{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:12:28Z","timestamp":1772169148298,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.19324.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000}}],"reference-count":21,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["203905"],"award-info":[{"award-number":["203905"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>Background Mortality associated with HIV-associated cryptococcal meningitis remains high even in the context of clinical trials (24\u201345% at 10 weeks); mortality at 12-months is up to 78% in resource limited settings. Co-prevalent tuberculosis (TB) is common and preventable, and likely contributes to poor patient outcomes. Innovative strategies to increase TB preventative therapy (TPT) provision and uptake within this high-risk group are needed. Protocol The IMPROVE trial (Integrated management of cryptococcal meningitis and concurrent opportunistic infections to improve outcomes in advanced HIV disease) is a nested open label, two arm, randomised controlled strategy trial to evaluate the safety (adverse events) and feasibility (adherence and tolerability) of two ultra-short course TPT strategies, in the context of recent diagnosis and treatment for cryptococcal meningitis. We will enrol 205 adults with HIV-associated cryptococcal meningitis from three hospitals in Uganda. Participants will be randomised to either inpatient initiation (early) or outpatient initiation (standard, week 6) of 1HP (one month of isoniazid and rifapentine). Participant follow-up is to include TB screening, 1HP pill counts and tolerability reviews on alternate weeks until week-18. The trial primary endpoint is TB-disease free 1HP treatment completion at 18-weeks, secondary endpoints: 1HP treatment completion, 1HP discontinuation, grade \u22653 adverse events and serious adverse events, drug-induced liver injury, incident active TB, 18-week survival; rifapentine, fluconazole and dolutegravir concentrations will be measured with intensive sampling in a pharmacokinetic sub-study of 15 eligible participants. Discussion The IMPROVE trial will provide preliminary safety and feasibility data to inform 1HP TPT strategies for adults with advanced HIV disease and cryptococcal meningitis. The potential impact of demonstrating that inpatient initiation of 1HP TPT is safe and feasible amongst this high-risk subpopulation with advanced HIV disease, would be to expand the range of clinical encounters in which clinicians can feasibly provide 1HP, and therefore increase the reach of TPT as a preventative intervention. ISRCTN registration ISRCTN18437550 (05\/11\/2021)<\/ns3:p>","DOI":"10.12688\/wellcomeopenres.19324.2","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T07:20:48Z","timestamp":1717572048000},"page":"14","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated management of cryptococcal meningitis and concurrent opportunistic infections to improve outcomes in advanced HIV disease: a randomised strategy trial"],"prefix":"10.12688","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-9144","authenticated-orcid":false,"given":"Jayne","family":"Ellis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Nsangi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0062-9434","authenticated-orcid":false,"given":"Ananta","family":"Bangdiwala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gila","family":"Hale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Gakuru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0291-651X","authenticated-orcid":false,"given":"Enock","family":"Kagimu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8820-288X","authenticated-orcid":false,"given":"Timothy","family":"Mugabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4503-4719","authenticated-orcid":false,"given":"Enos","family":"Kigozi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asmus","family":"Tukundane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8651-7478","authenticated-orcid":false,"given":"Michael","family":"Okirwoth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadeo Kiiza","family":"Kandole","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-532X","authenticated-orcid":false,"given":"Fiona","family":"Cresswel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas S.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3748-0154","authenticated-orcid":false,"given":"David","family":"Moore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Fielding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4138-240X","authenticated-orcid":false,"given":"David","family":"Meya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4715-0060","authenticated-orcid":false,"given":"David","family":"Boulware","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1459-5554","authenticated-orcid":false,"given":"Joseph N.","family":"Jarvis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"1748-1755","DOI":"10.1016\/S1473-3099(22)00499-6","article-title":"The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis.","volume":"22","author":"R Rajasingham","year":"2022","journal-title":"Lancet Infect Dis."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"1004-1017","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-3","doi-asserted-by":"publisher","first-page":"2487-2498","DOI":"10.1056\/NEJMoa1312884","article-title":"Timing of Antiretroviral Therapy after diagnosis of cryptococcal meningitis.","volume":"370","author":"D Boulware","year":"2014","journal-title":"N Engl J Med."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"542-554","DOI":"10.1056\/NEJMoa1509024","article-title":"Adjunctive dexamethasone in HIV-associated cryptococcal meningitis.","volume":"374","author":"J Beardsley","year":"2016","journal-title":"N Engl J Med."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"877-883","DOI":"10.1093\/infdis\/jiy602","article-title":"HIV-associated cryptococcal meningitis occurring at relatively higher CD4 counts.","volume":"219","author":"L Tugume","year":"2019","journal-title":"J Infect Dis."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"1122-1132","DOI":"10.1093\/cid\/cix870","article-title":"Long-term mortality and disability in cryptococcal meningitis: a systematic literature review.","volume":"66","author":"E Pasquier","year":"2018","journal-title":"Clin Infect Dis."},{"key":"ref-7","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofaa100","article-title":"Standardized urine-based Tuberculosis (TB) screening with TB-Lipoarabinomannan and Xpert MTB\/RIF ultra in Ugandan adults with advanced Human Immunodeficiency Virus disease and suspected meningitis.","volume":"7","author":"F Cresswell","year":"2020","journal-title":"Open Forum Infect Dis."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"722-724","DOI":"10.3201\/eid2004.131277","article-title":"Nosocomial drug-resistant bacteremia in 2 cohorts with cryptococcal meningitis, Africa.","volume":"20","author":"R Rajasingham","year":"2014","journal-title":"Emerg Infect Dis."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"525-531","DOI":"10.1093\/cid\/ciz864","article-title":"Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in sub-Saharan Africa.","volume":"71","author":"C Skipper","year":"2020","journal-title":"Clin Infect Dis."},{"key":"ref-10","article-title":"2020 WHO Global TB report.pdf"},{"key":"ref-11","article-title":"WHO consolidated guidelines on tuberculosis. module 1: prevention \u2013 tuberculosis preventive treatment","year":"2020"},{"key":"ref-12","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD000171.pub3","article-title":"Treatment of latent Tuberculosis infection in HIV infected persons.","volume":"2010","author":"C Akolo","year":"2010","journal-title":"Cochrane Database Syst Rev."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"1001-1011","DOI":"10.1056\/NEJMoa1806808","article-title":"One month of rifapentine plus isoniazid to prevent HIV-related Tuberculosis.","volume":"380","author":"S Swindells","year":"2019","journal-title":"N Engl J Med."},{"key":"ref-14","article-title":"Effectiveness of 3hp annually vs once for HIV-positive people: the whip3tb trial - CROI Conference"},{"key":"ref-15","article-title":"WHO End TB Strategy - World | ReliefWeb"},{"key":"ref-16","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s11908-020-00726-x","article-title":"Latent Tuberculosis and HIV Infection.","volume":"22","author":"S Bares","year":"2020","journal-title":"Curr Infect Dis Rep."},{"key":"ref-17","first-page":"804-808","article-title":"A study of TB-associated immune reconstitution inflammatory syndrome using the consensus case-definition.","volume":"131","author":"S Sharma","year":"2010","journal-title":"Indian J Med Res."},{"key":"ref-18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0040623","article-title":"Incidence, clinical spectrum, risk factors and impact of HIV-associated Immune Reconstitution Inflammatory Syndrome in South Africa.","volume":"7","author":"L Haddow","year":"2012","journal-title":"PLoS One."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"233-245","DOI":"10.1056\/NEJMoa1615822","article-title":"Enhanced prophylaxis plus Antiretroviral Therapy for advanced HIV infection in Africa.","volume":"377","author":"J Hakim","year":"2017","journal-title":"N Engl J Med."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"1269-1278","DOI":"10.1016\/S1473-3099(16)30216-X","article-title":"The cascade of care in diagnosis and treatment of latent Tuberculosis infection: a systematic review and meta-analysis.","volume":"16","author":"H Alsdurf","year":"2016","journal-title":"Lancet Infect Dis."},{"key":"ref-21","article-title":"Integrated management of cryptococcal meningitis and concurrent opportunistic infections to improve outcomes in advanced HIV disease: a randomised strategy trial","author":"J Ellis","year":"2023"}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T09:15:15Z","timestamp":1717665315000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,5]]},"references-count":21,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.19324.2","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.24870.r85833","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.24870.r85833","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.24870.r85832","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,5]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.21407.r73746, Ajay Rangaraj, Department of HIV, Hepatitis and STIs, World Health Organisation, Geneva, 26 Apr 2024, version 1, 3 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v1#referee-response-73746","order":0,"name":"referee-response-73746","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Jayne Ellis<\/b>; \n<i>Posted: 09 May 2024<\/i>; \n<b>Dear Ajay Rangaraj<\/b> \n<b>Thank you for taking the time to review the IMPROVE protocol - your feedback is very much appreciated. Please find below responses to each of your comments raised: <\/b>  \n<b>Please do include the rationale for why 18 weeks was chosen as an appropriate end-time period for the study.