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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. DHS/HIV/ARV Rx/PP. Opportunistic Infection: Update.

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DHS/HIV/ARV Rx/PP

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  1. HIV/AIDS Opportunistic Infection UpdateDavid H. Spach, MDMedical DirectorNorthwest AIDS Education and Training CenterAssociate Professor of MedicineDivision of Infectious DiseasesUniversity of Washington, Seattle DHS/HIV/ARV Rx/PP

  2. Opportunistic Infection: Update • Pneumocytis pneumonia • Toxoplasmosis • Mycobacteriumavium complex • Cytomegalovirus • Esophageal candidiasis • Cryptococcal meningitis • Cryptosporidiosis DHS/HIV/ARV RX/PP

  3. Pneumocystis Pneumonia DHS/HIV/PP

  4. Pneumocystis PneumoniaNew Developments • Basic Science- Pneumocystiscarinii changed to Pneumocystisjiroveci*- 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 *Pronounced “yee row vet zee” & named after the Czech pathologist Otto Jirovec DHS/HIV/Clin Manifestations/PP

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

  6. 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. DHS/ HIV/PP

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

  8. 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. DHS/ HIV/PP

  9. Toxoplasmosis DHS/HIV/PP

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

  11. Mycobacteriumavium Complex DHS/HIV/PP

  12. MAC: Immune Reconstitution Syndrome • 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 DHS/ID/Cases/PP

  13. Discontinuation of MAC ProphylaxisRecommendations from USPHS/IDSA Guidelines Criteria 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 From: MMWR 2001;50 (RR-11):1-52. DHS/HIV/OIs/PP

  14. Cytomegalovirus DHS/HIV/PP

  15. Valganciclovir (Valcyte)Induction Therapy for CMV Retinitis Study Design Week 4: Non-progression • 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 From: Martin DF et al. N Engl J Med 2002;346:1119-26. DHS/OIs/HIV

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

  17. Esophageal Candidiasis DHS/HIV/PP

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

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

  20. Caspofungin: Mechanism of Action Beta-Glucan Synthase Beta-Glucan Synthase Echinocandins Glucan Fibrils Cytoplasmic Membrane Cell Wall

  21. Fluconazole-Resistant Esophageal CandidiasisTreatment 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 Dose Drug DHS/HIV/OIs/PP

  22. Candida Species: In Vitro Testing • C. albicans- Fluconazole (S)- Fluconazole (R) • C. glabrata- Fluconazole (S)- Fluconazole (R) Organism Caspofungin (MIC 50) Fluconazole (MIC 50) 0.1640 1.2540 0.200.20 0.200.40 From: Vazquez JA et al. Antimicrob Agents Chemo 1997;41:1612-4. DHS/HIV/OIs/PP

  23. Caspofungin (Cancidas) vs. AmphotericinTreatment of Esophageal Candidiasis Study Design Clinical & Endoscopic Response (ITT) • Methods - N = 128 (123 HIV-infected*) -*Mean CD4 = 84 cells/mm3 - 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 From: Villanueva A et al. Clin Infect Dis 2001;33:1529-35. DHS/OIs/HIV

  24. Fluconazole-Resistant Esophageal CandidiasisTreatment with Caspofungin Study Design Clinical Response • 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 From: Kartsonis NK et al. J Acquir Immune Defic Syndr 2002;31:183-7. DHS/OIs/HIV

  25. Cryptococcal Meningitis DHS/HIV/PP

  26. Cryptococcal Meningitis: 14-Day Induction Therapy Suspected or Confirmed Cryptococcal Meningitis*Serial LPs ifOpening Pressure > 200 mm H2O 1 3 2 Ampho B0.7-1.0 mg/kg/d+5-Flucytosine100 mg/kg/d Ampho B0.7-1.0 mg/kg/d Fluconazole400-800 mg/d Initial LP: Reduce opening pressure by 50%Daily LPs: Maintain opening < 200 mm H2OCessation of LPs: once opening pressure normal for several consecutive days DHS/OI/PP

  27. Cryptococcal Meningitis: 10 Week Consolidation Therapy Cryptococcal Meningitis2 Week Lumbar Puncture with Negative Culture 1 3 2 Fluconazole400 mg/d Ampho B0.7-1.0 mg/kg/d Itraconazole400 mg/d DHS/OI/PP

  28. Cryptococcal MeningitisCSF Pressure Post-Treatment & Outcome Study Design Week 2 Outcome: Clinical Failure • Methods - N = 161 - HIV-infected - Cryptococcal meningitis - Retrospective analysis - Week 2 outcome - Compared pre/post CSF OP • Baseline - 60% > 250 mm H2O - 30% > 350 mm H2O From: Graybill JR et al. Clin Infect Dis 2000;30:47-54. DHS/OIs/HIV

  29. Cryptococcal MeningitisFeatures of High (> 350 mm H2O) 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. DHS/OIs/HIV

  30. Cryptococcal MeningitisStrategies for Reducing High CSF Pressure • Lumbar Puncture - 18 gauge needle - Drained until CSF pressure < 200 mm H2O - Repeat as often as needed • Medical Therapy - Corticosteroids? - Acetazolamide? - Mannitol? From: Graybill JR et al. Clin Infect Dis 2000;30:47-54. DHS/OIs/HIV

  31. Cryptococcal MeningitisAcetazolamide for Reducing High CSF Pressure • Background - N = 22 Thai HIV-infected - Confirmed cryptococcal meningitis - CSF pressure > 200 mm H2O - 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. DHS/OIs/HIV

  32. Cryptosporidiosis DHS/HIV/PP

  33. Cryptosporidiosis in HIV/AIDSCombination Therapy • Study Design- N = 13- CD4 count < 100 cells/mm3 (median 30 cells/mm3) - 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. Cryptosporidiosis: Combination Therapy Stool Frequency Oocyst Excretion From: Smith NH et al. J Infect Dis 1998;178:900-3. DHS/HIV/OIs/PP

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

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

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