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Latest Developments in the Treatment of Invasive Aspergillosis

Latest Developments in the Treatment of Invasive Aspergillosis. William J. Steinbach, MD Assistant Professor of Pediatrics, Molecular Genetics, and Microbiology Pediatric Infectious Diseases Duke University Medical Center Durham, NC USA. Possible Areas for Improving Outcome in IA.

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Latest Developments in the Treatment of Invasive Aspergillosis

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  1. Latest Developments in the Treatment of Invasive Aspergillosis William J. Steinbach, MD Assistant Professor of Pediatrics, Molecular Genetics, and Microbiology Pediatric Infectious Diseases Duke University Medical Center Durham, NC USA

  2. Possible Areas for Improving Outcome in IA • Understanding IA epidemiology • Host factors: Underlying & concomitant diseases • Immunosuppression / Corticosteroids • Antifungal prophylaxis • Early diagnosis • Early therapy • Antifungal resistance • Antifungal therapies • Immune reconstitution, Immunotherapy

  3. Invasive Aspergillosis Incidence1990-1998 at FHCRC Allograft recipients Autograft recipients 14 12 10 8 Incidence (%) 6 4 2 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 Year Marr KA, et al. Clin Infect Dis. 2002;34:909-917.

  4. Invasive Aspergillosis Epidemiology • 1990-1998 data from 533 total cases of IA 19901998 • Autologous HSCT <1 % 5.3% • Allogeneic HSCT  4%  12% 1993-951996-98 • Non-fumigatus Aspergillus 18.3% 33.7% • Average median survival of 29 days after diagnosis Marr KA, et al. Clin Infect Dis 2002;34:909-17 Wald A, et al. J Infect Dis 1997;175:1459-66.

  5. Probability of Developing Proven or Probable IA among patients alive at day 40 Overall P = 0.001 Marr KA, et al. Blood 2002;100:4358-4366.

  6. Corticosteroids as a Risk Factor • Pharmacologic doses of hydrocortisone (10-6 M), equivalent to 20 mg IV • In vitro mean specific growth rate of A. fumigatus at 37° C increased by 40% (p=0.0001) • A. fumigatus doubling time increased to 48 minutes Ng TTC, et al. Microbiology 1994;140:2475-79

  7. Host Susceptibility Variations:Different Inbred Mouse Strains Resistant: BalbC/ByJ, AKR/J, Balb/C, 129/SVJ, C57BL/6 Sensitive: CAST/Ei, C3H/HEJ, A/J, DBA/2J Intermediate: MRL/MPJ, NZW/LAC Zaas AK, et al. 7th European Conference on Fungal Genetics, 2004

  8. Antifungal Therapyfor Invasive Aspergillosis

  9. A. terreus Infection • Murine model • Amphotericin B resistance confirmed Graybill JR, et al. Antimicrob Agents Chemother 2004;48:3715-19. • Review of 28 in vitro analyses, 9 animal models, and 60 previously reported clinical cases • AmB resistance shown in vitro and in vivo Steinbach WJ, et al. Antimicrob Agents Chemother 2004;48:3217-25. • Multicenter retrospective analysis of 83 cases (1997-2002) • Mortality at 12 weeks decreased in those who received voriconazole (HR 0.29; 95% CI, 0.15-0.56) vs. AmB Steinbach WJ, et al. Clin Infect Dis 2004;39:192-8.

  10. Aspergillosis Survival with Amphotericin B by Site of Infection 1.0 0.9 0.8 Sinusitis (n=17) 0.7 0.6 Multi-site (n=11) Cumulative Survival Rate 0.5 Aspergilloma (n=10) 0.4 0.3 0.2 Pulmonary (n=83) 0.1 CNS or Disseminated (n=35) 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Days Lin et al. Clin Infect Dis. 2001;32:358-366.

