@article{Jarvis2023,
abstract = {Translating evidence from clinical trials to routine care can take many years, particularly in low-income and middle-income countries, delaying access to life-saving or life-changing treatments. As few as one in five evidence-based health interventions are incorporated into routine use, and the average time lag between evidence availability and practice change is up to 17 years. 1 The results of the AMBITION trial, which provided evidence supporting a simpler, safer treatment for HIV-associated cryptococcal meningitis, were published in full on March 24, 2022. 2 A WHO rapid advice notice was released less than 1 month later, and guidelines were published in July, 2022. 3 The rapid development of WHO guidelines facilitated incorporation of the new regimen into national guidelines in the African countries where the trial was done, and more broadly in other countries in Africa, Asia, Europe, and Latin America, with patients receiving the new treatment as part of routine care within 3 months. In this Comment, we highlight some key lessons to accelerate knowledge translation. 40 years ago, Yusuf and colleagues stated that a good clinical trial should ask an important question and answer it reliably. 4 Cryptococcal meningitis is a leading cause of HIV-associated mortality. 5 Until recently, the standard of care required 7-14 days of daily intravenous infusions of amphotericin B, causing significant toxicities and limiting safe use in most resource-constrained hospitals, with acute mortality rates of 40{\%} or more. 6 Guideline development relies on a comprehensive evidence assessment, appraised by a diverse, representative group of experts, providing an opportunity to identify crucial research gaps. The WHO cryptococcal disease guidelines from 2018 noted that simple treatments for cryptococcal meningitis suitable for low-resource settings were urgently needed. 7 The AMBITION trial evaluated a single high dose of liposomal amphotericin B for treating for HIV-associated cryptococcal meningitis. 2 The trial was sufficiently powered to evaluate safety and efficacy, and was done across five sub-Saharan African countries, enabling assessment of consistency of effects across different settings. The identification of the key questions was further supported by longstanding collaborations, including many African clinical researchers working in diverse health-care settings. Guideline development at WHO follows the Grading of Recommendations, Assessment, Development, and Evaluation process, with explicit consideration of four domains: certainty of the evidence, values and preferences, balance of benefits and harms, and resource implications. Other factors such as equity and human rights, acceptability, and feasibility are also considered. 8 Typically, trials focus only on safety and efficacy. To consider the full range of evidence-to-decision domains, guideline developers are often required to consider indirect evidence, rely on expert judgement, or await the findings of other relevant studies (such as qualitative Source of information Judgement Priority of the problem Published estimate of global disease burden 5 High priority: 152 000 cases of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths Balance of benefits and harms Phase 3 clinical endpoint trial (the AMBITION trial) 2 Benefits outweigh harms: non-inferior mortality; fewer adverse events Acceptability to key stakeholders Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; in-depth interviews with trial participants and providers; and direct observations Highly acceptable from the perspective of participants and providers Feasibility of implementation Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; direct observations; and in-depth interviews with trial investigators Feasible: simpler to administer, resulting in fewer side-effects and preferred to the previous standard of care Resource requirements Economic evaluation 9 embedded within the phase 3 clinical trial Cost-effective at a low incremental cost-effectiveness ratio; potentially cost saving in real-world implementation Effect on health equity Equity considerations provided during the guideline meeting Improves equity For a guideline panel to make a recommendation for or against a given intervention, each of these criteria listed in the first column needs to be considered. Gathering information early to inform these recommendations is crucial to accelerating guideline development. Table: Evidence-to-decision table for the treatment of cryptococcal meningitis},
author = {Jarvis, Joseph N and Chou, Roger and Harrison, Thomas S and Lawrence, David S and Muthoga, Charles and Mupeli, Kennedy and Meya, David B and Mwandumba, Henry C and Kanyama, Cecilia and Meintjes, Graeme A and Leeme, Tshepo B and Ndhlovu, Chiratidzo E and Beattie, Pauline and Sued, Omar and {P{\'{e}}rez Casas}, Carmen and Makanga, Michael and Ford, Nathan},
doi = {10.1016/S2214-109X(23)00412-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jarvis et al. - 2023 - Translating evidence into global impact lessons for HIV research and policy development from the AMBITION trial.pdf:pdf},
issn = {2214109X},
journal = {The Lancet Global Health},
keywords = {OA,OA{\_}PMC,commentary,fund{\_}not{\_}ack},
mendeley-tags = {OA,OA{\_}PMC,commentary,fund{\_}not{\_}ack},
month = {nov},
number = {11},
pages = {e1688--e1690},
pmid = {37858577},
publisher = {Elsevier Ltd},
title = {{Translating evidence into global impact: lessons for HIV research and policy development from the AMBITION trial}},
url = {http://www.thelancet.com/article/S2214109X23004126/fulltext http://www.thelancet.com/article/S2214109X23004126/abstract https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(23)00412-6/abstract},
volume = {11},
year = {2023}
}

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As few as one in five evidence-based health interventions are incorporated into routine use, and the average time lag between evidence availability and practice change is up to 17 years. 1 The results of the AMBITION trial, which provided evidence supporting a simpler, safer treatment for HIV-associated cryptococcal meningitis, were published in full on March 24, 2022. 2 A WHO rapid advice notice was released less than 1 month later, and guidelines were published in July, 2022. 3 The rapid development of WHO guidelines facilitated incorporation of the new regimen into national guidelines in the African countries where the trial was done, and more broadly in other countries in Africa, Asia, Europe, and Latin America, with patients receiving the new treatment as part of routine care within 3 months. In this Comment, we highlight some key lessons to accelerate knowledge translation. 40 years ago, Yusuf and colleagues stated that a good clinical trial should ask an important question and answer it reliably. 4 Cryptococcal meningitis is a leading cause of HIV-associated mortality. 