Cryptococcal meningitis: epidemiology and therapeutic options

Figures & data

Figure 1 Evolution of the incidence of cryptococcosis, by year of diagnosis in France (1985–2001), as reported to the National Reference Centre for Mycosis.

Note: Reproduced with permission from Dromer F, Mathoulin-Pelissier S, Fontanet A, Ronin O, Dupont B, Lortholary O, Epidemiology of HIV-associated cryptococcosis in France (1985–2001): comparison of the pre-and post-HAART eras, AIDS, 18:555–562.⁴¹ Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Lippincott williams & wilkins. Please contact [email protected] for further information.
Abbreviation: HIV, human immunodeficiency virus.

Figure 2 Global incidence and mortality from cryptococcal meningitis among United Nations global regions from 1997 to 2007.

Notes: Figures in brackets and italics indicate human immunodeficiency virus prevalence in 1,000s from each region during the period studied. Data from Park et al.³

Figure 3 (A–C) Diagnosis of cryptococcal meningitis. (A) Lumbar puncture being performed on a human immunodeficiency virus-infected patient with suspected meningitis in Malawi. (B) Lateral flow immunoassay test strips for cryptococcal antigen detection (the strip on the left shows a negative result, indicated by a single horizontal “control” band in the center; the strip on the right shows a positive result, indicated by adjacent horizontal “control” and “test” bands). (C) Cryptococcus neoformans growing on Sabouraud media. Images kindly supplied by Kate Gaskell, College of Medicine, University of Malawi, and Brigitte Denis, Malawi Liverpool wellcome Trust Clinical Research Programme.

Figure 4 Treatment options for cryptococcal meningitis (CM), summarized from infectious Diseases Society of America and world Health Organization guidelines.

Notes: ^aIn HIV-infected patients with renal impairment or concern about nephrotoxicity, LAmB or ABLC should be used. ^bIn settings of limited AmB availability or difficulty with toxicity monitoring, an abbreviated 5- to 7-day induction course of AmB may be used. ^cNon-HIV, nontransplant patients are a heterogeneous group, including individuals with hematological malignancies and immunocompetent hosts with Cryptococcus gattii infection. There is no consensus on optimal treatment; some authors suggest identical induction and consolidation therapy as for HIV-associated CM. ^dUndetectable Hiv viral load and CD4 > 100/μL should be demonstrated on two occasions 6 months apart before stopping fluconazole.
Abbreviations: HIV, human immunodeficiency virus; AmB, amphotericin B; LAmB, liposomal amphotericin B (3–6 mg/kg/day); ABLC, amphotericin B lipid complex (5 mg/kg/day); od, once daily; PO, per os (by mouth); ART, antiretroviral therapy.

Figure 5 A screening and management strategy for asymptomatic antigenemia.

Notes: Undetectable HIV viral load and CD4 >100/μL should be demonstrated on two occasions 6 months apart before stopping fluconazole. Jarvis JN, Govender N, Chiller T, et al, J Int Assoc Physicians AIDS Care (Chic) (11), pp 374–379, copyright © 2012 by SAGE Publications. Adapted by permission of SAGE Publications.¹⁵⁴
Abbreviations: HIV, human immunodeficiency virus; CrAg, cryptococcal antigen; LP, lumbar puncture; CM, cryptococcal meningitis; od, once daily; ART, antiretroviral therapy.

Figure 6 Types of immune restoration inflammatory syndrome (IRIS) in cryptococcal disease.

Note: ^aHIV-associated CM IRIS should occur within 12 months of ART initiation.
Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; CM, cryptococcal meningitis.

Table 1 Prospective open-label randomized trials to assess optimal timing of antiretroviral therapy (ART) initiation in human immunodefciency virus (HIV)-infected patients with cryptococcal meningitis (CM)

Study and site	Study design	Baseline CD4 count, cells/μL, median (IQR)	CM induction-phase drugs	Initiation of ART during CM therapy	Study outcomes
Zolopa et al,^Citation182 USAa and South Africa	282 patients with Ols (35 with CM) 48-week follow-up	29 (10–55)	Not stated	<2 weeks versus 4–32 weeks	All patients: fewer AIDS events/deaths in early (20 of 141 [14%]) versus late (34 of 141 [24%]) ART (OR 0.5, 95% CI 0.3–0.9) CM patients: no difference in AIDS events/deaths in early (one of 13 [8%]) versus late (three of 22 [14%]) ART (OR 0.5, 96% CI 0.1–5.7)
Makadzange et al,^Citation184 Zimbabwe	54 patients with CM 3-year follow-up	37 (17–69)	Fluconazole only	<72 hours versus > 10 weeks	Higher mortality in early (23 of 28 [82%]) versus late (12 of 26 [46%]) ART (HR 2.3, 95% CI 1.1–4.9)
Bisson et al,^Citation183 Botswana	27 patients with CM 24-week follow-up	29 (11–50)	AmB + fluconazole	<7 days versus >28 days	No difference in mortality in early (two of 13 [15%]) versus late (five of 14 [36%]) ART (OR 0.3, 95% CI 0.1–2.1)
Boulware et al,^Citation185 Uganda and South Africa	177 patients with CM 6-month follow-up	19 (9–69)	AmB + flucytosine	< 14 days versus >28 days	Higher mortality in early (40/88 [45%]) versus late (27 of 89 [30%]) ART (HR 1.7, 95% CI 1.1–2.8; P=0.03)

Note:

a Includes patients from Puerto Rico.

Abbreviations: IQR, interquartile range; AIDS, acquired immunodeficiency syndrome; OR, odds ratio; HR, hazard ratio; CI, confidence interval AmB, amphotericin B; OIs, opportunistic infections.

DromerFMathoulin-PelissierSFontanetARoninODupontBLortholaryOEpidemiology of HIV-associated cryptococcosis in France (1985–2001): comparison of the pre- and post-HAART erasAIDS20041855556215090810

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BissonGPMolefiMBellamySEarly versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitisClin Infect Dis2013561165117323362285

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BoulwareDMeyaDMuzooraCART initiation within the first 2 weeks of cryptococcal meningitis is associated with higher mortality: a multisite randomized trialPoster presented at: 20th Conference on Retroviruses and Opportunistic InfectionsMarch 3–6, 2013Atlanta, GA

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