  11. Outcomes Research: Treatment PracticesPatterson TF, et al. Medicine 2000;79:250-260 • IA cases after 1990, most from 1994-1995 (595 total cases of IA) • Asked for recent case records, non-sequential • Lipid formulations of AmB investigational, so few received • Outcome data from 34 patients with L-AmB excluded because patients were in other clinical trials • Few Combinations Used: AmB + 5-FC (2%) AmB + Rifampin (2%) AmB + Itraconazole (3%) Outcomes: AmBItraconazoleAmB  Itraconazole Pts treated 31% 10% 16% All pts CR 25% 40% 39% All pts PR 7% 17% 15%

  12. Outcomes Research: Treatment PracticesDenning DW, et al. J Infect 1998;37:173-180. • 1993-1994 (123 total cases of IA) • Monotherapy in 29 pts, “Combination” therapy in 91 pts AmBLipid AmBItraconazole5-FC 75% 36% 40% 12% Six month outcomes for IPA: Alive w/o IAAlive w/ IAExpired AmB 14% 41% 46% Lipid AmB 23% 31% 46% AmB + Itra 28% 56% 15% Itra 33% 17% 50% • 61% mortality within 28 days after diagnosis

  13. Outcomes Research: Open Label • Compassionate use itraconazole (125 patients) • Complete response 27%; Improved 36% Stevens DA and Lee JY. Arch Intern Med 1997;157:1857-62. • Multicenter open label itraconazole (76 patients) • Complete or partial response 39% Denning DW, et al. Am J Med 1994;97:135-144. • Open label ABLC (130 patients) • Complete or partial response 42% Walsh TJ, et al. Clin Infect Dis 1998;26:1383-96.

  14. Antifungal Pre-Exposure • Serial passages of 10 clinical isolates to fluconazole (x4) • 4-fold increase in MFC (but not MIC) of Itraconazole and Voriconazole • Fluconazole pre-exposure attenuates Itraconazole/ Voriconazole fungicidal activity, but no effect in AmB • XTT growth rates pre-exposed/no fluconazole were same Liu W, et al. Antimicrob Agents Chemother 2003;47:3592-7. • In vitro pre-exposure of A. fumigatus to Itraconazole or Caspofungin resulted in enhanced activity for either, in contrast to antagonistic effect of sequential itraconazole then AmB • Suggests a preferential role for azole-Caspofungin sequential combinations over azole-AmB regimens Kontoyiannis DP, et al. Diag Microbiol Infect Dis 2003;47:415-9.

  15. Aspergillus Antifungal Resistance ? • Itraconazole resistance described in 1997 Denning DW, et al. Antimicrob Agents Chemother 1997;41:1364-68. • Estimated 2.1% of > 900 A. fumigatus strains resistant to itraconazole Moore CB, et al. J Infect 2000;41:203-20. • 200 sequential A. fumigatus isolates from 26 immunocompromised patients • MICs similar pre- and post-treatment with AmB (n=100) or itraconazole (n=91) • Emergence of resistance while on antifungal therapy is likely low • Genotypic diversity and sequential colonization with multiple strains could explain low resistance Dannaoui, et al. J Med Microbiol 2004;53:129-134.

  16. Voriconazole Fungicidal Activity on Hyphae • Previous in vitro studies examined killing of conidia and germinated conidia (sporelings) • But patients have hyphae growing • Voriconazole killed hyphae in both time- and concentration-dependent fashions • Kill curve and MTT cell wall viability testing • Voriconazole had better fungicidal activity against A. fumigatus hyphae than AmB at 48 hours • VCZ 1 ug/ml >95% killed on agar (AmB 1 ug/ml 70% killed) • VCZ 1 ug/ml 99% killed in broth (AmB 1 ug/ml 82% killed) Krishnan S, et al. J Antimicrob Chemother ePub April 20005

  17. Only Three Randomized Clinical Trials ever completed for the Treatment of Invasive Aspergillosis

  18. Global Comparative Aspergillosis Study (307/602)DRC-Assessed Success at Week 12 (MITT) 76/144 Same outcome in each separate protocol 42/133 Voriconazole arm success = 52.8%; Amphotericin arm = 31.6% Difference (raw) = 21.2%, 95 % CI (9.9, 32.6) Difference (adjusted) = 21.8%, 95% CI (10.5, 33.0) Herbrecht R, et al. N Engl J Med 2002; 347:408-415

