cytomegalovirus prophylaxis in renal transplant patients ......cytomegalovirus (cmv) infection in...

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Cytomegalovirus Prophylaxis in Renal Transplant Patients: High Dose, Best Dose?

September 6th, 2019

Nina Maguire, PharmD

PGY-2 Infectious Diseases Pharmacy Resident

Ascension Seton

[email protected]

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Table of Contents

Presentation Slides…………………………………………………………..pages 3 to 11

Appendix A: Abbreviations……………………………………………………….page 12

Appendix B: Gabardi, et al. Figure…………………………………………….page 13

Appendix C: Rissling, et al. Figures………………………………..………….page 14

Appendix D: Khurana, et al. Figure…………………..……………………….page 15

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Cytomegalovirus Prophylaxis in Renal Transplant Patients: High Dose, Best Dose?

Nina Maguire, PharmDPGY-2 Infectious Diseases Pharmacy ResidentAscension TexasSeptember 6, 2019

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Disclosures

• No conflicts of interest to disclose

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Objectives

• Understand the manifestations and implications ofCytomegalovirus (CMV) infection in solid organ transplant patients

• Summarize different strategies for preventing CMV

• Apply CMV prophylaxis study results to the clinical settingin dose decision making for renal transplant patients

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Meet the patient…

• JC is a 40 year old male who is day 9 status post renaltransplant. His past medical history is significant for diabetes mellitus, hypothyroidism, and polycystic kidney disease.

Vitals:Temp: 99.5°FHR: 94 bpmBP: 109/64 mmHgRR: 18Weight: 75 kg

135

3.4

102

26

8

1.58.7

12.4

36215

Serostatus: D-/R+*

*D/R: donor/recipient

Estimated creatinine clearance 65 mL/min

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Meet the patient…

The decision is made to give JC prophylactic valganciclovir. Which regimen would you recommend?

A. 450 mg daily for 3 monthsB. 450 mg daily for 6 monthsC. 900 mg daily for 3 monthsD. 900 mg daily for 6 months

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What is Cytomegalovirus?

• Herpesviridae family doublestranded DNA virus

• 60 to 70% of people in United States are exposed

• Immunocompetent patients are asymptomatic and latent infection is established

Available at: pathology.washington.eduZhang LJ, et al. J Infect Dis. 1995;171:1002-06.

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Acute Infection

• CMV establishes lifelong latency after primary infection

• Re-activation of latent infection can occur inimmunocompromised patients

Acquired immunodeficiency syndrome

Solid organ transplant (SOT)

Bone marrow transplant

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Infection vs End Organ Disease

• Infection:• Evidence of CMV replication with virus isolation or

detection of viral proteins or nucleic acid in any bodyfluid or tissue specimens

• Often referred to as CMV viremia• Commonly diagnosed by serum polymerase chain

reaction testing (PCR)

• Disease:• Evidence of CMV infection with attributable symptoms

• Viral syndrome• End organ disease

• Diagnosed with tissue biopsy• Presents with viral syndrome

60%24%

13%3%

Gastrointestinal Disease

Hepatitis

Pneumonia

Other

Kotton CN, et al. Transplantation. 2018;102(6):900-31.Paya C, et al. Am J Transplant. 2004;4(4):611-20.

End Organ Disease Manifestations

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DiagnosticsVariables pp65 antigenemia assay CMV PCR

Processing Polymorphonuclear cells Blood or other body fluids

Turnaround time 6 hours 2-3 hours

Prevention of Disease Good Good

Units of measurement

Number of CMV infected cells per total number of cells IU/mL

Sensitivity 84% 95%

Specificity 98% 95%

Advantages Rapid diagnosis, assess severity Rapid diagnosis, assess severity, risk of CMV disease

Disadvantages Subjective interpretation of results, not useful in leukopenia

Wide viral threshold for predicting CMV disease, no standardization, may detect

latent CMV

Percivalle E, et al. J Clin Virology. 2008;43(1):13-17.Razonable RR, et al. Clin Microbiol Rev. 2013;26(4):703-27.

George, KS, et al. J Clin Microbiol. 2000;38(4):1430-33.10

Which transplant patients are at the highest risk for CMV?• Degree of immunosuppression with lymphocyte depleting agents• Allograft rejection• Serostatus

Brennan DC, et al. Am J Transplant. 2011;11:2453-62.Razonable RR, et al. J Infect Dis. 2001;184:1461-4.

