Research Article: Assessing Antimalarial Efficacy in a Time of Change to Artemisinin-Based Combination Therapies: The Role of Médecins Sans Frontières

Date Published: August 5, 2008

Publisher: Public Library of Science

Author(s): Jean-Paul Guthmann, Francesco Checchi, Ingrid van den Broek, Suna Balkan, Michel van Herp, Eric Comte, Oscar Bernal, Jean-Marie Kindermans, Sarah Venis, Dominique Legros, Philippe J Guerin

Abstract: Jean-Paul Guthmann and colleagues describe the output of MSF’s work in antimalarial
efficacy assessment during the last decade.

Partial Text: During the 1990s, high levels of Plasmodium
falciparum (Pf) resistance to common antimalarials were reported from malaria-endemic
countries, raising questions about the efficacy of chloroquine (CQ), then the mainstay of
antimalarial treatment. Drug resistance was considered a prime contributing factor to
increased malaria mortality and morbidity across Africa [1,2]. The natural successor to CQ, sulfadoxine-pyrimethamine (SP), had a
short therapeutic lifespan [3], and the choice of an effective first-line regimen emerged as a key
issue in Pf malaria control.
Artemisinin-based combination therapy (ACT), adopted in southeast Asia since the early
1990s, appeared to be the best available option [3].

Within these 18 countries and during 1996–2004, 455 treatment groups were
investigated, 112 (25%) by MSF (Table 2). The proportion of study groups investigated by MSF was higher for ACTs
(46%) than monotherapies (19%), and higher in Africa than in Asia,
both for monotherapies (23% versus 9%) and ACTs (57% versus
29%). Recommendations made by MSF were concordant with subsequent national
decisions regarding policy change in 13/18 (72%) of the countries of intervention
(Asia: two out of five [40%]; Africa: 11/13

These studies presented ethical dilemmas common to research in crisis-affected populations
[13]. Local
clinicians had strong anecdotal evidence of poor drug efficacy, but lack of scientific
evidence hindered advocacy to review treatment policies. Communities were particularly
vulnerable to the effects of antimalarial drug resistance since they had poor access to
health care, no recourse to efficacious second-line treatments, and limited civil rights and
governance structures within which to voice their patient perspective. Furthermore,
patients’ or caregivers’ ability to decide whether to participate in the
study was severely constrained: the study venue was often their sole health care option, and
their familiarity with biomedical concepts may have been insufficient to properly consider
the risks and benefits of participation. Adhering to the strict follow-up schedule was also
challenging, potentially entailing days of missed work.

Recently, several players have become involved in antimalarial efficacy assessment, and
there are global initiatives to co-ordinate studies [14]. Today’s challenges are different: (1) to
detect resistance to ACTs as early as possible, best done by combining molecular and in vivo
studies, and defining strategic surveillance sites where resistance is more likely to arise
de novo or be introduced from other regions; and (2) to demonstrate that new regimens (e.g.,
dihydroartemisinin-piperaquine) are at least as efficacious as current first-line ACTs and
carry additional benefits in terms of safety, cost, or feasibility: this would require
non-inferiority rather than comparative trial designs [15].

Our analysis shows that research can be performed in difficult settings to a high enough
standard to ensure publication and to be useful in policy change.



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