Karen I. Barnes

Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data

Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the ‘therapeutic’ day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23 % (95 % CI −1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98 % cure rates (if parasitemia <135,000/μL). Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.

WHO, the Global Fund, and medical malpractice in malaria treatment

Amir Attaran and colleagues highlight a very serious public-health issue. Provision of ineffective drugs for a life-threatening disease is indefensible. There is no doubt that chloroquine is now ineffective for the treatment of falciparum malaria in nearly all tropical countries and that its usual successor sulfadoxine-pyrimethamine is falling fast to resistance. As a result malaria mortality in eastern and southern Africa where hundreds of thousands of children die each year from the infection has doubled in the past decade. We have failed to roll back malaria and we in the developed world bear the responsibility for this humanitarian disaster. Malaria is not an insoluble problem. We already have the tools (insecticides bednets highly effective drugs) to reduce substantially the terrible death toll. But we are not providing them to the people who need them desperately but who cannot pay for them. Only a tiny fraction of the millions with malaria today receive highly effective treatments. The donors must take some responsibility for this failure. Given the choice between receiving donor support for ineffective chloroquine or sulfadoxine-pyrimethamine and receiving nothing most countries have naturally opted for the former. It is not easy to protest particularly when the main donors and the representatives of international organisations both claim these drugs are still “programmatically effective”. (excerpt)

Impact of the large-scale deployment of artemether/lumefantrine on the malaria disease burden in Africa: case studies of South Africa, Zambia and Ethiopia

Malaria is one of the most significant causes of morbidity and mortality worldwide. Every year, nearly one million deaths result from malaria infection. Malaria can be controlled in endemic countries by using artemisinin-based combination therapy (ACT) in combination with indoor residual spraying (IRS) and insecticide-treated nets (ITNs). At least 40 malaria-endemic countries in sub-Saharan Africa now recommend the use of ACT as first-line treatment for uncomplicated falciparum malaria as a cornerstone of their malaria case management. The scaling up of malaria control strategies in Zambia has dramatically reduced the burden of malaria. Zambia was the first African country to adopt artemether/lumefantrine (AL; Coartem®) as first-line therapy in national malaria treatment guidelines in 2002. Further, the vector control with IRS and ITNs was also scaled up. By 2008, the rates of in-patient malaria cases and deaths decreased by 61% and 66%, respectively, compared with the 2001-2002 reference period.Treatment with AL as first-line therapy against a malaria epidemic in the KwaZulu-Natal province of South Africa, in combination with strengthening of vector control, caused the number of malaria-related outpatient cases and hospital admissions to each fall by 99% from 2001 to 2003, and malaria-related deaths decreased by 97% over the same period. A prospective study also showed that gametocyte development was prevented in all patients receiving AL. This reduction in malaria morbidity has been sustained over the past seven years.AL was introduced as first-line anti-malarial treatment in 2004 in the Tigray region of Ethiopia. During a major malaria epidemic from May-October 2005, the district in which local community health workers were operating had half the rate of malaria-related deaths compared with the district in which AL was only available in state health facilities. Over the two-year study period, the community-based deployment of AL significantly lowered the risk of malaria-specific mortality by 37%. Additionally, the malaria parasite reservoir was three-fold lower in the intervention district than in the control district during the 2005 high-transmission season.Artemisinin-based combination therapy has made a substantial contribution to reducing the burden of malaria in sub-Saharan Africa.

Multiple Origins and Regional Dispersal of Resistant dhps in African Plasmodium falciparum Malaria.

Cally Roper and colleagues analyze the distribution of sulfadoxine resistance mutations and flanking microsatellite loci to trace the emergence and dispersal of drug-resistant Plasmodium falciparum malaria in Africa.

In vivo parasitological measures of artemisinin susceptibility.

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.

Antimalarial dosing regimens and drug resistance.

The contribution of underdosing to antimalarial treatment failure has been underappreciated. Most recommended dosage regimens are based on studies in non-pregnant adult patients. Young children and pregnant women, who bear the heaviest malaria burden, have the highest treatment failure rates. This has been attributed previously to lower immunity, although blood concentrations of many antimalarial drugs are significantly lower in pregnant women and young children than in non-pregnant adults. Nevertheless, there have been no studies of higher dosages. Sub-therapeutic concentrations will certainly contribute to poorer responses to treatment and will fuel the emergence and spread of antimalarial drug resistance. There is an urgent need for studies to optimise antimalarial dosage regimens in infants, young children and pregnant women, both to improve cure rates and to prolong the useful therapeutic lives of antimalarial drugs.

In Vivo Assessment of Drug Efficacy against Plasmodium falciparum Malaria: Duration of Follow-Up

ABSTRACT To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r2 = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.

Increased Gametocytemia after Treatment: An Early Parasitological Indicator of Emerging Sulfadoxine-Pyrimethamine Resistance in Falciparum Malaria

BACKGROUND Although malaria treatment aims primarily to eliminate the asexual blood stages that cause illness, reducing the carriage of gametocytes is critical for limiting malaria transmission and the spread of resistance. METHODS Clinical and parasitological responses to the fixed-dose combination of sulfadoxine and pyrimethamine in patients with uncomplicated falciparum malaria were assessed biannually since implementation of this treatment policy in 1998 in Mpumalanga Province, South Africa. RESULTS Despite sustained cure rates of > 90% (P = .14), the duration of gametocyte carriage increased from 3 to 22 weeks (per 1000 person-weeks) between 1998 and 2002 (P < .001). The dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance were the most important drivers of the increased gametocytemia, although these mutations were not associated with increased pretreatment asexual parasite density or slower asexual parasite clearance times. The geometric mean gametocyte duration and area under the gametocyte density time curve (per 1000 person-weeks) were 7.0 weeks and 60.8 gametocytes/microL per week, respectively, among patients with wild-type parasites, compared with 45.4 weeks (P = .016) and 1212 gametocytes/microL per week (P = .014), respectively, among those with parasites containing 1-5 dhfr/dhps mutations. CONCLUSIONS An increased duration and density of gametocyte carriage after sulfadoxine-pyrimethamine treatment was an early indicator of drug resistance. This increased gametocytemia among patients who have primary infections with drug-resistant Plasmodium falciparum fuels the spread of resistance even before treatment failure rates increase significantly.

Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data.

BackgroundGametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP).MethodsFactors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data.ResultsThe systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7–2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24–3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40–6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00–1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63–0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74–21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66–5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7.ConclusionsAS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.

Simplified antimalarial therapeutic monitoring: using the day-7 drug level?

The blood concentration profiles of most antimalarial drugs vary considerably between patients. The interpretation of antimalarial drug trials evaluating efficacy and effectiveness would be improved considerably if the exposure of the infecting parasite population to the antimalarial drug treatment could be measured. Artemisinin combination treatments are now recommended as first-line drugs for the treatment of falciparum malaria. Measurement of the blood, serum or plasma concentration of the slowly eliminated partner antimalarial drug on day 7 of follow-up is simpler and might be a better determinant of therapeutic response than the area under the concentration-time curve. Measurement of the day-7 drug level should be considered as a routine part of antimalarial drug trials.