{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:10:51Z","timestamp":1772169051188,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.16776.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000}},{"DOI":"10.12688\/wellcomeopenres.16776.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000}}],"reference-count":27,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["RO1AI118511"],"award-info":[{"award-number":["RO1AI118511"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K23AI38851"],"award-info":[{"award-number":["K23AI38851"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"CDC Foundation","doi-asserted-by":"publisher","award":["Project950"],"award-info":[{"award-number":["Project950"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"crossref","award":["RP-2017-08-ST2-012"],"award-info":[{"award-number":["RP-2017-08-ST2-012"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["212638"],"award-info":[{"award-number":["212638"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"\n Introduction:<\/ns4:bold>\n Access to and the cost of induction treatment for cryptococcal meningitis (CM) is rapidly changing. The newly-announced price for flucytosine ($0.75 per 500 mg pill) and possibly lower prices for liposomal amphotericin B (AmB-L) create opportunities to reduce CM treatment costs compared to the current standard treatment in low- and middle-income countries.\n <\/ns4:p>\n \n Methods:<\/ns4:bold>\n We developed an Excel-based cost model to estimate health system treatment costs for CM over a two-week induction phase for multiple treatment combinations, newly feasible with improved access to flucytosine and AmB-L. CM treatment costs include medications, laboratory tests and other hospital-based costs (bed-day costs and healthcare worker time). We report results from applying the model using country-specific information for South Africa, Uganda, Nigeria, and Botswana.\n <\/ns4:p>\n \n Results:<\/ns4:bold>\n A 14-day induction-phase of seven days of inpatient AmB-D with flucytosine, followed by seven days of high-dose fluconazole as an outpatient, will cost health systems less than a 14-day hospital stay with AmB-D and fluconazole. If daily AmB-L replaces AmB-D for those with baseline renal dysfunction, with a cost of $50 or less per 50 mg vial, incremental costs would still be less than the AmB-D with fluconazole regimen. Simple oral combinations (e.g., seven days of flucytosine with fluconazole as an inpatient) are practical when AmB-D is not available, and treatment costs would remain less than the current standard treatment.\n <\/ns4:p>\n \n Conclusions<\/ns4:bold>\n : Improved access to and lower prices for flucytosine and AmB-L create opportunities for improving CM treatment regimens. An induction regimen of flucytosine and AmB-D for seven days is less costly than standard care in the settings studied here. As this regimen has also been shown to be more effective than current standard care, countries should prioritize scaling up flucytosine access. The cost of AmB-L based regimens is highly dependent on the price of AmB-L, which currently remains unclear.\n <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.16776.3","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T05:11:32Z","timestamp":1655701892000},"page":"140","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Induction-phase treatment costs for cryptococcal meningitis in high HIV-burden African countries: New opportunities with lower costs"],"prefix":"10.12688","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9322-2387","authenticated-orcid":false,"given":"Bruce","family":"Larson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir","family":"Shroufi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Muthoga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Oladele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radha","family":"Rajasingham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7834-866X","authenticated-orcid":false,"given":"Alexander","family":"Jordan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph N.","family":"Jarvis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom M.","family":"Chiller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7869-9462","authenticated-orcid":false,"given":"Nelesh P.","family":"Govender","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"ref-1","article-title":"Guidelines 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.","year":"2018"},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"873-81","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis.","volume":"17","author":"R Rajasingham","year":"2017","journal-title":"Lancet Infect Dis."