Malaria Chemoprophylaxis With Atovaquone-Proguanil: Is a Shorter Regimen Fully Protective?
How Much Evidence Do We Need in Travel Medicine?
As in any other field of medicine, how much evidence do we need in travel medicine before we change daily practice and adapt guidelines and recommendations for prophylaxis or treatment, for example regarding malaria? Leshem and colleagues, rightfully stating that adherence to antimalarial chemoprophylaxis (in this case to atovaquone-proguanil—AP) may leave room for improvement, and that findings (evidence!) from clinical and pharmacokinetic studies informed such a bold move, put a shortened AP oral chemoprophylactic scheme to the test. Following intake of this regimen—in standard dosage, but only administered from the day before departure up to the day after return—outcomes were surveyed at 6 months post-travel, resulting in the conclusion that cessation of drug intake straight after return may convey full protection compared to a standard +7 days post-exposure regimen.
Correctly taken for the purpose of chemoprophylaxis, suitable antimalarials are considered as being of high efficacy. The problem, however, often is a reduced effectiveness, to which noncompliance (the definition in my view encompassing also not even embarking on a recommended regimen) or nonadherence (not appropriately seeing through the intake of a begun regimen) is a major contributor, as pointed out by Rombo and colleagues in this issue.
Leshem and colleagues assume a high level of adherence, although their study was not designed to assess it systematically. While the authors acknowledge several of the methodological shortcomings (possibly problematic choice of region with limited risk of exposure, insufficient level of evidence that the drugs were taken appropriately, possible recall bias), they suggest that travelers may discontinue AP prophylaxis 1 day after leaving endemic areas, and recommend their approach for further evaluation.
In earlier days, what we would now consider as limited evidence may have led to major practice change, as exemplified by the introduction of primaquine for treatment and prophylaxis of vivax and ovale malaria in the early 1950s. Those were certainly different times, and nowadays, significantly more sophistication with regard to clinical trial design, research capacity, and scientific standards is at hand. However, there is still a role for pioneering studies like the one discussed here, some of them acknowledging what may already be practiced by analyzing retrospectively and what may already constitute a silent practice change prior to the conduct of often technically and financially difficult-to-perform state-of-the-art clinical trials. An example from the malaria field is that, in the lack of appropriate funding for such an undertaking, evaluating, eg, the different treatment regimens for uncomplicated falciparum malaria in Europe as compared to utilizing data from children in endemic areas in a clinical trial turned out not to be feasible. Instead, only surrogate efforts such as prospective observational studies come closest to what would be wishful from a methodological point of view. In tuberculosis, the evaluation of moxifloxacin for inclusion into improved, shortened combination treatment regimens against drug-sensitive Mycobacterium tuberculosis may serve as an example from a different field. While the conduct of an adequately powered, controlled, randomized trial with complex inclusion and exclusion criteria in multiple sites requires substantial resources and takes several years to accomplish, sometimes simple designs, in this case a retrospective cohort analysis, may yield high quality results that are otherwise difficult to obtain. Such an analysis convincingly demonstrated that moxifloxacin offers a statistically significant survival-benefit if included in combination therapeutic regimens of extensively drug-resistant tuberculosis across South Africa. So, undeniably there is a need for bold approaches to stimulate innovation; the study by Leshem and colleagues, all methodological shortcomings notwithstanding, in my view falls into this category.
Would There Be Any Advantage of an AP Regimen Shortened by 6 Days?
But what would be the advantages of the abridged malaria chemoprophylactic regimen over the current regimen? The authors claim that if a shorter course is sufficient, adherence will rise. But with AP being generally comparably well tolerated, would 6 days less of medication (unless the trip is very short) make a difference to the traveler in any respect?
Assessing whether a shortened prophylactic regimen is going to be superior compared to the standard one, risk of exposure and a consideration of compliance and adherence are most important. Risk estimates are derived from epidemiological information and clinical studies performed in endemic areas and data on returning travelers, which usually lack a reliable denominator. Both are only proxies, and can only offer limited insight into true risk. In the case of the Leshem and colleagues' paper, the countries where malaria was contracted reflect, naturally, the preferred travel destinations of this cohort within East Africa—countries which do not constitute highest-risk areas any longer. For example, it appears that a considerable number of tourists (the exact figure is not disclosed) traveled to Zanzibar, which serves as a model region for currently successful malaria control, with a recent drop in prevalence from 35% to 40% in 1995 to under 2% 15 years later.
