Therapeutic failure after regimen with artemether-lumefantrine combination therapy: a report of three cases in Benin City, Nigeria

Abstract Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated malaria. Currently, there appears to be a downward trend in the efficacy of ACT in some parts of sub-Saharan Africa because some patients have been positive for Plasmodium parasite 3 days after artemether-lumefantrine treatment. We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.

In vitro effects of co-incubation of blood with artemether/lumefantrine & vitamin C on the viscosity & elasticity of blood.

Background & objectives: The antimalarial combination drug artemether/lumefantrine has been shown to be effective against malaria parasite through its haemolytic action. This drug is sometimes co-administered with vitamin C in patients with malaria. Vitamin C is associated with antioxidant properties which would be expected to protect against haemolytic effects of this antimalarial drug. This study was designed to investigate in vitro effects of co-incubation of artemether/lumefantrine with vitamin C on the viscosity and elasticity of blood. Methods: Blood was collected from 12 healthy female volunteers with normal haemoglobin genotype (HbAA). A Bioprofiler was used to measure the viscosity and elasticity of untreated blood samples (control) and samples exposed to artemether/lumefantrine (0.06/0.36 mg/ml) alone and with low or high dose vitamin C (equivalent to adult doses of 100 or 500 mg). Results: Artemether/lumefantrine significantly (P<0.05) reduced viscosity of blood from 4.72 ± 0.38 to 3.78 ± 0.17 mPa.s. Addition of vitamin C (500 mg) further reduced blood viscosity to 2.67 ± 0.05 mPa.s. The elasticity of blood was significantly (P<0.05) reduced from 0.33 ± 0.04 mPa.s to 0.24 ± 0.03 mPa.s by the antimalarial drug, and further reduced to 0.13 ± 0.02 mPa.s in the presence of vitamin C (500 mg). Interpretation & conclusions: Co-incubation of blood with vitamin C and antimalarial combination drug potentiates the haemolytic effects of the latter on reducing blood viscosity and elasticity in vitro. This may possibly have implications in relation to haemolysis in patients receiving vitamin C supplementation with artemether/lumefantrine during malaria therapy.

Prevalence of Pfmdr 1 N86Y and Y184F Alleles is Associated with Recurrent Parasitemia following Treatment of Uncomplicated Malaria with Artemether-Lumefantrine in Nigerian Patients.

We investigated and compared genetic variations in Plasmodium falciparum multidrug resistance 1 gene (Pfmdr 1) in patients showing good therapeutic response (GTR) and artemisinin resistance (AR) following artemether-lumefantrine (AL) treatment of uncomplicated malaria in Nigeria. Some 150 malaria patients were subjected to AL treatment and therapeutic efficacy was monitored for 28 days. Parasite genomic DNA was isolated followed by nested polymerase chain reaction (PCR). Genotyping of Pfmdr 1 gene for specific genetic variants: N86Y, Y184F, S1034C and N1042D were done using PCR-restriction fragment length polymorphism (PCR-RFLP).Out of 121 patients that were P. falciparum positive, 46 % (56) and 54 % (65) showed good therapeutic response and artemisinin resistance respectively, with 5.4 % and 98.3 % being mutated in the GTR and AR group respectively. The most prevalent mutations were Y184F (44.1 %) and N86Y (40.7 %). There was significant increase (p<0.001) in the prevalence of Pfmdr 1 mutation in the post treatment compared to the pre-treatment group.Prevalence of Pfmdr1 86Y and 184F alleles is associated with artemisinin resistance and presence of AL drug significantly induced genetic variation in the plasmodial gene.

Efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Northeast Ethiopia.

Background: The impact of resistance to antimalarials is insidious and unless efficacy studies are conducted, resistance may go unrecognized. The aim of this study was to assess the efficacy of artemether/lumefantrine, for the treatment of uncomplicated Plasmodium falciparum infections in Kemisie Health Center, Northeast Ethiopia. Methods: Artemether/lumefantrine efficacy study was conducted in Kemisie Health Center, Northeast Ethiopia from September, 2012 to May, 2013. The study participants were febrile people above the age of 6 months with confirmed uncomplicated P. falciparum infection. Patients were treated with artemether/lumefantrine. Clinical and parasitological parameters were monitored over a 28 days follow-up period to evaluate drug efficacy. The Kaplan–Meier method was used for statistical analysis of data on drug efficacy. Results: Among the 66 enrolled participants 72.7% were 15 and above years of age while 15.3% were less than 5 years old. Of these study participants, 53% were male. There was 89.4% fever clearance and 84.8% parasite clearance on day 1, whereas, there was 100% fever clearance and 96.8% parasite clearance on day 3 from the 62 participants who carried on the study. Among 66 participants who had started 28 days of follow-up one patient had an early parasitological failure (parasitemia on day 3) and another patient had a late parasitological failure (parasitemia on day 21). Conclusions: In general, this study discovered good clinical and parasitological response of P. falciparum to artemether/lumefantrine. Further polymeric chain reaction and plasma drug concentration based effectiveness study of artemether/ lumefantrine should be conducted throughout the country.

