1. April 2003 DHS/HIV/ARV Rx/PP HIV/AIDS Opportunistic Infection Update David H. Spach, MD Medical Director Northwest AIDS Education and Training Center Associate Professor of Medicine Division of Infectious Diseases University of Washington, Seattle

2. April 2003 DHS/HIV/ARV RX/PP Opportunistic Infection: Update  Pneumocytis pneumonia  Toxoplasmosis  Mycobacterium avium complex  Cytomegalovirus  Esophageal candidiasis  Cryptococcal meningitis  Cryptosporidiosis

3. April 2003 DHS/HIV/PP Pneumocystis Pneumonia

4. April 2003 Pneumocystis Pneumonia New Developments  Basic Science - Pneumocystis carinii changed to Pneumocystis jiroveci* - Characterization of 14-  demethylase enzyme  Epidemiology - Reactivation of latent organisms versus acute acquisition  New Diagnostics - PCR-based test on oral washes  Resistance to TMP-SMX - Mutations identified in dihydropterate synthase (DHPS) - Presence of mutation associated with increased mortality  Immune Reconstitution - Marked inflammatory response about 15-30 days after HAART DHS/HIV/Clin Manifestations/PP *Pronounced “yee row vet zee” & named after the Czech pathologist Otto Jirovec

5. April 2003 Pneumocystis: Lanosterol 14-  Demethylase Ergosterol Biosynthesis Lanosterol 14-  Demethylase (Erg 11) Ergosterol Cytoplasmic Membrane From: Morales IJ, et al. Am J Respir Mol Bio 2003;Feb 26 (e-Publication). Inherent Azole Resistance

6. April 2003 DHS/ HIV/PP Pneumocystis in Asymptomatic Individuals  Methods - N = 16 HIV-infected patients - BAL samples (n = 47) - Genotyping of P. jiroveci  Results - 35/47 from patients positive for P. jiroveci - 7 with P. jiroveci 7-10 months after acute PCP; all 7 had different genotype at follow-up than found during acute PJP - TMP-SMX did not always clear infection From: Wakefield AE et al. J Infect Dis 2003;187:901-8.

7. April 2003 Discontinuation of PCP Prophylaxis Recommendations from USPHS/IDSA Guidelines DHS/HIV/OIs/PP Setting Primary Prophylaxis Secondary Prophylaxis CD4 > 200 for > 3 months Criteria From: MMWR 2001;50 (RR-11):1-52.

8. April 2003 DHS/ HIV/PP Pneumocystis & Immune Reconstitution  Timing - Typically 7 to 30 days after starting HAART  Clinical Manifestations - High grade-fever - Patchy infiltrates - BAL: few Pneumocystis organisms, severe inflammatory foci  Treatment - Restart corticosteroids From: Wislez M et al. Am J Respir Crit Care Med 2001;164:847-51.

9. April 2003 DHS/HIV/PP Toxoplasmosis

10. April 2003 Discontinuation of Toxoplasmosis Prophylaxis Recommendations from USPHS/IDSA Guidelines Setting Primary Prophylaxis Secondary Prophylaxis CD4 > 200 for > 3 months CD4 > 200 for > 6 months and Completed Initial Rx and Asymptomatic for Toxo Criteria From: MMWR 2001;50 (RR-11):1-52. DHS/HIV/OIs/PP

11. April 2003 DHS/HIV/PP Mycobacterium avium Complex

12. April 2003 MAC: Immune Reconstitution Syndrome DHS/ID/Cases/PP Low CD4 (< 50): more severe illness; fevers, weight loss, leukocytosis, positive blood cultures (Race, Lancet, 1998) High CD4 (> 100-150): fewer systemic symptoms, more localized suppurative disease (Phillips, JAIDS, 1998) Treatment: continue HAART and MAC therapy, NSAIDS, steroids (for severe symptoms), local surgery? Slide From Bob Harrington, MD

13. April 2003 Discontinuation of MAC Prophylaxis Recommendations from USPHS/IDSA Guidelines Setting Primary Prophylaxis Secondary Prophylaxis CD4 > 100 for > 3 months CD4 > 100 for > 6 months and Completed 12 months MAC RX and Asymptomatic for MAC Criteria From: MMWR 2001;50 (RR-11):1-52. DHS/HIV/OIs/PP

