Elsevier

The Lancet

Volume 363, Issue 9402, 3 January 2004, Pages 9-17
The Lancet

Articles
Artesunate combinations for treatment of malaria: meta-analysis

https://doi.org/10.1016/S0140-6736(03)15162-8Get rights and content

Summary

Background

Addition of artemisinin derivatives to existing drug regimens for malaria could reduce treatment failure and transmission potential. We assessed the evidence for this hypothesis from randomised controlled trials.

Methods

We undertook a meta-analysis of individual patients' data from 16 randomised trials (n=5948) that studied the effects of the addition of artesunate to standard treatment of Plasmodium falciparum malaria. We estimated odds ratios (OR) of parasitological failure at days 14 and 28 (artesunate combination compared with standard treatment) and calculated combined summary ORs across trials using standard methods.

Findings

For all trials combined, parasitological failure was lower with 3 days of artesunate at day 14 (OR 0·20, 95% CI 0·17–0·25, n=4504) and at day 28 (excluding new infections, 0·23, 0·19–0·28, n=2908; including re-infections, 0·30, 0·26–0·35, n=4332). Parasite clearance was significantly faster (rate ratio 1·98, 95% CI 1·85–2·12, n=3517) with artesunate. In participants with no gametocytes at baseline, artesunate reduced gametocyte count on day 7 (OR 0·11, 95% CI 0·09–0·15, n=2734), with larger effects at days 14 and 28. Adding artesunate for 1 day (six trials) was associated with fewer failures by day 14 (0·61, 0·48–0·77, n=1980) and day 28 (adjusted to exclude new infections 0·68, 0·53– 0·89, n=1205; unadjusted including reinfections 0·77, 0·63–0·95, n=1958). In these trials, gametocytes were reduced by day 7 (in participants with no gametocytes at baseline 0·11, 0·09–0·15, n=2734). The occurrence of serious adverse events did not differ significantly between artesunate and placebo.

Interpretation

The addition of 3 days of artesunate to standard antimalarial treatments substantially reduce treatment failure, recrudescence, and gametocyte carriage.

Introduction

Malaria-related morbidity and mortality are rising as a consequence of drug resistance.1, 3 Treatment policy makers aim for cost-effective regimens that keep development of antimalarial drug resistance to a minimum. A strategy that could achieve both aims is the combination of standard antimalarial drugs with a second antimalarial drug, particularly artemisinin derivatives.4, 5 Resistance in P falciparum malaria to artemisinin compounds has not been reported.6 These drugs act rapidly, and kill malaria parasites that are resistant to other drugs. Their rapid elimination and high intrinsic effectiveness reduce the probability of development of resistance to them. However, if artemisinin or one of its derivatives is given alone, completion of a 7-day treatment course is needed. The objective of current artemisinin-based combination treatment is for a 3-day course to act over two asexual cycles to substantially reduce total parasite numbers, ensuring a rapid clinical response. This treatment leaves a residual maximum of less than 1×105 parasites in the body that a slowly eliminated combination drug can remove in the third and subsequent asexual cycles.7 Both drugs protect each other from the emergence of resistance.

Artemisinin compounds reduce gametocyte carriage and therefore infectivity.8, 9 Thus, combination treatment might also decrease malaria transmission, especially in areas of low endemicity. Such treatment has been used for over 10 years on the Thai-Myanmar border, where there is low seasonal transmission of multidrug resistant P falciparum. Despite the high prevalence of mefloquine-resistant P falciparum before use of this regimen, combination of artesunate and mefloquine has achieved sustained high cure rates (>95%), reduced P falciparum transmission and the incidence of falciparum malaria, and halted the progression of resistance to mefloquine.10

In 1998, experts agreed that WHO and the Special Programme in Research and Training in Tropical Diseases (WHO/TDR) should co-ordinate trials to assess the safety and effects of artemisinin combination treatment, concentrating on antimalarial drugs used in Africa (chloroquine, amodiaquine, and sulfadoxinepyrimethamine).11 Placebo-controlled trials were set up to assess various artemisinin combinations in different countries, so that workers in malaria-control programmes could estimate the potential use of these combinations for first-line drug treatment. This standardised approach allowed a prospective analysis of individual patient data analysis.

Such analysis, in comparison with aggregate metaanalysis, allows assessment of the quality of the randomisation procedure, incorporation of updated follow-up information, assessment of uniformity of data, management of missing information, improved analysis of time-to-event outcomes, and more robust subgroup analyses. Additionally, the process also allows a balanced interpretation of results, wide endorsement of the findings, clear definition of further research needed, and the ability to incorporate new results.12 Our analysis was prospective, because we wrote the analytical protocol for the metaanalysis before the results of most of the trials were known. We aimed to measure the effects of adding an artemisinin derivative (artesunate) to existing treatment regimens for participants with acute uncomplicated P falciparum malaria.

Section snippets

Trial identification and selection

Trials were eligible for inclusion if they were randomized and compared artesunate plus a standard antimalarial drug with the standard drug alone for treatment of acute, uncomplicated P falciparum malaria. In addition to the WHO/TDR sponsored studies,13, 14, 15 we systematically sought additional studies in MEDLINE and the Cochrane Central Register of Controlled Trials, using the terms malaria and artesunate. We wrote to investigators who had published trials16, 17, 18, 19 of artesunate for

Data analysis

We assessed trial quality by adequacy of random allocation, inclusion of all eligible randomised participants in the analysis, and completeness of follow-up. We analysed randomisation by tabulating the number of participants assigned to each treatment group in weekly intervals from the time of enrolment, and by comparing baseline characteristics between the treatment groups. For the WHO/TDR trials of artesunate combinations, one protocol was used and an analytical plan designed.21 Every trial

Statistical analysis

For binary outcomes (eg, parasitological failure by day 14), we used the Peto-Mantel-Haenszel method to test for differences in these outcomes between artesunate combination treatment and standard drug alone.22, 23, 24 This analysis is based on the difference (O–E) between the number of observed (O) failures in the artesunate combination treatment and the expected (E) number under the null hypothesis of no effect of the addition of artesunate to standard treatment. We calculated O–E and its

Role of funding source

The funding sources had no role in study design, data collection, data analysis, data interpretation, or in the writing of the report.

Results

27 studies were considered for inclusion; 11 did not meet the entry criteria (three were not randomised; five had different doses or timing; one used artesunate in both groups; two used different background drugs in the two groups). Sixteen trials met the inclusion criteria (table 1), and all provided data for individual patients (Table 2, Table 3). 12 were done in Africa, three in Thailand, and one in Peru. 12 were placebo-controlled and doubleblinded. The four trials outside Africa (Peru and

Discussion

Our results for parasite failure at day 14 showed a consistent, large effect of adding 3 days of artesunate treatment to any of the existing drug regimens, irrespective of background treatment. The overall rate of treatment failure with standard treatment by day 14 was about 32% in the 15 trials analysed. This rate is higher than was anticipated at the planning stage of these investigations. A summary OR of 0·20 for the addition of artesunate is equivalent (with this overall failure) to a

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