Sanjiv Lewin For the WHO Cryptococcal Disease Guideline Development Group

Guideline Development Group Graeme Meintjes, South Africa Nagalingeswaran Kumarasamy, India Ploenchan Chetchotisakd, Thailand Tom Harrison, UK Conrad Muzzora, Uganda John Perfect, US Tammy Meyers, South Africa Saye Khoo, UK Yazdanpanah Yazdan, France George Rutherford, US Benjamin Park, US Neeraj Mohan, India Papa Salif Sow, Senegal Nelesh Govender, South Africa Jonathan Kaplan, US Lut Lynen, Belgium Peter Pappas, US Emilia Rivadeneira, US WHO Philippa Easterbrook Lulu Muhe Marco Vittoria Frank Lule (AFRO) Omar Sued (PAHO) Shaffiq Essajee Masaya Kato Raul Gonzalez USAID Ryan Phelps UNAIDS  Carlos Avila Grade Reviewers  Andrew Anglemeyer, UD  Mary Louise Lindegren, US  Basile Njei, US  Alicen Spaulding, US  Tara Horvath, US Peer Review Group Members

 Child and Adolescent  Epidemiology  Diagnosis  Prevention  Treatment  Amphotericin B toxicities  ART Initiation Timing  Discontinuation

 Child: less than and equal to 10 years  Adolescent: 10 to 18 years

Incidence Rate: 24/100,000; yrs: 332/100,000

 Colombian children (under 16 years) with HIV- Cryptooccocus from was 2.7%. Likasitwattanakul S et al. Cryptococcosisin HIV-infected children. Southeast Asian J Trop Med Public Health. 2004, 35:935–939. Lizarazo J et al. Results of 9 years of the clinical and epidemiological survey on cryptococcosis in Colombia, Biomedica 2007, 27:94– 109.

 In the US, 4/473 (0.85%) HIV infected children developed cryptococcosis between for an average annual incidence of ……conclude that cryptococcosis is an infrequent opportunistic infection in pediatric HIV infection.

 Early diagnosis is key  Gold Standard  Fungal culture  Rapid Diagnostics  CrAg (CSF and Serum) ▪ Latex Agglutination LA ▪ Lateral Flow Assay LFA

 CSF  Serum/Plasma

CrAg Cryptoccal Antigen CSF or Serum-Plasma

Ideal LP: CSF Opening Pressure CSF CrAg (LA, LFA) RL LP: CSF Opening Pressure CSF India Ink Stain RL Serum CrAg (LA, LFA) RL Refer Culture is Gold Standard.

 Early initiation of ART  Most important  Cost effective  Low Incidence in Children  All Cause Mortality?  Cost

CrAg negative RRCrAg unknown RR Crypt Dis Incidence 0.15 ( ) Crypt Dis Incidence 0.11 ( ) All cause Mortality 0.99 ( ) All cause Mortality 1.12 ( ) Crypt Dis Incidence > 50 % ART 0.06 ( ) Crypt Dis Incidence > 50 % ART 0.20 ( ) All cause Mortality > 50% ART 1.02 ( ) All cause Mortality > 50% ART 0.64 ( ) Author(s): Larry W Chang, George W Rutherford, Andrew Anglemyer, Philippa J Easterbrook. Date: Question: Should primary antifungal prophylaxis to prevent cryptococcal disease be used in HIV-infected cryptococcal antigen (CrAg)- negative patients? Question: Should primary antifungal prophylaxis to prevent cryptococcal disease be used in HIV-infected patients with unknown cryptococcal antigen (CrAg) status?

NOT ON ART  No routine Antifungal primary prophylaxis irrespective of CD4 count and if CrAg unknown or negative ROUTINE CRAG SCREENING  Not recommended

 Best Anti-fungal therapy  Optimize  Survival  Neurological outcome  Fungal clearance  Minimizing Drug Toxicity  Hypokalemia  Nephrotoxicity

Limited paediatric data is available comparing antifungal agents in children

Blyth CC, Hale K, Palasanthiran P, O’Brien T, Bennett MH. Antifungal therapy in infants and children with proven, probable or suspected invasive fungal infections. Cochrane Database of Systematic Reviews 2010, Issue 2.

No differences in mortality or treatment efficacy when antifungal agents were compared.

