{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:11:40Z","timestamp":1791292300879,"version":"4.1.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,4,11]],"date-time":"2020-04-11T00:00:00Z","timestamp":1586563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1172544"],"award-info":[{"award-number":["OPP1172544"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P = .37), and number of diarrheal episodes increased by 2.32 (P = .87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical Trials Registration<\/jats:title>\n                  <jats:p>NCT03341767.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciaa421","type":"journal-article","created":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T19:14:00Z","timestamp":1586459640000},"page":"183-191","source":"Crossref","is-referenced-by-count":55,"title":["Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial"],"prefix":"10.1093","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3682-8892","authenticated-orcid":false,"given":"Py","family":"Iroh Tam","sequence":"first","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"},{"name":"Liverpool School of Tropical Medicine, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S L M","family":"Arnold","sequence":"additional","affiliation":[{"name":"Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L K","family":"Barrett","sequence":"additional","affiliation":[{"name":"Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C R","family":"Chen","sequence":"additional","affiliation":[{"name":"Emmes, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T M","family":"Conrad","sequence":"additional","affiliation":[{"name":"Emmes, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Douglas","sequence":"additional","affiliation":[{"name":"Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M A","family":"Gordon","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"},{"name":"Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Hebert","sequence":"additional","affiliation":[{"name":"Emmes, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Henrion","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"},{"name":"Liverpool School of Tropical Medicine, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Hermann","sequence":"additional","affiliation":[{"name":"Bill & Melinda Gates Foundation, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Hollingsworth","sequence":"additional","affiliation":[{"name":"Emmes, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Houpt","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K C","family":"Jere","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"},{"name":"Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Lindblad","sequence":"additional","affiliation":[{"name":"Emmes, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M S","family":"Love","sequence":"additional","affiliation":[{"name":"Calibr, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Makhaza","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C W","family":"McNamara","sequence":"additional","affiliation":[{"name":"Calibr, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Nedi","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Nyirenda","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D J","family":"Operario","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Phulusa","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"G V","family":"Quinnan","sequence":"additional","affiliation":[{"name":"Emmes, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L A","family":"Sawyer","sequence":"additional","affiliation":[{"name":"Emmes, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Thole","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Toto","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Winter","sequence":"additional","affiliation":[{"name":"Emmes, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W C","family":"Van Voorhis","sequence":"additional","affiliation":[{"name":"Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,11]]},"reference":[{"key":"2021071520102287300_CIT0001","doi-asserted-by":"crossref","first-page":"e564","DOI":"10.1016\/S2214-109X(15)00151-5","article-title":"Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED)","volume":"3","author":"Platts-Mills","year":"2015","journal-title":"Lancet Glob Health"},{"key":"2021071520102287300_CIT0002","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0140-6736(13)60844-2","article-title":"Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study","volume":"382","author":"Kotloff","year":"2013","journal-title":"Lancet"},{"key":"2021071520102287300_CIT0003","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/0016-5085(95)90205-8","article-title":"Intestinal function and injury in acquired immunodeficiency syndrome-related cryptosporidiosis","volume":"108","author":"Goodgame","year":"1995","journal-title":"Gastroenterology"},{"key":"2021071520102287300_CIT0004","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1136\/bmj.307.6901.417","article-title":"Cryptosporidiosis in infancy and childhood mortality in Guinea Bissau, West Africa","volume":"307","author":"M\u00f8lbak","year":"1993","journal-title":"BMJ"},{"key":"2021071520102287300_CIT0005","doi-asserted-by":"crossref","first-page":"e0004564","DOI":"10.1371\/journal.pntd.0004564","article-title":"Natural history of cryptosporidiosis in a longitudinal study of slum-dwelling Bangladeshi children: association with severe malnutrition","volume":"10","author":"Korpe","year":"2016","journal-title":"PLoS Negl Trop Dis"},{"key":"2021071520102287300_CIT0006","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/503189a","article-title":"Parasitic infections: time to tackle cryptosporidiosis","volume":"503","author":"Striepen","year":"2013","journal-title":"Nature"},{"key":"2021071520102287300_CIT0007","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/S0140-6736(02)11401-2","article-title":"Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial","volume":"360","author":"Amadi","year":"2002","journal-title":"Lancet"},{"key":"2021071520102287300_CIT0008","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/1471-2334-9-195","article-title":"High dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in HIV positive Zambian children: a randomised controlled trial","volume":"9","author":"Amadi","year":"2009","journal-title":"BMC Infect