6 | Ayres

Three Years After the SECURE Trial – Are We Still Feeling Secure with Isavuconazole?

Chase Ayres, PharmD PGY-1 Pharmacy Resident

Department of Pharmacotherapy and Pharmacy Services, University Health System Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, UT Health San Antonio November 22nd, 2019

Learning Objectives

1. Describe pathophysiology and diagnosis of invasive pulmonary aspergillosis (IPA) 2. Review current practices for treatment of IPA 3. Evaluate recent evidence for and against isavuconazole use for IPA 4. Identify preferred agent for primary treatment of IPA

08 Fall

2 | Ayres

Assessment Questions 1. Which of the following comorbidities confers the highest risk for developing IPA?

A. HIV-positive B. Allogeneic stem cell transplant C. Type II diabetes mellitus D. Colorectal cancer

2. True or False? Treatment of IPA should be initiated only after a pathogen has been isolated from sterile culture.

A. True B. False

3. Which of the following agents is NOT an appropriate first-line option for treatment of IPA?

A. Isavuconazole B. Liposomal Amphotericin B C. Voriconazole D. Caspofungin

***To obtain CE credit for attending this program please sign in. Attendees will be

emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***

Faculty (Speaker) Disclosure: Chase Ayres has indicated he has no relevant financial relationships to disclose relative to the content of his presentation

3 | Ayres

Background

I. Invasive Aspergillosis (IA)1-3 a. Potentially life-threatening infection caused by environmental molds, most

commonly affecting immunocompromised patients b. Epidemiology

i. Approximately 15,000 hospitalizations in the US attributed to IA yearly ii. Annual healthcare cost estimated at $1.2 billion

iii. Mortality rate >25-90% 1. If left untreated, 100%

iv. Incidence of 0.5-11% in at-risk populations II. Aspergillus species4

a. Genus of spore-forming, filamentous fungus found naturally in soil, water, air, decaying vegetation, and other organic debris

b. Favors warm, damp habitats c. Inhaled regularly but not pathogenic in most immunocompetent individuals d. Most common species isolated in human infections include A. fumigatus, A. flavus, A.

terreus, and A. niger1 Figure 1. Overview of Fungi4

III. Spectrum of disease a. Allergic bronchopulmonary, chronic, and invasive aspergillosis infections1-4

i. Pulmonary disease is most common due to direct environmental exposure 1. Conidia small enough (2.5 to 3 microns) to reach alveoli 2. Spores may eventually germinate into invasive hyphae, causing

infection ii. Invasive pulmonary aspergillosis (IPA) is the most common manifestation

IV. Invasive pulmonary aspergillosis (IPA)1-6 a. Accounts for >90% of all IA b. Advanced infection may disseminate elsewhere in the body, including the central

nervous system c. Patients with underlying pulmonary disease or immune compromise are at higher

risk (Figure 2)

Fungi

Yeasts

Candida Cryptococcus

Molds

Septate Fungi

Aspergillus Fusarium

Mucorales

Mucor Rhizopus

Dimorphic Fungi

4 | Ayres

d. Pathogenesis1,7 i. Immunocompetent

1. Aspergillus conidia regularly inhaled from environment 2. Respiratory epithelial cells provide physical barrier to infection 3. Alveolar macrophages help clear conidia and promote secondary

inflammation a. Recruit neutrophils and natural killer cells to site of infection

ii. Immunocompromised 1. Immune deficiency allows germination from conidia into hyphae,

subsequently leading to invasive fungal disease 2. Neutrophils are the main defense against invasive hyphae

a. Patients with severe, prolonged neutropenia are particularly vulnerable

i. ANC <500 cells/mcL for > 10 days Figure 2. Risk categories for IPA8

e. Diagnosis9,10 i. No gold standard diagnostic test available

ii. Clinical diagnosis based on multiple factors and classified as proven, probable, or possible (Appendix 1)

iii. Microbiological (Table 1) 1. Isolation of Aspergillus coupled with clinical manifestations of infection

a. Cultured from respiratory source (e.g. bronchoalveolar lavage) b. Risk factors must be accounted for with clinical presentation

2. Visualized via microscopy a. Morphology described as septated hyaline hyphae branching at

45 degree angles b. Sometimes confused other hyaline molds such as Fusarium spp

Highest Risk

•Chronic granulomatous disease •Allogenic stem cell transplant with graft-versus-host disease •Lung transplantation •Acute myeloid leukemia/myelodysplastic syndrome with induction therapy or in

relapse

Intermediate Risk

•Allogeneic stem cell transplant without graft-versus-host disease •Non-lung, non-kidney solid organ transplant •Acute lymphoblastic leukemia •Acute myeloid leukemia (consolidation phase) •Chronic lymphoblastic leukemia •Myelodysplastic syndrome