5 Until recently, the standard of care required 7-14 days of daily intravenous infusions of amphotericin B, causing significant toxicities and limiting safe use in most resource-constrained hospitals, with acute mortality rates of 40% or more. 6 Guideline development relies on a comprehensive evidence assessment, appraised by a diverse, representative group of experts, providing an opportunity to identify crucial research gaps. The WHO cryptococcal disease guidelines from 2018 noted that simple treatments for cryptococcal meningitis suitable for low-resource settings were urgently needed. 7 The AMBITION trial evaluated a single high dose of liposomal amphotericin B for treating for HIV-associated cryptococcal meningitis. 2 The trial was sufficiently powered to evaluate safety and efficacy, and was done across five sub-Saharan African countries, enabling assessment of consistency of effects across different settings. The identification of the key questions was further supported by longstanding collaborations, including many African clinical researchers working in diverse health-care settings. Guideline development at WHO follows the Grading of Recommendations, Assessment, Development, and Evaluation process, with explicit consideration of four domains: certainty of the evidence, values and preferences, balance of benefits and harms, and resource implications. Other factors such as equity and human rights, acceptability, and feasibility are also considered. 8 Typically, trials focus only on safety and efficacy. To consider the full range of evidence-to-decision domains, guideline developers are often required to consider indirect evidence, rely on expert judgement, or await the findings of other relevant studies (such as qualitative Source of information Judgement Priority of the problem Published estimate of global disease burden 5 High priority: 152 000 cases of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths Balance of benefits and harms Phase 3 clinical endpoint trial (the AMBITION trial) 2 Benefits outweigh harms: non-inferior mortality; fewer adverse events Acceptability to key stakeholders Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; in-depth interviews with trial participants and providers; and direct observations Highly acceptable from the perspective of participants and providers Feasibility of implementation Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; direct observations; and in-depth interviews with trial investigators Feasible: simpler to administer, resulting in fewer side-effects and preferred to the previous standard of care Resource requirements Economic evaluation 9 embedded within the phase 3 clinical trial Cost-effective at a low incremental cost-effectiveness ratio; potentially cost saving in real-world implementation Effect on health equity Equity considerations provided during the guideline meeting Improves equity For a guideline panel to make a recommendation for or against a given intervention, each of these criteria listed in the first column needs to be considered. Gathering information early to inform these recommendations is crucial to accelerating guideline development. 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As few as one in five evidence-based health interventions are incorporated into routine use, and the average time lag between evidence availability and practice change is up to 17 years. 1 The results of the AMBITION trial, which provided evidence supporting a simpler, safer treatment for HIV-associated cryptococcal meningitis, were published in full on March 24, 2022. 2 A WHO rapid advice notice was released less than 1 month later, and guidelines were published in July, 2022. 3 The rapid development of WHO guidelines facilitated incorporation of the new regimen into national guidelines in the African countries where the trial was done, and more broadly in other countries in Africa, Asia, Europe, and Latin America, with patients receiving the new treatment as part of routine care within 3 months. In this Comment, we highlight some key lessons to accelerate knowledge translation. 40 years ago, Yusuf and colleagues stated that a good clinical trial should ask an important question and answer it reliably. 4 Cryptococcal meningitis is a leading cause of HIV-associated mortality. 5 Until recently, the standard of care required 7-14 days of daily intravenous infusions of amphotericin B, causing significant toxicities and limiting safe use in most resource-constrained hospitals, with acute mortality rates of 40{\\%} or more. 6 Guideline development relies on a comprehensive evidence assessment, appraised by a diverse, representative group of experts, providing an opportunity to identify crucial research gaps. The WHO cryptococcal disease guidelines from 2018 noted that simple treatments for cryptococcal meningitis suitable for low-resource settings were urgently needed. 7 The AMBITION trial evaluated a single high dose of liposomal amphotericin B for treating for HIV-associated cryptococcal meningitis. 2 The trial was sufficiently powered to evaluate safety and efficacy, and was done across five sub-Saharan African countries, enabling assessment of consistency of effects across different settings. The identification of the key questions was further supported by longstanding collaborations, including many African clinical researchers working in diverse health-care settings. Guideline development at WHO follows the Grading of Recommendations, Assessment, Development, and Evaluation process, with explicit consideration of four domains: certainty of the evidence, values and preferences, balance of benefits and harms, and resource implications. Other factors such as equity and human rights, acceptability, and feasibility are also considered. 8 Typically, trials focus only on safety and efficacy. To consider the full range of evidence-to-decision domains, guideline developers are often required to consider indirect evidence, rely on expert judgement, or await the findings of other relevant studies (such as qualitative Source of information Judgement Priority of the problem Published estimate of global disease burden 5 High priority: 152 000 cases of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths Balance of benefits and harms Phase 3 clinical endpoint trial (the AMBITION trial) 2 Benefits outweigh harms: non-inferior mortality; fewer adverse events Acceptability to key stakeholders Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; in-depth interviews with trial participants and providers; and direct observations Highly acceptable from the perspective of participants and providers Feasibility of implementation Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; direct observations; and in-depth interviews with trial investigators Feasible: simpler to administer, resulting in fewer side-effects and preferred to the previous standard of care Resource requirements Economic evaluation 9 embedded within the phase 3 clinical trial Cost-effective at a low incremental cost-effectiveness ratio; potentially cost saving in real-world implementation Effect on health equity Equity considerations provided during the guideline meeting Improves equity For a guideline panel to make a recommendation for or against a given intervention, each of these criteria listed in the first column needs to be considered. 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