Dis"},{"key":"2021071520102287300_CIT0009","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1111\/j.1365-2036.2005.02394.x","article-title":"Nitazoxanide for persistent diarrhoea in Zambian acquired immune deficiency syndrome patients: a randomized-controlled trial","volume":"21","author":"Zulu","year":"2005","journal-title":"Aliment Pharmacol Ther"},{"key":"2021071520102287300_CIT0010","doi-asserted-by":"crossref","first-page":"e0005373","DOI":"10.1371\/journal.pntd.0005373","article-title":"A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis","volume":"11","author":"Love","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"key":"2021071520102287300_CIT0011","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1186\/s13063-018-2846-6","article-title":"Evaluating the safety, tolerability, pharmacokinetics and efficacy of clofazimine in cryptosporidiosis (CRYPTOFAZ): study protocol for a randomized controlled trial","volume":"19","author":"Nachipo","year":"2018","journal-title":"Trials"},{"key":"2021071520102287300_CIT0012","first-page":"135","article-title":"Lamprene (clofazimine) in leprosy. Basic information","volume":"50","author":"Yawalkar","year":"1979","journal-title":"Lepr Rev"},{"key":"2021071520102287300_CIT0013","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/S1473-3099(14)70808-4","article-title":"Development and assessment of molecular diagnostic tests for 15 enteropathogens causing childhood diarrhoea: a multicentre study","volume":"14","author":"Liu","year":"2014","journal-title":"Lancet Infect Dis"},{"key":"2021071520102287300_CIT0014","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/S0140-6736(16)31529-X","article-title":"Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study","volume":"388","author":"Liu","year":"2016","journal-title":"Lancet"},{"key":"2021071520102287300_CIT0015","doi-asserted-by":"crossref","first-page":"74","DOI":"10.2165\/00003088-198916020-00002","article-title":"Clinical pharmacokinetics of clofazimine. A review","volume":"16","author":"Holdiness","year":"1989","journal-title":"Clin Pharmacokinet"},{"key":"2021071520102287300_CIT0016","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1179\/136485911X12899838683160","article-title":"In a trial of the use of miltefosine to treat HIV-related cryptosporidiosis in Zambian adults, extreme metabolic disturbances contribute to high mortality","volume":"105","author":"Sinkala","year":"2011","journal-title":"Ann Trop Med Parasitol"},{"key":"2021071520102287300_CIT0017","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/S0140-6736(18)31267-4","article-title":"Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial","volume":"392","author":"Gupta-Wright","year":"2018","journal-title":"Lancet"},{"key":"2021071520102287300_CIT0018","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1086\/519842","article-title":"Differences in clinical manifestations among Cryptosporidium species and subtypes in HIV-infected persons","volume":"196","author":"Cama","year":"2007","journal-title":"J Infect Dis"},{"key":"2021071520102287300_CIT0019","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1086\/422649","article-title":"Health sequelae of human cryptosporidiosis in immunocompetent patients","volume":"39","author":"Hunter","year":"2004","journal-title":"Clin Infect Dis"},{"key":"2021071520102287300_CIT0020","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13071-019-3348-4","article-title":"A retrospective molecular study of Cryptosporidium species and genotypes in HIV-infected patients from Thailand","volume":"12","author":"Sannella","year":"2019","journal-title":"Parasit Vectors"},{"key":"2021071520102287300_CIT0021","doi-asserted-by":"crossref","first-page":"e0004729","DOI":"10.1371\/journal.pntd.0004729","article-title":"The burden of Cryptosporidium diarrheal disease among children &lt;24 months of age in moderate\/high mortality regions of sub-Saharan Africa and South Asia, utilizing data from the Global Enteric Multicenter Study (GEMS)","volume":"10","author":"Sow","year":"2016","journal-title":"PLoS Negl Trop Dis"},{"key":"2021071520102287300_CIT0022","doi-asserted-by":"crossref","first-page":"e2831","DOI":"10.1371\/journal.pntd.0002831","article-title":"Distribution and clinical manifestations of Cryptosporidium species and subtypes in HIV\/AIDS patients in Ethiopia","volume":"8","author":"Adamu","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"key":"2021071520102287300_CIT0023","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S1473-3099(14)70772-8","article-title":"A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for Cryptosporidium","volume":"15","author":"Checkley","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"2021071520102287300_CIT0024","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1093\/jac\/45.1.77","article-title":"Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection","volume":"45","author":"Peters","year":"2000","journal-title":"J Antimicrob Chemother"},{"key":"2021071520102287300_CIT0025","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1086\/318155","article-title":"Paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trial Group","volume":"31","author":"Hewitt","year":"2000","journal-title":"Clin Infect Dis"},{"key":"2021071520102287300_CIT0026","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1086\/321008","article-title":"Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of nitazoxanide","volume":"184","author":"Rossignol","year":"2001","journal-title":"J Infect Dis"},{"key":"2021071520102287300_CIT0027","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1093\/infdis\/170.2.419","article-title":"Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial","volume":"170","author":"White","year":"1994","journal-title":"J Infect Dis"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciaa421\/33640796\/ciaa421.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/73\/2\/183\/39065100\/ciaa421.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/73\/2\/183\/39065100\/ciaa421.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T20:10:55Z","timestamp":1626379855000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/73\/2\/183\/5819176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,11]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,4,11]]},"published-print":{"date-parts":[[2021,7,15]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciaa421","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,7,15]]},"published":{"date-parts":[[2020,4,11]]}}}