14. April 2003 DHS/HIV/PP Cytomegalovirus

15. April 2003 DHS/OIs/HIV Valganciclovir (Valcyte) Induction Therapy for CMV Retinitis  Methods - N = 160 - Newly diagnosed CMV retinitis  Regimens - Valganciclovir: 900 mg PO bid x 21d, 900 mg PO qd x 7d - Ganciclovir: 5 mg/kg IV bid x 21d, 5 mg/kg IV qd x 7d Study DesignWeek 4: Non-progression From: Martin DF et al. N Engl J Med 2002;346:1119-26.

16. April 2003 Discontinuation of CMV Prophylaxis Recommendations from USPHS/IDSA Guidelines Setting Primary Prophylaxis Secondary Prophylaxis Not Applicable CD4 > 100-150 for > 6 months and No evidence of active disease and Regular ophtho examinations Criteria From: MMWR 2001;50 (RR-11):1-52. DHS/HIV/OIs/PP

17. April 2003 DHS/HIV/PP Esophageal Candidiasis

18. April 2003 Fluconazole: Mechanism of Action Fluconazole Ergosterol Biosynthesis Lanosterol 14-  Demethylase Ergosterol Cytoplasmic Membrane

19. April 2003 Fluconazole: Mechanism of Resistance Fluconazole Ergosterol Biosynthesis Lanosterol 14-  Demethylase Ergosterol Efflux Pump Altered Binding Site Fluconazole

20. April 2003 Caspofungin: Mechanism of Action Cell WallCytoplasmic Membrane Glucan Fibrils Beta-Glucan Synthase Echinocandins

21. April 2003 Fluconazole-Resistant Esophageal Candidiasis Treatment Options  Fluconazole (Diflucan)400-800 mg PO qd  Itraconazole Solution (Sporonox)100 mg PO bid  Caspofungin (Cancidas) 50-70 mg IV qd  Amphotericin B 0.3-0.7 mg/kg IV qd  Liposomal Ampho B? Optimal Dose DHS/HIV/OIs/PP Drug Dose

22. April 2003 Candida Species: In Vitro Testing  C. albicans - Fluconazole (S) - Fluconazole (R)  C. glabrata - Fluconazole (S) - Fluconazole (R) DHS/HIV/OIs/PP 0.16 40 1.25 40 Organism Fluconazole (MIC 50) 0.20 0.20 0.40 Caspofungin (MIC 50) From: Vazquez JA et al. Antimicrob Agents Chemo 1997;41:1612-4.

23. April 2003 DHS/OIs/HIV Caspofungin (Cancidas) vs. Amphotericin Treatment of Esophageal Candidiasis  Methods - N = 128 (123 HIV-infected*) -*Mean CD4 = 84 cells/mm 3 - Documented Candida esophagitis - Randomized, double-blind study  Regimens (14 days) - Caspofungin: 50 mg IV qd - Caspofungin: 70 mg IV qd - Amphotericin B: 0. 5 mg/kg IV qd Study DesignClinical & Endoscopic Response (ITT) From: Villanueva A et al. Clin Infect Dis 2001;33:1529-35.

24. April 2003 DHS/OIs/HIV Fluconazole-Resistant Esophageal Candidiasis Treatment with Caspofungin  Methods - N = 14 - Esophageal candidiasis - Failed Fluconazole 200 mg/d or - Isolate with Fluconazole MIC > 16  Regimens - Caspofugin  Response - Defined as resolution of all symptoms and substantial improvement on endoscopy Study DesignClinical Response From: Kartsonis NK et al. J Acquir Immune Defic Syndr 2002;31:183-7.