Possible artemisinin-based combination therapy-resistant malaria in Nigeria: a report of three cases

Artemisinin-based combination therapy-resistant malaria is rare in Sub-Saharan Africa. The World Health Organization identifies monitoring and surveillance using day-3 parasitaemia post-treatment as the standard test for identifying suspected artemisinin resistance. We report three cases of early treatment failure due to possible artemisinin-based combination therapy-resistant Plasmodium falciparum malaria. All cases showed adequate clinical and parasitological responses to quinine. This study reveals a need to re-evaluate the quality and efficacy of artemisinin-based combination therapy agents in Nigeria and Sub-Saharan Africa.

Artesunate + amodiaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in the Colombian Pacific region: a noninferiority trial / Artesunato + amodiaquina versus artemether-limefantrina para o tratamento da malaria não complicada por Plamodium falciparum no Pacifico Colombiano: um estudo de não inferioridade

INTRODUCTION: In Colombia, there are no published studies for the treatment of uncomplicated Plasmodium falciparum malaria comparing artemisinin combination therapies. Hence, it is intended to demonstrate the non-inferior efficacy/safety profiles of artesunate + amodiaquine versus artemether-lumefantrine treatments. METHODS: A randomized, controlled, open-label, noninferiority (Δ≤5%) clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28‑day World Health Organization validated design/definitions. Patients were randomized 1:1 to either oral artesunate + amodiaquine or artemether-lumefantrine. The primary efficacy endpoint: adequate clinical and parasitological response; secondary endpoints: - treatment failures defined per the World Health Organization. Safety: assessed through adverse events. RESULTS: A total of 105 patients was included in each group: zero censored observations. Mean (95%CI - Confidence interval) adequate clinical and parasitological response rates: 100% for artesunate + amodiaquine and 99% for artemether-lumefantrine; the noninferiority criteria was met (Δ=1.7%). There was one late parasitological therapeutic failure (1%; artemether-lumefantrine group), typified by polymerase chain reaction as the MAD20 MSP1 allele. The fever clearance time (artesunate + amodiaquine group) was significantly shorter (p=0.002). Respectively, abdominal pain for artesunate + amodiaquine and artemether-lumefantrine was 1.9% and 3.8% at baseline (p=0.68) and 1% and 13.3% after treatment (p<0.001). CONCLUSIONS: Uncomplicated P. falciparum malaria treatment with artesunate + amodiaquine is noninferior to the artemether-lumefantrine standard treatment. The efficacy/safety profiles grant further studies in this and similar populations.

INTRODUÇÃO: Na Colômbia não existem estudos publicados sobre o tratamento da malária não complicada por Plasmodium falciparum comparando as terapias combinadas com artemisinina. Destarte, quer se demonstrar a não inferioridade dos perfis de eficácia/segurança dos tratamentos com artesunato+amodiaquina versus artemeter-lumefantrina. MÉTODOS: Foi realizado um estudo clínico de não inferioridade (∆≤5%), aleatório, controlado, aberto, em adultos com malária não complicada por P. falciparum usando o desenho validado de 28 dias e os desenhos validados/definidos pela Organização Mundial da Saúde. Os pacientes foram aleatorizados (1:1) para ambos artesunato+amodiaquina ou artemeter-lumefantrina orais. Critérios primários de eficácia: resposta clínica e parasitológica adequada; Criterios de eficácia secundários: as falhas de tratamento definidos pela Organização Mundial da Saúde. A segurança: avaliada através de eventos adversos. RESULTADOS: Foram incursos 105 pacientes em cada grupo: zero observações censuradas. As taxas médias da resposta clínica e parasitológica adequada (95% IC - intervalo de confiança): 100% para artesunato+amodiaquina e 99% para artemeter-lumefantrina; atingiu-se o critério de não inferioridade (∆=1.7%). Houve uma falha terapêutica parasitológica tardia (1%; grupo artemeter-lumefantrina), caracterizada mediante reação em cadeia da polimerase como o alelo MAD20 MSP1. Tempo de remissão da febre (grupo artesunato+amodiaquina), foi significativamente mais curto (p=0.002). Dor abdominal, para artesunato+amodiaquina e artemeter-lumefantrina, respectivamente, 1.9% e 3.8% (p=0.68) na linha de base, 1% e 13.3% pós-tratamento (p<0.001). CONCLUSÕES: O tratamento com artesunato+amodiaquina da malária não complicada por P. falciparum é não inferior ao tratamento normal com artemeter-lumefantrina. Os perfis de eficácia/segurança justificam estudos adicionais nesta e outras populações semelhantes.

