Economic evaluation of artesunate and three quinine regimens in the treatment of severe malaria in children at the Ebolowa Regional Hospital-Cameroon: a cost analysis.

BACKGROUND: Severe malaria is a leading cause of morbidity and mortality in under-fives in sub-Saharan Africa. Recently quinine has been replaced by artesunate as the first-line drug in the treatment of severe malaria in Cameroon. Artesunate has been shown to be cost-effective in African children, but whether these findings are transferable to Cameroonian children remains to be explored. OBJECTIVES: To conduct a cost-analysis of four different regimens used in the treatment from the perspective of the healthcare payer. METHODS: An economic evaluation alongside a randomized comparative study was conducted in children aged 3 months to 15 years, admitted at the Ebolowa Regional Hospital with severe malaria due to Plasmodium falciparum. Patients were randomized to receive one of the four treatment alternatives. Group 1 (ARTES) received parenteral artesunate at 2.4 mg/kg at H0, H12, H24 and then once daily; Group 2 (QLD) received a loading dose of quinine base at 16.6 mg/kg followed 8 h later by an 8-hourly maintenance dose of 8.3 mg/kg quinine base; Group 3 (QNLD3) received 8.3 mg/kg quinine base every 8 h, and Group 4 (QNLD2) received 12.5 mg/kg quinine base every 12 h. The main outcome measure for effectiveness of treatment was the parasite reduction rate. Based on a healthcare perspective, an evaluation of direct medical costs was done, including costs of anti-malarials, nursing care materials, adjuvant treatment, laboratory investigations, hospitalisation and professional fees. Guided by a cost minimalization approach, the relative costs of these treatment alternatives was compared and reported. RESULTS: Overall cost was higher for ARTES group at $65.14 (95% CI $57.68-72.60) than for quinine groups ($52.49-$62.40), but the difference was not statistically significant. Cost of the anti-malarial drug was significantly higher for artesunate-treated patients than for quinine-treated patients, whereas cost of hospitalization was significantly lower for artesunate-treated patients than for quinine-treated patients. Incremental analysis of ARTES against QLD as a baseline resulted in an ICER of $46.8/PRR24 and suggests ARTES as the most cost effective of all four treatment options. CONCLUSION: Artesunate is a cost effective malaria treatment option relative to quinine alternatives with the lowest incremental cost per unit of effectiveness. Trial registration clinicaltrials.gov identifier: NCT02563704. Registered 19 September 2015, retrospectively registered.

An operational comparative study of quinine and artesunate for the treatment of severe malaria in hospitals and health centres in the Democratic Republic of Congo: the MATIAS study.

BACKGROUND: The Democratic Republic of the Congo (DRC) has the highest number of severe malaria cases in the world. In early 2012, the National Malaria Control Programme (NMCP) changed the policy for treating severe malaria in children and adults from injectable quinine to injectable artesunate. To inform the scaling up of injectable artesunate nationwide, operational research is needed to identify constraints and challenges in the DRC's specific setting. METHODS: The implementation of injectable quinine treatment in 350 patients aged 2 months or older in eight health facilities from October 2012 to January 2013 and injectable artesunate in 399 patients in the same facilities from April to June 2013 was compared. Since this was an implementation study, concurrent randomized controls were not possible. Four key components were evaluated during each phase: 1) clinical assessment, 2) time and motion, 3) feasibility and acceptability, and 4) financial cost. RESULTS: The time to discharge was lower in the artesunate (median=2, 90% central range 1-9) compared to the quinine group (3 (1-9) days; p<0.001). Similarly, the interval between admission and the start of intravenous (IV) treatment (2 (0-15) compared to 3 (0-20) hours; p<0.001) and parasite clearance time (23 (11-49) compared to 24 (10-82) hours; p<0.001) were lower in the artesunate group. The overall staff pre-administration time (13 (6-38) compared to 20 (7-50) minutes; p<0.001) and the personnel time spent on patient management (9 (1-24) compared to 12 (3-52) minutes; p<0.001) were lower in the artesunate group. In hospitals and health centres, the mean (standard deviation, SD) total cost per patient treated for severe malaria with injectable artesunate was USD 51.94 (16.20) and 19.51 (9.58); and USD 60.35 (17.73) and 20.36 (6.80) with injectable quinine. CONCLUSIONS: This study demonstrates that injectable artesunate in the DRC is easier to use and it costs less than injectable quinine. These findings provide the basis for practical recommendations for rapid national deployment of injectable artesunate in the DRC.

