{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T23:29:35Z","timestamp":1783639775956,"version":"3.55.0"},"reference-count":17,"publisher":"The Royal Society","issue":"1938","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/national","name":"NIH","doi-asserted-by":"publisher","award":["K23NS137968"],"award-info":[{"award-number":["K23NS137968"]}],"id":[{"id":"10.13039\/national","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Phil. Trans. R. Soc. B"],"published-print":{"date-parts":[[2025,11,6]]},"abstract":"<jats:p>\n                    Mortality among adults hospitalized with advanced HIV disease (AHD; CD4 &lt;200 cells \u03bcl\n                    <jats:sup>\u22121<\/jats:sup>\n                    or a WHO stage 3 or 4 disease) is &gt;20%; there is an urgent need to evaluate strategies to reduce mortality within this extremely high-risk group. Approximately 50% of adults with CD4 counts &lt;100 cells \u03bcl\n                    <jats:sup>\u22121<\/jats:sup>\n                    have detectable cytomegalovirus (CMV) viraemia, and high-level CMV viraemia is associated with greater than double the hazard of death in this population. Despite this, there are no current treatment guidelines to inform treatment of CMV viraemia without end-organ disease in the context of AHD. The NIRVANA study is a double-blinded, placebo-controlled, multi-centre phase 2b trial to evaluate efficacy and safety of valganciclovir for patients with AHD and CMV viraemia. We will enrol 150 hospitalized adults and adolescents (aged \u226515 years) with CD4 &lt;100 cells \u03bcl\n                    <jats:sup>\u22121<\/jats:sup>\n                    , and CMV viraemia &gt;500 IU ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    from two hospitals in Uganda and South Africa. Participants will be randomized 1 : 1 to either valganciclovir 900 mg orally or matched placebo for 28 days. Safety monitoring and CMV viral load testing will occur weekly until week 4, and thereafter at week 8 and at study termination at week 12. The primary endpoint is a composite of adverse events of special interest, re-hospitalization or death within 8 weeks. Secondary endpoints include median reduction in CMV viral load at day 28 and week 12, proportion with CMV below the limit of detection at weeks 2, 4, 8 and 12, mortality, grade \u22653 adverse events and serious adverse events, duration of hospitalization, tolerability, HIV treatment response, proportion with ganciclovir resistance and valganciclovir pharmacokinetics. Data from the NIRVANA phase 2 trial including valganciclovir pharmacokinetic data will be used to inform design of a multi-site phase 3 randomized controlled trial powered for survival to investigate whether valganciclovir reduces mortality among hospitalized adults with AHD-associated CMV viraemia.This article is part of the discussion meeting issue \u2018The indirect effects of cytomegalovirus infection: mechanisms and consequences\u2019.\n                  <\/jats:p>","DOI":"10.1098\/rstb.2024.0402","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T08:08:23Z","timestamp":1762416503000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Valganciclovir for cytomegalovirus viraemia in advanced HIV disease: a phase 2b randomized placebo-controlled trial of valganciclovir for cytomegalovirus viraemia in adults and adolescents with advanced HIV disease"],"prefix":"10.1098","volume":"380","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-9144","authenticated-orcid":true,"given":"Jayne","family":"Ellis","sequence":"first","affiliation":[{"name":"Department of Clinical Research, London School of Hygiene and Tropical Medicine","place":["London WC1E 7HT, UK"]},{"name":"Infectious Diseases Institute, Makerere University","place":["Kampala, Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Joan","family":"Nsangi","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University","place":["Kampala, Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Rassool","sequence":"additional","affiliation":[{"name":"Clinical HIV Research Unit, a division of the Wits Health Consortium, Helen Joseph Hospital, Johannesburg 2193, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Musaazi","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University","place":["Kampala, Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, London School of Hygiene and Tropical Medicine","place":["London WC1E 7HT, UK"]},{"name":"Botswana Harvard Health Partnership","place":["Gaborone, Botswana"]},{"name":"School of Pathology, Faculty of Health Sciences, University of the Witwatersrand","place":["Johannesburg, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Skipper","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Boulware","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Meya","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University","place":["Kampala, Uganda"]},{"name":"Department of Medicine, University of Minnesota","place":["Minneapolis, USA"]},{"name":"School of Medicine, College of Health Sciences, Makerere University","place":["Kampala, Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Wasserman","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity, City St George's University of London","place":["London EC1V 0HB, UK"]},{"name":"Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph N.","family":"Jarvis","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, London School of Hygiene and Tropical Medicine","place":["London WC1E 7HT, UK"]},{"name":"Botswana Harvard Health Partnership","place":["Gaborone, Botswana"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Boyles","sequence":"additional","affiliation":[{"name":"Clinical HIV Research Unit, a division of the Wits Health Consortium, Helen Joseph Hospital, Johannesburg 2193, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"e_1_3_7_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2313777"},{"key":"e_1_3_7_3_2","volume-title":"Global burden of disease","author":"The Lancet Global Burden of Disease Resource Centre","year":"2022","unstructured":"The Lancet Global Burden of Disease Resource Centre. 2022 Global burden of disease. 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MMWR Recomm. Rep. 58 RR-4, 1\u2013207.","journal-title":"MMWR Recomm. Rep."},{"key":"e_1_3_7_17_2","doi-asserted-by":"publisher","DOI":"10.1592\/phco.22.13.1124.33527"},{"key":"e_1_3_7_18_2","article-title":"Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients","volume":"2013","author":"Hodson EM","year":"2013","unstructured":"Hodson EM, Ladhani M, Webster AC, Strippoli GFM, Craig JC. 2013 Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst. Rev. 2013, CD003774. (doi:10.1002\/14651858.CD003774.pub4)","journal-title":"Cochrane Database Syst. 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