Preventing Death from HIV-Associated Cryptococcal Meningitis: The Way Forward Authors
Epidemiologic Aspects of Fungal Infections (Tom M. Chiller, Section Editor)
First Online: 06 October 2011 DOI:
10.1007/s12281-011-0070-x Cite this article as: Roy, M. & Chiller, T.M. Curr Fungal Infect Rep (2011) 5: 206. doi:10.1007/s12281-011-0070-x
Cryptococcal meningitis (CM), a fungal disease caused by
Cryptococcus species, is one of the most common opportunistic infections among persons with HIV/AIDS. The highest burden of disease is in sub-Saharan Africa and Southeast Asia, where limited access to antiretroviral treatment and appropriate antifungal therapy contributes to high mortality rates. Increasing focus has been placed on earlier detection and prevention of disease. Primary prophylaxis and screening may provide a survival benefit and can be cost-effective in settings where CM prevalence is high. The development of a new point-of-care cryptococcal antigen assay has the potential to transform both disease prevention and diagnosis.
Cryptococcal antigen assay
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
• Park BJ et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23(4):525–30.
This article uses published data on cryptococcal incidence and mortality to estimate the global burden of cryptococcal disease. This type of estimate has not been done before, and it highlights the large impact of the disease
Bekondi C et al. Primary and opportunistic pathogens associated with meningitis in adults in Bangui, Central African Republic, in relation to human immunodeficiency virus serostatus. Int J Infect Dis. 2006;10(5):387–95.
Hakim JG et al. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS. 2000;14(10):1401–7.
Helbok R et al. Chronic meningitis in Thailand. Clinical characteristics, laboratory data and outcome in patients with specific reference to tuberculosis and cryptococcosis. Neuroepidemiology. 2006;26(1):37–44.
Jarvis JN et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. BMC Infect Dis. 2010;10:67.
Harling G, Orrel C, Wood R. Healthcare utilization of patients accessing an African national treatment program. BMC Heal Serv Res. 2007;7:80.
Inverarity D et al. The spectrum of HIV-related disease in rural Central Thailand. Southeast Asian J Trop Med Public Health. 2002;33(4):822–31.
d’Arminio Monforte A et al. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol. 2004;55(3):320–8.
Chen S et al. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis. 2000;31(2):499–508.
Dromer F et al. Epidemiology of HIV-associated cryptococcosis in France (1985–2001): comparison of the pre- and post-HAART eras. AIDS. 2004;18(3):555–62.
Mirza SA et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992–2000. Clin Infect Dis. 2003;36(6):789–94.
Kaplan JE et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;30 Suppl 1:S5–14.
van Elden LJ et al. Declining number of patients with cryptococcosis in the Netherlands in the era of highly active antiretroviral therapy. AIDS. 2000;14(17):2787–8.
Jarvis JN, Meintjes G, Harrison TS. Outcomes of cryptococcal meningitis in antiretroviral naive and experienced patients in South Africa. J Infect. 2010;60(6):496–8.
Kambugu A et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis. 2008;46(11):1694–701.
Kisenge PR et al. Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania. BMC Infect Dis. 2007;7:39.
McCarthy KM et al. Population-based surveillance for cryptococcosis in an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS. 2006;20(17):2199–206.
Mwaba P et al. Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J. 2001;77(914):769–73.
Chang, LW et al. Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. Cochrane Database of Syst Rev 2005(3).
Scharfstein JA, Paltiel AD, Freedberg KA. The cost-effectiveness of fluconazole prophylaxis against primary systemic fungal infections in AIDS patients. Med Decis Making. 1997;17(4):373–81.
Yazdanpanah Y et al. Prevention of human immunodeficiency virus-related opportunistic infections in France: A cost-effectiveness analysis. Clin Infect Dis. 2003;36:86–96.
Tuli K et al. Primary prophylaxis against fungal infections among persons living with AIDS in Thailand: a cost-effectiveness analysis. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, MA. 2003.
