The effect of #chloroquine dose and #primaquine on #Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis

Robert J Commons, FRACP, Prof Julie A Simpson, PhD, Kamala Thriemer, PhD, Georgina S Humphreys, PhD, Tesfay Abreha, MPH, Sisay G Alemu, MSc, Arletta Añez, PhD, Prof Nicholas M Anstey, PhD, Ghulam R Awab, PhD, Prof J Kevin Baird, PhD, Bridget E Barber, PhD, Isabelle Borghini-Fuhrer, PhD, Cindy S Chu, MD, Umberto D’Alessandro, PhD, Prabin Dahal, MSc, André Daher, MD, Peter J de Vries, PhD, Annette Erhart, MD, Margarete S M Gomes, PhD, Lilia Gonzalez-Ceron, PhD, Matthew J Grigg, PhD, Aliehsan Heidari, PhD, Jimee Hwang, MD, Prof Piet A Kager, MD, Tsige Ketema, PhD, Wasif A Khan, MHS, Prof Marcus V G Lacerda, PhD, Toby Leslie, PhD, Benedikt Ley, PhD, Kartini Lidia, MSc, Prof Wuelton M Monteiro, PhD, Prof Francois Nosten, PhD, Prof Dhelio B Pereira, MD, Giao T Phan, PhD, Aung P Phyo, PhD, Prof Mark Rowland, PhD, Prof Kavitha Saravu, MD, Prof Carol H Sibley, PhD, André M Siqueira, PhD, Kasia Stepniewska, PhD, ProfInge Sutanto, PhD, Walter R J Taylor, MD, Prof Guy Thwaites, FRCP, Binh Q Tran, MD, Prof Hien T Tran, MD, Neena Valecha, MD, José Luiz F Vieira, PhD, Sonam Wangchuk, PhD, Timothy William, MRCP, Charles J Woodrow, PhD, Lina Zuluaga-Idarraga, PhD, Prof Philippe J Guerin, MD, Prof Nicholas J White, FRS, Prof Ric N Price, FRCP

Published: 19 July 2018 / Open Access  / DOI: https://doi.org/10.1016/S1473-3099(18)30348-7

© 2018 The Author(s). Published by Elsevier Ltd.

 

Summary

Background

Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings.

Methods

A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310.

Findings

Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001).

Interpretation

Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax.

Funding

Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.

Keywords: Malaria; Plasmodium vivax; Chloroquine; Primaquine.

——

#Plasmodium-associated changes in #human #odor attract #mosquitoes (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Plasmodium-associated changes in human odor attract mosquitoes

Ailie Robinson, Annette O. Busula, Mirjam A. Voets, Khalid B. Beshir, John C. Caulfield, Stephen J. Powers, Niels O. Verhulst, Peter Winskill, Julian Muwanguzi, Michael A. Birkett, Renate C. Smallegange, Daniel K. Masiga, W. Richard Mukabana, Robert W. Sauerwein, Colin J. Sutherland, Teun Bousema, John A. Pickett, Willem Takken, James G. Logan and Jetske G. de Boer

PNAS April 16, 2018. 201721610; published ahead of print April 16, 2018. DOI: https://doi.org/10.1073/pnas.1721610115

Contributed by John A. Pickett, March 14, 2018 (sent for review December 13, 2017; reviewed by David L. Denlinger and Ana Rivero)

 

Significance

In vector-borne disease systems, there is mounting evidence that vertebrate hosts become more attractive to disease vectors during infection, yet in human malaria, the underlying mechanism has not been studied. We identified compounds, including aldehydes, that are produced in relatively greater amounts in the skin odor of individuals with malaria, thus demonstrating a basis for this phenomenon in the cues used during mosquito host location. By establishing the attractiveness of these compounds to malaria mosquito vectors in laboratory bioassays, we characterize a process by which Plasmodium infection of humans could lead to increased mosquito biting. These compounds may serve as biomarkers of malaria or be used to enhance the efficacy of chemical lures used to trap mosquitoes.