Harvala H, et al. J Med Virol. 2013;85(5):893-8.

D+/R-

• Viremia:11.9%

• Disease: 23.8%

D+/R+

• Viremia:4.6%

• Disease: 12.0%

D-/R+

• Viremia:0.2%

• Disease: 4.2%

D-/R-

• Viremia:0%

• Disease: 2.8%

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8 – 32%

22 – 29%

50 – 75%

50%

9 – 35%

Incidence of SOT CMV Disease without Prophylaxis

Available at: https://online.seterra.com/en-an/vgp/3801.Patel PC, et al. Clin Microbiol Rev. 1997;10:86-124.

Grossi P, et al. Transplantation. 1995;59:847-61..

22%

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Sequela of CMV Infection

DirectDirect• End organ disease• Allograft rejection

IndirectIndirect• Bacteremia• Invasive fungal infection• Epstein-Barr Virus associated malignancy• Vascular thrombosis• Diabetes mellitus

Freeman RB, et al. Am J Transplant. 2009;9:2453-8.

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Preventive Strategies

• Valganciclovir (VGCV) to all patients or a subset at risk for three to six months

Universal prophylaxisUniversal

prophylaxis

• CMV viral load checked weekly to detect replication• Treatment dose VGCV if viral load meets threshold

Preemptive therapy

Preemptive therapy

• CMV viral load checked weekly to detect replication for eight to twelve weeks after the end of prophylactic therapy

Surveillance after prophylaxis

Surveillance after prophylaxis

Kotton CN, et al. Transplantation. 2018;102(6):900-31. 14

Comparison of CMV Prophylaxis Strategies

Outcomes Prophylaxis Preemptive

Safety Drug side effects Less drug toxicity

CMV Viremia Rare Common

Prevention of Disease Good Good

Late CMV Common (D+/R-) Rare

Resistance Uncommon Uncommon

Prevention of other herpes viruses

Herpes simplex virus, varicella zoster virus Does not prevent

Prevention of rejection May prevent Unknown

Graft survival May improve May improve

Cost Increased drug cost Increased laboratory cost

Kotton CN, et al. Transplantation. 2018;102(6):900-31.

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Cost Comparison of CMV Prophylaxis Strategies

Preemptive Prophylaxis p value

Total, mean + SD $7130 + 3748 $7678 + 6486 0.611

VGCV, mean + SD $1705 + 1973 $4976 + 2386 <0.0001

Provider time $438 + 20 $134 + 19 <0.0001

CMV PCR $4363 + 297 $1368 + 272 <0.0001

Hospitalization $625 + 2446 $1200 + 4978 0.460

• Prophylaxis• VGCV 900 mg daily for 100 days

• Preemptive• PCR weekly (weeks 1-6) followed by PCR checks monthly to quarterly for one year• VGCV 900 mg twice daily for 21 days as treatment

Khoury JA, et al. Am J Transplant. 2006;6(9):2134-43. 16

Universal Screening vs Preemptive Therapy

Study Design Population Endpoint Intervention Findings

Reischig T, et al.n = 70

Prospective, randomized multi-center open label trial

D+/R+, D+/R-, D-/R+ renal transplant patients

12 month incidence of CMV diseaseand rejection

Screening vs. valacyclovir 2 g four times daily for three months

CMV disease comparable between preemptive and prophylactic groups (6% vs 9%, p = 0.601).

Witzke O, et al.n = 299

Prospective, randomized multi-center open label trial

D+/R+, D-/R+ renal transplant patients

Active CMV infection and disease within 12 months

Screening vs VGCV 450 mg twice daily for 100 days

Fewer prophylaxis patients had CMV infection (6.3 – 17% vs 39%, p < 0.0001) and disease (4.7% vs 15.9%, p = 0.0033).

Khoury JA, et al.n = 98

Prospective, randomized singlecenter trial

D+/R+, D+/R-, D-/R+ renal transplant patients

Occurrence of CMV infection and disease

Screening vs VGCV 900 mg daily for 100 days

Prophylaxis reduced CMV infection (6% vs 59%, p<0.001). Disease was comparable between preemptive and prophylactic groups (2% vs 8%, p = 0.362).

Witzke O, et al. Transplantation. 2018;102:876-82.Reischig T, et al. Am J Transplant. 2008;8:69-77.

Khoury JA, et al. Am J Transplant. 2006;6(9):2134-43.