  19. Global Comparative Aspergillosis Study (307/602) DRC-Assessed Success at Week 12 (MITT) Overall Pulmonary Extra Pulmonary Allogeneic BMT Autologous BMT / other hematological (e.g. leukemia) Other immunosuppressed state (e.g. SOT, HIV/AIDS) Neutropenic (ANC < 500) Non-Neutropenic (ANC  500) Proven IA Probable IA % Difference in Success Rates (95% CI) Herbrecht R, et al. N Engl J Med 2002; 347:408-415

  20. Global Comparative Aspergillosis Study (307/602) Time to Death (MITT) Voriconazole +/- OLAT Amphotericin B +/- OLAT Probability of Survival Day 84 survival: Voriconazole arm 71%; Amphotericin B arm 58% Hazard ratio = 0.60 95% CI (0.40, 0.89) Number of days of Therapy Herbrecht R, et al. N Engl J Med 2002; 347:408-415

  21. ABCD (6 mg/kg/d) vs. AmB-D (1.0–1.5 mg/kg/d) • Prospective, double-blind, randomized, controlled clinical trial, risk stratified before randomization; 1993-1997 ABCDAmB-D Evaluable Patients (n=50) (n=53) Therapeutic response 52% 50.9% p=0.96 (complete, partial, or stable) Overall Mortality 36% 45% p=0.4 Fungal Mortality 32% 26% p=0.7 Renal Toxicity 25% 49% p=0.002 Median time to renal toxicity 301 d 22 d p<0.001 Intent to Treat (n=88) (n=86) Complete Response 5.7% 3.5% Partial Response 6.8% 11.6% • ABCD equivalent efficacy and superior renal safety • Study terminated early due to low accrual Bowden R, et al. Clin Infect Dis 2002;35:359-66.

  22. Liposomal AmB1 mg/kg/d versus 4 mg/kg/d 1 mg/kg/d4 mg/kd/dp value (n=41) (n=46) Clinical CR + PR (inc. stable) 64% 48% 0.144 Radiologic CR + PR 58% 54% 0.694 6-month survival 43% 37% Overall deaths 59% 67% • Overall response rate of 55% • Overall 6-month mortality of 63% Ellis M, et al. Clin Infect Dis 1998;27:1406-12.

  23. Switching to Other Licensed Therapies • Received OLT in Voriconazole vs. AmB • Initial VCZ 36% (52/144) • Initial AmB 80% (107/133) • 159 total patients received OLT • 38% Lipid AmB formulation • 33% Itraconazole • 21% AmB deoxycholate (inc. reduced dose) • 8% Other antifungals • Switches due to Intolerance/Insufficient response • VCZ 24% (35/144) after median 12 days (1-83 days) • AmB 70% (93/133) after median 9 days (1-74 days) (p<0.000001) Boucher HW, et al. ICAAC 2003, Abstract M-964

  24. Use the Best Therapy First • Patient Success • 33% (31/93) AmB receiving OLT • 30% (14/47) AmB followed by lipid AmB (median 13 days) • 53% All randomized to VCZ (p<0.01) • Strategy of Voriconazole followed by OLT for intolerance or insufficient response was more successful than AmB with OLT (including lipid AmB) • Stresses the importance of initial therapy of voriconazole for IA Boucher HW, et al. ICAAC 2003, Abstract M-964

  25. Early Treatment is Critical • Mortality when treatment started after diagnosis: < 10 days 40% > 11 days 90% Von Eiff, et al. Respiration 1995;62:241-7.

  26. Voriconazole as Primary Therapy Therapy Complete Partial Stable Failure Total Primary 10 (17%) 25 (42%) 11 (18%) 14 (23%) 60 (52%) Salvage 6 (11%) 15 (27%) 13 (23%) 22 (39%) 56 (48%) Denning DW, et al. Clin Infect Dis 2002;34:563-71.