&nbsp;<\/b>  This end-time was chosen because the risk of mortality, opportunistic infections and immune reconstitution inflammatory syndrome (IRIS) events (including TB-IRIS) are considerably lower beyond 18-weeks following immune reconstitution with predominately DTG-based ART initiation\/switch at 4-6 weeks post cryptococcal meningitis diagnosis. &nbsp;  \n<b>It would be a great inclusion if the study can report on post-discharge outcomes - not just for TB, but also for CM. And to &nbsp;report the outcomes more systematically such as post discharge status (functional status), whether re-linked to care for ART, LTFU etc., &nbsp;as it is a highly relevant issue in AHD.&nbsp;<\/b>  In parallel to the IMPROVE trial, where consent is given, study participants are also followed up longitudinally as part of our open cohort study (Improving Diagnostics and Neurocognitive Outcomes in HIV\/AIDS-related Meningitis) which collects post-discharge outcomes including neuro-cognitive assessments at annual follow-up visits. &nbsp;  \n<b>It would be good to mention what regimen is being used in the antifungal treatment - as they are not all equal - particularly if conventional amphotericin-B is being used and\/or then single high dose liposomal amphotericin. This would also mean the study should track kidney parameters.&nbsp;<\/b>  All IMPROVE participants receive amphotericin-based induction anti-fungal therapy. The induction regimen received however, does depend upon drug availability (liposomal amphotericin vs. amphotericin deoxycholate) and whether the participant received induction anti-fungal therapy as part of a randomized controlled trial. Given this is a randomized trial however, we do anticipate any differences in induction regimens to be well balanced between IMPROVE trial arms. Study participants have both in-hospital, and post-discharge protocolized safety monitoring blood tests including kidney parameters, liver function, and complete blood counts. &nbsp;  \n<b>Under &quot;Consent&quot;- please do consider rephrasing the word illiterate&quot; - could perhaps be reworded to &quot;those that are unable to read or write&quot;.&nbsp;<\/b>  Thank you, this has been amended in the updated version of the protoc. &nbsp;  \n<b>The study's primary endpoint is &quot;Treatment completion is defined as participant reported adherence to &gt;90% of the study medications, to be completed within 6-weeks from treatment initiation.&quot; - I think I understand this as all the study medications - could you please clarify this?&nbsp;<\/b>  Yes this means that a participant must complete &gt;90% of both isoniazid and rifapentine within 6-weeks from initiation of the 1HP regimen i.e. they cannot miss more than 3 days of treatment. \n<b>Also if the individual is not conscious during the inpatient stay - how would adherence be calculated? Or would it be the case that it would be 100%?<\/b> Participants are randomised into the IMPROVE RCT at time of discharge (other than in instances, where the participant remains an inpatient for \u226514 days, randomisation will occur on day 14 rather than on the planned day of discharge), therefore participants rarely have reduced level of consciousness during the IMPROVE trial. In cases where a participant does have a reduced level of consciousness such that they are unable to self-medicate, a naso-gastric tube is inserted to ensure adherence with both IMPROVE study drugs, and with anti-fungal medications, and nutritional support. &nbsp;  \n<b>Is there any intention to look at resistance development in the study - would be important to mention if or if not.&nbsp;<\/b>  In cases of culture-proven incident TB disease (e.g. blood culture positive TB-cases) drug susceptibility testing is performed. This has been added to the manuscript.  \n<b>Could there have been additional arms in this trial to evaluate 3HP? Was there a rationale to not include it?&nbsp;<\/b>  Within IMPROVE, we are specifically interested in investigating whether TB preventive therapy (TPT) can be initiated as an inpatient for patients with advanced HIV disease and cryptococcal meningitis, such that TPT completion (and sterilisation of latent TB infection) can be achieved prior to ART initiation\/switch at ~6-weeks post cryptococcal meningitis diagnosis. We hypothesize that TPT completion prior to ART initiation\/switch will reduce the risk of unmasking TB-IRIS events in this population. Whilst 3HP would have been an interesting comparator arm (for example reduced pill-burden, +\/- reduced risk of drug-drug interactions as compared to 1HP in this group), it would not allow for TPT completion prior to ART initiation\/switch. Furthermore the limited budget and therein sample size, necessitated a two-arm trial only. &nbsp; Many thanks again for the review Very best Dr Jayne Ellis","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v2#referee-comment-5699","order":1,"name":"referee-comment-5699","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.24870.r85833, Vincent Ganu, Korle-Bu Teaching Hospital, Accra, 06 Jun 2024, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v2#referee-response-85833","order":2,"name":"referee-response-85833","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.21407.r78401, Sonal Munsiff, University of Rochester Medical Center: Strong Memorial Hospital, Rochester, NY, 02 May 2024, version 1, 3 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-14\/v1#referee-response-78401","order":3,"name":"referee-response-78401","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by Wellcome [203905, <a href=https:\/\/doi.org\/10.35802\/203905>https:\/\/doi.org\/10.35802\/203905<\/a>], sponsored by London School of Hygiene and Tropical Medicine, and hosted by the Infectious Diseases Institute, Uganda. The funders have had no role in the trial design, and will not be involved in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. 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"}]}}