Antimalarial Prophylaxis—Efficacy or Effectiveness?
While efficacy refers to the ability to produce a desired result, effectiveness signifies the degree to which something succeeds in producing it. To determine drug efficacy, controlled phase III studies are usually conducted where drug intake is observed, and, ideally, concentration in blood determined. Effectiveness, on the other hand, reflects the overall impact of the intervention as studied under normal conditions, allowing diverse confounding factors that may influence the outcome.
Various guidelines for prevention of malaria declare that no drug is 100% efficacious, and additional measures are therefore mandatory. These recommendations are based on experts' concern over constantly increasing drug resistance as well as ubiquitous reports of breakthrough infections despite stated appropriate drug prophylaxis. Such infections tend to be inadequately verified: the reports rarely contain figures for drug concentration, or if they do, the data are not always properly interpreted. Furthermore, intake has usually not been observed, which makes compliance a critical issue. Breakthrough reports thus reflect the effectiveness of a drug, ie, show to what degree it prevents infection in a real life setting.
Efficacy is typically estimated as the percent reduction of risk attributable to persons taking a prophylactic drug, compared with similarly exposed persons not taking prophylaxis. Percentage attack rates are given when control rates are unavailable. In semi-immune populations efficacy is measured as percentage of study participants with adequate clinical and parasitological response to treatment. The results can be applied to licensing a drug, dosage recommendations and, eventually, monitoring drug resistance.
Efficacy Versus Effectiveness
No less than 20% (44/225) of US marines on a 10-day mission in Liberia contracted laboratory-confirmed Plasmodium falciparum malaria. Mefloquine prophylaxis was recommended, but the drug intake was left unobserved. In addition, 16% of the marines were given presumptive antimalarial treatment for fever. Drug concentrations were not determined. In contrast to this striking percentage, not a single case of P. falciparum occurred in Swedish soldiers, who were later stationed in the same area in Liberia for as long as 1,800 man-months, and whose prophylactic treatment with mefloquine or atovaquone–proguanil was observed.
Earlier, during a time of no chloroquine resistance in Liberia, expatriates with malaria had chloroquine concentrations far below expected levels despite reported regular chemoprophylaxis. The conclusion was obvious: lack of compliance. Likewise, exceedingly low mefloquine concentrations were found in the majority of peace-corps volunteers in Africa, despite self-reported regular prophylaxis. Instead of concluding that they had failed to comply, the drug company chose to double the dosage recommendations.
In a recent study comprising all Finnish cases of P. falciparum between 2003 and 2011, regular use of prophylactic drug was only reported for 8 of 190 (4%) patients with P. falciparum malaria. Even they admitted to noncompliance, when the matter was rechecked in a follow-up interview.
There are similar problems in investigating chemoprophylaxis among semi-immunes. Even though drug intake should be supervised at all times, logistic problems are bound to arise when hundreds of participants are to take a daily dose for several weeks. Effectiveness might then be a better term.
To conclude, most studies of breakthrough infections provide an account of effectiveness, not efficacy. Unfortunately, they are generally interpreted as reports of efficacy. While verified breakthrough infections have been reported for a commonly used antimalarials, they are few,[6-8] and the risk of actual drug resistance against erythrocytic P. falciparum remains extremely low outside specific resistant foci in Southeast Asia. Pre-travel advice for drug prophylaxis should not draw on unconfirmed breakthrough reports, but instead, highlight the fact that correctly taken antimalarials provide an efficacy against P. falciparum that comes close to 100%.
Declaration of Interests
The authors state they have no conflicts of interest to declare.