Low Risk

•Multiple myeloma •Chronic obstructive pulmonary disease acute exacerbation •Acquired immunodeficiency syndrome •Non-hodgkins's lymphoma •Autologous stem cell transplant •Kidney transplant •Solid tumor •Autoimmune disorder

5 | Ayres

3. Respiratory culture should be evaluated in conjunction with histopathology or culture from sterile site

a. Both cultures and tissue microscopy have low sensitivities iv. Radiographic

1. Computed tomography (CT) scan of chest recommended when IPA suspected

2. Nodules with surrounding ground-glass opacities (halo-sign) common with early IPA and represent alveolar hemorrhage

v. Additional Laboratory Tests Table 1. Laboratory Diagnostics

Galactomannan (GM) antigen detection

Beta-D-glucan assay

Nucleic acid detection via polymerase chain reaction

(PCR)

Polysaccharide found in cell walls of Aspergillus

Presence of GM antigen in serum or bronchoscopy acts as an indirect marker of Aspergillus

Cross-reaction with other fungi may produce false-positive results

1,3-Beta-D-glucan is found in many fungi cell walls

May indicate presence of invasive fungal infection

Best utilized early if infection suspected

Recommended in hematologic malignancy and HSCT, but not specific for Aspergillus

May result positive for Candida spp or Pneumocystis jiroveci

Remains negative for Mucor and Cryptococcus

Evidence lacking to form consensus, should be employed alongside other diagnostic modalities, if at all

6 | Ayres

Table 2. Available Mold-Active Antifungals10-18

Drug Mechanism

of Action Dosing and

Formulations Half-life (h)

Enzyme Inhibition

Therapeutic Drug Monitoring

Adverse Effects Cost ($/d)

PRIMARY THERAPY Voriconazole (VRC)

Inhibits ergosterol synthesis

6 mg/kg Q12H IV for 1 d, then 4 mg/kg IV q12h (IV solution);

200-300 mg PO Q12H or 3-4

mg/kg PO Q12H (tablets and PO

suspension)

Variable, dose-dependent

CYP3A4 (strong) CYP2C19

(moderate)

Target trough 1.5-5 mcg/mL

Visual hallucinations, QTc prolongation,

hepatotoxicity, hyperkalemia and

hypokalemia, skin rash, hypertension

PO: 35 IV: 56

ALTERNATIVE THERAPY

Isavuconazole (ISA) Inhibits

ergosterol synthesis

200 mg Q8H for 6 doses, then 200 mg daily

(IV solution, PO capsules)

130 CYP3A4

(moderate) Not recommended

Hepatotoxicity, hypokalemia, QTc

shortening, skin rash, edema

PO:172 IV: 290

Amphotericin B (AmB)

Binds ergosterol

3-5 mg/kg/day (liposomal

suspension); 1-1.5 mg/kg/day (conventional

solution); 5 mg/kg/day

(lipid complex suspension)

7-10 on initial dosing, 100-153

terminally (liposomal); 15-

48 on initial dosing, 15 days

terminally (conventional);

170 (lipid complex)

N/A N/A

Nephrotoxicity, hypokalemia,

hypomagnesemia, hypotension, infusion

related reactions (chills, fever)

Conv’l: 35 Lipo: 300-540

SALVAGE THERAPY

Caspofungin Inhibits 1,3-beta-D-glucan

synthesis

70 mg/day x1, then 50 mg/day

(IV solution) 27-50 N/A N/A

Hypotension, edema, skin rash,

thrombocytopenia, neutropenia,

IV: 60

7 | Ayres

hepatotoxicity

Micafungin Inhibits 1,3-beta-D-glucan

synthesis

100-150 mg/day (IV

solution 14-17.2 N/A N/A

Anemia, hepatotoxicity, phlebitis

IV: 62

Posaconazole (POS)

Inhibits ergosterol synthesis

300 mg BID on day 1, then 300

mg daily (IV solution,

delayed-release tablet)

26-31 CYP3A4 (strong)

Prophylaxis: target trough ≥0.7 mcg/mL

Treatment: target trough ≥1 mcg/mL

Thrombophlebitis, rigors, QTc

prolongation, hypertension, edema,

skin rash, thrombocytopenia,

neutropenia, hepatotoxicity

PO:191 IV: 490

Itraconazole Inhibits

ergosterol synthesis

200 mg PO Q12H (PO

suspension) 25-50

CYP3A4 (strong)

0.5 – 3 mcg/mL

Edema, hypertension, skin rash, fever,

headache, hepatotoxicity

PO:20-64

8 | Ayres

Treatment of Invasive Pulmonary Aspergillosis10

I. Infectious Diseases Society of America (IDSA) 2016 Aspergillosis Guidelines recommend voriconazole for primary treatment of IPA (strong recommendation, high-quality evidence)