 

Abstract

Malaria parasites (Plasmodium) can change the attractiveness of their vertebrate hosts to Anopheles vectors, leading to a greater number of vector–host contacts and increased transmission. Indeed, naturally Plasmodium-infected children have been shown to attract more mosquitoes than parasite-free children. Here, we demonstrate Plasmodium-induced increases in the attractiveness of skin odor in Kenyan children and reveal quantitative differences in the production of specific odor components in infected vs. parasite-free individuals. We found the aldehydes heptanal, octanal, and nonanal to be produced in greater amounts by infected individuals and detected by mosquito antennae. In behavioral experiments, we demonstrated that these, and other, Plasmodium-induced aldehydes enhanced the attractiveness of a synthetic odor blend mimicking “healthy” human odor. Heptanal alone increased the attractiveness of “parasite-free” natural human odor. Should the increased production of these aldehydes by Plasmodium-infected humans lead to increased mosquito biting in a natural setting, this would likely affect the transmission of malaria.

malaria transmission – host attractiveness – parasite–vector–host interactions – aldehydes – disease biomarkers

 

Footnotes

1 To whom correspondence may be addressed. Email: Ailie.Robinson@lshtm.ac.uk, pickettj4@cardiff.ac.uk, James.Logan@lshtm.ac.uk, or J.deBoer@nioo.knaw.nl.

2 Present address: Department of Biological and Agricultural Sciences, Kaimosi Friends University College, Kaimosi, Kenya.

3 Present address: Institute of Parasitology, National Centre for Vector Entomology, University of Zurich, 8057 Zurich, Switzerland.

4 Present address: School of Chemistry, Cardiff University, Cardiff CF10 3AT, United Kingdom.

5 Present address: Netherlands Institute of Ecology, Wageningen 6708 PB, The Netherlands.

Author contributions: A.R., A.O.B., N.O.V., M.A.B., R.C.S., D.K.M., W.R.M., R.W.S., T.B., J.A.P., W.T., J.G.L., and J.G.d.B. designed research; A.R., A.O.B., M.A.V., J.C.C., J.M., J.A.P., and J.G.d.B. performed research; A.R., K.B.B., J.C.C., P.W., and J.G.d.B. contributed new reagents/analytic tools; A.R., A.O.B., K.B.B., J.C.C., S.J.P., N.O.V., P.W., C.J.S., T.B., W.T., J.G.L., and J.G.d.B. analyzed data; and A.R., T.B., J.A.P., W.T., J.G.L., and J.G.d.B. wrote the paper.

Reviewers: D.L.D., The Ohio State University; and A.R., French National Centre for Scientific Research (CNRS).

Conflict of interest statement: A.R., J.G.d.B., J.G.L., and W.T. are inventors on a patent application filed with the UK Intellectual Property Office (application no. 1805023.7).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1721610115/-/DCSupplemental. Published under the PNAS license.

Keywords: Malaria; Plasmodium spp.; Mosquitoes.

——-

Safety and #mosquitocidal efficacy of high-dose #ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated #malaria … (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial

Menno R Smit, MD, Eric O Ochomo, PhD, Ghaith Aljayyoussi, PhD, Titus K Kwambai, MD, Bernard O Abong’o, MSc, Tao Chen, PhD, Teun Bousema, PhD, Hannah C Slater, PhD, David Waterhouse, MSc, Nabie M Bayoh, PhD, John E Gimnig, PhD, Aaron M Samuels, MD, Meghna R Desai, PhD, Penelope A Phillips-Howard, PhD, Simon K Kariuki, PhD, ProfDuolao Wang, PhD, Prof Steve A Ward, PhD, Prof Feiko O ter Kuile, PhD

Published: 27 March 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30163-4

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment.

Methods

We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18–50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m2; women: <23 vs ≥23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353.

Findings

Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio [RR] 2·26, 95% CI 1·93–2·65, p<0·0001; hazard ratio [HR] 6·32, 4·61–8·67, p<0·0001; ivermectin 300 μg/kg per day RR 2·18, 1·86–2·57, p<0·0001; HR 4·21, 3·06–5·79, p<0·0001). Mosquito mortality remained significantly increased 28 days post treatment (ivermectin 600 μg/kg per day RR 1·23, 1·01–1·50, p=0·0374; and ivermectin 300 μg/kg per day 1·21, 1·01–1·44, p=0·0337). Five (11%) of 45 patients receiving ivermectin 600 μg/kg per day, two (4%) of 48 patients receiving ivermectin 300 μg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events.

Interpretation

Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days after treatment. Ivermectin 300 μg/kg per day for 3 days provided a good balance between efficacy and tolerability, and this drug shows promise as a potential new tool for malaria elimination.

Funding

Malaria Eradication Scientific Alliance (MESA) and US Centers for Disease Control and Prevention (CDC).

