Population Pharmacokinetics of Artemether, Dihydroartemisinin, and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated Plasmodium falciparum Malaria.

The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear, and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its active metabolite dihydroartemisinin, and lumefantrine in 22 Rwandese pregnant women in their second (n = 11) or third (n = 11) trimester with uncomplicated Plasmodium falciparum malaria. These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combination of 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. Venous plasma concentrations were quantified for all three analytes using liquid chromatography coupled with tandem mass spectroscopy, and data were analyzed using nonlinear mixed-effects modeling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 h, followed by a biphasic disposition model. The median area under the concentration-time curve from 0 h to infinity (AUC0-∞) for lumefantrine was 641 h · mg/liter. Model-based simulations indicated that 11.7% of the study population did not attain the target day 7 plasma concentration (280 ng/ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether was time dependent, and the autoinduction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 h. The typical oral clearance, which started at 467 liters/h, increased 1.43-fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared to be reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.

Community mobilization for malaria elimination: application of an open space methodology in Ruhuha sector, Rwanda.

BACKGROUND: Despite the significant reduction of malaria transmission in Rwanda, Ruhuha sector is still a highly endemic area for malaria. The objective of this activity was to explore and brainstorm the potential roles of various community stakeholders in malaria elimination. METHODS: Horizontal participatory approaches such as 'open space' have been deployed to explore local priorities, stimulate community contribution to project planning, and to promote local capacity to manage programmes. Two open space meetings were conducted with 62 and 82 participants in years 1 and 2, respectively. Participants included purposively selected community and local organizations' representatives. RESULTS: Malaria was perceived as a health concern by the respondents despite the reported reduction in prevalence from 60 to 20% for cases at the local health centre. Some misconceptions of the cause of malaria and misuse of preventive strategies were noted. Poverty was deemed to be a contributing factor to malaria transmission, with suggestions that improvement of living conditions for poor families might help malaria reduction. Participants expressed willingness to contribute to malaria elimination and underscored the need for constant education, sensitization and mobilization towards malaria control in general. Active diagnosis, preventative strategies and prompt treatment of malaria cases were all mentioned by participants as ways to reduce malaria. Participants suggested that partnership of stakeholders at various levels could speed up programme activities. A community rewards system was deemed important to motivate engaged participants, i.e., community health workers and households. Establishment of malaria clubs in schools settings was also suggested as crucial to speed up community awareness and increase skills towards further malaria reduction. CONCLUSIONS: This bottom-up approach was found useful in engaging the local community, enabling them to explore issues related to malaria in the area and suggest solutions for sustainable malaria elimination gains.

Pharmacovigilance of artemether-lumefantrine in pregnant women followed until delivery in Rwanda.

BACKGROUND: The World Health Organization presently recommends Artemisinin-based combination therapy (ACT) as first-line therapy for uncomplicated P. falciparum malaria. Many malaria-endemic countries, including Rwanda, have adopted these treatment guidelines. The Artemisinin derivative Artemether, in combination with lumefantrine, is currently used in Rwanda for malaria during the second and third trimesters of pregnancy. Safety data on the use of ACT in pregnancy are still limited though and more data are needed. METHODS: In this pharmacovigilance study, the exposed group (pregnant women with malaria given artemether-lumefantrine), and a matched non-exposed group (pregnant women without malaria and no exposure to artemether-lumefantrine) were followed until delivery. Data were collected at public health centres all over Rwanda during acute malaria, routine antenatal visits, after hospital delivery or within 48 hours after home delivery. Information gathered from patients included routine antenatal and peri-partum data, pregnancy outcomes (abortions, stillbirths, at term delivery), congenital malformations and other adverse events through history taking and physical examination of both mothers and newborns. RESULTS: The outcomes for the total sample of 2,050 women were for the treatment (n=1,072) and control groups (n=978) respectively: abortions: 1.3% and 0.4%; peri-natal mortality 3.7% and 2.8%; stillbirth 2.9% and 2.4%; neonatal death [less than or equal to]7 days after birth 0.5% and 0.4%; premature delivery 0.7% and 0.3%; congenital malformations 0.3% and 0.3%. A total of 129 obstetric adverse events in 127 subjects were reported (7.3% in the treatment group, 5.0% in the control group). In a multivariate regression model, obstetric complications were more frequent in the treatment group (OR (95% CI): 1.38 (0.95, 2.01)), and in primigravidae (OR (95% CI) 2.65 (1.71, 4.12) and at higher age (OR per year: 1.05 (1.01-1.09). CONCLUSIONS: There were no specific safety concerns related to artemether-lumefantrine treatment for uncomplicated falciparum malaria in pregnancy. However, more obstetric complications were observed in the treatment group. These increased occurrence of complications could, however, be caused by the malaria episode itself, but further assessment is required.

