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      Artemether-lumefantrine to treat malaria in pregnancy is associated with reduced placental haemozoin deposition compared to quinine in a randomized controlled trial

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          Abstract

          Background

          Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance.

          Methods

          Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data.

          Results

          Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria.

          Conclusions

          Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy.

          Trial registration

          REGISTRY: http://clinicaltrials.gov/ct2/show/NCT00495508

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          Most cited references35

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          Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.

          Arjen Dondorp, François Nosten, Kasia Stepniewska … (2005)
          In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat. We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009). Artesunate should become the treatment of choice for severe falciparum malaria in adults.
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            Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.

            George K. K. Lau, Teerha Piratvisuth, Kang Luo … (2005)
            Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.
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              The impact of placental malaria on gestational age and birth weight.

              Ahlam M. Ismail, John J. Aponte, P Ventura … (2000)
              Maternal malaria is associated with reduced birth weight, which is thought to be effected through placental insufficiency, which leads to intrauterine growth retardation (IUGR). The impact of malaria on preterm delivery is unclear. The effects of placental malaria-related changes on birth weight and gestational age were studied in 1177 mothers (and their newborns) from Tanzania. Evidence of malaria infection was found in 75.5% of placental samples. Only massive mononuclear intervillous inflammatory infiltration (MMI) was associated with increased risk of low birth weight (odds ratio ¿OR, 4.0). Maternal parasitized red blood cells and perivillous fibrin deposition both were associated independently with increased risk of premature delivery (OR, 3.2; OR, 2.1, respectively). MMI is an important mechanism in the pathogenesis of IUGR in malaria-infected placentas. This study also shows that placental malaria causes prematurity even in high-transmission areas. The impact of maternal malaria on infant mortality may be greater than was thought previously.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Malar J
                Journal ID (iso-abbrev): Malar. J
                Title: Malaria Journal
                Publisher: BioMed Central
                ISSN (Electronic): 1475-2875
                Publication date Collection: 2012
                Publication date (Electronic): 3 May 2012
                Volume: 11
                Page: 150
                Affiliations
                [1 ]Department of Pathology, University of Washington, Box 357470, 1959 NE Pacific Street, Seattle, WA, USA
                [2 ]Epicentre Mbarara Research Base, Mbarara, Uganda
                [3 ]Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand
                [4 ]Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
                [5 ]Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, CCVTM, Oxford, UK
                [6 ]Epicentre, Paris, France
                Article
                Publisher ID: 1475-2875-11-150
                DOI: 10.1186/1475-2875-11-150
                PMC ID: 3487992
                PubMed ID: 22554092
                SO-VID: 6116dcd0-386f-4855-bff9-62fd35feebe7
                Copyright © Copyright ©2012 Muehlenbachs et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 27 February 2012
                Date accepted : 3 May 2012
                Categories
                Subject: Research

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: artemether-lumefantrine,placental malaria,artemisinin-based combination therapy,quinine,pathology,haemozoin,malaria in pregnancy,randomized controlled trial,histology,falciparum
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: artemether-lumefantrine, placental malaria, artemisinin-based combination therapy, quinine, pathology, haemozoin, malaria in pregnancy, randomized controlled trial, histology, falciparum

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