Phase II and III clinical trials are aimed at identifying common adverse effects of drugs in carefully selected patients, but their sample size means that they are not suitable for identifying rare but potentially serious adverse effects or defining safety in high risk populations. Setting up and maintaining systems capable of collecting and collating data on adverse events will be challenging in most countries, but particularly so in Africa where it is anticipated the bulk of antimalarials will be used, and where the potentially most vulnerable populations reside. There is a particular concern about efficacy and safety in those co-infected with HIV/AIDs, who constitute a significant proportion of those requiring ACTs. Side-effects may be more common in those who are HIV-infected, efficacy of antimalarial treatment and IPTp in pregnancy is lower in HIV-positive individuals, and co-administration of antiretrovirals with other drugs may cause clinically significant drug interactions (increasing toxicity and/or decreasing efficacy). There are similar concerns about safety of antimalarials in infants and the malnourished.
Research questions to be addressed by the consortium
- How can existing networks and trials best be utilised to collect data on adverse events? This will include setting up an antimalarial adverse event database
- What is the frequency within the target population of adverse effects occurring with the different antimalarial combinations?
- What is the comparative tolerability of the different ACTs?
- What factors (e.g. age group, co-morbidity, repeated administration) predispose patients to developing adverse drug reactions?
- Are there any signals of new or unreported adverse events occurring with the ACTs or other new combination antimalarials?
- Are ACTs equally safe and efficacious in HIV-positive individuals, and are there clinically significant drug interactions between ACTs and antiretrovirals?
- Comprehensive reports, and regular policy briefs, on comparative safety of combination antimalarials in terms of the frequency and severity of different adverse drug reactions (ADRs) to ACTs (and other combination antimalarials)
- Testable hypotheses on the causation of adverse effects, and suggestions of possible interventions to minimise these risks that could be subject to trials.
- Determining risk factors associated with these ADRs, including data on the safety and efficacy of ACTs in those with HIV and on antiretrovirals.