This individual patient analysis has pooled data from 26 drug trials in a majority of paediatric malaria cases in sub-Saharan Africa identified through a systematic search and has focused on efficacy; safety will be reported separately. The trials reported herein were conducted between July 1999 and December 2006; thus, this analysis provide recent information on the current situation. Both absolute and comparative efficacy results varied between crude and PCR-adjusted results (i.e. whether reinfections are counted or discounted in the analysis).
The WHO recommends using treatments that are at least 90% effective after discounting reinfections . Overall, AS&AQ had an efficacy of ~94% after excluding reinfections by PCR. However, 10 sites in eight countries (out of 28 sites in 16 countries) failed to meet the WHO, Day 28, PCR-adjusted cut-off of >90% efficacy. These sites were in Congo, DRC, Kenya, Sierra Leone, South Sudan, Rwanda, Uganda, and Zanzibar. However, at other sites in some of these countries (DRC, Rwanda, South Sudan, Uganda, and Zanzibar), the PCR-adjusted efficacy exceeded 90%. Moreover, the PCR-adjusted efficacy in the comparator arm was >90% only in three sites (Kindamba-Congo, Amudat-Uganda, Micheweni-Zanzibar), and was not significantly superior to AS&AQ.
The definition of recrudescent failure was strict since recurrent parasitaemia that could not be successfully genotyped by PCR (indeterminate case) was considered conservatively as a recrudescent failure. This was done in order to prevent from introducing overestimation bias in assessing AS&AQ efficacy levels, in comparison to other attrition methods by modified intent-to-treat analysis that would increase the level of efficacy by excluding the PCR indeterminate cases from the analysis. Compared to other treatments, AS&AQ was either superior to non-ACTs or not different from AS+SP and AL but inferior to DP.
As expected, the AS&AQ crude efficacy, which counts reinfections as failures, was much lower, ~78% (with wide inter-country variability), than was the PCR-adjusted efficacy (~94%). During the 28 days of follow-up, the quotients of failure in the AS&AQ groups were the greatest on Day 21 and Day 28, in contrast with the other forms of ACT, for which the peak was reached on Day 28. When the risk of a reinfection is high in areas of intense transmission, treatment with longer post-treatment protection (AL, AS+SP, DP) fared better than AS&AQ. This probably reflects the relatively shorter residence time of AQ in the human body such that concentrations of the active metabolite, monodesethyl-amodiaquine, might be lower or absent when a reinfection occurs compared to other partner drugs combined to artemisinin derivatives. In the crude analysis of efficacy, AS&AQ was inferior to DP, AL and AS+SP.
Whether a short or a longer residence time for a drug is preferable is a matter of debate. Operationally, post-treatment protection against reinfection is a positive feature as it minimizes the number of treatments needed by the individual, the frequency of contacts with health providers, the risk of cumulative toxicity, and the costs (direct and indirect) incurred by households and health systems. Conversely, persisting concentrations of low drug levels may be insufficient to inhibit the replication of parasites arising from a new infection and potentially select for the parasites that can tolerate those levels. Furthermore, results depend on the study design and the duration of follow-up. It might be difficult to judge the operational implications of reinfections and re-treatment based on studies of treatment of single episodes of malaria; prospective cohort studies are best suited to assess the consequences of repeat treatments.
Based on the Day 28 efficacy results of these studies, AS&AQ would be suitable according to WHO standards as a potential alternative treatment for P. falciparum malaria in Angola, Burkina Faso, and Mali, where the current first line is AL. AS&AQ satisfied the criteria for continued use in some of the countries where is the current first-line treatment (Cameroon, Guinea, Madagascar, Gabon, Senegal, and Zanzibar), but AS&AQ would not qualify in some sites in Sierra Leone, Congo, DRC, North and South Sudan, Rwanda, Kenya, Uganda. However, where the AS&AQ efficacy PCR-adjusted was <90%, and the one of the comparators was >90%, the comparator groups were never significantly superior to AS&AQ whether in Congo (AL), Rwanda (DP), or Uganda (AS+SP).