Keywords: Malaria; Mosquitoes; Ivermectin.

——

Efficacy and safety of #primaquine and methylene blue for #prevention of #Plasmodium falciparum #transmission in #Mali: a phase 2, single-blind, randomised controlled trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial

Prof Alassane Dicko, MD*, Michelle E Roh, MPH*, , Halimatou Diawara, MD, Almahamoudou Mahamar, PharmD, Harouna M Soumare, PharmD, Kjerstin Lanke, BSc, John Bradley, PhD, Koualy Sanogo, MD, Daouda T Kone, MD, Kalifa Diarra, PharmD, Sekouba Keita, MS, Djibrilla Issiaka, MD, Prof Sekou F Traore, PhD, Prof Charles McCulloch, PhD, Will J R Stone, MSc, Jimee Hwang, MD, Prof Olaf Müller, PhD, Joelle M Brown, PhD, Vinay Srinivasan, BA, Prof Chris Drakeley, PhD, Prof Roly Gosling, MD†, Ingrid Chen, PhD†, Teun Bousema, PhD†

*Contributed equally

†Contributed equally

Published: 05 February 2018 / Open Access / DOI: https://doi.org/10.1016/S1473-3099(18)30044-6

© 2018 The Author(s). Published by Elsevier Ltd.

 

Summary

Background

Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants.

Methods

This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5–50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023.

Findings

Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; −10·2%, IQR −143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; −6·0%, IQR −126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild).

Interpretation

Adding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated.

Funding

Bill & Melinda Gates Foundation, European Research Council.

Keywords: Malaria; Mali; Piperaquine; Methylene Blue; Primaquine.

——

#Origins of the current #outbreak of #MDR #malaria in southeast #Asia: a retrospective genetic study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study

Roberto Amato, PhD, Richard D Pearson, PhD, Jacob Almagro-Garcia, PhD, Chanaki Amaratunga, PhD, Pharath Lim, MD, Seila Suon, MD, Sokunthea Sreng, Eleanor Drury, Sc, Jim Stalker, MA, Olivo Miotto, PhD, Rick M Fairhurst, MD, Prof Dominic P Kwiatkowski, FRCP

Published: 01 February 2018 / Open Access / DOI: https://doi.org/10.1016/S1473-3099(18)30068-9

© 2018 The Author(s). Published by Elsevier Ltd.

 

Summary

Background

Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin–piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports.

Methods

We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13artemisinin resistance locus and the plasmepsin 2–3 piperaquine resistance locus.

Findings

We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin–piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia.

Interpretation

The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin–piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia.

Funding

Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

Keywords: Malaria; Asia Region; Antibiotics; Drugs Resistance; Artemisin; Piperaquine.

——

Synthesis of #Thymoquinone – #Artemisinin Hybrids: New Potent #Antileukemia, #Antiviral, and #Antimalarial Agents (ACS Med Chem Lett., abstract)

[Source: ACS Medicinal Chemistry Letters, full page: (LINK). Abstract, edited.]

Synthesis of Thymoquinone–Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agents

Tony Fröhlich†, Christoph Reiter†, Mohamed E. M. Saeed‡, Corina Hutterer§, Friedrich Hahn§, Maria Leidenberger∥, Oliver Friedrich∥, Barbara Kappes∥, Manfred Marschall§, Thomas Efferth‡, and Svetlana B. Tsogoeva*†

† Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany; ‡ Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany; § Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany; ∥ Institute of Medical Biotechnology, Friedrich-Alexander University of Erlangen-Nürnberg, Paul-Gordon-Straße 3, 91052 Erlangen, Germany

ACS Med. Chem. Lett., Article ASAP / DOI: 10.1021/acsmedchemlett.7b00412

Publication Date (Web): December 21, 2017

Copyright © 2017 American Chemical Society

*Tel: (+) 49 9131 85 65573. E-mail: svetlana.tsogoeva@fau.de.