• Micol R et al. Cost-effectiveness of primary prophylaxis of AIDS associated cryptococcosis in Cambodia. PLoS One. 2010;5(11):e13856.
This article models the cost-effectiveness of primary prophylaxis and screening and compares the two interventions in a country with a high cryptococcal burden
John L, Nelson M. Primary prophylaxis for cryptococcal meningitis. HIV Med. 2004;5(3):131–2.
Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS–100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev. 1995;8(4):515–48.
Garcia-Hermoso D, Janbon G, Dromer F. Epidemiological evidence for dormant Cryptococcus neoformans infection. J Clin Microbiol. 1999;37(10):3204–9.
Jackson A, Hosseinipour MC. Management of cryptococcal meningitis in sub-saharan Africa. Curr HIV/AIDS Rep. 2010;7(3):134–42.
Perfect JR et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(3):291–322.
Friedman GD et al. Cryptococcosis: the 1981–2000 epidemic. Mycoses. 2005;48:122–5.
Lortholary O et al. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy. AIDS. 2006;20(17):2183–91.
van der Horst CM et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997;337(1):15–21.
Corbett EL et al. Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus. Clin Infect Dis. 2002;34(9):1251–8.
French N et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS. 2002;16(7):1031–8.
Okongo M et al. Causes of death in a rural, population-based human immunodeficiency virus type 1 (HIV-1) natural history cohort in Uganda. Int J Epidemiol. 1998;27(4):698–702.
Lessels R et al. Poor long-term outcomes from cryptococcal meningitis in rural South Africa. S Afr Med J. 2011;101:251–2.
Bicanic T et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007;45(1):76–80.
Bicanic T et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis. 2008;47(1):123–30.
Taelman H et al. Cryptococcosis, another growing burden for central Africa. Lancet. 1991;338:761.
Chhin S et al. Aetiology of meningitis in HIV-infected patients in a referral hospital in Phnom Penh, Cambodia. Int J STD AIDS. 2004;15:48–50.
Anekthananon T et al. HIV Infection/Acquired Immunodeficiency Syndrome at Sriraj Hospital, 2002: time for Secondary Prevention. J Med Assoc Thai. 2004;87(2):173–8.
Senya C et al. Spectrum of opportunistic infections in hospitalized HIV-infected patients in Phnom Penh, Cambodia. Int J STD AIDS. 2003;14(6):411–6.
Imwidthaya P, Poungvarin N. Cryptococcus in AIDS. Postgrad Med J. 2000;76:85–8.
Kumarasamy N et al. Natural history of human immunodeficiency virus desease in Southern India. Clin Infect Dis. 2003;36:79–85.
Pappalardo MC, Melhem MS. Cryptococcosis: a review of the Brazilian experience for the disease. Rev Inst Med Trop Sao Paulo. 2003;45(6):299–305.
Hamill RJ. Free fluconazole for cryptococcal meningitis: too little of a good thing? Clin Infect Dis. 2006;43(8):1074–6.
Bicanic T et al. Antiretroviral roll-out, antifungal roll-back: access to treatment for cryptococcal meningitis. Lancet Infect Dis. 2005;5(9):530–1.
Jarvis JN et al. Symptomatic relapse of HIV-associated cryptococcal meningitis in South Africa: the role of inadequate secondary prophylaxis. S Afr Med J. 2010;100(6):378–82.
Govender N et al. Trends in treatment of adults with incidenct cryptococcosis, South Africa 2005 to 2008. 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA. 2010.
Collett G, Parrish A. Fluconazole donation and outcomes assessment in cryptococcal meningitis. S Afr Med J. 2007;97(3):175–6.
Ingle SM et al. Outcome in patients waiting for antiretroviral treatment in the Free State Province, South Africa: prospective linkage study. AIDS. 2010;24(17):2717–25.
Lawn SD et al. Cryptococcocal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme. AIDS. 2005;19(17):2050–2.
Lawn SD et al. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2008;22(15):1897–908.
Bicanic T et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr. 2009;51(2):130–4.
