Amphotericin B has long been crucial for treating many serious infectious diseases, such as invasive fungal infections and visceral leishmaniasis, particularly for patients who are immunocompromised, including those with advanced HIV infection. The conventional amphotericin B deoxycholate formulation has largely been replaced in high-income countries with liposomal amphotericin B (LAmB), which has many advantages, including lower rates of adverse events, such as nephrotoxicity and anaemia. Despite an evident need for LAmB in low-income and middle-income countries, where mortality from invasive fungal infections is still substantial, many low-income and middle-income countries still often use the amphotericin B deoxycholate formulation because of a small number of generic formulations and the high price of the originator LAmB. The pricing of LAmB is also highly variable between countries. Overcoming supply barriers through the availability of additional quality-assured, generic formulations of LAmB at accessible prices would substantially facilitate equitable access and have a substantial effect on mortality attributable to deadly fungal infections.
A rapidly changing landscape of antiretrovirals and their procurement at scale has permitted the evaluation of new optimised second-line antiretroviral therapy (ART) in low- and middle-income countries. D2EFT is an open-label randomised controlled non-inferiority phase IIIB/IV trial in people living with HIV-1 (PWH) whose first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART is failing. At inception, it compared a standard of care of boosted darunavir with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) to the novel NRTI-sparing regimen of boosted darunavir with dolutegravir. Implemented in 2017, participating sites were across Africa, Asia and Latin America. Around the time of implementation, the World Health Organization updated its treatment guidelines and recommended scaling up tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD). This situation pushed D2EFT investigators to consider the impact of the roll-out of TLD on the D2EFT research question. The protocol team agreed it was important to study TLD in second-line when an NNRTI regimen was failing, and focused on options to expedite the work by studying the question within the existing trial and network. All key issues (statistical, programmatic and financial) were reviewed to assess the benefits and risks of adding a third arm to the ongoing study, as opposed to developing a new randomised clinical trial with the same control arm and within the same network. The development of a new trial was deemed to be longer than adding a third arm, and to create a challenging situation with two competing clinical trials at the same sites which would slow down recruitment and impair both trials. On the other hand, adding a third arm would be demanding in terms of operationalisation, increased sample size and statistical biases to control. The optimal strategy was deemed to be the addition of a third arm, arriving retrospectively at a simplified multi-arm multi-stage clinical trial design to achieve statistical validity. The D2EFT study maintains additional value in a quickly evolving second-line ART strategy allowed by the progress in global access to ART.
Background HIV, other sexually transmitted infections (STIs) and unintended pregnancies are critical and interlinked health risks for millions of women of reproductive age worldwide. Multipurpose prevention technologies (MPTs) offer an innovative approach for expanding combined pregnancy and/or disease prevention. So far, MPT development efforts have focused mostly on HIV prevention, but about half of product candidates comprise compounds active against non-HIV STIs as well. This review aims to provide a framework that promotes the efficient advancement of the most promising preclinical products through the development pathway and into the hands of end-users, with a focus on women in low- and middle-income countries (L/MICs). Methods This mini review provides a summary of the current landscape of the MPT field. It comprises a landscape assessment of MPTs in development, complemented by a series of 28 in-depth, semi-structured key informant interviews (KIIs) with experts representing different L/MIC perspectives. Main results We identified six primary action strategies to advance MPTs for L/MICs, including identification of key research gaps and priorities. For each action strategy, progress to date and key recommendations are included. Conclusions To realize the life-saving potential of MPTs and maximize the momentum made to date, a strategic, collaborative and well-funded response to the gaps and next steps outlined in this paper is critical. A coordinated response can add rigor and efficiency to the development process, to successfully advance the most promising MPT products to the hands of end-users.
