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Forgotten but not gone: HIV-associated cryptococcal meningitis
Comment
The introduction of effective antiretroviral therapy (ART) in the late 1990s led to a marked decline in the incidence of HIV-associated cryptococcal meningitis in high-income countries.1,2 The perception among many in the HIV research community was that cryptococcal meningitis had ceased to be a public health concern, and for almost 15 years after the landmark study by van der Horst and colleagues,3 no large clinical endpoint trials of cryptococcal meningitis treatments were reported. But, as Joshua Rhein and colleagues highlight in The Lancet Infectious Diseases,4 cryptococcal meningitis has far from disappeared in Africa. The high ongoing burden of HIV, coupled with overstretched health-care systems, results in large numbers of individuals with low CD4 counts at ART initiation.5,6 Cryptococcal meningitis remains the leading cause of adult meningitis in most of central, southern, and eastern Africa, accounting for 30–60% of all meningitis.7 In just 1 year at a single site in Uganda studied by Rhein and colleagues, 225 patients were admitted to the hospital with HIVassociated cryptococcal meningitis.4 Moreover, with the mainstay of treatment still being amphotericin B deoxycholate, a toxic and difficult to administer 50-yearold medication,8 or, in much of Africa, fluconazole monotherapy,9 treatment outcomes are poor. Acute mortality, even in clinical study settings, ranges from 30–55%.10–13 Novel treatments are urgently needed, and Rhein and colleagues should be commended for their work to develop practical, affordable, effective new antifungal regimens for HIV-associated cryptococcal meningitis. Recent phase-3 clinical trial data demonstrating the persisting high mortality with current amphotericin B-based combinations11,12 and the disappointing results from a trial12 of adjunctive steroids in HIVassociated cryptococcal meningitis highlight the need for new safe and rapidly fungicidal drug regimens. And sertraline certainly has an appeal—a safe, cheap, readily available, oral drug, with evidence for in-vitro and some evidence for in-vivo activity against Cryptococcus neoformans.4 Rhein and colleagues4 present the first data for sertraline administration in patients with HIVassociated cryptococccal meningitis. Sertraline was well
tolerated. The authors also extrapolate from plasma measurements to suggest that potentially therapeutic brain concentrations could be achieved at the higher sertraline dose of 400 mg/day. However, interpretation of the early fungicidal activity and outcome data from this initial study must be made with caution. Although the early fungicidal activity of these sertraline-containing regimens was favourable compared with historical cohorts from the same centre treated with amphotericin B plus fluconazole, early fungicidal activity measurements show high variability across trials and results from other studies using amphotericin B plus fluconazole have shown similar rates of early fungicidal activity to those reported by Rhein and colleagues with addition of sertraline.14–16 Randomised comparisons with a control group are needed. A further reason to exercise caution in the interpretation of these results is the lack of a clear doseresponse relation between sertraline dose and early fungicidal activity. The fastest rates of fungal clearance were seen with the sertraline dose of 200 mg/day, despite suggestions from the drug-level data that higher doses were needed to reliably achieve therapeutic brain concentrations. What is clear is that cryptococcal meningitis remains a major clinical challenge in Africa. The number of cases of cryptococcal meningitis remains high despite over a decade of ART rollout; but the profile of the population developing the disease is changing. In keeping with our own trials in east and southern Africa, Rhein and colleagues found that half of all cases of cryptococcal meningitis were presenting after ART initiation. Increasingly, cryptococcal meningitis is occurring in a group of patients who, despite widespread availability of HIV testing and treatment, are presenting very late to care, or failing in the current treatment programmes. Interestingly, despite the female predominance of HIV in Uganda, two-thirds of the patients developing cryptococcal meningitis in Kampala were men. The study by Rhein and colleagues also shows the high associated mortality (40% at 3 months) and high frequency of drug related toxic effects with cryptococcal meningitis treatments based on conventional amphotericin B.
