Clinical implications of Plasmodium resistance to atovaquone/proguanil: a systematic review and meta-analysis

Abstract

Background: Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in non-endemic countries and its prevention in travellers. Mutations in the cytochrome bc1 complex are causally associated with atovaquone resistance.

Methods: This systematic review assesses the clinical efficacy of atovaquone/proguanil treatment of uncomplicated malaria and examines the extent to which codon 268 mutation in cytochrome b influences treatment failure and recrudescence based on published information.

Results: Data suggest that atovaquone/proguanil treatment efficacy is 89%-98% for P. falciparum malaria (from 27 studies including between 18 and 253 patients in each case) and 20%-26% for Plasmodium vivax malaria (from 1 study including 25 patients). The in vitro P. falciparum phenotype of atovaquone resistance is an IC50 value >28 nM. Case report analyses predict that recrudescence in a patient presenting with parasites carrying cytochrome b codon 268 mutation will occur on average at day 29 (95% CI: 22, 35), 19 (95% CI: 7, 30) days longer than if the mutation is absent.

Conclusions: Evidence suggests atovaquone/proguanil treatment for P. falciparum malaria is effective. Late treatment failure is likely to be associated with a codon 268 mutation in cytochrome b, though recent evidence from animal models suggests these mutations may not spread within the population. However, early treatment failure is likely to arise through alternative mechanisms, requiring further investigation.

Figure 1.

Mechanisms of action and resistance to atovaquone/proguanil. Structures of atovaquone, proguanil and cycloguanil are shown. Atovaquone targets cytochrome b in the bc₁ complex [formed by cytochromes b and c₁ and the Rieske iron–sulphur protein (ISP)] of the Plasmodium mitochondrial electron transport chain. The mitochondrial electron transport chain is located on the inner membrane of mitochondria, separating the intermembrane space (the space between the outer and inner membranes) from the centrally located matrix. Atovaquone works in synergy with proguanil, but its activity is reduced by mutations in cytochrome b (and in particular Y268S/C/N). Proguanil is metabolized to cycloguanil by the liver enzyme CYP2C19. Cycloguanil targets the enzyme DHFR in the Plasmodium folate pathway. Activity of cycloguanil is reduced by mutations in DHFR, including A16V/S108N and S108N/N51I/C59R/I164L. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Study selection. AP, atovaquone/proguanil.

Figure 3.

Forest plots for the relative treatment successes at day 28 of patients treated with atovaquone/proguanil (AP) or (a) ACT, (b) amino alcohols (AA), (c) 4-aminoquinolines (4-A) or (d) sulfadoxine/pyrimethamine (SP).

Figure 4.

Relationship between the number of days until recrudescence of malaria infection and the status of codon 268 in PfCYTb. Numbers of cases of patients infected with P. falciparum parasites (a) with (white bars) or without (black bars) mutation at codon 268 in PfCYTb at the time of recrudescence and (b) with (white bars) or without (black bars) a change at codon 268 in PfCYTb between the initial infection and the time of recrudescence.

Figure 5.

Relationship between pretreatment parasitaemia and (a and b) minimum days until recrudescence and (c and d) post-treatment parasitaemia in the absence or presence of mutation at codon 268 in PfCYTb. Complete data sets (filled circles) are shown with predicted lines of fit by multiple imputation (continuous lines) and their 95% CI (broken lines).