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Learning Objectives

Learning Objectives

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Learning Objectives

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    2. Learning Objectives To discuss the challenges of managing cryptococcal disease in Mozambique and other resource limited settings To discuss strategies for prevention of severe cryptococcal disease in areas of high disease burden (such as sub-Saharan Africa) 2

    3. Case Presentation 42 yo African female admitted to HCM with papular rash x 3 months Began on back, then spread to involve face and extremities (UE>LE) 2 months prior to admission +pruritis Also had headache at the time of initial presentation Admitted to HC Machava when Sx first began and was followed in Dermatology clinic there. Also developed shortness of breath with dry cough 2 days prior to admission 3

    4. Additional Information HIV+, on ART x 3 months (?regimen) CD4 count unavailable (followed at outside hospital) No previous history of skin rash Family/social history, medication list, and allergies not obtained in ED when family members were present. ROS: No fevers, nausea, vomiting, or diarrhea; had been unable to walk prior to presentation 4

    5. Physical Examination T 37.2C, HR 80, RR 40, BP 120/80, SpO2 not done ill-appearing, tachypneic, prostrate oral thrush mild nuchal rigidity scattered rales & rhonchi on pulmonary exam Neuro exam limited due to altered mental status, normal strength, 1+ DTRs bilaterally, negative Babinski, pupils equal and reactive Skin: diffuse papular and vesicular lesions involving back, chest, extremities (palms and soles spared), and face; perineal region also spared Many lesions were umbilicated 5

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    10. Laboratory Data FBC WBC 7.10 x 103/L 89%N, 7%L, 3%M, 1%E Hgb 10 gm/dL Hct 28.4% MCV 85 fL Plt 228 x 103/mcL ESR 130 mm/hr Chemistries Na 130, K 4.6, normal glucose AST 60, ALT 24, ALP 201, GGT 223, LDH 625, tbili 9.1 mol/L (normal), TP 75 gm/L (65-81 ), alb 24 gm/L (35-50) BUN 10.5 mmol/L Normal 2.5-6.4 Creatinine 98.4 mol/L Normal 53-115 Malaria smear negative RPR NR 10

    11. CSF Studies Opening pressure not grossly elevated, but equipment to measure was not available. Clear, colorless fluid TP 0.38 grams/L (normal), glucose 50 mg/dL (normal), Cl 129 mmol/L (normal) No cells were observed Gram stain negative; culture sent India ink positive, CRAG negative VDRL negative 11

    12. Chest X-ray 12

    13. A diagnostic procedure had been performed prior to patients admission.. 13

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    16. How do you interpret this patients CSF results? A) The India ink was falsely positive, and the patient does not have cryptococcal meningitis. B) The CSF CRAG was falsely negative, and the patient has cryptococcal meningitis. C) A laboratory error likely occurred, and this CRAG result was for a different patient. D) The positive India ink is likely due to contamination from the patients skin lesions during the lumbar puncture. E) None of the above (other) 16

    17. How would you treat this patient? A) Treat for disseminated cryptococcosis, bacterial pneumonia, and Pneumocystis (including steroids if indicated). B) Treat for disseminated cryptococcosis, bacterial pneumonia, and Pneumocystis (without steroids even if indicated). C) Treat for disseminated cryptococcosis and bacterial pneumonia. D) Treat for disseminated cryptococcosis and continue ARVs. E) Other 17

    18. Hospital Course Initially started on ceftriaxone, hydrated with NS, and given paracetamol prn Started on oral fluconazole (600 mg BID) when results returned on HD2 Switched to amphotericin B on HD3 Died on HD3 (?cause) 18

    19. Additional Information Skin biopsy was performed on 05/08/2010. Results were available on 16/08/2010. Patient was admitted to HCM on 09/09/2010. Patient was on no antifungal treatment at the time of hospital admission. 19

    20. Cryptococcal Disease in Africa Sub-Saharan Africa has the highest burden of cryptococcal disease worldwide. Median incidence of 3.2% among all HIV+ individuals 720,000 cases annually High mortality rates (20-50%) even with ART Most cases reported with CD4=100 in ART-nave pts or as unmasking of undiagnosed infection in setting of ART 20 Meya et al, CID 2010;51(4):448-455

    21. Strategies to Prevent CM-related Mortality Earlier HIV diagnosis and ART initiation prior to AIDS Primary fluconazole prophylaxis in patients with AIDS Screening and treatment for occult cryptococcemia 21 Meya DB et al, CID 2010;51(4):448-55

    22. CRYPTOPRO Study 1,519 ART-nave patients in eastern Uganda randomized to receive fluconazole 200 mg 3x/week or placebo All had CD4<200, those with + serum CRAG excluded Primary outcomes: Invasive cryptococcal disease All-cause mortality Subjects enrolled in ART program (median time to ART 11 weeks, IQR 7-17) Similar baseline characteristics (median CD4 111, 65% female) 22 Parkes-Ratansh R et al, 16th Annual CROI, Abstract 32