www.thelancet.com/infection Published online March 9, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00128-6
Living Art Enterprises, LLC /Science Photo Library
Forgotten but not gone: HIV-associated cryptococcal meningitis
Lancet Infect Dis 2016 Published Online March 9, 2016 http://dx.doi.org/10.1016/ S1473-3099(16)00128-6 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(16)00074-8
1
Comment
Effective, safe, easy to administer treatments for HIVassociated cryptococcal meningitis, ideally avoiding the need for 2-week courses of amphotericin B, would prevent many thousands of deaths each year in Africa. Ongoing phase 3 (ISRCTN45035509), and phase 2–3 studies that aim to make best use of existing antifungal drugs (ISRCTN10248064), new drug development,18 and efforts to repurpose other drugs,19 are all urgently needed in order to provide new treatment options for use in resource-limited settings. Hopefully, sertraline might be one such treatment, but before its use in cryptococcal meningitis can be recommended, the results from Rhein and colleagues’ ongoing larger randomised trial are needed.
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*Joseph N Jarvis, Thomas S Harrison Botswana-UPenn Partnership, PO Box AC 157 ACH, Gaborone, Botswana (JNJ); Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA (JNJ); Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK (JNJ); and Institute of Infection and Immunity, St. George’s University of London, London, UK (TSH) [email protected] JNJ reports having received grants from Gilead Sciences Ltd and from National Institutes of Health outside the submitted work. TSH reports having received grants from Gilead Sciences and personal fees from Viamet Pharmaceuticals, outside the submitted work. 1
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Mirza SA, Phelan M, Rimland D, 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: 789–94. Pyrgos V, Seitz AE, Steiner CA, Prevots DR, Williamson PR. Epidemiology of cryptococcal meningitis in the US: 1997–2009. PLoS One2013; 8: e56269. van der Horst CM, Saag MS, Cloud GA, 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: 15–21.
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Rhein J, Morawski BM, Hullsiek KH, et al, on behalf of ASTRO-CM Study Team. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis 2016; published online March 9. http://dx.doi.org/10.1016/S14733099(16)00074-8. Siedner MJ, Ng CK, Bassett IV, Katz IT, Bangsberg DR, Tsai AC. Trends in CD4 count at presentation to care and treatment initiation in sub-Saharan Africa, 2002-2013: a meta-analysis. Clin Infect Dis 2015; 60: 1120–07. Ford N, Mills EJ, Egger M. Editorial commentary: immunodeficiency at start of antiretroviral therapy: the persistent problem of late presentation to care. Clin Infect Dis 2015; 60: 1128–30. Veltman JA, Bristow CC, Klausner JD. Meningitis in HIV-positive patients in sub-Saharan Africa: a review. J Int AIDS Soc 2014; 17: 19184. Bicanic T, Bottomley C, Loyse A, et al. Toxicity of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated cryptococcal meningitis. Antimicrob Agents Chemother 2015; 59: 7224–31. Loyse A, Thangaraj H, Easterbrook P, et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect Dis 2013; 13: 629–37. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370: 2487–98. Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 2013; 368: 1291–302. Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 2016; 374: 542–54. Gaskell KM, Rothe C, Gnanadurai R, et al. A prospective study of mortality from cryptococcal meningitis following treatment induction with 1200 mg oral fluconazole in Blantyre, Malawi. PLoS One 2014; 9: e110285. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363: 1764–67. Loyse A, Wilson D, Meintjes G, et al. Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis 2011; 54: 121–28. Jackson A, Nussbaum J, Phulusa J, et al. A phase II randomised controlled trial adding oral flucytosine to high dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis in Malawi. AIDS 2012; 26: 1363–70. Lockhart SR, Fothergill AW, Iqbal N, et al. The investigational fungal Cyp51 inhibitor VT-1129 demonstrates potent in vitro activity against Cryptococcus neoformans and Cryptococcus gattii. Antimicrob Agents Chemother 2015; 59: 7224–31. Butts A, Koselny K, Chabrier-Rosello Y, et al. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. MBio 2014; 5: e00765–13.