 

Abstract

A series of hybrid compounds based on the natural products artemisinin and thymoquinone was synthesized and investigated for their biological activity against the malaria parasite Plasmodium falciparum 3D7 strain, human cytomegalovirus (HCMV), and two leukemia cell lines (drug-sensitive CCRF-CEM and multidrug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10α-acetate 14 starting from a 1:1 mixture of C-10α- to C-10β-dihydroartemisinin was developed. The key step of this facile method is a mild decarboxylative activation of malonic acid mediated by DCC/DMAP. Ether-linked thymoquinone–artemisinin hybrids 6a/b stood out as the most active compounds in all categories, while showing no toxic side effects toward healthy human foreskin fibroblasts and thus being selective. They exhibited EC50values of 0.2 μM against the doxorubicin-sensitive as well as the multidrug-resistant leukemia cells and therefore can be regarded as superior to doxorubicin. Moreover, they showed to be five times more active than the standard drug ganciclovir and nearly eight times more active than artesunic acid against HCMV. In addition, hybrids 6a/b possessed excellent antimalarial activity (EC50 = 5.9/3.7 nM), which was better than that of artesunic acid (EC50 = 8.2 nM) and chloroquine (EC50 = 9.8 nM). Overall, most of the presented thymoquinone–artemisinin-based hybrids exhibit an excellent and broad variety of biological activities (anticancer, antimalarial, and antiviral) combined with a low toxicity/high selectivity profile.

Keywords: anticancer activity; antimalarial activity; antiviral activity; Artemisinin; natural product hybrid; thymoquinone

Keywords: Antivirals; Thymoquinone; Artemisin; Cancer; CMV; Malaria.

——

AQ-13, an investigational #antimalarial, versus #artemether plus #lumefantrine for the #treatment of uncomplicated #Plasmodium falciparum #malaria: … (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial

Prof Ousmane A Koita, PhD, Lansana Sangaré, PhD, Haiyan D Miller, BS, Aliou Sissako, MD, Moctar Coulibaly, MD, Trevor A Thompson, BS, Prof Saharé Fongoro, MD, Youssouf Diarra, PharmD, Mamadou Ba, PhD, Prof Ababacar Maiga, PhD, Prof Boubakar Diallo, MD, David M Mushatt, MD, Frances J Mather, PhD, Jeffrey G Shaffer, PhD, Asif H Anwar, MD

Published: 12 September 2017 / Open Access / DOI: http://dx.doi.org/10.1016/S1473-3099(17)30365-1

© 2017 The Author(s). Published by Elsevier Ltd.

 

Abstract

Background

Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria.

Methods

We did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparumparasites per μL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 μL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964.

Findings

Between Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2–4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93·9%] of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference −6·1%, 95% CI −14·7 to 2·4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84·8% for AQ-13 vs 31 of 33, 93·9% for artemether and lumefantrine; p=0·43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9·1%, 95% CI −5·6 to 23·8).

Interpretation

The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended.

Funding

US Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs-Wellcome Fund, US State Department, and WHO.

 

Research in context

Evidence before this study

Chloroquine was the treatment of choice for Plasmodium falciparum malaria until chloroquine-resistant parasites were identified more than 50 years ago. We have considered evidence from several studies done in our laboratories and those of colleagues worldwide, beginning in 1981. During this period, we have done many literature searches using different search terms without restriction to language each year. For these reasons, we have not listed the specific search criteria or results. Although chloroquine-resistant P falciparum have continued to be problem, our recent studies have shown that 4-aminoquinolines (4-AQs) with modified side chains, such as AQ-13, are active against chloroquine-resistant parasites and safe in human beings, and have pharmacokinetics similar to chloroquine.

Added value of this study

In this randomised, non-inferiority clinical trial of Malian men with uncomplicated P falciparum malaria, the per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three participants lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Adverse events were much the same in each group.

Implications of all the available evidence

Our results indicate that AQ-13 is not inferior to artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria due to chloroquine-resistant and chloroquine-susceptible parasites. Modified 4-AQs, such as AQ-13 might expand the currently limited number of antimalarial drugs active against drug-resistant parasites. Additional studies with non-immune patients and more participants are needed to decide whether to recommend widespread use of modified 4-AQs for uncomplicated malaria.

Keywords: Malaria; Drugs Resistance; Artemether; Lumefantrine; Chloroquine.

——-

Characteristics and #survival of #patients with #Ebola virus #infection, #malaria, or both in #SierraLeone: a retrospective cohort study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Characteristics and survival of patients with Ebola virus infection, malaria, or both in Sierra Leone: a retrospective cohort study

Matthew Waxman, MD, Adam R Aluisio, MD, Soham Rege, BS, Dr Adam C Levine, MD

Published: 28 February 2017 / Article has an altmetric score of 12 / DOI: http://dx.doi.org/10.1016/S1473-3099(17)30112-3

© 2017 Elsevier Ltd. All rights reserved.

