دورية أكاديمية
Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology.
| العنوان: | Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology. |
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| المؤلفون: | Mousa A; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Cuomo-Dannenburg G; MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom., Thompson HA; Malaria and Neglected Tropical Diseases, PATH, Seattle, Washington, United States of America., Chico RM; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Beshir KB; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Sutherland CJ; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Schellenberg D; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Gosling R; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.; Malaria Elimination Initiative, Institute of Global Health, University of California, San Francisco, California, United States of America., Alifrangis M; Center for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Hocke EF; Center for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Hansson H; Center for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark., Chopo-Pizarro A; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Mbacham WF; The Biotechnology Centre, University of Yaoundé, Yaoundé, Cameroon.; The Fobang Institutes for Innovation in Science and Technology, Yaoundé, Cameroon.; The Faculty of Northwest University, Faculty of Natural and Agricultural Sciences, Potchefstroom, South Africa., Ali IM; The Biotechnology Centre, University of Yaoundé, Yaoundé, Cameroon.; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon., Chaponda M; Department of Clinical Sciences, Tropical Diseases Research Centre, Ndola, Zambia., Roper C; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Okell LC; MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. |
| المصدر: | PLoS medicine [PLoS Med] 2024 May 09; Vol. 21 (5), pp. e1004376. Date of Electronic Publication: 2024 May 09 (Print Publication: 2024). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101231360 Publication Model: eCollection Cited Medium: Internet ISSN: 1549-1676 (Electronic) Linking ISSN: 15491277 NLM ISO Abbreviation: PLoS Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: San Francisco, CA : Public Library of Science, [2004]- |
| مواضيع طبية MeSH: | Antimalarials*/therapeutic use , Drug Resistance*/genetics , Malaria*/prevention & control , Malaria*/transmission , Malaria*/epidemiology , Chemoprevention*/methods, Humans ; Bayes Theorem ; Genotype ; Research Design |
| مستخلص: | Background: Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings. Methods and Findings: We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common. Conclusions: These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance. Competing Interests: LCO has received a research grant from Merck pharmaceutical. RG is funded through a Unitaid grant that funds the Plus Project for his work at the London School of Hygiene and Tropical Medicine and works as an independent consultant paid by USAID, Population Services International and Bill and Melinda Gates Foundation. (Copyright: © 2024 Mousa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.) |
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| المشرفين على المادة: | 0 (Antimalarials) |
| تواريخ الأحداث: | Date Created: 20240509 Date Completed: 20240509 Latest Revision: 20240512 |
| رمز التحديث: | 20240512 |
| مُعرف محوري في PubMed: | PMC11081503 |
| DOI: | 10.1371/journal.pmed.1004376 |
| PMID: | 38723040 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1549-1676 |
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| DOI: | 10.1371/journal.pmed.1004376 |