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.1Morris ZS Wooding S Grant J The answer is 17 years, what is the question: understanding time lags in translational research.J R Soc Med. 2011; 104: 510-520Crossref PubMed Scopus (1670) Google Scholar 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, 2022.2Jarvis JN Lawrence DS Meya DB et al.Single-dose liposomal amphotericin b treatment for cryptococcal meningitis.N Engl J Med. 2022; 386: 1109-1120Crossref PubMed Scopus (75) Google Scholar A WHO rapid advice notice was released less than 1 month later, and guidelines were published in July, 2022.3WHOGuidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV.https://www.who.int/publications/i/item/9789240052178Date: June 27, 2022Date accessed: September 22, 2023Google Scholar 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.4Yusuf S Collins R Peto R Why do we need some large, simple randomized trials?.Stat Med. 1984; 3: 409-422Crossref PubMed Scopus (599) Google Scholar Cryptococcal meningitis is a leading cause of HIV-associated mortality.5Rajasingham R Govender NP Jordan A et al.The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis.Lancet Infect Dis. 2022; 22: 1748-1755Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar 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.6Tenforde MW Shapiro AE Rouse B et al.Treatment for HIV-associated cryptococcal meningitis.Cochrane Database Syst Rev. 2018; 7CD005647PubMed Google Scholar 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.7WHOGuidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children: supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.https://www.who.int/publications/i/item/9789241550277Date: March 1, 2018Date accessed: September 22, 2023Google Scholar The AMBITION trial evaluated a single high dose of liposomal amphotericin B for treating for HIV-associated cryptococcal meningitis.2Jarvis JN Lawrence DS Meya DB et al.Single-dose liposomal amphotericin b treatment for cryptococcal meningitis.N Engl J Med. 2022; 386: 1109-1120Crossref PubMed Scopus (75) Google Scholar 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.8WHOWHO handbook for guideline development, 2nd edition.https://www.who.int/groups/guidelines-review-committeeDate: Dec 18, 2014Date accessed: September 22, 2023Google Scholar 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 surveys to assess acceptability), potentially adding months or years to guideline development. The AMBITION trial took these broader considerations into account from the outset through nested cost-effectiveness,9Lawrence DS Muthoga C Meya DB et al.Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.Lancet Glob Health. 2022; 10: e1845-e1854Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar acceptability, and feasibility10Lawrence DS Ssali A Moshashane N et al.The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: findings from a qualitative methods study of participants and researchers in Botswana and Uganda.PLoS Negl Trop Dis. 2022; 16e0010825Crossref PubMed Scopus (3) Google Scholar studies (table). Funding to perform these analyses within the main trial was crucial to ensuring that guideline developers were provided with all the information required to formulate a recommendation.TableEvidence-to-decision table for the treatment of cryptococcal meningitisSource of informationJudgementPriority of the problemPublished estimate of global disease burden5Rajasingham R Govender NP Jordan A et al.The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis.Lancet Infect Dis. 2022; 22: 1748-1755Summary Full Text Full Text PDF PubMed Scopus (89) Google ScholarHigh priority: 152 000 cases of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deathsBalance of benefits and harmsPhase 3 clinical endpoint trial (the AMBITION trial)2Jarvis JN Lawrence DS Meya DB et al.Single-dose liposomal amphotericin b treatment for cryptococcal meningitis.N Engl J Med. 2022; 386: 1109-1120Crossref PubMed Scopus (75) Google ScholarBenefits outweigh harms: non-inferior mortality; fewer adverse eventsAcceptability to key stakeholdersEthnographic study (the LEOPARD study)10Lawrence DS Ssali A Moshashane N et al.The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: findings from a qualitative methods study of participants and researchers in Botswana and Uganda.PLoS Negl Trop Dis. 2022; 16e0010825Crossref PubMed Scopus (3) Google Scholar embedded within the phase 3 clinical trial; in-depth interviews with trial participants and providers; and direct observationsHighly acceptable from the perspective of participants and providersFeasibility of implementationEthnographic study (the LEOPARD study)10Lawrence DS Ssali A Moshashane N et al.The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: findings from a qualitative methods study of participants and researchers in Botswana and Uganda.PLoS Negl Trop Dis. 2022; 16e0010825Crossref PubMed Scopus (3) Google Scholar embedded within the phase 3 clinical trial; direct observations; and in-depth interviews with trial investigatorsFeasible: simpler to administer, resulting in fewer side-effects and preferred to the previous standard of careResource requirementsEconomic evaluation9Lawrence DS Muthoga C Meya DB et al.Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.Lancet Glob Health. 2022; 10: e1845-e1854Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar embedded within the phase 3 clinical trialCost-effective at a low incremental cost-effectiveness ratio; potentially cost saving in real-world implementationEffect on health equityEquity considerations provided during the guideline meetingImproves equityFor 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. Open table in a new tab 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. Throughout the trial, investigators engaged stakeholders and policy makers, including ministries of health, global organisations, and the pharmaceutical industry. WHO technical staff kept in close contact with trial investigators to anticipate when trial results would be available, so that a guideline panel could be convened, with investigators sharing efficacy, costing, feasibility, and acceptability data before publication. Engaging communities affected by HIV-associated cryptococcal meningitis enriched trial development and conduct, and was essential in showing acceptability and feasibility10Lawrence DS Ssali A Moshashane N et al.The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: findings from a qualitative methods study of participants and researchers in Botswana and Uganda.PLoS Negl Trop Dis. 2022; 16e0010825Crossref PubMed Scopus (3) Google Scholar and helping to ensure that results were widely disseminated. Senior