 

Summary

Background

The 2014–15 Ebola virus disease (EVD) epidemic strained health systems in west Africa already overburdened with other diseases, including malaria. Because EVD and malaria can be difficult to distinguish clinically, and rapid testing was not available in many Ebola Treatment Units (ETUs), guidelines recommended empirical malaria treatment. Little is known, however, about the prevalence and characteristics of patients entering an ETU who were infected with malaria parasites, either alone or concurrently with Ebola virus.

Methods

Data for sociodemographics, disease characteristics, and mortality were analysed for patients with suspected EVD admitted to three ETUs in Sierra Leone using a retrospective cohort design. Testing for Ebola virus was done by real-time PCR and for malaria by a rapid diagnostic test. Characteristics of patients were compared and survival analyses were done to evaluate the effect of infection status on mortality.

Findings

Between Dec 1, 2014, and Oct 15, 2015, 1524 cases were treated at the three ETUs for suspected EVD, of whom 1368 (90%) had diagnostic data for malaria and EVD. Median age of patients was 29 years (IQR 20–44) and 715 (52%) were men. 1114 patients were EVD negative, of whom 365 (33%) tested positive for malaria. Of 254 EVD positive patients, 53 (21%) also tested positive for malaria. Mortality risk was highest in patients diagnosed with both EVD and malaria (35 [66%] of 53 died) and patients diagnosed with EVD alone (105 [52%] of 201 died). Compared with patients presenting to ETUs without malaria or EVD, mortality was increased in the malaria positive and EVD positive group (adjusted hazard ratio 9·36, 95% CI 6·18–14·18, p<0·0001), and the malaria negative and EVD positive group (5·97, 4·44–8·02, p<0·0001), but reduced in the malaria positive and EVD negative group (0·37, 0·20–1·23, p=0·0010).

Interpretation

Malaria parasite co-infection was common in patients presenting to ETUs and conferred an increased mortality risk in patients infected with Ebola virus, supporting empirical malaria treatment in ETUs. The high mortality among patients without EVD or malaria suggests expanded testing and treatment might improve care in future EVD epidemics.

Funding

International Medical Corps.

Keywords: Ebola; Malaria; Sierra Leone.

——

#Measuring #Haitian #children’s exposure to #chikungunya, #dengue and #malaria (Bull World Health Org., abstract)

[Source: Bulletin of the World Health Organization, full PDF file: (LINK). Abstract, edited.]

Measuring Haitian children’s exposure to chikungunya, dengue and malaria

Mathieu JP Poirier,a Delynn M Moss,b Karla R Feeser,b Thomas G Streit,a Gwong-Jen J Chang,c Matthew Whitney,c Brandy J Russell,c Barbara W Johnson,c Alison J Basile,c Christin H Goodman,c Amanda K Barry b& Patrick J Lammie b

a University of Notre Dame Haiti Program, Hôpital Sainte Croix, Rue D’ Accenil No.1, Léogâne, Haiti. b Centers for Disease Control and Prevention, Atlanta, United States of America (USA). c Centers for Disease Control and Prevention, Fort Collins, USA.
Correspondence to Mathieu JP Poirier Y (email: poiriemj@mcmaster.ca).

(Submitted: 12 March 2016 – Revised version received: 29 June 2016 – Accepted: 1 July 2016 – Published online: 31 August 2016 )

Bull World Health Organ 2016;94:817–825A | doi: http://dx.doi.org/10.2471/BLT.16.173252

 

Abstract

Objective

To differentiate exposure to the newly introduced chikungunya virus from exposure to endemic dengue virus and other pathogens in Haiti.

Methods

We used a multiplex bead assay to detect immunoglobulin G (IgG) responses to a recombinant chikungunya virus antigen, two dengue virus-like particles and three recombinant Plasmodium falciparum antigens. Most (217) of the blood samples investigated were collected longitudinally, from each of 61 children, between 2011 and 2014 but another 127 were collected from a cross-sectional sample of children in 2014.

