Date Published: December 23, 2008
Publisher: Public Library of Science
Author(s): Rose McGready, Saw Oo Tan, Elizabeth A Ashley, Mupawjay Pimanpanarak, Jacher Viladpai-nguen, Lucy Phaiphun, Katja Wüstefeld, Marion Barends, Natthapon Laochan, Lily Keereecharoen, Niklas Lindegardh, Pratap Singhasivanon, Nicholas J White, François Nosten, Stephen Rogerson
Abstract: BackgroundTo date no comparative trials have been done, to our knowledge, of fixed-dose artemisinin combination therapies (ACTs) for the treatment of Plasmodium falciparum malaria in pregnancy. Evidence on the safety and efficacy of ACTs in pregnancy is needed as these drugs are being used increasingly throughout the malaria-affected world. The objective of this study was to compare the efficacy, tolerability, and safety of artemether-lumefantrine, the most widely used fixed ACT, with 7 d artesunate monotherapy in the second and third trimesters of pregnancy.Methods and FindingsAn open-label randomised controlled trial comparing directly observed treatment with artemether-lumefantrine 3 d (AL) or artesunate monotherapy 7 d (AS7) was conducted in Karen women in the border area of northwestern Thailand who had uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy. The primary endpoint was efficacy defined as the P. falciparum PCR-adjusted cure rates assessed at delivery or by day 42 if this occurred later than delivery, as estimated by Kaplan-Meier survival analysis. Infants were assessed at birth and followed until 1 y of life. Blood sampling was performed to characterise the pharmacokinetics of lumefantrine in pregnancy. Both regimens were very well tolerated. The cure rates (95% confidence interval) for the intention to treat (ITT) population were: AS7 89.2% (82.3%–96.1%) and AL 82.0% (74.8%–89.3%), p = 0.054 (ITT); and AS7 89.7% (82.6%–96.8%) and AL 81.2% (73.6%–88.8%), p = 0.031 (per-protocol population). One-third of the PCR-confirmed recrudescent cases occurred after 42 d of follow-up. Birth outcomes and infant (up to age 1 y) outcomes did not differ significantly between the two groups. The pharmacokinetic study indicated that low concentrations of artemether and lumefantrine were the main contributors to the poor efficacy of AL.ConclusionThe current standard six-dose artemether-lumefantrine regimen was well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy was inferior to 7 d artesunate monotherapy and was unsatisfactory for general deployment in this geographic area. Reduced efficacy probably results from low drug concentrations in later pregnancy. A longer or more frequent AL dose regimen may be needed to treat pregnant women effectively and should now be evaluated. Parasitological endpoints in clinical trials of any antimalarial drug treatment in pregnancy should be extended to delivery or day 42 if it comes later.Trial Registration: Current Controlled Trials ISRCTN86353884.
Partial Text: Plasmodium falciparum infections in pregnancy account for a high proportion of maternal mortality in malaria-endemic countries [1,2], particularly in areas of low and unstable transmission. The northwestern border of Thailand is an area of low seasonal malaria transmission complicated by high levels of multidrug resistance in P. falciparum. In this region in 1986 an estimated 1% of all pregnant women died from malaria annually. Since then there has been no safe and effective chemoprophylaxis that could be offered to pregnant women. A system of weekly antenatal clinics (ANCs) was therefore started. The ANCs provided early detection and treatment of malaria and reduced both morbidity and mortality . Other malaria-preventive approaches in pregnancy such as insecticide-treated nets  and insect repellents applied to the skin  did not show a significant preventive effect in this area. The therapeutic responses to various antimalarial drug treatments of multidrug-resistant falciparum malaria in pregnancy have been disappointing. In this geographic area, quinine currently cures less than 60% of pregnant patients [6,7]. This low cure rate is improved by combining quinine with clindamycin, but the poor tolerability of quinine and the consequent poor adherence to 7 d treatment regimens compromise effectiveness . Short course (3 d) fixed-dose artemisinin combination therapies (ACTs) are now recommended by the World Health Organization as first-line treatments of falciparum malaria in all endemic areas, and endorsed for use in the second and third trimesters of pregnancy .
The CONSORT checklist and trial protocol can be found in Text S1 and S2, respectively.
Between 23 April 2004 and 29 August 2006, 252 women with 253 episodes of acute falciparum malaria (one woman randomised twice to AS7) were enrolled; 128 patients were randomised to receive artesunate (AS7) and 125 to receive artemether-lumefantrine (AL) (Figure 1). The average gestational age (range) of patients at enrolment was 24 (13–39) wk (Table 1). Four patients did not receive a full course of treatment: three became hyperparasitaemic in the first 6 h, requiring rescue treatment (including re-randomised woman) and one developed artesunate allergy. Only eight (three AS7 and five AL) women defaulted from the study before the delivery outcome was known. The last delivery date for the study was 21 January 2007 and the last infant was followed up on 12 February 2008.
ACTs are now recommended as first-line treatment for falciparum malaria throughout the malaria-endemic world, and are now specifically recommended for the treatment of falciparum malaria in the second and third trimesters of pregnancy. This is a pragmatic compromise, as ACTs may become the only available effective antimalarials, pregnant women are at increased risk from falciparum malaria, and the evidence to date indicates that artemisinin derivatives are safe in later pregnancy. This is, to our knowledge, the first randomised controlled trial of fixed-dose ACT in the treatment of uncomplicated malaria in pregnancy. Artemether with lumefantrine was very well tolerated with no adverse effects either for the mother or for the foetus, yet its efficacy was lower than expected. Both artesunate monotherapy for 7 d and the standard 3 d regimen of artemether and lumefantrine resulted in cure rates below the 90% efficacy threshold recommended by WHO . Cure rates are likely to be even lower outside the setting of a trial when all doses cannot be directly supervised. Failure rates were over twice as high as those in non-pregnant adults, given the same dose in this same location, for whom AL cure rates consistently exceed 95% . The cure rates in pregnant women are lower than observed in young children in this area, a patient group with little or no immunity, which suggests that the poor therapeutic response is not explained by the malaria-specific immunosuppression of pregnancy. The significantly lower cure rates with AL were largely explained by the difference in cure rates for recrudescent infections (i.e., women presenting with a recrudescence of a previous infection). This study initially recruited women with a recurrent P. falciparum infection only, as there had been no previous experience to establish the safety of AL in pregnancy. This trial was not originally designed to compare cure rates in recrudescent with those in new or primary infections (Figure 5; Table 5), but the exploratory analysis shows a clear superiority of AS7 over AL in this particular subgroup. There was no difference in efficacy between AL and AS7 in the treatment of primary or new infections. This difference between primary and recrudescent infections presumably reflects reduced class susceptibility of the recrudescent infections to quinine, mefloquine, and lumefantrine . Although AL is not routinely used in the study area, there is cross-resistance with mefloquine, which is combined with artesunate in the first-line treatment in the non-pregnant population. Resistance is associated with an increase in Pfmdr1 copy numbers [33–35]. Parasites with increased Pfmdr1 copy number are also slightly less sensitive to artemisinin derivatives, although the differences are much less than for lumefantrine .