Cryptococcosis: Antifungal therapy management Prof. Thomas S. Harrison Centre for Global Health, Institute of Infection and Immunity St. George’s, University of London; St George's University Hospitals NHS Foundation Trust

Intended learning outcomes To be aware of the different phases of antifungal management of cryptococcal meningitis (CM) To be aware of the different antifungal regimens used in the different phases AND New data re importance flucytosine (5-FC), duration Amphotericin B (in HIV-CM) To be aware of the timing of initiation/modification of ART after HIV-related cryptococcal meningitis To be aware of the antifungal management of pulmonary and other forms of cryptococcosis

Management Patients with suspected symptomatic CNS or systemic cryptococcosis Admission to hospital for thorough evaluation Optimal antifungal therapy for:- Cryptococcal Meningo-encephalitis Severe Pulmonary / Disseminated non-pulmonary non-CNS cryptococcosis IF CM confirmed - Measurement and Management of intracranial pressure IF HIV-seropositive – appropriate Timing of Initiation / Re-introduction or modification of Antiretroviral Therapy (ART)

Acute HIV-associated cryptococcal meningitis Phased antifungal therapy Induction phase Consolidation phase Maintenance 2 weeks Amphotericin-based combination therapy 8 weeks Based on... Van der Horst et al. NEJM 1997; 337:15–21 Supported by… Brouwer et al. Lancet 2004; 363:1764–67 Survival advantage with combination shown by… Day et al. NEJM 2013; 368:1291 Long term therapy (at least 1 year) Until immune reconstitution Van der Horst et al. NEJM 1997; 337:15–21 Brouwer et al. Lancet 2004; 363:1764–67 Day et al. NEJM 2013; 368:1291

Acute HIV-related cryptococcal meningitis Management of intracranial hypertension Extra 1L Normal Saline/day Electrolyte replacement and monitoring Monitor Hb, neutrophils, creatinine Phlebitis: flush lines well, replace early Investigate & treat for other HIV-related complications: TB, bacterial infections Monitor for and manage CM-IRIS Rx Adjuncts Induction phase Consolidation phase Maintenance Antifungal treatment WHO Rapid advice guideline, WHO November, 2011 NB with AmB plus Flucytosine Phlebitis – flush lines well, replace promptly Saline and Fluid loading – reduces nephrotoxicity Pre-emptive K+ and Mg+ replacement Monitoring: Renal function / electrolytes, Anaemia – transfuse if needed Adjust flucytosine dose if renal impairment If managed appropriately, 6% discontinuation within 2 wks But anaemia in particular & renal impair associated with reduced survival Bicanic T et al. Antimicrob Agents Chem. 2015; 59:7224

Acute HIV-related cryptococcal meningitis Phase Antifungal agent(dose) Duration Primary Induction therapy AmBd (0.7-1mg/kg/d) + 5-Flucytosine (5-FC) (100mg/kg/d) 2 weeks Initial combination therapy with amphotericin B (AmB) and flucytosine is associated with reduced mortality among patients with HIV-associated cryptococcal meningitis compared with AmB alone Large effect 40% reduction in mortality at 10 wks Amb plus flucon appeared intermediate Day et al N Engl J Med. 2013;368: 1291–1302.

Acute HIV-related cryptococcal meningitis NEW data ACTA trial (IAS Paris, 2017) Flucytosine is superior to fluconazole as partner drug with AmB Hazard Ratio (95% CI) AmB+FLU vs AmB vs 5FC p-value (log-rank test) 10 week mortality 1.62 (1.19 to 2.20) 0.002 Very confident this will drive generic 5FC in next 1-2 years Molloy et al IAS Paris 2017 http://programme.ias2017.org/People/PeopleDetailStandalone/4291

Acute HIV-related cryptococcal meningitis NEW data ACTA trial (IAS Paris, 2017) AmB+5FC for one week: at least as good, better tolerated than 2 weeks. 2-weeks Fluconazole 1200mg/d+5FC – also highly effective So 1 week amb 5fc best arm and oral flucon 5fc second best alternative Can reduce mortality to 25-35% at 10 weeks compared with 50-60% with flucon mono, and 40-45% with 2 wks AmB combination Until 5fc there 2 weeks ampho plus fluconazole Molloy et al IAS Paris 2017 http://programme.ias2017.org/People/PeopleDetailStandalone/4291

Acute Cryptococcal meningitis – resource rich settings Liposomal Amphotericin B vs Conventional AmB Liposomal amphotericin B (at 3-4 mg/kg/d) Not more effective, but Less side effects than conventional AmB deoxycholate Hamill et al. Clin Infect Dis. 2010; 51:225-32

Non-HIV-related cryptococcal meningitis Phase Antifungal agent (dose) Duration Transplant-related: L-AMB 3-4mg/kg/d Plus 5-FC 100mg/day L-AMB 6mg/kg/d (if no 5FC) 2-4 weeks 4-6 weeks Non-HIV, non-transplant, including apparently immunocompetent: AmBd 0.7-1mg/kg/d or L-AMB 3-4mg/kg/d Duration Induction therapy Long induction – usually start of switch to L-AmB – if you can Adapted from Perfect et al Clin Infect Dis. 2010 ;50(3):291-322.

Acute cryptococcal meningitis Phase Antifungal agent (dose) Duration Consolidation Fluconazole 400mg-800mg/d 8 weeks Was concern re flucon and nevirapine Not substantiated as cilnical issue and now nev not used, and given safety of flucon many use 800 to 10 weeks

Acute cryptococcal meningitis Phase Antifungal agent(dose) Duration Maintenance Fluconazole 200mg/d [Itraconazole 200mg BD or AmBd 1mg/kg IV weekly are inferior alternatives, rarely if ever needed] 1 year or longer* Flucon resistance v rare with rapidly active induction (not flucon mono) *After 1 year of suppression therapy, if CD4 counts reconstitutes to >100 and viral load is undetectable for >3 months, consider discontinuation of therapy : Re-institute if CD4<100. Adapted from Perfect et al Clin Infect Dis. 2010;50(3):291-322.

Timing of antiretroviral therapy Early ART initiation is associated with:- Increased mortality Increased risk of IRIS Defer ART for 4-6 weeks after starting antifungal therapy. In unmasking CM-IRIS (first presentation CM early after ART start) – continue ART In those presenting with CM with non- adherence /failing ART, defer re-start of ART, with/without switch to second line ART, until 4 weeks Boulware et al. N Engl J Med. 2014; 370:2487-2498

Pulmonary cryptococcosis, other sites Mild pulmonary disease: And Other sites: – if CNS disease ruled out§, no fungemia, single site of infection, no immunosuppressive risk factors Fluconazole for 6-12 months*, Severe disease any site, or Concomitant CNS disease: Treat as for CNS disease *IF solitary pulmonary nodule completely resected, no evidence extrapulmonary disease and immunocompetent patient, Then some experts suggest can hold or stop antifungal therapy and observe § important to do LP especially if immunosuppressed in any way Adapted from Perfect et al Clin Infect Dis. 2010;50(3):291-322.

Summary Antifungal Recommendations Amphotericin B-based induction kills C. neoformans faster and improves both short and long term outcome from cryptococcal meningitis compared with fluconazole monotherapy Flucytosine as partner drug improves survival Fluid and saline load during AmB therapy. Monitor infusion sites, and for anaemia and renal function and potassium loss during AmB-based therapy. Pre-emptively replace potassium, magnesium Defer initiation or re-starting or switch of antiretroviral therapy for 4-6 weeks after cryptococcal meningitis Fluconazole is highly effective as maintenance to prevent disease relapse

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