II. Isavuconazole, liposomal amphotericin B (L-AmB), and amphotericin B lipid complex (ABLC) recommended as alternatives (ISA, L-AmB: strong recommendation, moderate-quality evidence; ABLC: weak recommendation, low-quality evidence)

Figure 3. History of Treatment

III. Amphotericin B11

a. Polyene antifungal brought to market in 1959 b. Broad spectrum of activity against molds and yeasts alike c. Considered first-line treatment prior to 2000s

i. Lack of available agents with in vitro activity against Aspergillus ii. Significant adverse effect (AE) profile limited use

iii. Mortality rates with amphotericin B deoxcholate (AmB-D) remained high d. Improved liposomal formulations developed in the late 1990s

i. Widened therapeutic index and enhanced tolerability IV. Voriconazole

a. Compared to AmB-D for treatment of IA in randomized controlled trial by Herbrecht and colleagues in 2002 (Table 2)19

Table 2. VRC versus AmB-D Design Overview

i. VRC patients achieved successful outcome in 52.8% compared to 31.6% of

AmB-D patients (95% CI, 10.4-32.9) ii. VRC patients experienced significantly fewer adverse events

Development of amphotericin B (conventional)

1958

1990s

Liposomal formulations of amphotericin B

emerge

Voriconazole proven superior to amphotericin

B

for IPA

2002

2015

Isavuconazole approved

(SECURE trial)

Design Patient Population Intervention Primary Outcome Randomized control trial (RCT) comparing VRC to AmB-D as primary therapy for IA

≥ 12 years of age immunocompromised Definite or probable IA

Voriconazole (n=144)

Amphotericin B

deoxycholate (n=133)

Response rate at Week 12

Complete or partial response

9 | Ayres

1. Superior safety profile for renal impairment, hypokalemia, systemic events (fever, chills, anaphylaxis, asthenia, or myalgia), dyspnea

2. Fewer treatment discontinuations in VRC arm a. VRC 13.4% vs AmB-D 24.3%, p=0.008

iii. Non-inferiority trial showed VRC to be superior to AmB-D 1. VRC supplanted amphotericin B as drug of choice for IA 2. Rapid shift in standard of care for IPA

a. Ease of administration (oral therapy) b. Tolerable c. Efficacious

V. Isavuconazole15,21 a. Newest triazole antifungal

i. Approved in 2015 ii. Activity against Aspergillus and other molds, including Mucorales

b. Formulated as prodrug, isavuconazonium sulfate

Table 3. SECURE Trial Design Overview

c. Results i. All-cause mortality

1. Day 42: ISA 19%, VRC 20% a. Adjusted treatment difference -1.0%, 95% CI -7.8 to 5.7

2. Day 84: ISA 29%, VRC 31% a. Adjusted treatment difference -1.4%, 95% CI -9.2 to 6.3

ii. Overall response at end of treatment 1. Complete or partial success: ISA 35%, VRC 36%

d. ISA met noninferiority endpoints compared to VRC e. ISA patients experienced significantly fewer drug-related AE overall (42% vs 60%,

p<0.001) i. Treatment-emergent AE: significantly fewer skin and subcutaneous skin

disorders (33% vs 42%, p=0.037), eye disorders (15% vs 27%, p=0.002), and hepatobiliary disorders (9% vs 16%, p=0.016)

ii. Drug discontinuation rates lower in ISA arm (significance not reported) 1. Discontinuation due to treatment-emergent AE: ISA 14% vs VRC

23% 2. Discontinuation due to drug-related AE: ISA 8% vs VRC 14%

f. ISA granted FDA approval for treatment of IA i. VRC remains primary treatment recommendation in 2016 aspergillosis

guidelines 1. Older option with evidence and experience supporting its use 2. Therapeutic drug monitoring available and validated 3. Significant drug-drug interactions and side effect profile

ii. ISA recommended as alternative therapy based on SECURE22 1. Less evidence outside clinical trials to lend confidence to its use

Design Patient Population Intervention Primary Outcome

Double-blind, RCT conducted in population of primarily IA patients

≥ 18 years of age Criteria for proven,

probable, or possible invasive mold disease

Isavuconazole (n=258)

Voriconazole

(n=258)

All-cause mortality by day 42

10 | Ayres

2. Therapeutic drug monitoring not validated, but also may not be necessary23,24

3. Fewer drug-drug interactions and significantly more favorable safety profile compared to VRC25

SECURE Case

reports Real-world

studies

Clinical Question: Should isavuconazole be preferred therapy in the treatment of IPA?

8 | Ayres

Abbreviations: HCT, hematopoietic stem cell transplant; HM, hematologic malignancy; IFI, invasive fungal infection; ISA, isavuconazole; L-AmB, liposomal amphotericin B

ISA affected by hepatic function o No dosing recommendations currently available o Insufficient data to compare to VRC in hepatic failure

Early breakthrough data concerning o ISA expected to be equal with VRC based on SECURE results o Requires more thorough investigation

Table 4. Early Real-World Experience with Isavuconazole

Article Design/Purpose Population Drug Regimen Results (Efficacy/Safety)

Arsiè E, et al. 201826 Case report

58 year old male with history of

HBV-cirrhosis (Child Pugh Score

class C). Treated for possible IPA.

L-AmB x1 dose, then

ISA 200 mg daily post

loading regimen x1

week, followed by 200

mg every other day

ISA concentration after 1 week

200 mg daily = 7.5 mg/L

ISA concentration after 1 week

200 mg every other day = 9.5

mg/L

Patient eventually died of

multiorgan failure in setting of

worsening infection

Dadwal S, et al.

201627

Abstract report HM and HCT patients who received

≥7 days ISA for IFI treatment

n=131

ISA (dosing not

reported) 6 patients (4.6%) developed

breakthrough IFI

4 with Aspergillus, 1

with Rhizopus spp., and 1

with Candida

norvegensis

All patients had detectable

trough levels (range 1.4-4.8

mg/L)

Fung M, et al. 201828 Single-center

retrospective

observational report

≥18 years old with HM or solid

organ transplant with confirmed

breakthrough IFI while on ISA

n=5

ISA 200 mg daily,

with or without

loading dose, for

either prophylaxis or

treatment

All patients presented with

pneumonia

2 patients with Aspergillus niger

1 each of Rhizopus spp.,

Scedosporium apiospermum,

Aspergillus fumigatus

3 of 5 patients died

12 | Ayres

Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole

Rausch CR, DiPippo AJ, Bose P, et al. Clin Infect Dis. 201829

Objective Report evidence of breakthrough invasive fungal infections (b-IFI) in patients receiving isavuconazole

Methods Design Single-center retrospective observational case series Patient Population

681 bed academic medical center in Houston, Texas Inclusion Criteria Exclusion Criteria

Adult patients in leukemia service Received ISA for prophylaxis or treatment of IFIs ≥ 7 days

Concomitant antifungal agent for IFI treatment

Results Demographics (n=100)

Male gender, 73 (73%) Median age, 68 years [range 24-91] Neutropenia at time of ISA initiation, 69 (69%); > 14 days, 61 (61%) Malignancy types: AML (70%), ALL (10%), CML blast crisis (2%), CLL (6%), other

(12%) Treatment of aspergillosis, 57 (57%) Primary prophylaxis, 27 (27%) Secondary prophylaxis, 16 (16%) ISA started in 39 patients previously on posaconazole

o Switched due to intolerance or failure to reach therapeutic levels

Results

Total b-IFI rate of 13% o Treatment, n=6/13 (46%) o Primary prophylaxis, n=5/13 (39%) o Secondary prophylaxis, n=2/13 (15%)

Mold-causing b-IFI, n=6 (46%) o Mortality rate, 50% o Aspergillus spp. rate, 7.7%

Rate of b-IFIs nonneutropenic at diagnosis, n=4 (31%) Additional 7 patients had possible breakthrough fungal pneumonia

Table 1. Occurrence of proven or probable breakthrough IFIs Patient Age/Sex

ANC, cells/mcL

ISA indication

Duration of ISA, d

b-IFI Breakthrough pathogen

ISA MIC, mcg/mL

45/F <100 Secondary

prophylaxis 146 Esophagitis

Candida albicans

N/A

71/M 500-1000 Treatment 7 Fungemia Candida

parapsillosis N/A

52/M <100 Primary

prophylaxis 53 Fungemia

Trichosporon asahii

0.5

76/M 500-1000 Primary

prophylaxis 14

Disseminated

Rhizopus spp. 2

61/F <100 Primary

prophylaxis 34 Pneumonia

Mucorales spp.

N/A

13 | Ayres

o Real-world data necessary to evaluate ISA’s place in therapy o Breakthrough infections a concern for anti-fungal agents

Isavuconazole b-IFI rates ranged 4.6-13% Previously reported b-IFI rates across retrospective studies30-35

Posaconazole: 7.5% Voriconazole: 2.4-14%

o ISA and VRC are likely equally efficacious for IPA What other evidence has emerged since ISA approved?

30/M <100 Secondary

prophylaxis 63 Fungemia

Candida guilliermondii

1

76/F 100-500 Treatment 81 Pneumonia Fusarium spp. N/A

54/F <100 Treatment 160 Disseminat

ed Candida

krusei 4

34/M <10 Primary

prophylaxis 24 Fungemia

Candida glabrata

4

51/F >1000 Primary

prophylaxis 41 Fungemia

Candida glabrata

4

60/F 500-1000 Treatment 157 Pneumonia,

fungemia

Rhizopus spp.; C.

glabrata N/A

61/M 100-500 Treatment 194 Pneumonia Rhizomucor

spp. N/A

78/F <100 Treatment 26 Disseminat

ed Aspergillus

spp. N/A

ANC, absolute neutrophil count (at time of b-IFI diagnosis); b-IFI, breakthrough invasive fungal infection; ISA, isavuconazole; MIC, minimum inhibitory concentration; N/A, nonapplicable

Author’s Conclusions

Single-agent ISA resulted in higher than expected rate of breakthrough infection Breakthrough infections occurred primarily in non-Aspergillus spp.

Reviewer’s Critique Strengths Most comprehensive report to date for b-IFIs on ISA Limitations Retrospective, observational

Small, single-center Previous posaconazole exposure in many patients ISA MICs not tested for all patients Limited to leukemia patients No comorbidities reported

Overall Conclusions

ISA associated with relatively high rates of b-IFI Candida spp. represent most common b-IFI pathogens on ISA

14 | Ayres

Studies conducted with isavuconazole since SECURE

Lack of Toxicity With Long-term Isavuconazole Use in Patients With Hematologic Malignancy

DiPippo A, Kontoyiannis D. Clin Infect Dis. 201936

Objective Present real-world tolerability data in hematologic malignancy patients on long-term isavuconazole

Methods Design Single-center retrospective report Patient Population

681 bed academic medical center in Houston, Texas Inclusion Criteria Exclusion Criteria

Consecutive patients receiving isavuconazole continuously for ≥ 6 months

Diagnosed with hematologic malignancy

N/A

Results Demographics (n=50)

Male gender, n=35/50 (70%) Median age, 61 years (range, 23-91) Malignancy types: AML/MDS (60%), ALL (12%), B-cell lymphomas (8%), CLL (6%),

CML (6%), MM (4%), aplastic anemia (4%) Median ISA duration, 356 days (range, 180-832) Indication for ISA

o Possible or presumed infection (66%) o Mold-active prophylaxis (34%)

Results Table 1. Toxicity Indicators of Chronic (≥6 Months) ISA Use

Indicator Baseline 3 Months 6 Months 12 Monthsa 24 Monthsa

ECG QTc 421 (324-

531)b 405 (371–

473)d 400 (372–

476)f 425.5

(371–471)h 391 (362–

399)k Endocrine SBP, mm Hg 124.5 (94–

171)

126 (96–155)

122.5 (88–163)

125.5 (90–

149)i

119.5

(102–154)l

Serum potassium,

mg/dL

3.8 (2.7–5.7)

4.1 (3–5.3)

4.25 (3.1–5.2)

4.2 (3.1–

5.9)i

3.9 (3.3–

5.1)l

Liver function tests ALT, U/L 37 (12–

426) 33 (12–

155) 33.5 (14–

224)

33 (16–

460)i

26 (6–63)l

AST, U/L 31 (12-245)c

29.5 (15-185)e

29 (17-184)g

29 (13-325)j

26 (11-83)m

Alkaline phosphatase, U/L

103 (38–570)

86 (52–357)

90.5 (43–240)

97.5 (48–

434)i

83.5 (58–

330)l

15 | Ayres

Total bilirubin, mg/dL

0.8 (0.2–3.7)

0.7 (0.3–4.2)

0.6 (0.2–5.9)

0.6 (0.2–

14.1)i

0.5 (0.2–1.4)l

All values presented as median (range) Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; SBP, systolic blood pressure. aOr last date of isavuconazole (ISA) as appropriate. bn = 33.. cn = 34. dn = 24. en = 44. fn = 21. gn = 49. hn = 27. in = 46. jn = 38. kn = 6. ln = 18. mn = 15. Sixteen occurrences of toxicity possibly related to ISA use

o Hepatotoxicity: 4 (8%) o Skin rash: 6 (12%) o Blurry vision: 3 (6%) o Squamous cell carcinoma: 2 (4%) o Neurologic toxicity: 1 (2%)

Author’s Conclusions

First real-world data assessing long-term tolerability of ISA ISA was well tolerated overall

Reviewer’s Critique Strengths First real-world report of effects of chronic ISA use

Spectra of ISA-attributed toxicity largely consistent with SECURE o Primarily hepatobiliary, skin, ophthalmic events

Limitations No comparator group Retrospective, single-center

o Incidence of adverse events lower than reported in clinical trials Small sample size Comorbidities not reported

Overall Conclusions

Practical evidence of successful long-term use of ISA

Comparative evaluation of isavuconazonium sulfate, voriconazole, and posaconazole for the management of invasive fungal infections in an academic medical center

Van Matre ET, Evans SL, Mueller SW, et al. Ann Clin Microbiol Antimicrob. 201937

Objective Compare safety end points between triazole antifungals in the treatment of IFIs Methods

Design Single-center retrospective matched cohort study Patient Population

678-bed academic hospital in Aurora, Colorado Inclusion Criteria Exclusion Criteria

Adult patients > 18 years of age Receipt of isavuconazole (ISA), voriconazole (VRC), or

posaconazole (POS) for active treatment of confirmed

Patients in vulnerable category such as pregnancy, prisoners

16 | Ayres

or suspected fungal infection Intervention Compared patients who received ISA vs VRC vs PSC Outcome Primary: Composite safety outcome

QTc prolongation (>470 ms for females, >450 ms for males) Liver function tests five times the upper limit of normal (ALT > 260 units/L, AST > 195

units/L) Any documented antifungal treatment related adverse event based on primary team

documentation Secondary:

Individual components of composite outcome (percent change in QTc length from baseline, percent change in calcineurin inhibitor serum concentration)

Total cost of inpatient antifungal therapy per day All-cause in-hospital mortality In hospital and ICU LOS

Statistics 30 patients needed in each group to detect 30% difference in primary outcome between groups with 80% power and 5% alpha

Categorical data compared using chi-squared test, with pairwise comparisons if statistical significance was found

Continuous, normally distributed data compared with analysis of variance test followed by pairwise t-test

Non-normally distributed data with Kruskal-Wallis test, then Mann-Whitney U tests Results

Demographics n = 100

Characteristic Total

(n=100) ISA (n=33) VRC (n=34) POS (n=33) P-value

Age, years ± SD 55.9 ± 13.7

58.8 ± 14.0 56.9 ± 11.4 52.1 ± 15.1 0.124

Primary diagnosis of oncology, n (%)

62 (62) 17 (51.5) 23 (67.6) 22 (66.7 0.097

Hematologic malignancy, n (%)

58 (93.6)

16 (94.1) 22 (95.6) 20 (90.9) 0.806

Primary diagnosis of solid organ transplant, n (%)

26 (26) 14 (42.4) 5 (14.7) 7 (21.2) 0.097

Baseline AST, units/L ± SD

27.3 ± 36.0

22.0 ± 17.7 21.9 ± 15.5 36.4 ± 41.8 0.053

Baseline ALT, units/L ± SD

26.8 ± 28.2

22.2 ± 22.0 22.5 ± 22.1 37.1 ± 53.3 0.160

Baseline QTc, ms ± SD

457 ± 40 478 ± 46 445 ± 29 450 ± 35 0.001

Concurrent echinocandin therapy, n(%)

23 (23) 8 (24.2) 5 (14.7) 10 (30.3) 0.298

Concurrent QTc prolonging medications, n (%)

83 (83) 24 (72.7) 28 (82.35) 31 (93.9) 0.057

17 | Ayres

Concurrent immunosuppression, n (%)

52 (52) 20 (60.6) 17 (50.0) 15 (45.4) 0.447

Formal infectious disease team consultation, n (%)

71 (71) 28 (84.8) 20 (58.8) 23 (69.7) 0.055

Indication for use Primary, n (%) 58 (58) 10 (30.3) 28 (82.4) 20 (60.6) < 0.001 Refractory, n (%) 24 (24) 13 (39.4) 4 (11.8) 7 (21.2) 0.027 Intolerance, n (%) 16 (16) 9 (27.3) 1 (2.9) 6 (18.2) 0.011 Other, n (%) 2 (2) 1 (3.0) 1 (2.9) 0 (0) 0.444 Treatment diagnosis Zygomycosis, n (%)

8 (8.33) 3 (9.1) 0 (0) 5 (15.2) 0.101

Aspergillosis, n (%)

30 (31.2)

12 (36.4) 10 (33.3) 8 (24.2)

Empiric treatment, n (%)

58 (60.4)

18 (54.6) 20 (66.7) 20 (60.6)

Results Clinical Outcomes

Characteristic Total

(n=100) ISA (n=33) VRC (n=34)

POS (n=33)

P-value

Primary outcome: Composite safety, n (%)

40 (40) 8 (24.2) 19 (55.9) 13 (39.4) 0.028

QTc prolongation following drug initiation, n (%)

28 (28) 4 (12.1) 13 (38.2) 11 (33.3) 0.037

LFT elevation, n (%)

8 (8.0) 2 (6.1) 3 (8.8) 3 (9.1) 0.876

Adverse reaction, n (%)

9 (9) 2 (6.1) 5 (15.2) 2 (6.1) 0.356

Change in QTc, ms ± SD

7.5 ± 42.0

-18.0 ± 37.6 20.5 ± 37.8 22.6 ± 38.6 0.001

Max QTc, ms ± SD 464.2 ± 35.1

460.0 ± 29.5 465.4 ±

33.8 467.4 ± 42.2 0.739

Change in ALT, units/L ± SD

93.2 ± 393.6

95.1 ± 440.3 105.6 ± 448.5

78.5 ± 281.2 0.964

Change in AST, units/L ± SD

192.4 ± 894.7

159.5 ± 717.3 259.2 ± 1226.2

155.4 ± 629.8 0.875

Mortality, n (%) 48 (48) 15 (45.5) 16 (47.1) 17 (51.5) 0.878 Hospital LOS, days ± SD