Evaluation of biochemical indices following administration of artemether, halofantrine and a combination of artemether and lumefantrine in guinea pigs.

Combination of artemether and lumefantrine (artemether-lumefantrine) is an orally effective artemisinin-based combination therapy, used widely in the treatment of Plasmodium falciparum infections. The present study investigates the comparative effects of artemether, halofantrine and artemether-lumefantrine on biochemical indices in the male guinea pig. Half, normal and double therapeutic doses of the drugs were given to different groups of animals (n=5) by oral gavage. After the drug treatments, serum levels of biochemical parameters were measured using standard methods. Artemether significantly (p<0.05) reduced uric acid (UA) level (10.44%), but produced no significant effects on the other parameters measured. Halofantrine and artemether-lumefantrine significantly increased acid phosphatase- ACPT (56.13 and 26.45%) and prostatic acid phosphatase-ACPP (100.00 and 78.95%) respectively, while alkaline phosphatase (ALP) was not affected. In addition, halofantrine and artemether-lumefantrine significantly and dose-dependently decreased UA, while urea and creatinine levels were increased. UA was decreased by 12.15 and 17.92%; urea was increased by 84.42 and 53.25%; and creatinine was increased by 42.15 and 30.25%, respectively. Furthermore, both drugs had no significant effects on serum levels of total protein and cholesterol. The results show that halofantrine and artemether-lumefantrine may cause toxicity to renal and reproductive functions in the male guinea pig, halofantrine likely to cause more of these effects.

Malaria healthcare policy change in Kenya: Implications on sales and marketing of antimalarials.

Background & objectives: Malaria healthcare policy change in Kenya aimed at improving the control of malaria but faced a number of challenges in implementation related to marketing of the drugs. This research investigated the effect of the change of the national malaria policy on drug sales and strategic marketing responses of antimalarial pharmaceutical companies in Kenya. Study design: A descriptive cross-sectional design was employed to describe the existing state of antimalarials market in Kenya after the change of the malaria healthcare policy. Results & conclusion: Policy change did result in an increase in the sales of Coartem®. Novartis Pharma recorded a 97% growth in sales of Coartem® between 2003 and 2004. However, this increase was not experienced by all the companies. Further, SPs (which had been replaced as first-line therapy for malaria) registered good sales. In most cases, these sales were higher than the sales of Coartem®. Generally, the sales contribution of SPs and generic antimalarial medicines exceeded that of Coartem® for most distributors. The most common change made to marketing strategies by distributors (62.5%) was to increase imports of antimalarials. A total of 40% of the manufacturers preferred to increase their budgetary allocation for marketing activities. In view of the fact that continued sale of SP drugs and limited availability of AL poses the risk of increasing the incidence of malaria in Kenya, it is therefore, recommended that pharmacy surveillance systems be strengthened to ensure drugs that have been rendered non-viable or that prescription-only medicines are not sold contrary to the national guidelines.

Clinical efficacy of chloroquine versus artemether-lumefantrine for Plasmodium vivax treatment in Thailand

Chloroquine remains the drug of choice for the treatment of vivax malaria in Thailand. Mixed infections of falciparum and vivax malaria are also common in South-East Asia. Laboratory confirmation of malaria species is not generally available. This study aimed to find alternative regimens for treating both malaria species by using falciparum antimalarial drugs. From June 2004 to May 2005, 98 patients with Plasmodium vivax were randomly treated with either artemether-lumefantrine (n = 47) or chloroquine (n = 51). Both treatments were followed by 15 mg of primaquine over 14 days. Adverse events and clinical and parasitological outcomes were recorded and revealed similar in both groups. The cure rate was 97.4% for the artemether-lumefantrine treated group and 100% for the chloroquine treated group. We concluded that the combination of artemether-lumefantrine and primaquine was well tolerated, as effective as chloroquine and primaquine, and can be an alternative regimen for treatment of vivax malaria especially in the event that a mixed infection of falciparum and vivax malaria could not be ruled out.