ACT is now regarded as the first-line treatments for uncomplicated P. falciparum malaria in most malaria-endemic countries, as advocated by the WHO [4, 5], and is gaining widespread acceptance in both the private and public sectors for the treatment of adults and children in malaria-endemic African countries. ACT, such as ASAQ, can reduce the parasite biomass rapidly and substantially, resulting in fast parasite clearance and resolution of clinical symptoms. Together with its efficacy against multidrug-resistant P. falciparum, its ability to reduce gametocyte carriage and to help reduce transmission of resistant alleles makes ACT an essential tool in malaria control and the fight to eliminate the disease . The efficacy of ASAQ given as a FDC is supported by findings of clinical studies performed in locations throughout sub-Saharan Africa [12, 13].
Pharmacovigilance, involving the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems, of ACT has been advocated to establish its safety in African populations. This is especially important because such treatments may be repeatedly used in treating recurrent episodes in those geographical areas where the disease is endemic. Most notably, there have been concerns about the potential of AQ monotherapy to cause haematological and hepatic toxicity when used prophylactically . Post-marketing safety usually relies on the spontaneous reporting of adverse reactions, but is often incomplete in the developing countries of sub-Saharan Africa due to an inadequate safety-monitoring infrastructure . However, collaboration between academic investigators, drug companies and governments can assist in the pharmacovigilance of new anti-malarial drugs.
FDCs are important candidates for pharmacovigilance, given their potential advantages in the management of malaria. The FDC of AL was the first fixed-dose ACT to be approved, after the demonstration of its efficacy in the treatment of uncomplicated P. falciparum malaria when administered twice daily for three days. Subsequently, the FDC of ASAQ became available. This product only requires a three-day dosing regimen, but also offers the added convenience of once-daily dosing.
The present collaborative Phase IV study was conducted in a rural area of Senegal where malaria is endemic and highly seasonal, occurring between September and December, with an entomological inoculation rate of between 9 and 12 during that period (Faye O, unpublished data). The vector responsible for malaria transmission is Anopheles gambiae. In order to increase the possibility of repeat malaria episodes, the study was conducted over two periods of malaria transmission.
The present study confirmed that the once-daily dosing regimen of the ASAQ FDC did not compromise efficacy. The PCR-corrected ACPR rate - the primary efficacy endpoint - achieved with ASAQ FDC was non-inferior to that of the AL FDC administered twice daily. The resolution of fever and elimination of parasites was rapid with either treatment. Patients who are asymptomatic, however, may remain gametocyte carriers and serve as an important reservoir for further disease transmission . Without eradication of gametocytes, asymptomatic infection may persist beyond the rainy season and perpetuate disease transmission into the next season . The relatively small number of patients returning with a second, and particularly a third, malaria episode suggests that there may have been an effective eradication of sexual parasites in this study. Both FDCs proved equally effective in treating the second and third episodes.
Adherence to medication is fundamental to the successful treatment of malaria and is assisted by use of a FDC. Direct supervision ensures total treatment compliance by the patient, as was the case for the treatment of the first episode in this study. In day-to-day practice, however, this approach is not feasible and the health-care worker is reliant on the patient understanding and following instructions. Therefore, the simpler the regimen, the greater the likelihood is of total compliance. Although there is potential for poor adherence to dosing that involves taking more than one tablet on each occasion in the absence of supervision, there was only one patient in this study who did not take the full dose when unsupervised. However, the mistake made by this patient was quickly identified (only one dose was missed) and the problem was rectified. Compliance is likely to be poorer if a patient is not participating in a trial or is not being closely monitored. The simplicity of dosing using a FDC may also be particularly advantageous when treating children .
The clinical safety in terms of adverse events and clinical laboratory findings was found to be comparable for ASAQ and AL in our study, with no evidence of haematological and hepatic toxicity associated with the use of ASAQ. In our study, based on observations in nearly 400 patients, treatment-related adverse events were recorded in <12% of the patients. The incidences of these events were comparable with the ASAQ and the AL FDCs, with most events being mild or moderate in intensity. The persistent anaemia observed in three children was probably attributable to helminthiasis as prevalence of intestinal parasites in children is high in this area of Senegal. Although a relatively small proportion of patients received a second or third course of treatment for subsequent episodes, there was no evidence of any difference in adverse event reporting with repeated use of either FDC. Similarly, there was no evidence of a negative impact of either FDC on clinical laboratory findings.
An important feature of the present study is that, in addition to the monitoring of safety as routinely performed in clinical studies, the possible effects of ASAQ and AL on the impairment of hearing and the QTc interval were evaluated. Audiometric assessments did not detect any significant deleterious auditory effects in normal hearing associated with either FDC given for 3 days in adult patients. A QTc prolongation was observed in both treatment groups between day 0 and day 3. The prolongation of the QTc interval observed in patients experiencing malaria episode resulted probably from a real effect of treatments on depolarization, as well as from an interfering artefact due to fever resolution and its induced chronotropic effect, this later was greater in the ASAQ group. It should be noted that no cardiac adverse events occurred during the follow-up period. No clinical impact was observed.
One of the limitations of this study was that provision of highly effective FDC treatment in a moderate and highly seasonal transmission area, such as this study area, resulted in relatively few patients presenting with a second or third episode of malaria. The safety evaluation of repeated FDC use, therefore, is restricted in the present study, but suggests that repeated use of FDC ASAQ and AL in the clinical trial setting should present no major safety issues. Nevertheless, there is a need for more extensive systems of pharmacovigilance for FDC ACT when it is regularly used in routine clinical practice . Currently, adverse events often go unreported in routine clinical practice [26, 27]. Health-care workers are often unfamiliar with formal reporting procedures, and tend to consider that the costs and additional workload outweigh any benefits. Improving voluntary pharmacovigilance reporting in malaria-endemic areas of Africa requires the active participation of patients and health-care workers, and should encompass both public and private sectors. Another challenge is to ensure the reliability and validity of data generated by community health-care workers for a community-based pharmacovigilance system.