    23. Cryptococcal Events 23 Parkes-Ratansh R et al, 16th Annual CROI, Abstract 32

    24. All-Cause Mortality 24 Parkes-Ratansh R et al, 16th Annual CROI, Abstract 32

    25. Summary of Results 25 Parkes-Ratansh R et al, 16th Annual CROI, Abstract 32

    26. CRAG Screening Prior to ART Antigenemia is detectable for a median of 22 days prior to onset of symptoms in pts with cryptococcal disease. Detectable in 11% of patients >100 days prior to symptoms Is this an opportunity to test and start antifungal therapy prior to initiation of ART in patients with low CD4 counts? 26 French N et al, AIDS 2002;16:1031-8

    27. CRAG Screening in RSA Cohort Jarvis JN et al, CID 2009;48:856-62 Retrospective analysis of well-characterized clinical cohort in Cape Town of patients started on ART according to WHO 2002 guidelines CRAG testing on blood plasma samples collected prior to and (for subset) 16 weeks after ART initiation Meridian Cryptococcal Latex Agglutination System used, validated for BP specimens Primary Endpoints: Antigenemia (=1:2) at baseline Microbiologically confirmed cryptococcal meningitis in first year of follow-up 27

    28. Baseline Characteristics and Outcomes (all patients) 28

    29. Baseline Characteristics and Outcomes (CD4=100) 29

    30. Antigenemia and Clinical Outcomes CRAG+ patients had much higher mortality risk than CRAG- patients during 1-year follow-up, regardless of history of disease 14/41(34%) CRAG+ vs. 64/574(11%), p<0.001 Adjusted hazard ratio 3.2 (95%CI 1.5-6.6, p<0.01) Mortality risk strongly associated with antigen titer. 30 Jarvis JN et al, CID 2009;48:856-62

    31. 31 Jarvis JN et al, CID 2009;48:856-62

    32. What about screening and treatment? Cost-effectiveness analysis of CRAG screening of patients with CD4=100 at time of ART initiation in Uganda (Meya DB et al, CID 2010;51(4):448-55) Data analyzed from prospective cohort of 609 patients Initiated on ART if CD4=200 or WHO Stage IV d4T or AZT/3TC/NVP or EFV; all received CTZ Qualitative serum CRAG performed in all (Wampole Laboratories) Median follow-up period: 3.9 years (min. 2.5) 17 pts with prior known history of cryptococcosis were excluded. 32

    33. Model Characteristics 2010 cost of CRAG testing at this center was US$16.75 NHLS cost US$5.61 Cost of fluconazole not included in model Average anti-fungal use was less in screened/treated group than in untreated group 33 Meya DB et al, CID 2010;51(4):448-55

    34. Results Of 295 patients with CD4=100 and no prior history of CM, 26 were CRAG+ (8.8%, 95%CI 5.8-12.6%) 21 given fluconazole (200-400 mg x 2-4 wks) Mortality rate of 42% (11/26, 95%CI 23-63%) in CRAG+ 6(29%) of fluconazole-treated pts (3 from CM) 5(100%) of ART-only group died within 2 months of ART (2 from CM) 34 Meya DB et al, CID 2010;51(4):448-55

    35. Cost-effectiveness Analysis (for CRAG+, CD4=100, no prior Hx CM) Number needed to test to detect 1 CRAG+ person = 11.3 (95%CI 7.9-17.1) Number needed to screen & treat to prevent 1 death = 15.9 (95%CI 11.1-24) Cost to detect 1 asymptomatic person = US$190 (95%CI $132-$286) Cost to save 1 life within first month of ART with preemptive Tx = US$266 (95%CI $185-$402) 35 Meya DB et al, CID 2010;51(4):448-55

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    37. Issues to Consider Cost of implementing new preventive measures in already overburdened health care systems Risk of selecting for fluconazole resistance (Cryptococcus, Candida species) Dose of fluconazole for preemptive treatment In which asymptomatic patients with antigenemia should LP be done to rule out meningeal involvement? 37

    38. Points for Discussion What is the best way to decrease the burden of severe cryptococcal disease in sub-Saharan Africa? What is the best way to prevent complications of cryptococcal meningitis in areas where manometers to measure CSF opening pressure are not available? 38

    39. Based on currently available data, what is the best approach for the prevention of severe cryptococcal disease in patients starting ART areas of high disease burden? A) CRAG screening of patients with CD4=100 and treatment with fluconazole (200-400 mg) in CRAG+. B) CRAG screening of patients with CD4=100 and treatment with fluconazole (800 mg) in CRAG+. C) Prophylactic fluconazole (200-400 mg) for all patients with CD4=200. D) Prophylactic fluconazole (800 mg) for all patients with CD4=200. E) CRAG screening of patients with CD4=200 and treatment with fluconazole (200-400 mg) in CRAG+. F) CRAG screening of patients with CD4=200 and treatment with fluconazole (800 mg) in CRAG+. G) None of the above (Other) 39

    40. Obrigado pela ateno! Thank you for your attention! 40