Cryptococcal polysaccharide antigen (CrAg) screening and preemptive antifungal therapy for people who are CrAg positive improves survival and reduces development of invasive cryptococcal disease.[30]Awotiwon AA, Johnson S, Rutherford GW, et al. Primary antifungal prophylaxis for cryptococcal disease in HIV-positive people. Cochrane Database Syst Rev. 2018 Aug 29;(8):CD004773.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004773.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/30156270?tool=bestpractice.com
[31]Mfinanga S, Chanda D, Kivuyo SL, et al. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet. 2015 May 30;385(9983):2173-82.
http://www.ncbi.nlm.nih.gov/pubmed/25765698?tool=bestpractice.com
[32]Rajasingham R, Meya DB, Greene GS, et al. Evaluation of a national cryptococcal antigen screening program for HIV-infected patients in Uganda: a cost-effectiveness modeling analysis. PLoS One. 2019 Jan 10;14(1):e0210105.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210105
http://www.ncbi.nlm.nih.gov/pubmed/30629619?tool=bestpractice.com
[33]Powderly WG, Finkelstein D, Feinberg J, et al; NIAID AIDS Clinical Trials Group. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N Engl J Med. 1995 Mar 16;332(11):700-5.
https://www.nejm.org/doi/full/10.1056/NEJM199503163321102
http://www.ncbi.nlm.nih.gov/pubmed/7854376?tool=bestpractice.com
[34]McKinsey DS, Wheat LJ, Cloud GA, et al; National Institute of Allergy and Infectious Diseases Mycoses Study Group. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis. 1999 May;28(5):1049-56.
http://www.ncbi.nlm.nih.gov/pubmed/10452633?tool=bestpractice.com
This has been most rigorously studied in the REMSTART trial, which randomized 2000 individuals with HIV infection and CD4 count <200 cells/microliter to either standard care or standard care plus CrAg screening and adherence counseling.[31]Mfinanga S, Chanda D, Kivuyo SL, et al. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet. 2015 May 30;385(9983):2173-82.
http://www.ncbi.nlm.nih.gov/pubmed/25765698?tool=bestpractice.com
The trial noted a 28% relative reduction in mortality for patients who received CrAg screening and adherence counseling.
The World Health Organization (WHO) and other international guidelines recommend screening all adults and adolescents with HIV infection and a CD4 count <100 cells/microliter before initiating or reinitiating antiretroviral therapy (ART).[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
US guidelines recommend routine surveillance testing for serum CrAg in people newly presenting to HIV care who have no overt clinical signs of meningitis and whose CD4 counts are ≤200 cells/microliter, and particularly in those with CD4 counts ≤50 cells/microliter.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
People with a positive screening test should undergo cerebrospinal fluid evaluation for central nervous system infection.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Those who are CrAg positive, without signs or symptoms of meningitis, should be given preemptive antifungal therapy (fluconazole, given as induction, consolidation, and maintenance regimens).[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
In settings where antigen screening is not available, the WHO recommends initiating fluconazole primary prophylaxis in people with HIV infection and a CD4 count <100 cells/microliter (may also be considered at a higher CD4 count threshold of <200 cells/microliter).[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
Antifungal prophylaxis in the absence of a positive serum CrAg test is not recommended by US guidelines.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis