The favourable results of this study support the policy decision of using AS+AQ in Senegal. It is premature to speculate how long this treatment will last but after six years of use, AS+AQ is still highly effective in the district of Oussouye where the rate of in vitro chloroquine resistance is > 60% . The patients from this study represent approximately one third of the more than 3000 patients who have already received AS+AQ as part of its deployment as first-line treatment at the district level. Reassuringly, the in vitro susceptibility of P. falciparum parasites to desethyl-AQ and artemisinin has not changed under drug pressure during this initial phase of deployment .
The efficacy of AS+AQ was well above the 90% threshold recommended by the WHO despite the conservative approach used in analysing the data: ITT dataset, adverse events considered as treatment failures and no adjustment for PCR proven new infections. As such, this study reflects more the effectiveness of AS+AQ in the field, while probably underestimating the real efficacy of this treatment. Interestingly, failure rates even in children under 10 years of age were considerably lower than those detected in 1998 in the same age group . It is difficult to explain these differences; in both cases, 28 day crude, non PCR-adjusted were measured, while patients were recruited during the rainy season in 1998 and all year round in 2000–05. Reinfections would be less frequent outside the rainy seasons; furthermore, the number of malaria cases has been decreasing after 2000.
Despite the good parasitological efficacy, treatment did not produce haematological recovery, a softer marker of efficacy. This may have been due to a combination of a relatively high mean, pretreatment haematocrit, the negative effect of AS on reticulocytes, and the short follow up period. Haematological recovery requires more than four weeks in some malaria settings . Treatment was well-tolerated as testified by the very low withdrawal rate (<1%), including two hospital admissions, because of drug induced toxicity. No significant clinical laboratory toxicities were detected.
AS+AQ was equally effective whether given based on body weight as loose combination or by age as co-blistered products (as per the manufacturer's instructions); however, the latter induced more TESS and all the treatment withdrawals due to intolerance. The use of the co-blister did result in patients receiving doses of both drugs, in mg/kg, that were close to the recommended, weight based, mg/kg dosing regimen, though the co-blistered AQ mg/kg dose looked to be a little higher than the loose AQ and had a broader spread of the 95% CIs. Gastrointestinal complaints accounted for seven of the nine withdrawals and were probably AQ rather than AS related, given that AS has excellent tolerability. Five patients received AQ doses ≥20% than the weight based dose of 10 mg/kg and four were within the 15 mg/kg upper limit of the newly defined therapeutic window. Never the less, the AQ dose may have contributed to their gastro-intestinal complaints.
The results obtained when patients are dosed more loosely by age are important because more practical regimens may expose patients to drug doses that are outside of the recommended, strictly defined, weight based doses. A more refined practical dosing has been developed for a new, aged dosed, fixed dose combination of AS+AQ . It is generally accepted that making treatments easier to understand and use by patients or e.g. their parents results in better compliance and that using fixed dose combinations enhances this [15, 16]. The AS-AQ fixed-dose combination will become available later in 2007 and plans are afoot to test it in Casamance. Its tolerability will be evaluated.
No cases of hepatitis or severe leukopenia (as a surrogate marker of neutropaenia) were detected, the two amodiaquine-associated toxicities that have caused fatalities in the past, when used as prophylaxis in travelers . However, the number of closely monitored patients was too low to detect rare toxicities, and differential WBC counts could not be done. Intensified monitoring of possible AS+AQ related AEs needs to be conducted in parallel with its widespread deployment, a practice which should be adopted systematically with all other ACTs.
This study confirms that, in this area of moderate/intense transmission, the risk of clinical malaria is present throughout life and that children between 6–15 years of age are most affected. This is important as clinical studies in these areas normally enroll patients up to 10 years old, and thus would miss an important segment of the patient population. In this study, although treatment was statistically less efficacious in children under 11 years of age than in older patients, efficacy rates were still high in both, 95% and 97%, respectively.
To conclude, this field study has shown a high and stable cure rate for AS+AQ even when dosed by age. Tolerability was good but continued intensive safety monitoring is still required in large numbers of patients for this ACT. Further research is planned to continue on the AS/AQ fixed dose combination.