www.thelancet.com/infection Published online March 9, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00128-6
The introduction of effective antiretroviral therapy (ART) in the late 1990s led to a marked decline in the incidence of HIV-associated cryptococcal meningitis in high-income countries.1,2 The perception among many in the HIV research community was that cryptococcal meningitis had ceased to be a public health concern, and for almost 15 years after the landmark study by van der Horst and colleagues,3 no large clinical endpoint trials of cryptococcal meningitis treatments were reported. But, as Joshua Rhein and colleagues highlight in The Lancet Infectious Diseases,4 cryptococcal meningitis has far from disappeared in Africa. The high ongoing burden of HIV, coupled with overstretched health-care systems, results in large numbers of individuals with low CD4 counts at ART initiation.5,6 Cryptococcal meningitis remains the leading cause of adult meningitis in most of central, southern, and eastern Africa, accounting for 30–60% of all meningitis.7 In just 1 year at a single site in Uganda studied by Rhein and colleagues, 225 patients were admitted to the hospital with HIVassociated cryptococcal meningitis.4 Moreover, with the mainstay of treatment still being amphotericin B deoxycholate, a toxic and difficult to administer 50-yearold medication,8 or, in much of Africa, fluconazole monotherapy,9 treatment outcomes are poor. Acute mortality, even in clinical study settings, ranges from 30–55%.10–13 Novel treatments are urgently needed, and Rhein and colleagues should be commended for their work to develop practical, affordable, effective new antifungal regimens for HIV-associated cryptococcal meningitis. Recent phase-3 clinical trial data demonstrating the persisting high mortality with current amphotericin B-based combinations11,12 and the disappointing results from a trial12 of adjunctive steroids in HIVassociated cryptococcal meningitis highlight the need for new safe and rapidly fungicidal drug regimens. And sertraline certainly has an appeal—a safe, cheap, readily available, oral drug, with evidence for in-vitro and some evidence for in-vivo activity against Cryptococcus neoformans.4 Rhein and colleagues4 present the first data for sertraline administration in patients with HIVassociated cryptococccal meningitis. Sertraline was well
tolerated. The authors also extrapolate from plasma measurements to suggest that potentially therapeutic brain concentrations could be achieved at the higher sertraline dose of 400 mg/day. However, interpretation of the early fungicidal activity and outcome data from this initial study must be made with caution. Although the early fungicidal activity of these sertraline-containing regimens was favourable compared with historical cohorts from the same centre treated with amphotericin B plus fluconazole, early fungicidal activity measurements show high variability across trials and results from other studies using amphotericin B plus fluconazole have shown similar rates of early fungicidal activity to those reported by Rhein and colleagues with addition of sertraline.14–16 Randomised comparisons with a control group are needed. A further reason to exercise caution in the interpretation of these results is the lack of a clear doseresponse relation between sertraline dose and early fungicidal activity. The fastest rates of fungal clearance were seen with the sertraline dose of 200 mg/day, despite suggestions from the drug-level data that higher doses were needed to reliably achieve therapeutic brain concentrations. What is clear is that cryptococcal meningitis remains a major clinical challenge in Africa. The number of cases of cryptococcal meningitis remains high despite over a decade of ART rollout; but the profile of the population developing the disease is changing. In keeping with our own trials in east and southern Africa, Rhein and colleagues found that half of all cases of cryptococcal meningitis were presenting after ART initiation. Increasingly, cryptococcal meningitis is occurring in a group of patients who, despite widespread availability of HIV testing and treatment, are presenting very late to care, or failing in the current treatment programmes. Interestingly, despite the female predominance of HIV in Uganda, two-thirds of the patients developing cryptococcal meningitis in Kampala were men. The study by Rhein and colleagues also shows the high associated mortality (40% at 3 months) and high frequency of drug related toxic effects with cryptococcal meningitis treatments based on conventional amphotericin B.