  27. Echinocandin Activity on Aspergillus Hyphal Tip • Caspofungin (0.3 ug/ml)-treated, DiBAC-stained A. fumigatus • 6 hours incubation • 2,000X magnification Bowman JC, et al. Antimicrob Agents Chemother 2002;46:3001-3012.

  28. Caspofungin Salvage Therapy • Open, non-comparative, multi-center trial • 90 patients with IA enrolled (median 51 yrs; 15-73) • Efficacy evaluation of 83 patients • 71 patients (86%) refractory to therapy • 12 patients (14%) intolerant to therapy • 45% (37/83) with favorable outcome • 50% (32/64) with pulmonary IA • 23% (3/13) with disseminated IA Maertens J, et al. Clin Infect Dis 2004; 39:1563-71. • 46 Neutropenic patients with IA • Favorable response (35%) • 42% as primary therapy • 32% as salvage therapy Kartsonis N, et al. 14th ECCMID, Abstract 0422

  29. Concentration-Dependent Caspofungin Activity • Murine model of pulmonary IA • Substantial differences in fungal burden as determined by qPCR • Largest reduction in burden by those dosing regimens achieving the highest peak concentrations • Histological apical hyphal damage most at highest dose • Trend toward improving survival with maximal dosing • Paradoxical “Eagle Effect” at highest dose, with an increase in tissue burden (but no decrease in survival) • Same effect seen in other cell-wall active antibacterials Wiederhold NP, et al. J Infect Dis 2004;190:1464-71.

  30. Micafungin Monotherapy Open-Label Trial in Japan • 70 patients at 29 sites; 56 pts eval. for efficacy (IA = 42) DiseaseResponse Invasive pulmonary (n=10) 60% (8 pts with leukemia or lymphoma; 2 neutropenic) Max dose 50 mg/d 50% (1/2) 75 mg/d 33% (1/3) 150 mg/d 80% (4/5) Disseminated (n=1) 0% Chronic necrotizing pulmonary (n=9) 67% Pulmonary aspergilloma (n=22) 55% • AE related to micafungin reported in 30% of patients Kohno S, et al. Scand J Infect Dis 2004;36:372-9.

  31. Posaconazole Monotherapy • Multicenter study for salvage therapy • Included 25 pts with IA • Effective in 53% (8/15) at week 4 • Effective in 85% (6/7) at week 8 • No mention of patients without complete follow-up Hachem RY, et al. ICAAC 2000, Abstract 1109 • Multi-center study of patients with IA refractory to or intolerant of AmB formulations and itraconazole • 107 posaconazole, 86 controls • Global response rate at end of treatment • Posaconazole 42% • Controls 26% Walsh TJ, et al. ASH 2003, Abstract 682

  32. Cerebral Aspergillosis • 86 patients (9 mo - 81yo) with proven or probable CNS aspergillosis • A. fumigatus (n=34); A. nidulans (n=5); Aspergillus spp. (n=24) • Underlying disease • BMT (n=33); Hem malignancy (n=14) • SOT (n=12); Acquired/Cong immunosuppression (n=15) • Other (n=12) • Only 13/86 received VCZ primary therapy (others with previous antifungal therapy before VCZ use) • Global Clinical Outcome • Complete / Partial Response 34% • Stable / Failed response 66% • BMT Recipient Response 15% • All Others Response 42-50% Troke PF, et al. ICAAC 2003, Abstract M-1755

  33. Bone Aspergillosis • 20 patients from Clinical trials and Compassionate use • Bone Involvement • Spondylodiscitis (n=9); Sternum/Rib (n=6); Peripheral (n=5) • Immunocompromised (n=14) • Largest population: Chronic Granulomatous Disease (n=5) • Bone was the only infection site in 10 patients • Salvage voriconazole therapy in 18/20 patients • Median duration of voriconazole 83.5 days (4-395 days) • Global Clinical Outcome • Complete / Partial Response 55% (11/20) • Complete (n=4); Partial (n=7), Failure (n=9) Mouas H, et al. Clin Infect Dis 2005;40:1141-7.