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Management of CMV in SOT GuidelinesWe recommend either universal prophylaxis or preemptive therapy for prevention of CMV disease (strong, high LOE). ¥

D+/R-* D+/R+* D-/R+* D-/R-• Prophylaxis for six

months is preferable• Prophylaxis for three months

• Preemptive therapy

• Prophylaxis for three months

• Preemptive therapy

• Monitor for clinical signs and symptoms

• Consider prophylaxis against other herpes infections such as herpes simple virus

¥ Use of surveillance after prophylaxis may be considered in patients at increased risk for post-prophylaxis CMV disease for eightto twelve weeks (weak, low LOE).*Prophylaxis may be preferred in donor and/or recipient seropositive patients whose risk for CMV may be increased. A longerduration of prophylaxis (ie, 6 months) may be more effective (weak, moderate LOE).

Kotton CN, et al. Transplantation. 2018;102(6):900-31. 18

CMV Prophylaxis Options

Creatinine clearance (mL/min)

Treatment Dose Maintenance/Preventive Dose

> 60 900 mg every 12 h 900 mg once daily

40 - 59 450 mg every 12 h 450 mg once daily

25 - 39 450 mg once daily 450 mg every 2 days

10 - 24 450 mg every 2 days 450 mg twice weekly

<10 200 mg 3 times a week after HD

100 mg 3 times a week after HD

HD: hemodialysis

• Valganciclovir, ganciclovir, and valacyclovir can all beused in renal transplant patients

• VGCV is most commonly used

Kotton CN, et al. Transplantation. 2018;102(6):900-31.

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Absorption

• Well absorbed• High fat meal

increases AUC by 30%

Distribution

• 0.7 L/kg

Metabolism

• 60% bioavailable

• Converted to GCV by

intestinal mucosal cells

Elimination

• Half life:6 hours

• 80% excretedin urine

Adverse Effects

• Anemia 31%• Thrombocytopenia

<22%• Neutropenia

3-19%• Increased SCr

12-50%• Tremor 12-28%

Valganciclovir Pharmacokinetics

Available at: http://online.lexi.com.Le Page AK, et al. Transplantation. 2013;95:1455.

In an international survey on CMV management, 24% of respondents acknowledged using low dose VGCV prophylaxis in high risk patients

AUC: area under the curveGCV: ganciclovirSCr: serum creatine

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Low Dose vs Standard Dose Pharmacokinetics

0 10 20 30 40 50 60 70

AUC0-24hrs (mcg/hr/mL)

Chamberlain CE, et al. Am J Transplant. 2008;8(6):1297-1302.

VGCV 900 mg qDay

PO GCV 1 gm q8h

IV GCV 2.5 mg/kg q12h

VGCV 450 mg qDay

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Controversies in CMV Prophylaxis

Which strategy is appropriate?

Prophylaxis vs preemptive

Which dose is appropriate?

900 mg daily vs 450 mg daily

Do doses need to be renally adjusted?

Dose of 450 mg daily in CrCl <60 mL/min

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Increased risk of breakthrough infection among CMV D+/R- renal transplant recipients receiving 450 mg VGCV prophylaxis

Introduction Methods Results Conclusion

Stevens DR, et al. Trans Inf Dis. 2015:17:163-73.

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Design Single-center, retrospective cohort study

Objective Evaluate prevalence of CMV infection and disease in D+/R- renal transplant patients receiving high dose vs low dose VGCV prophylaxis

Endpoints Rates of CMV infection and disease

Inclusion Criteria > 18 years of age, D+/R- serostatus, induction with ATG, standard maintenance immunosuppressive therapy

Intervention VGCV 450 mg vs 900 mg daily for six months

Monitoring CMV screening if symptomatic or abnormal labs using PCR based assays

Definitions

Infection: active viral replication as detected by PCRDisease: infection with attributable symptoms to CMV

Late onset (LO) CMV: any case of CMV infection or disease arising after discontinuation of prophylaxis


ATG: anti-thymocyte globulin

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450 mg VGCV, n = 45 900 mg VGCV, n = 45

Median age, years (IQR) 53.2 (33.9 – 58.8) 54.2 (46.8 – 58.7)

Deceased donor, n (%) 29 (64.4) 35 (77.8)

Mean follow up in days, (SD) 320 (103) 357 (25.5)