Lortholary O et al. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS. 2005;19(10):1043–9.
Shelburne 3rd SA et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis. 2005;40(7):1049–52.
Sungkanuparph, S., et al., Cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in AIDS patients with cryptococcal meningitis: a prospective multicenter study. Clin Infect Dis. 2009. 2009(49).
• Lawn SD, Torok ME, Wood R. Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections. Curr Opin Infect Dis. 2011;24(1):34–42.
Given growing awareness of cryptococcal IRIS, this article, which discusses when antiretroviral therapy should be started in patients with CM, is particularly important
Makadzange AT et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010;50(11):1532–8.
Zolopa AR et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575.
Havlir DV et al. Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS. Clin Infect Dis. 1998;27(6):1369–75.
Powderly WG et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med. 1995;332(11):700–5.
McKinsey DS et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis. 1999;28(5):1049–56.
Smith DE et al. A randomized, double-blind, placebo-controlled study of itraconazole capsules for the prevention of deep fungal infections in immunodeficient patients with HIV infection. HIV Med. 2001;2(2):78–83.
Chariyalertsak S et al. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. Clin Infect Dis. 2002;34(2):277–84.
Chetchotisakd P et al. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency. HIV Med. 2004;5(3):140–3.
Parkes-Ratansh R et al. Succesful primary prevention of cryptococcal disease using fluconazole prophylaxis in HIV-infected Ugandan adults. 16th Annual Conference on Retroviruses and Opportunistic Infections, Alexandria, VA. 2009.
World Health Organization. Macroeconomics and health: investing in health for economic development. Report of the commission on macroeconomics and health. 2001;
, Accessed August 30, 2011.
World Health Organization. Essential prevention and care preventions for adults and adolescents living with HIV in resource-limited settings. 2008;
, Accessed August 30, 2011.
Department of Disease Control, MOPH, Thailand, National Guidelines for the clinical management of HIV in children and adults. 7th Edition. Bangkok, Thailand. 2002.
Ministry of Health. National Center for HIV/AIDS, Dermatology, and STD, Second Quarterly Comprehensive Report, 2009 HIV/AIDS & STI Prevention and Care Programme. 2009;
, Accessed August 30, 2011.
Apisarnthanarak A, Mundy LM. The impact of primary prophylaxis for cryptococcosis on fluconazole resistance in Candida species. J Acquir Immune Defic Syndr. 2008;47(5):644–5.
Manosuthi W et al. Antifungal susceptibilities of Cryptococcus neoformans cerebrospinal fluid isolates and clinical outcomes of cryptococcal meningitis in HIV-infected patients with/without fluconazole prophylaxis. J Med Assoc Thai. 2006;89(6):795–802.
Thanprasertsuk S et al. HIV/AIDS care and treatment in three provinces in northern Thailand before the national scale-up of highly-active antiretroviral therapy. Southeast Asian J Trop Med Public Health. 2006;37(1):83–9.
Wright P, Inverarity D. Human immunodeficiency virus (HIV) related cryptococcal meningitis in rural central Thailand- treatment difficulties and prevention strategies. Southeast Asian J Trop Med Public Health. 2007;38(1):58–61.
Saha DC, Xess I, Jain N. Evaluation of conventional & serological methods for rapid diagnosis of cryptococcosis. Indian J Med Res. 2008;127(5):483–8.
Tanner DC et al. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol. 1994;32(7):1680–4.
Feldmesser M et al. Serum cryptococcal antigen in patients with AIDS. Clin Infect Dis. 1996;23(4):827–30.
Frank UK et al. Evaluation of an enzyme immunoassay for detection of cryptococcal capsular polysaccharide antigen in serum and cerebrospinal fluid. J Clin Microbiol. 1993;31(1):97–101.
• Lindsley MD et al. Evaluation of a newly developed lateral flow immunoassay for the diagnosis of Cryptococcosis. Clin Infect Dis. 2011;53(4):321–5.