  34. Combination Antifungal Therapyin Invasive Aspergillosis

  35. Combination Therapy Rationale • Widened spectrum and potency • More rapid antifungal effect • Additive or synergistic efficacy effects • Lowered dosing or less toxicity • Reduce risk of emerging resistance • Historic poor outcomes with monotherapy • Increased penetration / transport • Inhibit different stages of the same biochemical pathway • Simultaneous inhibition of different fungal targets • Creation of a fungicidal combination

  36. 1966-2001 Review of Combination Therapy StudiesSynAddIndiff Antag In vitro (n=28) 36% 24% 28% 11% In vivo (n=18) 14% 20% 51% 14% • AmB + Itraconazole generally indifferent interactions in vitro, in vivo, and clinically • 249 cases met combination Rx inclusion criteria • Most common combinations: • AmB + Flucytosine (49%) • AmB + Itraconazole (16%) • AmB + Rifampin (11%) • Overall 63% of clinical cases reported improvement Steinbach WJ, et al. Clin Infect Dis 2003;37 (suppl 3): S188-224

  37. Only Clinical Trial of Combination Antifungal Therapy for Aspergillosis • 28 neutropenic adult pts with proven IFI • AmB (0.5 mg/kg/d) (n=14) • AmB + 5-FC (n=14) • Survival: • AmB alone: 2/14 (mortality 86%) • AmB + 5-FC: 3/14 (mortality 79%) • 15/18 with invasive aspergillosis died • 3 who survived had immune recovery • Study terminated early, problems included: • IA so far advanced at initiation • Low dose AmB used Verweij PE, et al. Infection 1994;22:81-5.

  38. Experimental:Voriconazole + Caspofungin • In Vitro • 48 isolates, Synergy (87.5%) of interactions (FICI < 1.0) Perea S, et al. Antimicrob Agents Chemother 2002;46:3039-41 • In Vivo: Neutropenic guinea pig model • Mortality (0/12 animals) and survival time (8 days) SAME in EACH of these arms: • VCZ 5mg/kg/d • CAS (1 mg/kg/d) + VCZ • CAS (2.5 mg/kg/d) + VCZ • Fungal burden (CFU) with combination better than untreated controls only • Number of organs with positive cultures with combination better than monotherapy Kirkpatrick WR, et al. Antimicrob Agents Chemother 2002;46:2564-8

  39. Experimental:Ravuconazole + Micafungin • Neutropenic rabbit model • Survival • Micafungin monotherapy (0/8) • Ravuconazole monotherapy (2/8) • Micafungin + Ravuconazole (9/12) • Fungal burden, GM assay, Pulmonary injury, Pulmonary infiltrates all less in the combination Petraitis V, et al. J Infect Dis 2003;187:1834-43

  40. Ravuconazole + Micafungin Petraitis V, et al. J Infect Dis 2003;187:1834-43

  41. Ravuconazole + Micafungin Hyphal Damage Micafungin Untreated Control Ravuconazole + Micafungin Ravuconazole • The spherical chlamydoconidial structures are evidence of the effect of echinocandins • The focal hyphal disintegration and disruption are compatible with the effects of triazoles • Original magnification ×630; Insert, ×1000; Scale bar 20 um Petraitis V, et al. J Infect Dis 2003;187:1834-43

  42. Clinical Combination Therapy Reports • Caspofungin + L-AmB salvage after previous L-AmB (n=48) • Overall response rate 42%; Response in progressive IA 18% Kontoyiannis DP, et al. Cancer 2003;15:292-9 • Micafungin + existing antifungal in 85 BMT pts • 39% (28%) complete/partial response Ratanatharathorn V, et al. ASH 2002, Abstract A-2472 • Open-label Micafungin salvage therapy in 283 patients • In salvage patients (IA, >7d prior therapy & >7d micafungin) 11/49 (22%) allogeneic HSCT responded 22/45 (49%) leukemia patients responded Ullman AJ, et al. ECCMID 2003, Abstract 0400 • Salvage therapy with posaconazole • Posaconazole 29% • AmB lipid 8% (p=0.01) • AmB lipid + Itraconazole 16%(p=0.2) Raad II, et al. IDSA 2004, Abstract 678