This multi-centre analysis provides also interesting information on malaria and response to treatment. It confirms that children under 5 years of age are particularly vulnerable, as they are more likely to have on presentation higher baseline parasitaemia, be anaemic and carry gametocytes, and have a higher risk of failure compared to older children for all treatments evaluated, consistent with a lack of malaria-acquired immunity .
Being young and anaemic increases the risk for antimalarial treatment to fail to clear parasites and to be reinfected after clearing the current infection, suggesting a relationship between anaemia and transmission intensity, and between anaemia and susceptibility to infection. Conversely, young age alone predicts recrudescence after initial clearance.
Young children are a major reservoir of gametocytes and hence the engine of malaria transmission. Gametocyte carriage is highest when asexual parasitaemia is low.
Fever clearance was fast with AS&AQ, similar to other forms of ACT and AQ+SP, but faster than AL, and other non-ACT. Parasite clearance was fast with AS&AQ, generally faster than non-ACT and similar to other forms of ACT.
The presence of gametocytes on admission ranged from 0 to ~50% across the studies, and was related to young age and low asexual parasitaemia. The cumulative risk of gametocytes appearing post-treatment was ~20% with 36 PGW carriage per 1000 weeks of follow-up. The gametocyte clearance time in AS&AQ groups was the same (median 14 days) whether patients presented with gametocytes or developed gametocytaemia thereafter, but the peak distributions of time to clearance were Day 2 and Day 14, respectively. Compared to AS&AQ, the risk of appearance of gametocytes was higher and the carriage duration was longer with the non-ACTs and AS+SP, but lower with DP and AL in one Ugandan site, consistent with their better efficacy against asexual parasites.
Endemic countries are faced with the challenge of identifying the treatment(s) best adapted to their needs. To inform decisions, both locally generated data and more general information are needed. Systematic reviews and meta-analyses are useful to summarize evidence and assist policy makers. Pooling individual patient data offers advantages over aggregate patient data meta-analysis because it allows standardizing patient attrition and analyses. Each study can then be re-analysed based on common criteria for efficacy and safety and different drug regimens can be combined and compared. Data can also be combined and analysed together while stratifying by site. Efficacy analyses can be done on modified intent-to-treat basis of all randomized patients and use Kaplan-Meier product-limit estimates of time to event. This is now the preferred analytical method for anti-malarial drug efficacy trials .
Individual studies are not usually designed and, therefore, not powered to detect differences in a variety of secondary outcomes (e.g. gametocyte carriage, parasite or fever clearance time). Results of this analysis of individual patient data were presented using similar methods to that used for a conventional meta-analysis of trials (for instance in Cochrane's review) with graphical representation of risks, recommended for communicating in medical research . Compared to a meta-analysis from published studies, combining and standardizing these data at patient level increases statistical power by facilitating analytical practice (sub-group and multivariate analyses stratified by site) despite significant heterogeneity between trials. It also enables standardized estimates of drug efficacy across different studies, and the identification of at-risk groups to help target public health strategies.
However, this individual patient multi-centre analysis is not without limitations. First, the analysis included only half, 25 of the 46 trials that met criteria of quality for inclusion. It also has excluded additional trials published past August 2008, due to the time needed to adequately harmonize published data, obtain additional reported data and conduct the analyses. This might be a source of bias. The Worldwide Antimalarial Resistance Network (WARN) [47, 48] intends to create a living database, which might become the basis for updated assessments of drug efficacy. Second, these results apply primarily to children under five years of age (75% of the patients enrolled) and less to older children or adults. However, young children are indeed those at higher risk and are the primary target of malaria interventions. Finally, this analysis showed heterogeneity of study results both across and within countries, a finding that illustrates the challenges faced when making drug policy decisions. Differences in efficacy between sites might have resulted from the variability in the composition of the study drug, as well as PCR methods that have been used according to sites facilities.
A Cochrane systematic review and meta-analysis which includes AS&AQ  has just been published with consistent results.
At a bare minimum, malaria control programmes need up-to-date, dynamic, and comparative data on anti-malarial drug efficacy and safety in order to recommend optimal drug treatments for their countries. Prospective multi-centre analysis could be a key element for deciding drug policy at national and regional levels.