Malaria has no effect on birth weight in Rwanda.

BACKGROUND: Malaria has a negative effect on pregnancy outcome, causing low birth weight, premature birth and stillbirths, particularly in areas with high malaria transmission. In Rwanda, malaria transmission intensity ranges from high to nil, probably associated with variable altitudes. Overall, the incidence decreased over the last six years (2002-2007). Therefore, the impact of malaria on birth outcomes is also expected to vary over time and space. METHODS: Obstetric indicators (birth weight and pregnancy outcome) and malaria incidence were compared and analyzed to their association over time (2002-2007) and space. Birth data from 12,526 deliveries were collected from maternity registers of 11 different primary health centers located in different malaria endemic areas. Malaria data for the same communities were collected from the National Malaria Control Programme. Associations were sought with mixed effects models and logistic regression. RESULTS: In all health centres, a significant increase of birth weight over the years was observed (p < 0.001) with a significant seasonal fluctuation. Malaria incidence had no significant effect on birth weight. There was a slight but significant decreasing effect of malaria incidence on the occurrence of premature delivery (p-value 0.045) and still birth (p-value 0.009). Altitude showed a slight but significant negative correlation with birth weight. Overall, a decrease over the years of premature delivery (p = 0.010) and still birth (p = 0.036) was observed. CONCLUSION: In Rwanda, birth weight and pregnancy outcome are not directly influenced by malaria, which is in contrast to many other studied areas. Although malaria incidence overall has declined and mean birth weight increased over the studied period, no direct association was found between the two. Socio-economic factors and improved nutrition could be responsible for birth weight changes in recent years.

Fetal and maternal hemodynamics in acute malaria during pregnancy.

OBJECTIVE: To measure maternal and fetal hemodynamics during acute malaria in pregnancy. METHODS: Time courses of maternal heart rate (MHR), maternal blood pressure (BP), and fetal heart rate (FHR) were performed until 56 days after initiation of anti-malarial treatment with artemether-lumefantrine. Women with malaria were hospitalized for at least 3 days until recovery. RESULTS: Mean baseline characteristics of pregnant women with malaria (n=38) versus pregnant women without malaria (n=39) were as follows: gestational age (28.8 vs 24.6 weeks; P=0.006); maximum FHR (165.3 vs 158.3 beats per minute [bpm]; P=0.054); minimum FHR (137.6 vs 128.7 bpm; P=0.016); mean BP (74.7 vs 80.9 mm Hg; P=0.001); pulse pressure (40.3 vs 42.1mm Hg; P=0.300); and MHR (107.4 vs 81.3 bpm; P<0.001). The geometric mean parasite count was 13 795 per µL. Complete time courses were collected from a subgroup of participants. For women with malaria, maternal body temperature and BP normalized within 24 hours and after 72 hours, respectively. The MHR among pregnant women without malaria showed a physiologic increase during pregnancy of approximately 7 bpm between days 0 and 56. The mean FHR among women with malaria normalized after 72 hours. CONCLUSION: Acute malaria induces maternal and fetal hemodynamic changes.