  43. Voriconazole + Terbinafine • Previously reported in vitro synergistic/additive effect with terbinafine against Aspergillus • Immunosuppressed rat model A. fumigatus • AmB 1 mg/kg/d • VCZ 6 or 9 mg/kg/d • Terbinafine 150 mg/kg/d • VCZ 9 mg/kg/d (41%) increased survival over AmB (28%) (p< 0.05) • All treatment groups except AmB significantly increased survival compared to Terbinafine (13%) • Addition of Terbinafine to VCZ did not improve survival • Combination reduced fungal counts compared to control and AmB Gavalda J, et al. ICAAC 2004, Abstract M-224

  44. New Data:Combination Therapy for IA • 47 patients with proven/probable IA from 1997-2001 • Patients experienced failure of initial therapy with AmB formulations • Received either voriconazole (n=31) or voriconazole + caspofungin (n=16) as salvage therapy • Voriconazole + Caspofungin with improved 3-month survival rate compared to voriconazole monotherapy (HR 0.42; 95% CI 0.17-1.1; p=0.048) • Multivariate model, combination with reduced mortality (HR 0.28; 95% CI 0.28-0.92; p=0.11) Marr KA, et al. Clin Infect Dis 2004;39:797-802.

  45. Voriconazole vs. Voriconazole + Caspofungin Kaplan-Meier probability of survival after diagnosis P = .048, calculated from the likelihood ratio test using Cox regression Marr KA, et al. Clin Infect Dis 2004;39:797-802.

  46. Primary Combination Therapy • Retrospective single center cohort review of consecutive patients with IA and an underlying hematologic malignancy (Jan 98 – July 03) • Proven (n=17) / Probable (n=17) / Possible (n=11) by EORTC/MSG • Data presented below for Proven / Probable cases only ALL ComboMonoP value (n=34) (n=10) (n=24) 12 wk Survival 53% 50% 54% 0.82 Median Survival (d) 110 102 115 --- CR/PR 41% 50% 37.5% 0.5 Stable 5.9% 0% 8.3% -- Failure 53% 50% 54% 0.86 • No differences in survival between primary therapy with mono vs. combo Munoz LS, et al. ICAAC 2004, Abstract M-1024

  47. In Vitro Treatment PRIOR to Combination Antifungal Therapy • Subinhibitory concentration of AmB against Caspo + Vori or Caspo + Ravuconazole Percentage of further reduction in growth following AmB addition AmB 0.1 ug/mlAmB 0.2 ug/ml • Caspo + VCZ 33% (14-57%) 34% (13-59%) • Caspo + RVZ 11% (0-30%) 28% (16-48%) • Significant for all species except A. terreus for Cas/VCZ and A. fumigatus Cas/RVZ at AmB 0.1 ug/ml • FICI (0.5-1.9) for each triple combination improved by adding subinhibitory concentration of AmB – additive to indifferent effect O’Shaughnessy EM, et al. ICAAC 2004, Abstract M-249

  48. Pediatric Antifungal Data

  49. Pediatric Voriconazole • Elimination by Linear pharmacokinetics in children following doses of 3 and 4 mg/kg/q12h • Single dose, Open, two center study in UK • 11 Children ages 2-11 yrs (mean 5.9 yrs) • Multiple dose, Open, 8 center, two-cohort (ages 2-6, 6-12) • 28 children, mean age 6.4 yrs • Higher elimination capacity on a weight basis than do adult healthy volunteers Walsh TJ, et al. Antimicrob Agents Chemother 2004;48:2166-72.

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