This is one of the first published studies validating use of the lateral flow immunoassay in the diagnosis of cryptococcosis
Antinori S et al. The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis. J Clin Microbiol. 2005;43(11):5828–9.
Asawavichienjinda T, Sitthi-Amorn C, Tanyanont V. Serum cryptococcal antigen: diagnostic value in the diagnosis of AIDS-related cryptococcal meningitis. J Med Assoc Thai. 1999;82(1):65–71.
Lara-Paredo O et al. Cryptococcal infection in an HIV-positive Ugandan population. J Infect. 2000;41:195–9.
Swinne D et al. Evaluation of the cryptococcal antigen test as a diagnostic tool of AIDS-associated cryptococcosis in Rwanda. Ann Soc Belge Med Trop. 1992;72:283–8.
Lin TY et al. Cryptococcal disease in patients with or without human immunodeficiency virus: clinical presentation and monitoring of serum cryptococcal antigen titers. J Microbiol Immunol Infect. 2009;42:220–6.
Aberg JA et al. Clinical utility of monitoring serum cryptococcal antigen (sCRAG) titers in patients with AIDS-related cryptococcal disease. HIV Clin Trials. 2000;1(1):1–6.
Brouwer AE et al. Baseline correlation and comparative kinetics of cerebrospinal fluid colony-forming unit counts and antigen titers in cryptococcal meningitis. J Infect Dis. 2005;192:681–4.
Powderly WG et al. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis. 1994;18(5):789–92.
• Pongsai P, Atamasirikul K, Sungkanuparph S. The role of serum cryptococcal antigen screening for the early diagnosis of cryptococcosis in HIV-infected patients with different ranges of CD4 cell counts. J Infect. 2010;60(6):474–7.
This paper presents recent data on the prevalence of CRAG positivity in a country with a high cryptococcal burden
• Jarvis JN et al. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin Infect Dis. 2009;48(7):856–62.
This retrospective paper highlights the high positive and negative predictive values of serum CRAG
Liechty CA et al. Asymptomatic serum cryptococcal antigenemia and early mortality during antiretroviral therapy in rural Uganda. Tropical Medicine and International Health. 2007;12(8):929–35.
Desmet P, Kayembe KD, De Vroey C. The value of cryptococcal serum antigen screening among HIV-positive/AIDS patients in Kinshasa, Zaire. AIDS. 1989;3(2):77–8.
Hoffman S, Stenderup J, Mathiessen LR. Low yield of screening for cryptococcal antigen by latex agglutination assay on serum and cerebrospinal fluid from Danish patients with AIDS or ARC. Scand J Infect Dis. 1991;23(6):697–702.
•• Meya DB et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin Infect Dis. 2010;51(4):448–55.
This key article evaluates the cost-effectiveness of cryptococcal screening
Micol R et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defic Syndr. 2007;45(5):555–9.
Yazdanpanah Y et al. Clinical impact and cost-effectiveness of co-trimazole prophylaxis in patients with HIV/AIDS in Cote d’Ivoire: a trial based analysis. AIDS. 2005;19(12):1299–308.
Shrestha RK et al. Cost-utility of tuberculosis prevention among HIV-infected adults in Kampala, Uganda. Int J Tuberc Lung Dis. 2007;11:747–54.
Jarvis JN et al. Testing but not treating: missed opportunities and lost lives in the South African anti-retroviral therapy programme. AIDS. 2010;24:1233–35.
Morpeth SC et al. Predicting CD4 lymphocyte count < 200 cells/mm
in an HIV type 1-infected Arican population. AIDS Res Hum Retroviruses. 2007;23(10):1230–6.
Singh N et al. Low-dose fluconazole as primary prophylaxis for cryptococcal infection in AIDS patients with CD4 cell counts of < or = 100/mm
: demonstration of efficacy in a positive, multicenter trial. Clin Infect Dis. 1996;23(6):1282–6.
Tassie JM et al. Systematic screening of cryptococcal antigenemia in HIV-positive adults in Uganda. J Acquir Immune Defic Syndr. 2003;33(3):411–2.
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