32.9 ± 37.4

31.8 ± 25.9 28.2 ± 19.5 38.7 ± 56.7 0.515

30 day readmission, n (%)

29 (42) 8 (34.78) 7 (30.4) 14 (60.9) 0.077

Recurrent infection, n (%)

9 (14.1) 1 (4.5) 4 (19.1) 4 (19.1) 0.230

18 | Ayres

Percent change in immunosuppression dose [IQR]

-46.1 [-27.8, -57.8]

-34.3 [-4.04, -46.5]

-48.4 [-35.1, -65.9]

-46.4 [-35.1, -65.9]

0.029

Primary outcome pairwise comparison

o ISA < VRC, p=0.008 Cost Outcomes

Characteristic Total

(n=100) ISA (n=33) VRC (n=34) POS (n=33) P-value

Total drug cost, $ [IQR]

3912 [2499-6635]

3570 [2476-6458]

3891 [3013-4904]

4798 [2546-8011]

0.360

Total drug cost per day, $ [IQR]

478 [369-625]

500 [396-625]

369 [302-474]

624 [485-787]

<0.001

Therapeutic drug monitoring, n (%)

22 (22)

0 (0)

14 (41.2)

8 (24.2)

<0.001

Total cost, $ [IQR]

4032 [2499- 6703]

3571 [2476- 6458]

4011 [3013- 4904]

4798 [2546- 8131]

0.360

Author’s Conclusions

Primary outcome difference was driven by ISA’s lower incidence of QTc prolongation Increase in transaminases with ISA numerically lower than VRC, although not compared 1:1

for significance ISA required less immunosuppressive dose reduction than other triazoles Drug cost and overall total cost were similar across drug groups, but cost per day was lowest

with voriconazole Reviewer’s Critique

Strengths Cohort mostly well-matched at baseline Representation of patients outside of hematologic malignancy

Limitations Retrospective single-center study o Inherent bias in baseline drug selection o Limited external validity

Small population Adverse effects not well-characterized Reliance on biomarkers as surrogates for safety outcomes Potential confounders with echinocandin therapy Unable to follow up with patients past 30 days from discharge

Overall Conclusions

Evidence from a practical setting that generally validates previous data regarding outcomes with ISA compared to other triazoles for treatment of invasive fungal infections

19 | Ayres

Conclusions

I. Efficacy data outside of clinical trials for ISA are limited a. Evidence suggests ISA is similarly effective to its comparators

II. Therapeutic drug monitoring may be warranted in select populations (e.g. hepatic failure)

III. Role of prophylaxis in settings outside IPA remain unclear IV. Breakthrough rates appear consistent with VRC and POS V. Safety data continue to favor ISA over VRC

Summary

I. Recent evidence upholds the conclusions of SECURE II. ISA has comparable efficacy and a clearly favorable adverse effect profile relative to VRC

III. ISA is a compelling first line option for treatment of IPA

Recommendations

I. Recommend ISA for primary IPA II. Recommend VRC for extrapulmonary IA

Voriconazole

Practical experience

Isavuconazole

Tolerability

Safety

20 | Ayres

References 1. Segal BH. Aspergillosis. N Engl J Med. 2009;360(18):1870. 2. Aspergillosis statistics. Centers for Disease Control and Prevention.

https://www.cdc.gov/fungal/diseases/aspergillosis/statistics.html#five 3. Webb BJ, Ferraro JP, Rea S, et al. Epidemiology and Clinical Features of Invasive Fungal Infection in a US Health Care

Network. Open Forum Infect Dis 2018 Jul 31;5(8):ofy187. 4. Ryan, KJ. 46. The Opportunistic Fungi: Candida, Aspergillus, the zygomycetes, and Pneumocystis. (Chapter) In: Sherris

Medical Microbiology, 7e New York, NY: McGraw-Hill. http://accessmedicine.mhmedical.com.libproxy.uthscsa.edu/content.aspx?bookid=2268&sectionid=176088518. Accessed September 18, 2019.

5. Cornillet A, Camus C, Nimubona S, et al. Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey. Clin Infect Dis 2006; 43:577.

6. Fukuda T, Boeckh M, Carter RA, et al. Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning. Blood. 2003;102(3):827-33.

7. Carver, PL. 99. Invasive Fungal Infections. (Chapter) In: Pharmacotherapy 9e New York, NY: McGraw-Hill. 8. Cadena J, Thompson GR, Patterson TF. Invasive Aspergillosis: Current Strategies for Diagnosis and Management. Infect

Dis Clin North Am. 2016 Mar;30(1):125-42. 9. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization

for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46:1813–21.