Artemisinin resistance--modelling the potential human and economic costs.

BACKGROUND: Artemisinin combination therapy is recommended as first-line treatment for falciparum malaria across the endemic world and is increasingly relied upon for treating vivax malaria where chloroquine is failing. Artemisinin resistance was first detected in western Cambodia in 2007, and is now confirmed in the Greater Mekong region, raising the spectre of a malaria resurgence that could undo a decade of progress in control, and threaten the feasibility of elimination. The magnitude of this threat has not been quantified. METHODS: This analysis compares the health and economic consequences of two future scenarios occurring once artemisinin-based treatments are available with high coverage. In the first scenario, artemisinin combination therapy (ACT) is largely effective in the management of uncomplicated malaria and severe malaria is treated with artesunate, while in the second scenario ACT are failing at a rate of 30%, and treatment of severe malaria reverts to quinine. The model is applied to all malaria-endemic countries using their specific estimates for malaria incidence, transmission intensity and GDP. The model describes the direct medical costs for repeated diagnosis and retreatment of clinical failures as well as admission costs for severe malaria. For productivity losses, the conservative friction costing method is used, which assumes a limited economic impact for individuals that are no longer economically active until they are replaced from the unemployment pool. RESULTS: Using conservative assumptions and parameter estimates, the model projects an excess of 116,000 deaths annually in the scenario of widespread artemisinin resistance. The predicted medical costs for retreatment of clinical failures and for management of severe malaria exceed US$32 million per year. Productivity losses resulting from excess morbidity and mortality were estimated at US$385 million for each year during which failing ACT remained in use as first-line treatment. CONCLUSIONS: These 'ballpark' figures for the magnitude of the health and economic threat posed by artemisinin resistance add weight to the call for urgent action to detect the emergence of resistance as early as possible and contain its spread from known locations in the Mekong region to elsewhere in the endemic world.

Cost of treating inpatient falciparum malaria on the Thai-Myanmar border.

BACKGROUND: Despite demonstrated benefits and World Health Organization (WHO) endorsement, parenteral artesunate is the recommended treatment for patients with severe Plasmodium falciparum malaria in only one fifth of endemic countries. One possible reason for this slow uptake is that a treatment course of parenteral artesunate is costlier than quinine and might, therefore, pose a substantial economic burden to health care systems. This analysis presents a detailed account of the resources used in treating falciparum malaria by either parenteral artesunate or quinine in a hospital on the Thai-Myanmar border. METHODS: The analysis used data from four studies, with random allocation of inpatients with falciparum malaria to treatment with parenteral artesunate or quinine, conducted in Mae Sot Hospital, Thailand from 1995 to 2001. Detailed resource use data were collected during admission and unit costs from the 2008 hospital price list were applied to these. Total admission costs were broken down into five categories: 1) medication; 2) intravenous fluids; 3) disposables; 4) laboratory tests; and 5) services. RESULTS: While the medication costs were higher for patients treated with artesunate, total admission costs were similar in those treated with quinine, US$ 243 (95% CI: 167.5-349.7) and in those treated with artesunate US$ 190 (95% CI: 131.0-263.2) (P=0.375). For cases classified as severe malaria (59%), the total cost of admission was US$ 298 (95% CI: 203.6-438.7) in the quinine group as compared with US$ 284 (95% CI: 181.3-407) in the artesunate group (P=0.869). CONCLUSION: This analysis finds no evidence for a difference in total admission costs for malaria inpatients treated with artesunate as compared with quinine. Assuming this is generalizable to other settings, the higher cost of a course of artesunate should not be considered a barrier for its implementation in the treatment of malaria.

The association between price, competition, and demand factors on private sector anti-malarial stocking and sales in western Kenya: considerations for the AMFm subsidy.

BACKGROUND: Households in sub-Saharan Africa are highly reliant on the retail sector for obtaining treatment for malaria fevers and other illnesses. As donors and governments seek to promote the use of artemisinin combination therapy in malaria-endemic areas through subsidized anti-malarials offered in the retail sector, understanding the stocking and pricing decisions of retail outlets is vital. METHODS: A survey of all medicine retailers serving Bungoma East District in western Kenya was conducted three months after the launch of the AMFm subsidy in Kenya. The survey obtained information on each anti-malarial in stock: brand name, price, sales volume, outlet characteristics and GPS co-ordinates. These data were matched to household-level data from the Webuye Health and Demographic Surveillance System, from which population density and fever prevalence near each shop were determined. Regression analysis was used to identify the factors associated with retailers' likelihood of stocking subsidized artemether lumefantrine (AL) and the association between price and sales for AL, quinine and sulphadoxine-pyrimethamine (SP). RESULTS: Ninety-seven retail outlets in the study area were surveyed; 11% of outlets stocked subsidized AL. Size of the outlet and having a pharmacist on staff were associated with greater likelihood of stocking subsidized AL. In the multivariable model, total volume of anti-malarial sales was associated with greater likelihood of stocking subsidized AL and competition was important; likelihood of stocking subsidized AL was considerably higher if the nearest neighbour stocked subsidized AL. Price was a significant predictor of sales volume for all three types of anti-malarials but the relationship varied, with the largest price sensitivity found for SP drugs. CONCLUSION: The results suggest that helping small outlets overcome the constraints to stocking subsidized AL should be a priority. Competition between retailers and prices can play an important role in greater adoption of AL.

Cost-effectiveness of artesunate for the treatment of severe malaria.

OBJECTIVE: To explore the cost-effectiveness of artesunate against quinine based principally on the findings of a large multi-centre trial carried out in Southeast Asia. METHODS: Trial data were used to compare mortality of patients with severe malaria, treated with either artesunate or quinine. This was combined with retrospectively collected cost data to estimate the incremental cost per death averted with the use of artesunate instead of quinine. RESULTS: The incremental cost per death averted using artesunate was approximately 140 USD. Artesunate maintained this high level of cost-effectiveness also when allowing for the uncertainty surrounding the cost and effectiveness assessments. CONCLUSION: This analysis confirms the vast superiority of artesunate for treatment of severe malaria from an economic as well as a clinical perspective.

Cost-effectiveness analysis of artesunate and quinine + tetracycline for the treatment of uncomplicated falciparum malaria in Chanthaburi, Thailand.

A randomized, controlled, malaria-clinic-based field trial was carried out to compare the cost-effectiveness of a 5-day 700-mg oral artesunate and a 7-day quinine + tetracycline regimen for the treatment of uncomplicated falciparum malaria in Thailand. Cost-effectiveness was determined from the providers' perspective and based on curative effectiveness. A total of 137 patients, aged 15-60 years, attending a malaria clinic were followed for 28 days, 60 of them received quinine + tetracycline and 77 received artesunate. Cure rates were assessed on day 5 (artesunate) and day 7 (quinine + tetracycline), using the intention-to-treat approach. Cost-effectiveness and sensitivity analyses were performed by varying the day 5/day 7 curative effectiveness and cost of artesunate. The cure rate with artesunate (100%) was significantly higher than with quinine + tetracycline (77.4%) (relative risk adjusted for sex (aRR) = 1.32, 95% confidence interval (CI) = 1.12-1.55; referent quinine + tetracycline). Artesunate was more cost-effective than quinine + tetracycline at the following costs: artesunate, < or = US$0.36 per 50-mg tablet; quinine, US$0.06 per 300-mg tablet; tetracycline, US$0.02 per 250-mg capsule; and services per case found, < or = US$11.49. Because of the higher cure rate and higher cost-effectiveness of the artesunate regimen compared with quinine + tetracycline, we recommend its use for the treatment of uncomplicated falciparum malaria in malaria clinics in Thailand.