 No RCTs  3 Observational Studies (Induction Phase) Am-B + Flu = Am-B + Flucyto > Fluconazole

Induction 2 wks Consolidation 8 wks Maintenance

2 WEEK INDUCTION 1. Am B + Flucytosine 2. Am B + Fluconazole 3. SC-Am B 5-7 d + HD-Fluconazole 2 wk 4. HD-Fluconazole + Flucytosine 5. HD-Fluconazole 8 WEEK CONSOLIDATION  If 2 wk Am B regimen,  Fluconazole 6-12 mg/kg/day; max 800 mg/day  If SC-Am B or Fluconazole regimen,  Fluconazole 12 mg/kg/day ; max 800 mg/day

 Maintenance/ secondary prophylaxis  Fluconazole Oral 6 mg/kg/day; max 200 mg/day

AMPHOTERICIN B  mg/kg/day  4-6 hr infusion FLUCONAZOLE  12 mg/kg/day  Max: 800 mg/day if Induction phase  6-12 mg/kg/day  Max: 400 mg if Consolidation phase  6 mg/kg/day  Max: 200 mg if Maintenance phase FLUCYTOSINE: 100 mg/kg/day

Blyth CC, Hale K, Palasanthiran P, O’Brien T, Bennett MH. Antifungal therapy in infants and children with proven, probable or suspected invasive fungal infections. Cochrane Database of Systematic Reviews 2010, Issue 2..

Children are less likely to develop nephrotoxicity with a lipid Am-B compared with Am-B.

RISK FACTORS  Cumulative dose:  Each 0.1 mg/kg/day is associated with a 1.8-fold increased risk of nephrotoxicity.  Duration of use:  HR 1.03 per day  Use of nephrotoxic drugs:  Aminoglycosides PREVENTIVE PRINCIPLES  Pre Therapy Fluid  Normal Saline  10–15 ml/kg, max 1 Lt  Infused over 2-4 hrs  Add Potassium 20 mEq/L, if no renal insufficiency

 8%  Significant increase in Creatinine  20%  Severe Hypokalemia

 Avoid Toxicities  Hypokalemia 11-33% (5 RCTs)  Renal Insufficiency % (3 RCTs)  Minimal Pre therapy package  Fluid bolus  Potassium supplements  Monitoring protocol  Creatinine, Potassium 2/wk, esp 2 nd wk  Hemoglobin 1/wk

Benefits of Early ART IRIS (13-15% of all CD), Pill Load

 No immediate ART – IRIS  Deferred until sustained clinical response  2-4 wks, if Am B regimen used  4-6 wks, if HD-Fluconazole regimen used

 Less than 2 yr age  Never discontinue maintenance  2-5 yr age  Stable +  Adherent to ART and Maintenance (1 yr) +  CD4 > 25% or > 750 cells/cmm x 2  > 5 yrs age  As above with CD4 > 200 cells/cmm x 2

 “Infrequent”  LP and CrAg  Early ART  Induction with Am-B + Flu; Consolidation with Flu; Maintenance with Flu  Pre-therapy fluids and Potassium with monitoring  Deferred ART for 2-4 wks  Discontinuation 2yrs stable with immune reconstitution

Slide Courtesy: Tammy Meyers Dept Paediatrics Chris Hani Baragwanath Hospital, Soweto and University of the Witwaterrand, Johannesburg, South Africa

 Asymptomatic to fulminant disseminated disease but frequently appears with subtle symptoms and signs.  The serum CrAg was a useful tool for therapeutic monitoring.  All patients responded to Am-B followed by antifungal suppression. Cryptococcosis is an uncommon life-threatening but treatable opportunistic infection that warrants consideration when evaluating febrile HIV-infected children.

 Of all cases of C. neoformans reported to GERMS-SA in 2005 and 2006, 2% occurred among children.  Compared to the number of adults, the number of children who acquire cryptococcosis has always been unaccountably low, even in sub-Saharan Africa, which is home to almost 90% of all children with HIV, most of whom were infected by maternal transmission.  One of the largest published case series to date was reported from a 2-year surveillance program in Gauteng Province, South Africa. From 2002 through 2004, a total of 2,753 cases of cryptococcosis were documented, and 24 patients (0.9%) were less than 15 years old. Earlier studies estimated a similar prevalence of about 1% for childhood coinfections with HIV and Cryptococcus.  However, an 8-year summary of cases in Chiang Mai, Thailand, conducted from 1994 to 2001, reported 707 hospitalized patients with HIV and cryptococcal meningitis, and 21 (2.97%) were children (34). Similarly, the incidence of cryptococcosis among Colombian children (16 years) with AIDS from 1997 to 2005 was 2.7% (40). Overall, most reported pediatric cases have involved older children, aged 6 to 12 years.  In Gauteng Province from 2002 to 2004, the rate of cryptococcosis per 100,000 cases with HIV infection was 2.5 times higher in adults than in children