25. April 2003 DHS/HIV/PP Cryptococcal Meningitis

26. April 2003 Cryptococcal Meningitis: 14-Day Induction Therapy DHS/OI/PP Initial LP: Reduce opening pressure by 50% Daily LPs: Maintain opening < 200 mm H 2 O Cessation of LPs: once opening pressure normal for several consecutive days Ampho B 0.7-1.0 mg/kg/d + 5-Flucytosine 100 mg/kg/d Suspected or Confirmed Cryptococcal Meningitis * Serial LPs if Opening Pressure > 200 mm H 2 O Ampho B 0.7-1.0 mg/kg/d Fluconazole 400-800 mg/d 2 3 1

27. April 2003 Cryptococcal Meningitis: 10 Week Consolidation Therapy DHS/OI/PP Itraconazole 400 mg/d Cryptococcal Meningitis 2 Week Lumbar Puncture with Negative Culture Ampho B 0.7-1.0 mg/kg/d Fluconazole 400 mg/d 2 3 1

28. April 2003 DHS/OIs/HIV Cryptococcal Meningitis CSF Pressure Post-Treatment & Outcome  Methods - N = 161 - HIV-infected - Cryptococcal meningitis - Retrospective analysis - Week 2 outcome - Compared pre/post CSF OP  Baseline - 60% > 250 mm H 2 O - 30% > 350 mm H 2 O Study DesignWeek 2 Outcome: Clinical Failure From: Graybill JR et al. Clin Infect Dis 2000;30:47-54.

29. April 2003 DHS/OIs/HIV Cryptococcal Meningitis Features of High (> 350 mm H 2 O) CSF Pressure  Clinical Features - More frequent headache & meningismus - More frequent papilledema & abnormal reflexes  Lab Features - Higher CSF Cryptococcal antigen - More frequent positive India ink  Outcome Features - Reduced short-term survival if CSF pressure > 250 From: Graybill JR et al. Clin Infect Dis 2000;30:47-54.

30. April 2003 DHS/OIs/HIV Cryptococcal Meningitis Strategies for Reducing High CSF Pressure  Lumbar Puncture - 18 gauge needle - Drained until CSF pressure < 200 mm H 2 O - Repeat as often as needed  Medical Therapy - Corticosteroids? - Acetazolamide? - Mannitol? From: Graybill JR et al. Clin Infect Dis 2000;30:47-54.

31. April 2003 DHS/OIs/HIV Cryptococcal Meningitis Acetazolamide for Reducing High CSF Pressure  Background - N = 22 Thai HIV-infected - Confirmed cryptococcal meningitis - CSF pressure > 200 mm H 2 O - Randomized, placebo-controlled  Regimens - Acetazolamide versusPlacebo  Results - No benefit, trial stopped secondary adverse effects From: Newton PN et al. Clin Infect Dis 2002;35:769-72.

32. April 2003 DHS/HIV/PP Cryptosporidiosis

33. April 2003 Cryptosporidiosis in HIV/AIDS Combination Therapy  Study Design - N = 13 - CD4 count < 100 cells/mm 3 (median 30 cells/mm 3 ) - Chronic cryptosporidiosis (median duration 12 weeks)  Regimen - Paromomycin 1g bid + Azithromycin 600 mg qd x 28d followed by Paromomycin 1g bid x 12 weeks From:Smith NH et al. J Infect Dis 1998;178:900-3. DHS/HIV/Clin Manifestations/PP

34. April 2003 Cryptosporidiosis: Combination Therapy Stool FrequencyOocyst Excretion From: Smith NH et al. J Infect Dis 1998;178:900-3. DHS/HIV/OIs/PP

35. April 2003 DHS/OIs/HIV Cryptosporidiosis:Nitazoxanide Therapy  Methods - N = 100 (50 adults, 50 children) - Cryptosporidiosis diarrhea - HIV testing not performed  Regimens* - Nitazoxanide: 500 mg bid x 3d - Placebo: bid x 3d Study DesignResponse From: Rossignol J-F et al. J Infect Dis 2001;184:103-6. Children - Age 4-11 yrs: 200 mg bid x 3d - Age 1-3 yrs: 100 mg bid x 3d

36. April 2003 DHS/HIV/ARV RX/PP Cryptosporidiosis: Treatment HAART Antimicrobial Agents - Paromomycin - Azithromycin - Nitazoxanide Antimotility Agents From: Chen X-M, et al. N Engl J Med 2002;346;1723-31.