Mean tacrolimus trough at 30

days, ng/mL + SD*9.7 + 2.3 10 + 2.4


SD: standard deviationIQR: interquartile range

*Goal tacrolimus level with thymoglobulin induction at day 30: 5 to 10 ng/mL

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25



40%

26.7%

0%

10%

20%

30%

40%

50%

Rates of CMV Infection and Disease

VGCV 450 mg VGCV 900 mg

p = 0.18

CMV

Occ

urre

nce

Rate

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• No difference • Overall survival or graft loss at six and twelve months• GCV resistant CMV infection• Acute rejection in first six months

• Patients on 900 mg VGCV were more likely to experience leukopenia (75% vs 44.4%, p <0.01)


Primary Composite Components 450 mg VGCV, n = 45 900 mg VGCV, n = 45 p value

Breakthrough infection, n (%) 6 (13.3) 1 (2.2) 0.11

Late onset infection ordisease, n (%) 12 (26.7) 11 (24.4) 0.86

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Conclusions• Increased rates of breakthrough

infection and a single case of GCV-resistant infection in patients taking450 mg VGCV was observed

• VGCV 900 mg was associated with increase risk of leukopenia and rejectioncompared with VGCV 450 mg

Comments• 450 mg group had significantly shorter

follow up

• Conclusions were drawn from non-significant findings

• Higher rates of leukopenia comparedto literature

• Trial stopped prior to reaching power due to identified trends

• No routine screening

• No PCR diagnostics definition

Stevens DR, et al. Trans Inf Dis. 2015:17:163-73. 28

Evaluation of VGCV 450 mg versus 900 mg for prevention of CMV disease in D+/R- renal transplant recipients


Gabardi S, et al. Transpantation. 2015;99: 1499-1505.

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Design Multicenter, retrospective cohort study

Objective Compare the efficacy and safety of six months of VGCV 450 mg with 900 mg in high risk renal transplant patients

Endpoints 12 month CMV disease rates

Inclusion Criteria 18 to 75 years old, D+/R-, induction with ATG or interleukin-2 antagonist, maintenance on tacrolimus and mycophenolic acid

Intervention VGCV 450 mg vs 900 mg daily for 6 months

Monitoring CMV screening if symptomatic or abnormal labs using PCR based assays

Definitions

Disease: viral syndrome or tissue invasive Viral syndrome: CMV viremia PCR or pp65 and one of the following: >38°C, flu

symptoms, leukopenia on 2 successive measurementsTissue invasive: presence of localized CMV infection in a biopsy along with

symptoms of organ dysfunction

Gabardi S, et al. Transpantation. 2015;99: 1499-1505. 30


450 mg VGCV, n = 130 900 mg VGCV, n = 107

Mean age, years + SD 48.7 + 12.0 48.8 + 12.8

Deceased donor, n (%) 12 (9.2) 12 (11.2)

BPAR, n (%) 18 (13.9) 14 (13.1)

Antibody-mediated rejection, n (%) 3 (2.3) 1 (0.9)

Mean tacrolimus trough at 30 days,

ng/mL + SD9.4 + 3.5 11 + 4.4


BPAR: biopsy proven acute rejection

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14.6%

24.3%

0%

10%

20%

30%

12 Month CMV Disease Rates

VGCV 450 mg VGCV 900 mg

p = 0.068

CMV

Occ

urre

nce

Rate

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Kaplan-Meier plot of time to CMV disease up to month 12 after transplantation

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• Multivariate logistic regression • Low dose VGCV prophylaxis had a 57% lower risk of developing CMV

disease compare to those receiving high dose

• No difference in rates of BPAR, graft loss, patient survival, opportunistic infection, and new onset diabetes mellitus after transplantation

• Higher rates of leukopenia in the 900 mg group reported at months 5 and 6 (20.6% vs 9.9; p = 0.034), but no differences in grades of leukopenia

• Using low dose VGCV can provide $14,000 in savings per patient

Components of Primary Outcome 450 mg VGCV, n = 19 900 mg VGCV, n = 26 p value

Viral syndrome, n (%) 13 (68.4) 24 (92.3) 0.055

Tissue invasive disease, n (%) 6 (31.6) 2 (7.7) 0.055

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Conclusions• Low and standard dose VGCV regimens

provide similar efficacy in preventing CMV disease in D+/R- renal transplant patients

• VGCV 450 mg may have a higher risk oftissue invasive disease than 900 mg

• VGCV 900 mg is associated with significantly lower white blood cell counts at months five and six, but no difference inrates of discontinuation observed

Comments• One year follow up

• Did not report rates of CMV viremia

• VGCV dose reductions due to adverse events were not recorded

• Trend towards higher breakthrough CMV on 900 mg dose after discontinuation

• D+/R- only


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High rates of inappropriate VGCV dosing for CMV prophylaxis after renal transplantation


Rissling O, et al. Clin Kidney J. 2018; 11(4):564-73. 36


Design Retrospective, single center cohort study

ObjectiveEvaluate routine prescribing frequency for all GFR classes in relation to

under dosing/recommended dosing or over dosing due to current recommendations

Endpoints Occurrence of CMV viremia and infection at days 30 and 60

Inclusion Criteria > 18 years old renal transplant patients

Intervention VGCV 900 mg daily

Definitions CMV viremia: CMV PCR > 750 copies/mLCMV infection: positive PCR with clinical symptoms

Rissling O, et al. Clin Kidney J. 2018; 11(4):564-73.

GFR: glomerular filtration rate

9

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All patients, n = 635

Under dosing, n = 426

Recommended Dose, n =137

Overdosing, n = 43

Mean age, years + SD 51 + 14 49 + 14 54 + 13 55 + 13

Deceased donor, n (%) 465 (73.2) 299 (71.4) 106 (77.4) 37 (86.0)

D+/R-, n (%) 103 (16.2) 75 (17.9) 21 (15.9) 5 (11.6)

Mean prophylaxis duration, days + SD 129 + 68 127 + 67 134 + 69 135 + 71

Mean prophylaxis daily dose, mg + SD 248 + 152 227 + 119 315 + 210 256 + 160

Basiliximab indication therapy, n (%) 468 (73.7) 347 (81.5) 91 (66.4) 29 (67.4)




Different dosing frequencies according to CG-CrCl on day 30

CG-CrCl: Cockcroft-Gault Creatinine Clearance

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VGCV dosing frequency in relation to CrCl on day 30 post transplant

Dosin

g fre

quen

cy

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• Other findings included• Renal function was lower in patients developing CMV viremia (p<0.001),

but was not identified as a risk factor• Logistic regression analysis revealed that D+/R- serostatus and shorter

duration of prophylaxis were risk factors for developing CMV viremia

• Dosing frequency was similar between patients with and without leukopenia at day 60 (p = 0.790)

• CMV positive patients had significantly shorter prophylaxis duration(89.5 vs 112 days, p <0.001)


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Conclusions• VGCV has comparable tolerability and

safety with high variability in dosing

• Large variabilities in dosing observed, especially in those with CrCl <25 mL/min

• Standard or low dose VGCV are comparable regarding CMV preventionand adverse events

Comments• Low mean dose

• Unclear appropriate duration of therapy

• Duration of inappropriate doses werenot clarified

• Various SOT

• Evaluated at 30 days


Risk factors for failure of (val)ganciclovir prophylaxis against CMV infection and disease in solid organ transplant recipients


Khurana MP, et al. Open Forum Infect Dis. 2019;6(6):ofz215

10

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Design Retrospective, single center cohort study

Objective Investigate if, and to what extent, different dosages of (val)ganciclovir prophylaxis affect the risk of breakthrough during prophylaxis

Endpoints CMV breakthrough within 90 days based on prophylactic score.*

Inclusion Criteria

> 18 years old with heart, lung, liver, or kidney transplants anticipated to receive prophylaxis for at least 90 days

Intervention VGCV 450 mg every other day for renal transplants; VGCV 900 mg daily for all other SOT

Monitoring Once monthly CMV PCR for 90 days

DefinitionsCMV breakthrough: CMV infection within the first 90 days post transplant

CMV infection: 2 consecutive PCRs > 273 IU/mL within 14 days of each other or 1 CMV PCR > 2,730 IU/mL

Khurana MP, et al. Open Forum Infect Dis. 2019;6(6):1-10.