PIP: Findings are presented from a randomized, controlled, malaria clinic-based field trial conducted to compare the cost-effectiveness of a 5-day 700 mg oral artesunate and a 7-day quinine and tetracycline regimen to treat uncomplicated falciparum malaria in Thailand. Cost-effectiveness was determined from the providers' perspective and based upon curative effectiveness. 137 patients, aged 15-60 years, attending a malaria clinic were followed for 28 days. 60 received quinine and tetracycline, while 77 received artesunate. Cure rates were assessed on day 5 (artesunate) and day 7 (quinine and tetracycline). The cure rate with artesunate was 100%, significantly higher than the 77.4% rate with quinine and tetracycline. Artesunate was more cost-effective than quinine and tetracycline, with artesunate costing a maximum of US$0.36 per 50 mg tablet, quinine at US$0.06 per 300 mg tablet, tetracycline at US$0.02 per 250 mg capsule, and services per case found no higher than US$11.49.

Comparative efficacy and safety of chloroquine and alternative antimalarial drugs: a meta-analysis from six African countries.

OBJECTIVE: To evaluate the safety and efficacy of the currently used antimalarial drugs in six African countries. DESIGN: A meta-analysis. MAIN OUTCOME MEASURES: The role of efficacy, safety and cost on the selection of antimalarial drugs. RESULTS: The comparative efficacy study showed that amodiaquine (with > 90% cure rate) was superior to chloroquine and sulphadoxine-pyrimethamine at seven days schedule. The efficacy of amodiaquine was also observed to be comparable to that of mefloquine and halofantrine. The parasite clearance time (PCT) of these drugs ranged between two days and a week and the fever clearance time (FCT) was within 48 hours. The recrudescence rate at D14-D21 was found to be 12-17% in chloroquine and amodiaquine, while sulphadoxine-pyrimethamine showed a trend similar to halofantrine and mefloquine (0-12% recrudescence rate). Similarly, a big difference was also noted in the cost of the different antimalarial drugs. The pharmacokinetic data, however, showed that they are of similar profile, except in adverse features and contraindications, and values like their half-life (t1/2) where the long (t1/2) in drugs like sulphadoxine-pyrimethamine endows them with suppressive-cure feature, especially against recrudescent strains. Nevertheless, as these data are obtained from resident population in Africa, who however naive are exposed to few malaria challenges in their life, the results should not be directly extrapolated to total non immunes such as visitors from Europe. CONCLUSION: The choice of alternative antimalarial drugs should be mainly based on their relative efficacy, safety and cost.

PIP: A meta-analysis study evaluating the efficacy and safety of chloroquine and alternative antimalarial drugs used in six African countries including Ethiopia, Kenya, Uganda, Cote D'Ivoire, Gambia and Nigeria is presented. Findings from the six countries showed a higher efficacy of amodiaquine and quinine (over 90%) in malaria treatment compared to chloroquine, which was found to be 70% or more effective. The efficacy of amodiaquine can also be compared to other antimalarial drugs such as mefloquine and halofantrine. Data showed that fever clearance time of these drugs was less than 2 days, but parasite clearance time ranged from 2.5 days to 1 week. Recrudescence rate also varied among the different drugs. This is a very important indicator in determining which drug can be used for prophylactic or suppressive treatment of malaria. Pharmacokinetic profile demonstrates that all these drugs have similar therapeutic effects, but differ in their adverse reactions, contraindications, and half-life. A significant difference was also noted in the cost of these antimalarial drugs; chloroquine was the cheapest, while halofantrine was the most expensive among the drugs. Based on these results, the study recommends that different aspects of antimalarial drugs have to be considered before deciding which drug is the best alternative treatment.