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"3129","DOI":"10.1038\/s41598-017-03384-7","article-title":"Effects of high CD4 cell counts on death and attrition among HIV patients receiving antiretroviral treatment: An observational cohort study.","volume":"7","author":"Z Tang","year":"2017","journal-title":"Sci Rep."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"21673","DOI":"10.7448\/IAS.20.5.21673","article-title":"High rates of viral suppression in adults and children with high CD4+ counts using a streamlined ART delivery model in the SEARCH trial in rural Uganda and Kenya.","volume":"20","author":"D Kwarisiima","year":"2017","journal-title":"J Int AIDS Soc."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"e1002463","DOI":"10.1371\/journal.pmed.1002463","article-title":"Treatment eligibility and retention in clinical HIV care: A regression discontinuity study in South Africa.","volume":"14","author":"J Bor","year":"2017","journal-title":"PLoS Med."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"3599-606","DOI":"10.1093\/jac\/dkw325","article-title":"Global access to antifungal therapy and its variable cost.","volume":"71","author":"M Kneale","year":"2016","journal-title":"J Antimicrob Chemother."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"e143-7","DOI":"10.1016\/S1473-3099(18)30493-6","article-title":"Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries.","volume":"19","author":"A Loyse","year":"2019","journal-title":"Lancet Infect Dis."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"2435-44","DOI":"10.1093\/jac\/dkt221","article-title":"Flucytosine and cryptococcosis: Time to urgently address the worldwide accessibility of a 50-year-old antifungal.","volume":"68","author":"A Loyse","year":"2013","journal-title":"J Antimicrob Chemother."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"629-37","DOI":"10.1016\/S1473-3099(13)70078-1","article-title":"Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries.","volume":"13","author":"A Loyse","year":"2013","journal-title":"Lancet Infect Dis."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"1004-17","DOI":"10.1056\/NEJMoa1710922","article-title":"Antifungal combinations for treatment of cryptococcal meningitis in Africa.","volume":"378","author":"S Molloy","year":"2018","journal-title":"N Engl J Med."},{"key":"ref-11","article-title":"Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy.","year":"2017"},{"key":"ref-12","article-title":"Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children.","year":"2011"},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"76-81","DOI":"10.1016\/j.jinf.2011.10.014","article-title":"Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis.","volume":"64","author":"C Muzoora","year":"2012","journal-title":"J Infect."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"1564-8","DOI":"10.1093\/cid\/ciw151","article-title":"Cryptococcal Meningitis Treatment Strategies Affected by the Explosive Cost of Flucytosine in the United States: A Cost-effectiveness Analysis.","volume":"62","author":"M Merry","year":"2016","journal-title":"Clin Infect Dis."},{"key":"ref-15","doi-asserted-by":"publisher","first-page":"459-61","DOI":"10.1016\/j.ijid.2020.02.057","article-title":"Time to embrace access programmes for medicines: lessons from the South African flucytosine access programme.","volume":"95","author":"A Shroufi","year":"2020","journal-title":"Int J Infect Dis."},{"key":"ref-16","article-title":"Gilead Sciences Announces Steep Discounts for Ambisome to Treat Cryptococcal Meningitis in Low- and Middle-Income Countries","year":"2020"},{"key":"ref-17","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1186\/s13063-018-3026-4","article-title":"AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.","volume":"19","author":"D Lawrence","year":"2018","journal-title":"Trials."},{"key":"ref-18","article-title":"Costing guidelines for tuberculosis interventions","author":"L Cunnama","year":"2019"},{"key":"ref-19","first-page":"243","article-title":"Methods for the Economic Evaluation of Health Care Programmes.","volume":"14","author":"M Drummond","year":"Second Edition. Oxford University Press; 1998","journal-title":"American Journal of Preventive Medicine."},{"key":"ref-20","article-title":"An Excel-based template for estimating induction-phase treatment costs for cryptococcal meningitis in high HIV-burden African countries","author":"B Larson","year":"2021"},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"e02575-19","DOI":"10.1128\/mBio.02575-19","article-title":"Fluconazole monotherapy is a suboptimal option for initial treatment of cryptococcal meningitis because of emergence of resistance.","volume":"10","author":"W Hope","year":"2019","journal-title":"mBio."