*Prophylactic score = recommended dose (adjusted for eGFR)/actual dose.Optimal prophylaxis = 100, half the optimal dose = 50

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All Recipients, n = 585 No Breakthrough, n = 547 Breakthrough, n =38

Median age, years (IQR) 50.5 (40.9-58.9) 50.8 (41.1-58.9) 48.2 (35.5-59.4)

Transplant type

Kidney, n (%) 311 (53.2) 284 (91.3) 27 (8.7)

Heart, n (%) 51 (8.7) 50 (98.0) 1 (2.0)

Liver, n (%) 117 (20.0) 114 (97.4) 3 (2.6)

Lung, n (%) 106 (18.1) 99 (93.4) 7 (6.6)

D+/R- serostatus, n (%) 124 (21.2) 104 (83.9) 20 (16.1)


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Breakthrough, n =38 No breakthrough, n = 547 p value

Median day 15 prophylaxis score, IQR 78.7 100.3 <0.01

• Trend toward increased rates of prophylaxis breakthrough rates with lungs and kidneys over hearts and livers (p = 0.067)

• For every 10% more days spent during follow up with a prophylaxis score <90,the risk of breakthrough infection increased by 15% (HR, 1.15; 95% CI, 1.07 to 1.24; p <0.01)

• D+/R- serostatus patients were more likely to develop a breakthrough infection compared with D+/R+ or D-/R+ (16.1% vs 4.6% vs 2.2%, p <0.01)

Khurana MP, et al. Open Forum Infect Dis. 2019;6(6):1-10. 46


Average prophylaxis scores for renal transplant patients from days 15 to 89

Days Post Transplant

Prop

hyla

xis

Scor

e


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Conclusions• SOT patients receiving prophylactic doses

of VGCV below manufacturer recommended are at an increased risk of experiencing prophylaxis breakthrough

• Low dose VGCV may be suboptimal in preventing breakthrough CMV infection in solid organ transplant patients

Comments• Definition of breakthrough

• Various SOT types

• Monitoring of immunosuppressants notrecorded

• Follow up period of 90 days

• No p value at 90 days

• Baseline dose for renal transplant patients

Khurana MP, et al. Open Forum Infect Dis. 2019;6(6):1-10. 48

Applying to Clinical Practice

Renal Transplant Recipient

D+/R-VGCV 900 mg

daily for 6 months

D+/R+VGCV 450 mg

daily for 3 months

D-/R+VGCV 450 mg

daily for 3 months

D-/R- No prophylaxis needed

Close follow up for renal dose adjustment is recommended.

11

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Meet the patient…

• JC is a 40 year old male who is day 9 status post renaltransplant. His past medical history is significant for diabetes mellitus, hypothyroidism, and polycystic kidney disease.

Vitals:Temp: 99.5°FHR: 94 bpmBP: 109/64 mmHgRR: 18Weight: 75 kg

135

3.4

102

26

8

1.58.7

12.4

36215

Serostatus: D-/R+*

*D/R: donor/recipient

Estimated creatinine clearance 65 mL/min

50

Meet the patient…

The decision is made to give JC prophylactic valganciclovir. Which regimen would you recommend?

A. 450 mg daily for 3 monthsB. 450 mg daily for 6 monthsC. 900 mg daily for 3 monthsD. 900 mg daily for 6 months

51

Conclusions

• Low dose CMV prophylaxis may be appropriate in D+/R+and D-/R+ renal transplant patients

• Standard dose VGCV should be continued for D+/R- renaltransplant patients

• There is not sufficient data to apply these findings to otherSOT patients

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Acknowledgements

• Dr. Andrew Hunter, PharmD, BCPS (AQ-ID)• Dr. Dusten Rose, PharmD, BCIDP, AAHIVP• Dr. Terry Jaso, PharmD, BCPS (AQ-ID)• Dr. Julia Sapozhnikov, PharmD

53

Questions?

Cytomegalovirus Prophylaxis in Kidney Transplant Patients: High Dose, Best Dose?

Nina Maguire, PharmDPGY-2 Infectious Diseases Pharmacy ResidentAscension Seton at the University of TexasSeptember 6, 2019

Appendix A: Abbreviations

CMV: cytomegalovirus

D/R: donor/recipient serostatus

SOT: solid organ transplant

PCR: polymerase chain reaction

VGCV: valganciclovir

AUC: area under the curve

GCV: ganciclovir

SCr: serum creatinine

ATG: anti-thymocyte globulin

LO CMV: late onset CMV

SD: standard deviation

IQR: interquartile range

BPAR: biopsy proven acute rejection

GFR: glomerular filtration rate

CG-CrCl: Cockcroft-Gault creatinine clearance

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Appendix B: Gabardi, et al. Figure

13

Appendix C: Rissling, et al. Figures

14

Appendix D: Khurana, et al. Figure

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cytomegalovirus prophylaxis in renal transplant patients ......cytomegalovirus (cmv) infection in...

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