[Evaluation of the treatment of malaria using a 3-day regimen of quinine in Dakar]. / Evaluation du traitement du paludisme par la quinine en cure de 3 jours à Dakar.

The efficacy of quinine treatment for Plasmodium falciparum strains remains sound. However reports of decreased sensitivity and resistance of some strains in Asia and East Africa indicate that current treatment regimens should be re-adjusted. The purpose for the present study carried out in Dakar, Senegal, was to evaluate the local regimen for acute Plasmodium falciparum malaria using quinine at a dose of 20 mg/kg per day in two daily injections on 3 consecutive days. Thirty-seven patients with acute Plasmodium falciparum malaria including 10 severe cases were treated using the standard regimen and followed up clinically and parasitologically from Day 0 to Day 7. On Day 7 parasites were still detectable in the blood of four patients for a failure rate of 10.8%. Persistence of parasites despite disappearance of clinical symptoms suggests that the regimen should be increased to 25 mg/kg per day for at least for 3 days or longer if symptoms persist. Due to its adverse effects and cost (10 times higher than chloroquine treatment), quinine treatment should be prescribed only for patients with severe malaria forms.

Management of malaria before and after introduction of a treatment protocol at the Eldoret District Hospital.

A prospective study on the management of suspected malaria using a protocol on a general medical ward during the months of February and March, 1992 was done and the results compared with those of a retrospective study covering the months of November and December, 1991. The retrospective analysis showed that 78 (65%) from a total of 120 patients received antimalarial drugs despite negative or absent blood smears for malarial parasites. In 41 (34%) of the 120 patients, the first line treatment given was quinine. In the prospective study the overall quinine use dropped sharply to 19% from 54% in the retrospective study. 94 (49%) from a total of 193 patients with suspected malaria had negative blood smears of whom only 8 (4%) received quinine while 63 (33%) did not receive any antimalarial therapy and 38 of these 63 patients ended up with different final diagnoses; the remaining 25 were observed on no antimalarial treatment and discharged home feeling well. These results emphasize the need for proper diagnosis of malaria and suggest that chloroquine is still acceptable and effective as a first line drug for proven cases of malaria in adult patients in Eldoret. Unnecessary quinine use is discouraged as the drug is more expensive with more toxic effects compared to chloroquine.

PIP: In Kenya, health professionals compared prospective data on 193 suspected malaria patients at the Eldoret District Hospital during February-March, 1992, with retrospective data on 120 suspected malaria cases at the same hospital during November-December, 1991, to examine the protocol on the management of suspected malaria cases. Between these 2 periods, physicians introduced a simple algorithm to follow in suspected malaria cases. The use of quinine as the 1st choice drug fell considerably between the 2 periods (54.2-19%). There was an increase in the use of chloroquine as the 1st choice drug for uncomplicated malaria (38.4-63.9%). The proportion of blood smear positive patients increased (27.5-51.3%), probably because the department technician was more careful conducting repeat blood smears than were technicians at the busy hospital laboratory. Blood smear negative patients were less likely to automatically receive any antimalarial treatment or quinine in 1992 than in 1991 (14.6% vs. 47.5% and 4.1% vs. 30.9%, respectively). The proportion of patients whose final diagnosis was an illness other than malaria was higher in 1992 than in 1991 (19.7% vs. 15.8%). No clear diagnosis other than flu-like illness was the case for 28 (14.5%) of the prospective patients. The tendency for clinicians to accept a diagnosis of malaria without enough evidence to confirm it can have the damaging effect of masking other serious diagnoses (e.g., dysentery [8 cases], meningitis [6 cases], and HIV infection [2 case]). These findings show that hospital physicians should develop simple protocols for inpatient management of suspected malaria cases, a properly quantified blood smear should be done of all suspected malaria cases to confirm or refute the diagnosis, and chloroquine should be the 1st line of treatment in the Kenyan highlands, until considerable parasite resistance is confirmed.