www.thelancet.com/infection Published online March 9, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00128-6
Living Art Enterprises, LLC /Science Photo Library
Forgotten but not gone: HIV-associated cryptococcal meningitis
Lancet Infect Dis 2016 Published Online March 9, 2016 http://dx.doi.org/10.1016/ S1473-3099(16)00128-6 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(16)00074-8
1
Comment
Effective, safe, easy to administer treatments for HIVassociated cryptococcal meningitis, ideally avoiding the need for 2-week courses of amphotericin B, would prevent many thousands of deaths each year in Africa. Ongoing phase 3 (ISRCTN45035509), and phase 2–3 studies that aim to make best use of existing antifungal drugs (ISRCTN10248064), new drug development,18 and efforts to repurpose other drugs,19 are all urgently needed in order to provide new treatment options for use in resource-limited settings. Hopefully, sertraline might be one such treatment, but before its use in cryptococcal meningitis can be recommended, the results from Rhein and colleagues’ ongoing larger randomised trial are needed.
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*Joseph N Jarvis, Thomas S Harrison Botswana-UPenn Partnership, PO Box AC 157 ACH, Gaborone, Botswana (JNJ); Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA (JNJ); Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK (JNJ); and Institute of Infection and Immunity, St. George’s University of London, London, UK (TSH) [email protected] JNJ reports having received grants from Gilead Sciences Ltd and from National Institutes of Health outside the submitted work. TSH reports having received grants from Gilead Sciences and personal fees from Viamet Pharmaceuticals, outside the submitted work. 1
2 3
2
Mirza SA, Phelan M, Rimland D, 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: 789–94. Pyrgos V, Seitz AE, Steiner CA, Prevots DR, Williamson PR. Epidemiology of cryptococcal meningitis in the US: 1997–2009. PLoS One2013; 8: e56269. van der Horst CM, Saag MS, Cloud GA, 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: 15–21.
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Rhein J, Morawski BM, Hullsiek KH, et al, on behalf of ASTRO-CM Study Team. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis 2016; published online March 9. http://dx.doi.org/10.1016/S14733099(16)00074-8. Siedner MJ, Ng CK, Bassett IV, Katz IT, Bangsberg DR, Tsai AC. Trends in CD4 count at presentation to care and treatment initiation in sub-Saharan Africa, 2002-2013: a meta-analysis. Clin Infect Dis 2015; 60: 1120–07. Ford N, Mills EJ, Egger M. Editorial commentary: immunodeficiency at start of antiretroviral therapy: the persistent problem of late presentation to care. Clin Infect Dis 2015; 60: 1128–30. Veltman JA, Bristow CC, Klausner JD. Meningitis in HIV-positive patients in sub-Saharan Africa: a review. J Int AIDS Soc 2014; 17: 19184. Bicanic T, Bottomley C, Loyse A, et al. Toxicity of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated cryptococcal meningitis. Antimicrob Agents Chemother 2015; 59: 7224–31. Loyse A, Thangaraj H, Easterbrook P, et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect Dis 2013; 13: 629–37. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370: 2487–98. Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 2013; 368: 1291–302. Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 2016; 374: 542–54. Gaskell KM, Rothe C, Gnanadurai R, et al. A prospective study of mortality from cryptococcal meningitis following treatment induction with 1200 mg oral fluconazole in Blantyre, Malawi. PLoS One 2014; 9: e110285. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363: 1764–67. Loyse A, Wilson D, Meintjes G, et al. Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis 2011; 54: 121–28. Jackson A, Nussbaum J, Phulusa J, et al. A phase II randomised controlled trial adding oral flucytosine to high dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis in Malawi. AIDS 2012; 26: 1363–70. Lockhart SR, Fothergill AW, Iqbal N, et al. The investigational fungal Cyp51 inhibitor VT-1129 demonstrates potent in vitro activity against Cryptococcus neoformans and Cryptococcus gattii. Antimicrob Agents Chemother 2015; 59: 7224–31. Butts A, Koselny K, Chabrier-Rosello Y, et al. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. MBio 2014; 5: e00765–13.
www.thelancet.com/infection Published online March 9, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00128-6