trial investigators contributed to national guideline-writing committees in countries where the trial was done, engagement with the Drugs for Neglected Diseases Initiative and generic drug manufactures has led to increased availability and reduced costs of the essential companion drug flucytosine, and work with Médecins Sans Frontières and other implementing partners facilitated access to and uptake of the novel treatment. Gilead supported the preliminary phase 2 studies, donated liposomal amphotericin B for the trial, and stated their commitment to preferential pricing following trial completion, although this remains to be fully honoured. Catalytic funding from Unitaid to the Clinton Health Access Initiative established initial access to the key commodities needed for roll-out of the new treatment in African markets, a crucial factor in rapid uptake and implementation of WHO guidelines. Extensive advocacy activities were done throughout the trial, highlighting the ongoing burden of disease and the need for new treatments,5Rajasingham R Govender NP Jordan A et al.The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis.Lancet Infect Dis. 2022; 22: 1748-1755Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar leading to an increase in global flucytosine production by generic manufacturers, substantial cost reduction, and widespread uptake in several African countries; however, considerable challenges remain. Access to both liposomal amphotericin B and flucytosine is far from universal, and the cost of liposomal amphotericin B is excessively high in several countries where exclusive distribution contracts prevent access to Gilead's preferential pricing.11Burry J Perez Casas C Ford N Access to medicines for treating people with cryptococcal meningitis.Clin Infect Dis. 2023; 76: e773-e775Crossref PubMed Scopus (3) Google Scholar The AMBITION trial shows that a single large and well done trial can rapidly and credibly translate research evidence to international clinical practice. Research teams who reliably answer important questions, simultaneously generate all evidence for decision making, and work with diverse stakeholders to advocate for change are more likely to rapidly change policy and practice and improve human health. We would like to thank all investigators and participants in the AMBITION trial and associated substudies, community members, and the funders of the trial. The AMBITION trial was supported by a grant through the European Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (TRIA2015-1092), and the Wellcome Trust/Medical Research Council (MRC) UK/UKAID Joint Global Health Trials (MR/P006922/1). Additional funding was provided by the National Institute for Health Research (NIHR) through a Global Health Research Professorship (RP-2017-08-ST2-012, to JNJ) with aid from the UK Government to support global health research. JNJ is funded by the National Institute for Health and Care Research (NIHR) through a Global Health Research Professorship (RP-2017-08-ST2-012) using UK aid from the UK Government to support global health research and received grant payments from the NIHR and EDCTP to his institution. RC received consulting fees to serve as methodologist for the updated WHO guideline on cryptococcal meningitis. TSH and DSL received support for the underlying AMBITION trial to institution from EDCTP, MRC, and Wellcome Trust, UK aid from the UK Government to support global health research, and provision of drug for the underlying AMBITION trial from Gilead. All other authors declare no competing interests. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The writing of this Comment was supported by a grant from the Bill & Melinda Gates Foundation. We are grateful to Susan L Norris and Rebekah Thomas for providing comments on an earlier draft.
To discuss how aligning the collective power of scientists, regulators, drug companies, donors, implementers and advocates to achieve a single goal - accelerating access to simpler, safer, more robust and more affordable HIV treatment - can rapidly advance antiretroviral optimization efforts and enable scale-up.Harmonization of traditionally sequential processes can address the delays commonly experienced in introducing new products to low-income and middle-income countries, by facilitating an 'end-to-end' approach that mitigates risk and encourages early planning for all aspects of product introduction.Planning with the 'end-in-mind' can facilitate healthy markets, benefit the application of new technologies, and accelerate the development of improved products in parallel (versus traditionally sequential efforts).
In high-risk individuals in Johannesburg, during the Delta coronavirus disease 2019 wave, 22% (125/561) were positive, with 33% symptomatic (2 hospitalizations; 1 death). During Omicron, 56% (232/411) were infected, with 24% symptomatic (no hospitalizations or deaths). The remarkable speed of infection of Omicron over Delta poses challenges to conventional severe acute respiratory syndrome coronavirus 2 control measures.
Introduction The ADVANCE and NAMSAL trials evaluating antiretroviral drugs have both reported substantial levels of clinical obesity in participants. As one of the main risk factors for metabolic syndrome, growing rates of obesity may drive metabolic syndrome development. This study aims to evaluate the risk of metabolic syndrome in the ADVANCE and NAMSAL trials. Methods The number of participants with metabolic syndrome was calculated at baseline and week 192 as central obesity and any of the following two factors: raised triglycerides, reduced HDL-cholesterol, raised blood pressure and raised fasting glucose. Differences between the treatment arms were calculated using the χ 2 test. Results Across all visits to week 192, treatment-emergent metabolic syndrome was 15% (TAF/FTC + DTG), 10% (TDF/FTC + DTG) and 7% (TDF/FTC/EFV) in ADVANCE. The results were significantly higher in the TAF/FTC + DTG arm compared to the TDF/FTC/EFV arm ( p < 0.001), and the TDF/FTC + DTG vs. the TDF/FTC/EFV arms ( p < 0.05) in all patients, and in females. In NAMSAL, the incidence of treatment-emergent metabolic syndrome at any time point was 14% (TDF/3TC + DTG) and 5% (TDF/3TC + EFV) ( p < 0.001). This incidence was significantly greater in the TDF/3TC/DTG arm compared to the TDF/3TC/EFV arm in all patients ( p < 0.001), and in males ( p < 0.001) Conclusion In this analysis, we highlight treatment-emergent metabolic syndrome associated with dolutegravir, likely driven by obesity. Clinicians initiating or monitoring patients on INSTI-based ART must counsel for lifestyle optimisation to prevent these effects.
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