},{"key":"ref-22","first-page":"1","article-title":"Milan 5FC Product Sheet","year":"2020"},{"key":"ref-23","first-page":"1-5","article-title":"The Unitaid \/ CHAI Advanced HIV Disease Newsletter.","year":"2020"},{"key":"ref-24","article-title":"Gilead reduces price of AmBisome (liposomal amphotericin B) for cryptococcal meningitis in HIV\/AIDS","year":"2020"},{"key":"ref-25","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.4102\/sajhivmed.v20i1.1030","article-title":"Southern African HIV Clinicians Society guideline for the prevention, diagnosis and management of cryptococcal disease among HIV-infected persons: 2019 update.","volume":"20","author":"N Govender","year":"2019","journal-title":"South Afr J HIV Med."},{"key":"ref-26","article-title":"Liposomal amphotericin B as a 2nd-line agent for induction treatment of cryptococcal meningitis in South African hospitals.","author":"N Govender","year":"2016"},{"key":"ref-27","article-title":"Estimates of National Expenditure 2019.","year":"2019"}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v3\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v3\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v3\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T05:11:37Z","timestamp":1655701897000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,20]]},"references-count":27,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.16776.3","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.19938.r51146","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,20]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v3#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.19667.r49536, Angela Kairu, Health Economics Research Unit, KEMRI-Wellcome Trust Research Programme Nairobi, Nairobi, Kenya, 13 Apr 2022, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v2#referee-response-49536","order":0,"name":"referee-response-49536","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.18501.r47861, Katharine Elizabeth Stott, Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK, 24 Jan 2022, version 1, 2 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v1#referee-response-47861","order":1,"name":"referee-response-47861","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Bruce Larson<\/b>; \nPosted: 10 Mar 2022<\/i>; \nAuthors\u2019 responses and revisions based on Reviewer Reports (on Version1)<\/b> In the following, we provide a point-by-point response to each comment and suggestion provided by Reviewer 2.  We have numbered each comment to ensure a complete response and to note information across comments and reviewers. \nReviewer 2<\/b> 24 Jan 2022 | for Version 1 Katharine Elizabeth Stott, Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK Approved With Reservations This paper addresses an important question for the long overdue implementation of flucytosine and amphotericin-B based induction treatment regimens for HIV-associated cryptococcal meningitis in LMICs \u2013 namely, the costs associated with those regimens. By comparing historically-recommended induction regimens to those currently recommended, the authors conclude that flucytosine and amphotericin-B-based regimens are affordable. This has positive implications for ongoing advocacy efforts to increase access to these essential medications. My comments mainly concern the clarity with which the analysis is presented and the rationale behind some of the analytical decisions. In addition, a number of assumptions are [necessarily] made and these should be highlighted more clearly. Clarity 1. The first two paragraphs of the methods section would be more appropriately included in the introduction section, since they provide background information. \nAuthors: Thank you for the recommendation.  We have revised and moved the paragraphs as recommended. Based on comments from the other Reviewer (Reviewer 1, comment 2), we deleted the original last paragraph of the introduction given that such information is also included in the conclusions section. <\/b> 2. The authors state that they estimated costs for fluconazole monotherapy (second paragraph, \u2018Model overview\u2019). However, these estimates are not presented or stated in the paper, nor could I see them in the Excel downloads. I would recommend either including the data if they are available, or not stating that costs were estimated for fluconazole monotherapy, if these estimates are not available (in which case the authors might state why they decided against modelling those estimates - presumably because this regimen is not recommended). \nAuthors.  Thank you for catching this omission. We originally included fluconazole monotherapy in our analysis, but then excluded given its poor effectiveness.  We have revised the Model Overview section to explain this point.  <\/b> Assumptions 3. A major assumption made is that patients who are administered AmB-D plus 5FC for 7 days, followed by fluconazole for 7 days, are able to complete days 8 to 14 of their induction therapy as outpatients. Can the authors discuss what proportion of patients are able to be discharged from hospital after 7 days? Many patients may require ongoing inpatient care? \nAuthors: This is a very relevant point for real-world patient care.  Patients may need to remain in hospital even after their intravenous treatment is completed for continued management of raised intracranial pressure, for example. As noted in the introduction, the main focus of this Research Note is on treatment costs based on WHO guidelines. The 4 country-specific case studies (in the Excel files), however, can be used to address other questions and sensitivity analyses.  For example, as noted above for Reviewer 1, comment 3, future data from a clinical trial or monitoring patient care in routine settings might suggest that actual in-patient care typically extends to 10 inpatient days on average for the flucytosine plus fluconazole regimen. Such adjustments can be easily estimated using the models provided (e.g., cost of this regimen in South Africa for 7 in patient days is $1,101 and $1,484 for 10 days.  We have added this point into the main text of the paper (Section AmB-D plus flucytosine (seven hospital days)).  <\/b> 4. As discussed by the authors, there is uncertainty surrounding the cost of AmB-L. In the absence of accurate cost information and because potential costs of AmB-L vary so widely, have the authors considered a highest and lowest potential cost calculation for the treatment strategies that contain AmB-L? i.e. offer a range of potential costs? \nAuthors: We have added a last paragraph into the AmB-L section to include the recommendation of the reviewer.  \u201cWhile a substantially lower price ($16.25 per vial) has been reported by advocacy organizations (e.g., <\/b>\nhttps:\/\/www.gaffi.org\/gilead-reduces-price-of-ambisome-liposomal-amphotericin-b-for-cryptococcal-meningitis-in-hiv-aids\/<\/b>\n), this price has not yet been confirmed by Gilead. Obviously, costs would fall substantially for this regimen with the lower price. For example, costs per day for AmB-L would fall from $150 to $60 per patient with this cost (a low-end estimate), but overall costs would remain substantially higher than with AmB-D.\u201d <\/b> 5. I\u2019m not sure I understand the third paragraph under \u2018Target AmB-L to patients with baseline renal dysfunction\u2019 in the results section (\u2018Note that the\u2026\u2019). I don't see that the statements made are reflected in figure 1? It appears to me that in all country case studies, the AmB-L\/5FC option incurs the highest cost, with the option of AmB-L targeted to those with renal dysfunction incurring a lower cost than the reference regimen in all cases? \nAuthors: Thank you very much for highlighting the confusing paragraph.  We have revised the section to clarify the comparisons being made.  The AmB-L to patients with baseline renal dysfunction approach is the fourth option provided in Figure 1, which is mainly compared to the second option in Figure 1 AmB-D plus flucytosine for all patients. We then note that when compared to the 14-day regimen of AmB-D plus fluconazole (first regimen in Figure 1), costs for this fourth regimen are lower per 1,000 patients.    <\/b>   Additional comments 6. Second sentence in Introduction section: deaths are also due to ART failure; data show that improved access to ART does not necessarily correlate with reduction in deaths from HIV-associated CM. \nAuthors: We agree with the reviewer\u2019s comment.  We have revised this sentence to include diagnose, initiate, retain, and achieve viral suppression\u2026. We think the addition of \u201cretain and achieve viral suppression\u201d includes a broader set of reasons for ART failure.  <\/b> 7. Under Model structure and assumptions subheading: should \u2018\u2026incident RD for a standard two regimen\u2026\u2019 read, \u2018\u2026incident RD for a standard two week regimen\u2026\u2019? \nAuthors: Yes.  Thank you.  We have revised.<\/b>","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v3#referee-comment-4932","order":2,"name":"referee-comment-4932","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.19667.r50590, Clinton J Pecenka, Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA, 09 Jun 2022, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-140\/v2#referee-response-50590","order":3,"name":"referee-response-50590","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by the Wellcome Trust [212638]; the CDC Foundation [Project 950]; the National Institute of Allergy and Infectious Diseases [RO1AI118511; K23 AI38851]; and the National Institute for Health Research [RP-2017-08-ST2-012]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}