Clinical Case 1: CMV in Transplantationprograms.rmei.com/CMV053materials/PPT.pdf · 2018. 3....

Clinical Case 1: CMV in Hematopoietic Stem CellHematopoietic Stem Cell

Transplantation

Michael J. Boeckh, MDAssociate Member, Program of Infectious Diseases

Fred Hutchinson Cancer Research CenterAssociate Professor, University of Washington School of Medicine

Seattle, Washington

Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestMichael J. Boeckh, MD

Dr. Michael J. Boeckh has an affiliation with ViroPharma Incorporated, Roche, Novartis, and AlphaVax (Consulting Fees); Vi Ph I t d R h d Vi lViroPharma Incorporated, Roche, and VicalInc. (Contracted Research); and Baxter (Other)(Other).

Clinical CaseClinical Case• 58-year-old woman, 9 months after NM PBSCT y

for ALL in 1st remission• Pretransplant serostatus: VZV+, CMV R+/D+,

HSV−HSV• Early posttransplant complications

– 2 episodes of CMV reactivation (+ one pre-Tx)– Acute GvHD– RSV URI

• Now severe GI GVHD diagnosed 4 weeks agoNow severe GI GVHD, diagnosed 4 weeks ago – 1 mg/kg steroids, FK506 and B & B

• Admitted with respiratory failure requiring i t b tiintubation

Clinical Case (continued)Clinical Case (continued)• CMV reactivation 7 weeks prior to admission:

plasma PCR 1100 treated with valganciclovir, initially with 900 mg twice daily, switched to450 mg/day after 1 week switched back to low dose450 mg/day after 1 week, switched back to low-dose acyclovir prophylaxis 2 days prior to admission

• Lab: Creatinine 0 2 bilirubin 23 4 AST 390Lab: Creatinine 0.2, bilirubin 23.4, AST 390• PCP prophylaxis: atovaquone 1500 mg/d, acyclovir

800 mg BID, fluconazole 400 mg, penicillin 750 mg g , g, p gtwice daily

• Other medications: prednisone 2 mg/kg, B & B, FK506

Clinical Case (continued)Clinical Case (continued)Question 1: Differential Diagnosis

A. Viral pneumonia (CMV, respiratory viruses)B. Fungal pneumonia (PCP, Aspergillus)B. Fungal pneumonia (PCP, Aspergillus)C. Bacterial pneumoniaD BOOPD. BOOPE. All of the above

Clinical Case (continued)

Th ti t t t d b d t tibi ti

Clinical Case (continued)Question 2: Initial Management

The patient was started on broad spectrum antibiotics (imipenem, vancomycin, gentamicin, levofloxacin). Which additional agents would you start empirically?

A. High-dose TMP-SMX, ganciclovir (induction) therapyB High-dose TMP-SMX ganciclovir (induction) therapyB. High dose TMP SMX, ganciclovir (induction) therapy,

aerosolized ribavirinC. High-dose TMP-SMX, ganciclovir (induction) therapy,

i lvoriconazoleD. All 4 drugsE. No additional empiric therapy – wait until BAL results

are available

Clinical Case (continued)Clinical Case (continued)Additional Information

• IT aspirate: GPC, GPR, GNR (mixed flora), yeast• BAL:

G ’ t i GPC GNR– Gram’s stain: GPC, GNR– Viral DFA; negative for ADV, RSV, FLU, PIV, HMPV– PCP DFA: negative

CMV h ll i l di– CMV shell vial: pending– Respiratory virus multiplex PCR (12 viruses): pending– Aspergillus GM: positive– Aspergillus PCR: pending– Legionella DFA: negative

• CMV PCR (plasma): 2 million copies/mL(p ) p

Clinical Case (continued)Clinical Case (continued)Question 3: Further Treatment

How would you adjust treatment?

A. Switch to foscarnetB Add foscarnetB. Add foscarnetC. Add voriconazoleD Add both foscarnet and voriconazoleD. Add both foscarnet and voriconazoleE. No change

Clinical Case (continued)Clinical Case (continued)Internal Working Diagnoses

• Presumed CMV pneumonia– Drug resistance possible (to probable)– Treatment: ganciclovir + foscarnet

• Probable pulmonary aspergillosis– Treatment: voriconazole

• Bacterial pneumonia– Treatment: imipenem, levofloxacin

Utility of Aspergillus GalactomannanUtility of Aspergillus GalactomannanDetection in BAL Samples

# pt

160

Sens

(%)

Spec

(%)

PPV

(%)

NPV

(%)

Serum 47 93 73 82

BAL 85 100 100 88

Becker MJ, et al. Br J Haematol. 2003;121:448-457.Musher B, et al. J Clin Microbiol. 2004:42:5517-5522.

Ganciclovir Resistance against CMVGanciclovir Resistance against CMVPrevalence 2008

SOT >>> HCT

Ganciclovir Resistance against CMVGanciclovir Resistance against CMVPrevalence 2008

SOT >>> HCT

HoweverHowever . . .

CMV Drug ResistanceProlonged

CMV Drug Resistance

drug administration(pre- and/or posttransplant) +

Low antiviral drug levelsResistance

++

Low immune status• Drug induced

Subclinical CMV load

+

++

• Drug induced• T-cell depletion (e.g.,

haploidentical donor transplants)C d bl d• Cord blood transplantation

CMV Drug Resistance gHigh-Risk Situation

• Ganciclovir-experienced patient (prophylaxis, preemptive therapy, pretransplant use), especially with low doses

• Increase of viral load > 2 weeks • High-risk transplant setting

L K P t l t (D+/R )

Ganciclovir

– Lung, K-P transplant (D+/R−)– HSCT (severe TCD or immunosuppression, e.g., haplo Tx)

ViralLoad

Ganciclovir

Months after Transplant

CMV Drug Resistance Low-Risk Situation

G i l i ï ti t• Ganciclovir-naïve patient• Increase of viral load during the first 2–3 weeks of therapy• Low-risk setting (R+, kidney Tx, liver Tx, heart Tx, HCT)

Ganciclovir

g ( y )

ViralLoad

Months after Transplant

Viral Load IncreasesViral Load IncreasesExample: Early Response to Ganciclovir in HCT

↑ A > 2 ↑ A > 5↑ Ag > 2x ↑ Ag > 5x adj OR 95% CI adj OR 95% CI

Conditioning regimenNon-TBI containing 1.0 * 1.0 *

TBI-containing 2.6 1.0-6.8 1.8 0.9–4.2gSteroid use at 1st Ag +ve

None 1.0 * 1.0 *

< 1 mg/kg 5 0 1 0–24 5 4 3 0 4–51 3< 1 mg/kg 5.0 1.0 24.5 4.3 0.4 51.31–2 mg/kg 4.3 1.2–5.3 14.3 1.8-110.7> 2 mg/kg 10.5 3.1–35.8 28.6 3.6–229.7

P < 0.05Nichols WG, et al. Blood. 2001;97:867-874.

Efficacy of GanciclovirEfficacy of Ganciclovir

Route/Dose Wild Type MutantRoute/Dose Wild-Type Mutant

IntravenousIntravenous 5 mg/kg bid 91.5% 62%

OralOral 1 g tid 46.5% 35%

Emery VC, Griffiths PD. Proc Natl Acad Sci U S A. 2000;97:8039-8044.

CMV Drug ResistanceCMV Drug Resistance Mutation Map for the UL97 Gene

Chou S. Rev Med Virol. 2008;18:233-246.

CMV Drug ResistanceCMV Drug Resistance Mutation Map for the DNA Polymerase Gene

Chou S. Rev Med Virol. 2008;18:233-246.

CMV Drug ResistanceCMV Drug ResistanceDiagnosis

f f• Increases of viral load as surrogate marker for resistance– Drug-naïve subjects, early during treatment, low-risk settingDrug naïve subjects, early during treatment, low risk setting

(R+): • Drug resistance unlikely• Increases most likely due to the underlying immunosuppression

– After significant exposure (especially low-dose), high-risk setting

• More likelyT i l l d i 0 5 l ( 3 b li )• True viral load increase: > 0.5 log10 (> 3x baseline)

• Testing: direct genotypic testing if resistance is suspectedp– UL97 gene: CMV, maribavir– UL 54 gene: foscarnet, cidofovir, ganciclovir (high level)

CMV Drug ResistanceCMV Drug ResistanceManagement Strategies

• Switch to alternative drug– Ganciclovir Foscarnet

Cidofovir (some cross-resistance)

MaribavirMaribavir

– Foscarnet Ganciclovir

Cidofovir

Maribavir

• Reduce immunosuppression (if possible)


• In refractory situations (viral load increases, clinical deterioration):

R d i i if f ibl– Reduce immunosuppression if feasible– Consider dose increase if possible1

– Consider combination therapy• Continue ganciclovir in addition to foscarnet2• Foscarnet + maribavir (no clinical data)• Cidofovir + maribavir (no clinical data)

NOT i l i ib i 3• NOT: ganciclovir + maribavir3

1. West P, et al. Transpl Infect Dis. 2008;10:129-132.2. Emery VC, Griffiths PD. Proc Natl Acad Sci U S A. 2000;97:8039-8044.3. Chou S, Marousek GI. Antimicrob Agents Chemother. 2006;50:3470-3472.


• In refractory situations – continued: – Consider alternative agents (alone or in combination)

CASE REPORTS ONLY NO CONSISTENTCASE REPORTS ONLY – NO CONSISTENT EVIDENCE• Leflunomide1,2

• Artesunate3 4• Artesunate3,4

– Consider alternative immunosuppressive agents• Sirolimus5

1. Avery RK, et al. Bone Marrow Transplant. 2004;34:1071-1075.y , p ;2. Battiwalla M, et al. Transpl Infect Dis. 2007;9:28-32.3. Shapira MY, et al. Clin Infect Dis. 2008;46:1455-1457.4. Efferth T, et al. Clin Infect Dis. 2008;47:804-811.5. Chou S. Rev Med Virol. 2008;18:233-246.

Panel Discussion

Clinical Case 2: CMV in Hematopoietic Stem CellHematopoietic Stem Cell

Transplantation

John R Wingard MDJohn R. Wingard, MDProfessor and Price Chair of MedicineProfessor, Department of Pediatrics

Director Blood and Bone Marrow Transplant ProgramDirector, Blood and Bone Marrow Transplant ProgramUniversity of Florida Shands Cancer Center

Gainesville, Florida

Di l f C fli t f I t tDisclosure of Conflicts of Interest

John R. Wingard, MD

Dr. John R. Wingard has an affiliation with Merck & Co., Inc., and Pfizer Inc. (C )(Consulting Fees); and Astellas, Merck & Co., Inc., and Pfizer Inc. (Fees for Non CME Services Received DirectlyNon-CME Services Received Directly from a Commercial Interest or their agents, e.g., speakers’ bureaus).agents, e.g., speakers bureaus).

Clinical CaseClinical Case

• 47-year-old man underwent a matched unrelated donor HCT 5 months ago for acute myelogenous leukemia aftermyelogenous leukemia after cyclophosphamide + total body irradiation

• Tacrolimus + methotrexate given as GvHD• Tacrolimus + methotrexate given as GvHD prophylaxis

• Engrafted on day 20Engrafted on day 20• Valacyclovir and trimethoprim-

sulfamethoxazole prophylaxis givensulfamethoxazole prophylaxis given

Clinical Case (continued)Clinical Case (continued)

• Developed cutaneous and gastrointestinal• Developed cutaneous and gastrointestinal GvHD on day 38

• Prednisone given at a dose of 2 mg/kg/dPrednisone given at a dose of 2 mg/kg/d• GvHD improved• Prednisone tapered weekly by 0 5 mg/kg/d• Prednisone tapered weekly by 0.5 mg/kg/d

(and discontinued on day 70)


• Weekly CMV assessed by quantitative PCR


• Weekly CMV assessed by quantitative PCR• CMV PCR + on day 54

V l i l i i f 2 k• Valganciclovir given for 2 wks• CMV PCR negative and valganciclovir stopped


• Day 100 no active infections or GvHD• Tacrolimus on slow taper• Patient discharged to local community with

monthly follow-up• On day 120, pt developed rash and dry mouth


• Skin biopsy showed lichenoid chronic GvHD• Prednisone started at 1 mg/kg/d with gradual

taper to alternate-day schedule


D 140 t d l d l d f d


• Day 140, pt developed low-grade fever, dry cough, dyspnea on exertionS tt d l t d• Scattered rales noted

• Chest radiograph performed

Question 1Question 1

This is unlikely to be CMV pneumonia becauseThis is unlikely to be CMV pneumonia because most CMV pneumonias occur before day 100.

A. TrueB. False

Shifts in CMV infectionsShifts in CMV infections

• Historically, CMV pneumonia usually

d b f doccurred before day 100Rising rate of late onset• Rising rate of late-onset disease

• Resistance• Resistance• New oral agents

Valganciclovir– Valganciclovir– Maribavir

Late CMV Disease in HCTLate CMV Disease in HCTIncidence Variability

• Incidence 3%–17%• Incidence is variable in different series;

reasons include: – Risk groups– Denominator (day of transplantation vs 3 months)Denominator (day of transplantation vs 3 months)– Different stem cell sources? – Duration of follow-up

Work up variable– Work-up variableBoeckh M, et al. Blood. 2003;101:407-414.Junghanss C, et al. Blood. 2002;99:1978-1985.Boeckh M, et al. Biol Blood Marrow Transplant. 2003;9:543-558.Boeckh M, Nichols WG. Blood. 2004;103:2003-2008.Einsele H, et al. Bone Marrow Transplant. 2000;25:757-763.Reusser P, et al. Blood. 2002;99:1159-1164.Kim DH, et al. Bone Marrow Transplant. 2004;34:21-27.

Differential DiagnosisDifferential Diagnosis

N i f ti• Non-infectious– Idiopathic pneumonitis

Bronchiolitis obliterans with organizing pneumonia– Bronchiolitis obliterans with organizing pneumonia• Infectious

PCP– PCP– CMV– Respiratory virusRespiratory virus– Adenovirus– Legionella

Diagnostic EvaluationDiagnostic Evaluation

Pl CMV PCR• Plasma CMV PCR +• Bronchoscopy with bronchoalveolar lavage and

t b hi l bitransbronchial biopsy• CMV demonstrated

G i l i i iti t d• Ganciclovir initiated

Question 2Question 2

Risk factors for late CMV pneumonia are:A. Acute GvHDB. Early CMV infectionC. Ganciclovir prophylaxisD All f th bD. All of the aboveE. All patients are equally at risk

Current Issues for CMV Therapy: Should I Worry About Late Disease?

y of

Lat

e D

isea

se

0.50pp65 antigenemia <day 95

+ CD4 <50/mm2

0.40

0.30 AG pos or T4 <50 (n=92)

GvHD

y of

Lat

e D

isea

se

0.50

0.40

0.30

P=.02 P=.03

0.23Any GvHD before

day 95 (n=119)of P

atie

nts

CMV disease before day 100CMV disease after day 100

35

30

25

20

Prob

abili

tyCM

V D

Months

0.20

0.10

0.000 12 24 36

Prob

abili

tyCM

V D

0.20

0.10

0.000 12 24 36

Months

0.08AG neg or

T4 >50 (n=92) No GvHD before day 95 (n=27)

day 95 (n 119)

Perc

ent

o

15

10

5

01986 1987 1988 1989 1990 1991 1992 19931994

CMV Boeckh M. Biol Blood Marrow Transplant. 2003;9:543-558.

Months Since Transplant

Months Since TransplantYear of Transplant

Risk factors:Early CMV or low CD4GvHD

3 mos 6 129

CMV Disease:CMV Disease:Effect of Ganciclovir Strategy on Late Disease

CMV Disease Prophylaxis Preemptive P Value

Up to day 100 2.7% 14.1% 0.002

Beyond day 100 13.4% 6.1% —

Total before day 400 16.1% 20.2% 0.42

Boeckh M, et al. Blood. 1996;88:4063-4071.

Prevention of Late CMV DiseasePrevention of Late CMV Disease Who is at Risk? Current Data

• Continued surveillance of high-risk patients – Allogeneic transplantation– CMV recipient seropositive or D+/R−

• CMV infection < day 100 or• Ganciclovir/valganciclovir/FSC prophylaxis (mainly in R+)Ganciclovir/valganciclovir/FSC prophylaxis (mainly in R )plus• GvHD

Hi h d t id f th• High-dose steroids for other reasons• T-cell depletion• DLI

Late CMV PreventionCIBMTR Survey

• Prophylaxis or preemptive therapy in HIGH RISK recipients after day• Prophylaxis or preemptive therapy in HIGH RISK recipients after day 100(i.e., recipients with CMV infection before day 100, steroid or ATG use, GvHD, or low CD4 counts) ?use, GvHD, or low CD4 counts) ?

YES (122 centers, 70%)NO (52 t 30%)NO (52 centers, 30%)

• Among centers with after day 100 strategies:– Most (79%) used virologic surveillance/preemptive therapy– 12% used symptomatic surveillance based on clinical signs– 3.3% used prophylaxis with high-dose VACV– 1.6% (2 centers) used prophylaxis with oral VGCV

Heugel J, et al. ASBMT 2008. Abstract 76.

Prevention of Late CMV Disease

Diagnostic Test Ganciclovir/Foscarnet

Current StrategiesDiagnostic Test Ganciclovir/Foscarnet(e.g., PCR> 1000 copies/mL)

0 200 days100 days

• Duration of monitoring: until 6–12 mo after HCTD t t bl CMV ifi T ll f ti– Detectable CMV-specific T-cell function

– No or minimal systemic immunosuppression• No or minimal systemic steroids• No anti–T-cell agentsNo anti T cell agents• No DLI

– Surveillance assays negative on several determinations

Prevention of Late CMV Infection and DiseaseIssues

• Logistics and cost of testingg g– Availability: CMV vs hematologic/chemistry

testing– Cost– Cost– Adherence

• Direct vs indirect effects– Prophylaxis may reduce both

• Available agents– Valganciclovir: ASBMT 2008 abstract a ga c c o S 008 abst act– Valacyclovir: no studies– Cidofovir: no studies

In the future: maribavir?– In the future: maribavir?

Panel Discussion

Clinical Case 3: CMV in SolidOrgan Transplantation

Raymund R. Razonable, MDAssociate Professor of MedicineCollege of Medicine, Mayo Clinic

Rochester, Minnesota

Disclosure of Conflicts of InterestDisclosure of Conflicts of Interest

Raymund R Razonable MDRaymund R. Razonable, MD

Dr Raymund R Razonable has an affiliationDr. Raymund R. Razonable has an affiliation with Roche (Contracted Research).

Clinical CaseClinical Case

55 ld C i f L• 55-year-old Caucasian woman from Las VegasPMH astroc toma sei res d slipidemia• PMHx: astrocytoma, seizures, dyslipidemia, diabetes, idiopathic pulmonary fibrosis

• 10-05-2005: Right single-lung transplant• 10-05-2005: Right single-lung transplant• Induction with muromunab-CD3 (OKT3)• Maintenance therapy: cyclosporineMaintenance therapy: cyclosporine,

azathioprine, and prednisone• CMV D+/R−; EBV R+• Uncomplicated early posttransplant course

CMV=cytomegalovirus; D+R-=donor positive/recipient negative; EBV R+=Epstein-Barr virus positive.

Prevention of CMV After SOTPrevention of CMV After SOT100% • Prophylaxis

– Universal or targeted

Prophylaxis

– Universal or targeted– Reduces direct and

indirect effects of CMV– Risk of late-onset CMV

25%Preemptive Tx

disease after prophylaxis

Months after transplantation1 2 3

• Preemptive therapy

0

p py– Antiviral drug initiated based on virologic markers – Minimizes drug exposure (lower risk of drug toxicity and resistance)– May not eliminate the indirect effects of CMV– Some episodes may escape detection

SOT=solid organ transplantation.

Preemptive Therapy: Meta-AnalysesPreemptive Therapy: Meta Analyses

Study Author CMV Disease All-Cause MortalityStudy ut o C seaseRelative Risk

(95% CI)

Cause o ta tyRelative Risk

(95% CI)

0 29 1 23Hodson et al. 0.29(0.11–0.80)

1.23(0.35–04.30)

Kalil et al. 0.28(0.11–0.69)

0.94(0.32–2.76)

Small et al. 0.30(0.15–0.60)

0.94(0.43–2.07)

Eid AJ, Razonable RR. Curr Opin Organ Transplant. 2007;12:610-617.Strippoli GF, et al. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005133.Kalil AC, et al. Ann Intern Med. 2005;143:870-880.Small N, et al. Clin Infect Dis. 2006;43:869-880.

Oral GCV vs VGCV ProphylaxisOral GCV vs VGCV Prophylaxisin CMV D+/R- Non-Lung SOT Patients

CMV Disease by 6 Months

Valganciclovir900 mg QD until

Ganciclovir1 g TID until

Total (n=364)by 6 Months 900 mg QD until

D+100 (n=239)1 g TID until

D+100 (n=125)(n=364)

Endpoint 12.1% 15.2% 13.2%Endpoint committee

12.1% 15.2% 13.2%

Protocol definition 11.3% (27) 12.8% 11.8%( )

Investigator-treated disease

23.0% 21.6% 22.5%

GCV=ganciclovir; VGCV=valganciclovir.

Paya CV, et al. Am J Transplant. 2004;4:611-620.

Antiviral Prophylaxis: Meta-AnalysesAntiviral Prophylaxis: Meta Analyses

Study Author CMV DiseaseRelative Risk

All-Cause MortalityRelative Risk

(95% CI) (95% CI)Hodson et al. 0.42

(0 34 0 52)0.63

(0 43 0 92)(0.34–0.52) (0.43–0.92)Kalil et al. 0.20

(0 13–0 31)0.62

(0 40–0 96)(0.13–0.31) (0.40–0.96)Small et al. 0.34

(0.24–0.48)0.99

(0.68–1.43)(0.24 0.48) (0.68 1.43)Eid AJ, Razonable RR. Curr Opin Organ Transplant. 2007;12:610-617.Strippoli GF, et al. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005133.Kalil AC, et al. Ann Intern Med. 2005;143:870-880.Small N, et al. Clin Infect Dis. 2006;43:869-880.


• Valganciclovir 900 mg PO BID × 1 year• 10-05-2006: End of valganciclovir prophylaxis• 11-21-2006: URI symptoms, low-grade fever,

malaise, weakness, cough, shortness of breath and r nn nosebreath, and runny nose– Local physician: Amoxicillin-clavulanic acid and

increase prednisone no responseincrease prednisone no response

URI=upper respiratory infection.


11 27 2006 L fl i 500 PO BID• 11-27-2006: Levofloxacin 500 mg PO BID• 12-04-2006: High-grade fever (104°F)

– Local hospital admission– Chest x-ray: Left-sided pneumonia

Blood and sputum culture negative– Blood and sputum culture – negative– Linezolid, moxifloxacin, cefepime, oseltamivir– TMP-SMX/itraconazole prophylaxisTMP SMX/itraconazole prophylaxis

• 12-06-2006: Transferred to transplant center

TMP-SMX=trimethoprim sulfamethoxazole.


• Physical examination: O2 requirement bynasal cannula, afebrile, ill-looking, crackles in left lung with scant crackles in the right baseleft lung, with scant crackles in the right base, mild right upper quadrant tenderness

• Initial laboratory examination: WBC 5 2• Initial laboratory examination: WBC 5.2, hemoglobin 8.6, platelet 99, AST 124, LDH 577

• Chest radiographic studiesChest radiographic studies

AST=aspartate transaminase; LDH=lactate dehydrogenase; WBC=white blood cell count.


12 07 2008 CMV PCR 224 500 i / L• 12-07-2008: CMV PCR 224,500 copies/mLblood12 07 2008: Bronchoscopy TBBx and• 12-07-2008: Bronchoscopy, TBBx, andBAL-ICH– Shell vial culture: cytomegalovirus– Shell vial culture: cytomegalovirus– Histology: acute CMV pneumonitis

BAL-ICH=bronchoalveolar lavage in immunocompromised host; PCR=polymerase chain reaction; TBBx=transbronchial biopsy.

Late-Onset Primary CMV DiseaseLate Onset Primary CMV Diseasein D+/R- SOT Patients

17.215.2

18.420

VGCV 900 mg QDGCV 1000 mg TID

12.1

10

15

atie

nts

5

10

% P

a

03 6 12

0.8 1.6

Paya CV, et al. Am J Transplant. 2004;4:611-620.

3 mos 6 mos 12 mos

Late-Onset CMV DiseaseLate Onset CMV Disease• CMV syndrome 60%

– Fever with myelosuppression

• Invasive CMV disease 40% – Hepatitis– Pneumonia

– Gastrointestinal disease (90%)– RetinitisRetinitis – Encephalitis – Others

Eid AJ, Razonable RR. Curr Opin Organ Transpl. 2007;12:610-617.

Risk Factors for Late CMV DiseaseRisk Factors for Late CMV DiseaseVariable Hazard Ratio

CMV D+/R− 11.00

Allograft rejection 6.60

Female gender 2.19

Blood group A 2.36g p

Low creatinine clearance 4.28Mycophenolate mofetil use at end of 1.99prophylaxisPrednisone use at end of prophylaxis 2.70

Razonable RR, et al. J Infect Dis. 2001;184:1461-1464. Freeman RB, et al. Transplantation. 2004;78:1765-1773.Limaye AP, et al. Transplantation. 2004;78:1390-1396. Arthurs SK, Razonable RR (in press).

Treatment of CMV Disease After SOTTreatment of CMV Disease After SOT

• IV ganciclovir is the preferred drug for treating CMV disease in SOT recipientsD i i di id li d ( l 2 4 k )• Duration individualized (at least 2–4 weeks)– Guided by molecular methods

Challenge compartmentali ed CMV diseases– Challenge: compartmentalized CMV diseases• Reduction in immunosuppression

V l i l i f t t t f CMV di• Valganciclovir for treatment of CMV disease

IV=intravenous.

AST ID COP. Am J Transplant. 2004;4(S10);51-58.

Clinical Case (continued)Clinical Case (continued)IV Ganciclovir + CMV Ig

V l i l i 900 BIDValganciclovir 900 BIDValganciclovir 900 QD

Ig=immunoglobulin.

Valganciclovir Treatment of CMV Disease in SOT Recipients

90

708090

IV GCV VGCV

405060

Patie

nts

203040

% o

f P

010

D+21 D+49 D+21 D+49D+21 D+49 D+21 D+49

Viral load eradication Clinical resolutionÅsberg A, et al. Am J Transplant. 2007;7:2106-2113.


f C• Resolution of CMV pneumonia• Persistent bilateral leg weakness (possible

CMV l di l th )CMV polyradiculopathy)• Valganciclovir secondary prophylaxis• Persistently CMV IgG-seronegative at 1 year

later (IgM-seropositive)

Question 1Question 1What is the optimal duration of antiviral prophylaxis after solid organ transplantation?

A. 1 monthB. 3 monthsC. 6 monthsD. 12 monthsE. Indefinite duration

Question 2Question 2Which of the following statements is TRUE?

A. Preemptive therapy is the preferred approach for the prevention of primary CMV disease.

B. Treatment for CMV disease after SOT is for fi d d ti f 3 ka fixed duration of 3 weeks.

C. Antiviral prophylaxis is complicated by the f l t t CMV dioccurrence of late-onset CMV disease.

D. Valganciclovir is a proven effective oral option for treatment of all cases of CMVoption for treatment of all cases of CMV disease after SOT.

Panel Discussion

Clinical Case 4: CMV in Solid Organ Transplantation

Ajit P Limaye MDAjit P. Limaye, MDAssociate Professor, Laboratory Medicine

Director, Organ Transplant Infectious Diseases ProgramUniversity of Washington Medical CenterUniversity of Washington Medical Center

Seattle, Washington

Disclosure of Conflicts of Interest

Ajit P. Limaye, MD

Dr. Ajit P. Limaye has an affiliation with Roche (Consulting Fees, Contracted Research) and ViroPharma Incorporated (Contracted Research).

Clinical Case

45-year-old man receives a cadaveric kidney/pancreas transplant y y p pCMV serostatus: Donor+, Recipient−Immunosuppression: ATG, tacrolimus, MMF, prednisone CMV prevention: oral GCV × 3 monthsC p e e o o a GC 3 o s

1 mo post-txp Allograft rejection, methylpred pulse × 3

4.5 mo post-txp CMV pneumonia, IV GCV + IVIG × 3 wk then oral GCV × 3 mo (as secondary

prophylaxis)prophylaxis)

9 mo post-txp CMV syndrome pp65 Ag >100 but culture9 mo post-txp CMV syndrome, pp65 Ag >100 but culturenegative. IV GCV, but slow clinicalresponse and increasing viral load.

Clinical Case (continued)9.5 mo post-txp Progressive SOB, pulmonary infiltrates

and rising pp65 Ag despite IV GCV. Lung biopsy==> CMV pneumoniaLung biopsy CMV pneumonia IV FSC + GCV and CMVIG, reduced immunosuppression. Nephrotoxicity and electrolyte abnelectrolyte abn.

10 mo post-txp Patient dies of respiratory failureAutopsy = CMV pneumonia

(no other pathogens)

10.5 mo post-txp Genotype = UL97 mutation Phenotype = pending

IssuesIssues

1. Incidence2. Risk Factors and Pathogenesis3. Diagnosis4. Treatment

Which of the following is considered the most

Question 1Which of the following is considered the most important risk factor for development of ganciclovir-resistant CMV in SOT recipients?ganciclovir resistant CMV in SOT recipients?

A. Female genderB. Recipient CMV seropositive status (R+)C. Liver vs other organ-type transplantg yp pD. Donor positive, recipient negative CMV

serostatusE. Use of cyclosporine

Question 2

Which of the following statements regarding ganciclovir resistance in CMV is CORRECT?

A. Mutations in UL97 are the most common mechanism

B. Resistant strains are not capable of causing tissue-invasive disease

C. Assessment of IC50 (phenotypic testing) is the preferred diagnostic method

D M i i UL97 f iD. Mutations in UL97 confer cross-resistance to foscarnet and cidofovir

Antiviral-Resistant CMV:I id (Abd i l O )Incidence (Abdominal Organs)

Transplant Type Overall IncidenceLi 1%Liver < 1%Kidney <1%–3%

Kidney/pancreas or pancreas

1%–13%

Intestinal Not reportedIntestinal Not reported

Boivin G, et al. J Infect Dis. 2004;189:1615-1618.Limaye AP, et al. Lancet. 2000;356(9230):645-649.Limaye AP, et al. Transplantation. 2006;81:1645-1652.Lurain NS, et al. J Infect Dis. 2002;186:760-768.

Antiviral-Resistant CMV:I id (Th i O )Incidence (Thoracic Organs)

Transplant Type Overall IncidenceHeart <1%–5%Lung 5%–16%Lung 5% 16%

Bhorade SM, et al. J Heart Lung Transplant. 2002;21:1274-1282.g pHumar A, et al. J Infect Dis. 2005;192:1154-1157.Kruger RM, et al. Transplantation. 1999;68:1272-1279.Limaye AP, et al. J Infect Dis. 2002;185:20-27.Li F, et al. Clin Infect Dis. 2007;45:439-447.

Ganciclovir-Resistant CMV in SOT Recipients:Ganciclovir-Resistant CMV in SOT Recipients:Risk Factors

• CMV D+R− serostatus• High CMV viral loadHigh CMV viral load

(==> subclinical reactivation)• Highly potent immunosuppressionHighly potent immunosuppression

(antilymphocyte antibodies)• Prolonged (suboptimal) ganciclovir exposure g ( p ) g p

(?oral ganciclovir)

Ganciclovir-Resistant CMV:L b Di iLaboratory Diagnosis

Phenotypic Methods• Plaque reduction assayq y• DNA hybridization

G t i M th dGenotypic Methods• UL97 and UL54 mutation analysis*

(sequencing RE digestion)(sequencing, RE digestion)

*Detection of CMV mutations directly from clinical samples.

CMV UL97 PhosphotransferaseMutation Map

397Codon

GCVr mutations460 520 590-607GW1263-R

Mutation Map

574337345

Codon

Kinase subdomain

1 707453462

481483

520527 579

VIB VII VIII IX

Nuclear localizationsignal

Substrate bindingPutative function ATPbinding P-transfer

StrainVariation (Lurain NS AACTG CMV Labs)

D605EA582T

VariationMutations conferring GCV resistance

in marker transfer studies

(Lurain NS, AACTG CMV Labs)

≥ 4-fold resistance <4-fold resistance

Most common UL97 mutations detected in GCV-resistant CMV

All resistant isolates(n=79)

Oral GCV recipients(n=29)M460V

M460IH520QA594VL595SL595FK599T

A591VC592GA594TE596Gdel600C607F

(n=79)

A594V (29%)L595S (23%)M460V (14%)C592G (13%)M460I (9%)

(n=29)

C592G (37%)A594V (26%)M460I (22%)A594T (15%)

(Roche 1654 study)K599TC603WC607Ydel595

del590-3/591-4del595-603del591-607

M460I (9%)H520Q (5%)

(Portland, OR data)

Chou S, et al. J Infect Dis. 2002;185:162-169.

Ganciclovir-Resistant CMV:Ganciclovir Resistant CMV: Mechanism(s)

UL97 mutations1

• Point mutation(s) or deletion(s)• Lead to decreased levels of ganciclovir triphosphate in

CMV i f t d llCMV-infected cells• Mutations at 3 specific codons (460 [22%], 594 [21%],

595 [25%]) account for the majority of clinical ganciclovir-595 [25%]) account for the majority of clinical ganciclovirresistant isolates (~70%)

• Do not generally confer cross-resistance to either id f i fcidofovir or foscarnet

1. Chou S, et al. J Infect Dis. 2002;185:162-169.

Ganciclovir-Resistant CMV:Ganciclovir Resistant CMV: Treatment

Current antiviral options– High-dose ganciclovir1,2

F t– Foscarnet– Cidofovir– Ganciclovir + foscarnet3,4Ganciclovir foscarnet

Other interventions– Reduction in immunosuppression– CMV-IG5

1. West P, et al. Transpl Infect Dis. 2008;10:129-132.2. Limaye AP, et al. Transplantation. 2006;81:1645-1652.3. Mylonakis E, et al. Clin Infect Dis. 2002;34:1337-1341.4. SOCA Research Group. Arch Ophthalmol. 1996;114:848-855.5. Limaye AP, et al. Semin Respir Infect. 2002;17:265-273.

Ganciclovir-Resistant CMV:Ganciclovir Resistant CMV: Treatment

Potential future considerations• Leflunomide/FK 7786

• Maribavir7

• Lipid ester cidofovir conjugates8

Artesunate9• Artesunate9

6. Waldman WJ, et al. Intervirology. 1999;42:412-418.7. Williams SL, Hartline CB, Kushner NL, et al. Antimicrob Agents Chemother. 2003;47:2186-2192.8. Williams-Aziz SL, et al. Antimicrob Agents Chemother. 2005;49:3724-3733.9. Kaptein SJ, et al. Antiviral Res 2006;69(2):60-9

Clinical Approach to Suspected pp pResistant CMV

Cli i l d/ i l i f il

Prolonged antiviral drug exposure

Clinical and/or virologic failure• No clinical improvement at 2 wks• No reduction in viral load at 2 wks

YES NO(Drug resistance unlikely)

Host factorsDrug dosing

> 2 risk factors for resistance(D+R-, potent IS, K/P or lung tx)

Drug dosing

YESDrug resistance possible/probable

Genotypic testing, reduce IS, addition of foscarnet+/- CMVIg

NODrug resistance unlikely (possible)

Non–life-threatening CMVGenotypic testing, reduce IS,

higher doses of GCV,+/- CMVIg

Life-threatening CMVGenotypic testing, reduce IS

Addition of foscarnet+/- CMVIg

Panel Discussion

Question-and-Answer Session

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