 However, most cases of cryptococcal disease manifest as meningitis and the extent of subclinical infections among South African children is unknown.  Antibodies to C. neoformans have been detected in healthy children and adults, a finding that documents the occurrence of latent, asymptomatic infections.  The duration of latency from infection with C.neoformans to the manifestation of meningitis may be protracted and extend from childhood to adulthood in most patients, even those with HIV. Consequently, the few children who develop cryptococcal disease may represent the low end of the normal age distribution for cryptococcosis.  In contrast, 84% (16/19) of our pediatric patients infected with isolates of ST8 were boys. Assuming that the number of HIV-infected girls is equal to or larger than the population of boys at risk, this finding that the most prevalent sequence type (ST8) occurred more frequently in males suggests that the infecting strain has a significant impact on the development of cryptococcal disease.  Sex-related differences in exposure to C. neoformans are unlikely to explain this result because the rate of cryptococcosis due to the other STs is similar for boys and girls.  The allelic profile of ST8 reveals the presence of unique polymorphisms at two loci, and a third allele is found in only one other ST

 Active, prospective, laboratory-based, population-based surveillance  Between 1 March 2002 and 29 February 2004, 2753 incident cases were identified. The overall incidence rate was 15.6/  Among HIV-infected persons, the rate was 95/ , and among persons living with AIDS 14/1000.  Males and children under 15 years accounted for 49 and 0.9% of cases, respectively.  The median age was 34 years (range, 1 month-74 years).  Almost all cases (97%) presented with meningitis.  Antifungal therapy was given to 2460 (89%) cases of which 72% received fluconazole only. In-hospital mortality was 27% (749 cases).  Recurrences occurred in 263 (9.5%) incident cases.  Factors associated with death included altered mental status, coma or wasting; factors associated with survival included employment in the mining industry, visual changes or headache on presentation.

FluidTestTypeSensitivitySpecificityComments CSFCrAgLA96%97%Low Cost, Low Tech CrAgLFA100% Lower Cost, Lower Tech, Shorter time min, No fridge EIA %High Cost, Higher Tech India Ink 82%100%Low Cost, Tech Training, Tech SerumCrAgLA LFA 97% 100% 99% 100% PICO 1a: What is the optimal assay or combination of assays or diagnostic algorithm for the diagnosis of cryptococcal disease in patients with HIV infection? Authors: George W. Rutherford, Tara Horvath, Andrew T. Anglemyer

LFALAEIAIndia InkCulture Affordable$2/test$2-4/test$4-6/test<<$1/test<$1/test Sensitivity Specificity User Friendly Rapid/Robust Equipment-Free Delivered WHO A.S.S.U.R.E.D. Characteristics

WHO ASSURED India inkCultureLALFAEIA Affordable Sensitive73% - 94%Reference90% - 100%98% - 100%93% - 100% Specific95% - 100%Reference83% -100%Not fully defined 93% - 100% User-friendly Rapid and robust 5 minDays35 min10 minHours Equipment- free Delivered Courtesy Nelesh Govender, 2011

 Potassium supplementation 20 – 40 mEq/L IV Infusion or Oral  Monitor Potassium daily  If uncorrected, add Magnesium Oral

 Stop all Nephrotoxic Drugs  Fluid bolus to flush kidney  Monitor Creatinine  Improved,  Restart mg/kg.day or alternate day AM-B  Monitor Creatinine daily  Worsening or status quo,  Change to HD-Fluconazole 12 mg/kg/day max 1200 mg/day  Monitor Creatinine daily

5 Easy Steps Results in 10 mins Alternatives to serum and CSF Plasma – using samples taken for CD4 analysis Whole blood – fingerprick Urine – available at sites with no laboratory infrastructure

 Age: Any  If CD4 < 100 cells/cmm  If WHO Clinical Stage 4 event  Age: 2-5 yr  If CD4 < 25% OR < 750 cells/cmm