10. Patterson TF, Thompson GR, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Jun.

11. Amphotericin B deoxycholate. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019.

12. Amphotericin B liposomal. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019.

13. Amphotericin B lipid complex. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019.

14. Voriconazole. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019.

15. Isavuconazole. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019.

16. Caspofungin. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019.

17. Micafungin. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019. 18. Posaconazole. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.;

2019. 19. Itraconazole. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019. 20. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive

aspergillosis. N Engl J Med 2002; 347:408–15 21. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould

disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016; 387:760–9.

22. Pettit NN, Carver PL. Isavuconazole: A New Option for the Management of Invasive Fungal Infections. Ann Pharmacother2015, Vol. 49(7) 825–842

23. Andes, D, Kovanda L, Desai A, Kitt T, Zhao M, Walsh TJ. 2018. Isavuconazole concentration in real-world practice: consistency with results from clinical trials. Antimicrob Agents Chemother 62:e00585-18.

24. Dutch Working Party on Antibiotic Policy. SWAB Guidelines for the Management of Invasive Fungal Infections. Revised version. Released: 14 December 2017. Available at http://www.swab.nl/swab/ cms3.nsf/uploads/3AA7A56CE879587BC12581F80061297F/ $FILE/SWAB%20Richtlijn%20Mycosen%202017%20(final).pdf (last access, January 31, 2018)

25. Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J Antimicrob Chemother 2018; 73(Suppl 1):i26–32

26. Arsiè E, Piconi S, Iavarone M, et al. High isavuconazole plasma levels in a patient with possible invasive pulmonary aspergillosis and cirrhosis. Eur J Clin Pharmacol. 2018.

27. Dadwal S, Kriengkauykiat J, Tegtmeier D, Breakthrough Invasive Fungal Infections in Patients With Hematologic Malignancy (HM) and Hematopoietic Cell Transplantation (HCT) Receiving Isavuconazole for Empiric or Directed Antifungal Therapy. Mycologyabstract

28. Fung M, Schwartz B, Doernberg S, et al. Breakthrough Invasive Fungal Infections on Isavuconazole Prophylaxis and Treatment: What Is Happening in the Real-World Setting? Clin Infect Dis. 2018.

21 | Ayres

29. Rausch CR, DiPippo AJ, Bose P, et al. Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole. Clin Infect Dis. 2018

30. Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004; 350:950–2.

31. Kim SB, Cho SY, Lee DG, et al. Breakthrough invasive fungal diseases during voriconazole treatment for aspergillosis: a 5-year retrospective cohort study. Med Mycol 2017; 55:237–45.

32. Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 2004; 39:743–6.

33. Trifilio S, Singhal S, Williams S, et al. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant 2007; 40:451–6.

34. Wingard JR, Carter SL, Walsh TJ, et al.; Blood and Marrow Transplant Clinical Trials Network. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 2010; 116:5111–8.

35. Marks DI, Pagliuca A, Kibbler CC, et al.; IMPROVIT Study Group. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation. Br J Haematol 2011; 155:318–27.

36. DiPippo A, Kontoyiannis D. Lack of Toxicity with Long-term Isavuconazole Use in Patients with Hematologic Malignancy. Clin Infect Dis. 2019

37. Van Matre et al. Comparative evaluation of isavuconazonium sulfate, voriconazole, and posaconazole for the management of invasive fungal infections in an academic medical center. Ann Clin Microbiol Antimicrob. 2019

Appendix 1. Invasive fungal disease (IFD) criteria

Category Diagnostic Criteria Proven IFD One of the following:

1) Microscopic analysis: Histopathologic, cytopathologic, or direct microscopic examination obtained by needle aspiration or biopsy in which hyphae or melanized yeast-like forms are seen accompanied by evidence of associated tissue damage

2) Culture: recovery of a mold or “black yeast” from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding bronchoalveolar lavage fluid, cranial sinus cavity specimen, and urine

Probable IFD One from EACH of the following three categories: 1) Host Factors: Recent history of neutropenia temporally

related to the onset of fungal disease, receipt of an allogeneic stem cell transplant, prolonged use of corticosteroids at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for > 3 weeks, treatment with other recognized T-cell immunosuppressants in the past 90 days, or inherited severe immunodeficiency

2) Clinical Criteria: Dense well-circumcised lesions with or without a halo sign, air-crescent sign, or cavity

3) Mycologic Criteria: Mold in sputum, bronchoalveolar lavage (BAL) fluid, bronchial brush, or aspirate samples indicated by presence of fungal elements indicating a mold or recovery by culture of a mold, galactomannan antigen detected in plasma, serum, BAL fluid, or cerebrospinal fluid

Possible IFD One Host Factor and one Clinical Criteria as defined above