Measuring true exposure and thus being able to precisely assess how many (chemoprophylaxis-protected) travelers were actually infected with Plasmodium species but protected by a blood schizontozide (in the case of AP with a considerable degree of causal prophylactic activity, attributable to the atovaquone portion) remains difficult, as sporozoite antibody measurements were for long considered as being of limited sensitivity. However, a more recent work suggests that in a larger Dutch travelers cohort to a wide range of destinations, the incidence rate of anticircumsporozoite seroconversion was 0.8 of 100 person-months. In this group, at least 75% of travelers took their recommended prophylaxis during travel. In controlled trials with supervised drug intake, protective efficacy of AP against falciparum malaria, with a high level of confidence, has been reported as offering 97% to 100% protection, and the “true” estimated failure rate in 100% adherent travelers is estimated at 2 of 100,000 prescriptions. Adherence rates vary across studies and have been reported for AP prophylaxis as between 70 and 90%, but a destination in Africa, medium length travel duration (14–29 days) and concurrent use of DEET appear to be associated with good adherence practice. With the recent Dutch study comparing different chemoprophylactic regimens, adherence to AP was high (although interestingly in this case, lower as compared to the mefloquine group) with 374 of 394 (94%) individuals who took AP as recommended during their travels. However, adherence AFTER leaving endemic areas dropped to 300 of 449; ie, 76% for some reason—suggesting that Leshem and colleagues may have another point, to that end, with their approach.
What Pharmacokinetic Evidence Do We Have in Support of a Shortened Regimen?
Some evidence comes from the study by Shapiro and colleagues from as early as 1999, which established the causal prophylactic activity of the drug, with drug levels peaking during the hepatic life cycle stage. Drug levels decreased below therapeutic levels up from day 6, highlighting the large inter-individual variance in absorption. While pharmocogenetic data on “host” effects on metabolism are lacking (in contrast to other antimalarials) these results are supported by recent (atovaquone only) pharmacokinetic data by Deye and colleagues. Even more, their data from a human challenge model suggest that even a once-weekly dosing may be protective. Interestingly, there is another relevant aspect of AP pharmacokinetics to consider, namely the very long blood schizontocidal effect which makes this combination attractive to be considered as a chemoprophylactic in the first place.
Are Even More Radical Approaches Thinkable?
Thinking more radically, at least with the short-term traveler in mind, Shanks and colleagues proposed to consider a short pre-travel-only course of AP as a chemoprophylaxis effectiveness-enhancing strategy in view of earlier studies of AP administered in curative dosages, delaying first asymptomatic blood parasitaemia by a minimum of 35 days in Western Kenya—very much in line with AP prophylactic drug action being observed in experimental blood stage parasite infections. In both studies, inter-individual variances in drug absorption, undercutting the generally long half life were not observed. However, to the best of my knowledge, this approach has so far not been systematically put to the test, for trial design reasons not difficult to imagine, and in line with what would make a systematic, methodologically satisfying evaluation of the more conservative change of practice as suggested by Leshem and colleagues very difficult in practice.
In my view, the study discussed here is important and although limited in its methodological approach, it would be wishful if it stimulated a more systematic evaluation.
The question is which level of approach would warrant a comprehensive, methodologically convincing answer. A further series of individual studies (requiring long follow-up data collection periods), as suggested by the authors, may lead to a collection of piecemeal information only, which in the end may be difficult to compare by meta-analysis. All technical problems (eg, including the absence of a highly reliable surrogate marker of exposure, large-scale drug level testing) notwithstanding, a single, well-designed multicenter study comparing the abridged regimen against the “gold-standard” of end-of-exposure day +7, with a thorough post-chemoprophylaxis follow-up of a fairly large number (thousands) of individuals, would probably yield an answer. However, it has to be acknowledged that in the absence of comprehensive funding opportunities such an effort may be practically almost impossible and the same would apply to the more radical approach suggested by Shanks and colleagues. In my view, the only realistic way forward for further coordinated evaluation of those novel approaches to malaria chemoprophylaxis would be to decide, within the travel medicine community, on the research priority level such an undertaking should be given, and to define harmonized criteria for a study design in order to make individual, smaller-scale studies aiming at identifying a statistical trend that is comparable in the end.
Declaration of Interests
The author states he has no conflicts of interest to declare.