additional $US780,180 per year, while achieving a further 5% reduction in the number of malaria cases, compared with that of AL + DhP. CONCLUSION: The use of DhP as the second-line drug to treat uncomplicated malaria in children in Tanzania is slightly cost saving. However, the policy that uses DhP as the first-line drug is somewhat more expensive but with more health benefits.

Malaria surveillance in low-transmission areas of Zambia using reactive case detection.

BACKGROUND: Repeat national household surveys suggest highly variable malaria transmission and increasing coverage of high-impact malaria interventions throughout Zambia. Many areas of very low malaria transmission, especially across southern and central regions, are driving efforts towards sub-national elimination. CASE DESCRIPTION: Reactive case detection (RCD) is conducted in Southern Province and urban areas of Lusaka in connection with confirmed incident malaria cases presenting to a community health worker (CHW) or clinic and suspected of being the result of local transmission. CHWs travel to the household of the incident malaria case and screen individuals living in adjacent houses in urban Lusaka and within 140 m in Southern Province for malaria infection using a rapid diagnostic test, treating those testing positive with artemether-lumefantrine. DISCUSSION: Reactive case detection improves access to health care and increases the capacity for the health system to identify malaria infections. The system is useful for targeting malaria interventions, and was instrumental for guiding focal indoor residual spraying in Lusaka during the 2014/2015 spray season. Variations to maximize impact of the current RCD protocol are being considered, including the use of anti-malarials with a longer lasting, post-treatment prophylaxis. CONCLUSION: The RCD system in Zambia is one example of a malaria elimination surveillance system which has increased access to health care within rural communities while leveraging community members to build malaria surveillance capacity.