Findings

Of the samples from the longitudinal cohort, none of the 153 collected between 2011 and 2013 but 78.7% (48/61) of those collected in 2014 were positive for IgG responses to the chikungunya virus antigen. In the cross-sectional sample, such responses were detected in 96 (75.6%) of the children and occurred at similar prevalence across all age groups. In the same sample, responses to malarial antigen were only detected in eight children (6.3%) but the prevalence of IgG responses to dengue virus antigens was 60.6% (77/127) overall and increased steadily with age. Spatial analysis indicated that the prevalence of IgG responses to the chikungunya virus and one of the dengue virus-like particles decreased as the sampling site moved away from the city of Léogâne and towards the ocean.

Conclusion

Serological evidence indicates that there had been a rapid and intense dissemination of chikungunya virus in Haiti. The multiplex bead assay appears to be an appropriate serological platform to monitor the seroprevalence of multiple pathogens simultaneously.

Keywords: Haiti; Chikungunya; Dengue; Malaria.

——

Safety and #Immunogenicity of #EBA-175 RII-NG #Malaria #Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placebo Controlled Dosage Escalation Study (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]

OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE

Safety and Immunogenicity of EBA-175 RII-NG Malaria Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placebo Controlled Dosage Escalation Study

Kwadwo A. Koram , Bright Adu, Josephine Ocran, Yaa S. Karikari, Susan Adu-Amankwah, Michael Ntiri, Benjamin Abuaku, Daniel Dodoo, Ben Gyan, Karl C. Kronmann, Francis Nkrumah

Published: September 19, 2016 / http://dx.doi.org/10.1371/journal.pone.0163066

 

Abstract

The erythrocyte binding antigen region II (EBA-175 RII) is a Plasmodium falciparum ligand that mediates erythrocyte invasion and is considered an important malaria vaccine candidate. A phase Ia trial in malaria naïve adults living in the United States found the recombinant non-glycosylated vaccine antigen, EBA-175 RII-NG adjuvanted with aluminium phosphate to be safe, immunogenic and capable of inducing biologically active antibodies that can inhibit parasite growth in vitro. The aim of the current study was to assess the safety and immunogenicity of this vaccine in malaria exposed semi-immune healthy adults living in a malaria endemic country, Ghana. In this double-blinded, placebo controlled, dose escalation phase I trial, eighteen subjects per group received ascending dose concentrations (5 μg, 20 μg or 80 μg) of the vaccine intramuscularly at 0, 1 and 6 months, while 6 subjects received placebo (normal saline). The primary end point was the number of subjects experiencing Grade 3 systemic or local adverse events within 14 days post-vaccination. Serious adverse events were assessed throughout the study period. Blood samples for immunological analyses were collected at days 0, 14, 28, 42, 180 and 194. A total of 52 subjects received three doses of the vaccine in the respective groups. No serious adverse events were reported. The majority of all adverse events reported were mild to moderate in severity, with local pain and tenderness being the most common. All adverse events, irrespective of severity, resolved without any sequelae. Subjects who received any of the EBA-175 RII-NG doses had high immunoglobulin G levels which moderately inhibited P. falciparum growth in vitro, compared to those in the placebo group. In conclusion, the EBA-175 RII-NG vaccine was safe, well tolerated and immunogenic in malaria semi-immune Ghanaian adults. Its further development is recommended.

Trial registration ClinicalTrials.gov. Identifier: NCT01026246

_____

Citation: Koram KA, Adu B, Ocran J, Karikari YS, Adu-Amankwah S, Ntiri M, et al. (2016) Safety and Immunogenicity of EBA-175 RII-NG Malaria Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placebo Controlled Dosage Escalation Study. PLoS ONE 11(9): e0163066. doi:10.1371/journal.pone.0163066

Editor: Mohammad Ali, Johns Hopkins Bloomberg School of Public Health, UNITED STATES

Received: May 7, 2016; Accepted: August 29, 2016; Published: September 19, 2016
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The study product was developed by Leidos with support from National Institute of Allergy and Infectious Diseases (NIAID) (https://www.niaid.nih.gov) [contract N01-AI-05421 awarded to Leidos]. The study was sponsored by the Division of Microbiology and Infectious Diseases (DMID), NIAID/ US NIH (https://www.niaid.nih.gov) under Contract No. HHSN266200400016C awarded to Noguchi Memorial Institute for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The product developed in this study is owned by DMID /NIAID. Leidos was a contract manufacturer and has no commercial interests whatsoever after delivering the product to DMID/NIAID. Leidos had no part in the design, conduct, analysis or interpretation of data from the study. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Keywords: Research; Abstracts; Malaria; Vaccines.

——