Transcript 5-1-Kotton

How I Manage CMV in the PostTransplant Patient
Camille Nelson Kotton M.D.
Clinical Director, Transplant and Immunocompromised Host Infectious Diseases Group
Massachusetts General Hospital, Associate Prof.,Harvard Medical School
Chair, Infectious Disease Community of Practice, American Society of Transplantation
Past-President, The Transplant Infectious Disease Section, The Transplantation Society
Disclosures
Camille Nelson Kotton MD, FIDSA, FAST
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Consultant:
– Merck, Genentech (CMV therapeutics)
– Astellas, AstraZeneca (CMV Vaccines)
– Roche Molecular Systems, Cellestis-QIAGEN & Oxford Immunotec
(transplant infectious disease diagnostics)
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Adjudication committees: Merck, Astellas
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Research projects with Oxford Immunotec and Cellestis-QIAGEN
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Spouse has no significant financial disclosures
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May discuss off-label use of diagnostics, medications, and vaccines
How I Manage CMV after Transplant
• Prevention
• Diagnostics
– Molecular
– Immunologic
• Therapeutics
• Vaccines
• Genetic risk stratification
• Focus on what’s new in 2015
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Direct Effects of CMV Infection
Direct Effects
CMV Viral Syndrome
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Tissue-Invasive Disease
Flu-like syndrome: fever,
malaise, myalgias
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Leukopenia,
thrombocytopenia
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Colitis
Hepatitis
Pneumonitis
Myocarditis
Nephritis
Encephalitis
Retinitis
Pancreatitis
Adapted from Torres-Madriz G, Boucher HW. Clin Infect Dis. 2008;47:702-11.
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Indirect Effects of CMV
General indirect effects–elevated risks
Transplant-specific indirect effects
•Bacterial, fungal, viral infections
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Chronic allograft nephropathy and/or
allograft loss after renal transplant
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Accelerated hepatitis C recurrence
after liver transplant
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Hepatic artery thrombosis after liver
transplant
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Allograft vasculopathy after cardiac
transplant
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Bronchiolitis obliterans after lung
transplant
•Post-transplant lymphoma (PTLD)
•Cardiovascular events
•New-onset diabetes mellitus after
transplantation
•Immunosenescence
•Acute rejection
•Mortality
from Kotton, CMV: Prevention, Diagnosis and Therapy, AJT 2013
Transplantation 2015
D+R-
D+R-
prophylaxis
prophylaxis
61,927 adult recipients of deceased donor kidney transplant
1990 to 2012 in the Collaborative Transplant Study
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PREVENTION:
Prophylaxis versus Preemptive Therapy
Prophylaxis period (typically 3–6 months) after transplantation
More common
after SOT
Antiviral prophylaxis
Preemptive monitoring period (once weekly for 12-16 weeks);
If CMV is detected (PCR or pp65 Ag), treat until CMV is cleared
0
4
8
12
16
Weeks
Humar A, Snydman D. Am J Transplant. 2009;9 (suppl 4):S78-86.
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More common
after HSCT
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Comparison of Known Benefits and Limitations
of Prophylaxis vs Preemptive Therapy
Prophylaxis
Preemptive Therapy
Rare
Common
Good efficacy
Good efficacy*
(*less optimal in high risk populations)
Common
Rare
Uncommon
Uncommon
Relatively easy
More difficult
Prevents HSV, VZV
Does not prevent
May prevent
Unknown
Drug costs
Monitoring costs
Drug side effects
Less drug toxicity
Prevention of rejection
May prevent
Unknown
Graft survival
May improve
May improve
Early CMV DNAemia
Prevention of CMV disease
Late CMV (infection/disease)
Resistance
Ease of implementation
Other herpesviruses
Other Opportunistic infections
Cost
Safety
Kotton CN et al. Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ
Transplantation. Transplantation. 2013;96(4):333-360.
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Massachusetts General Hospital Protocol:
CMV/Herpes/Varicella Prophylaxis after Renal, Liver,
Heart, or Pancreas Transplant
Induction
Donor
agent
CMV Antibody
Recipient CMV
Antibody
Prophylaxis
Thymoglobulin
+
+
(polyclononal
antithymocyte
globulin)
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+
+
-
Valganciclovir x 6 months
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acyclovir/famvir/valacyclovir x 3 mos
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+
-
+
+
-
-
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+
+
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+
+
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-
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Basiliximab (IL-2
antagonist)
None
Monitoring with
CMV viral load
while on
prophylaxis
valganciclovir x 3 mos plus monthly
monitoring afterwards x 3 months
valganciclovir x 3 mos
acyclovir/famvir/valacyclovir x 3 mos
valganciclovir x 3 mos
acyclovir/famvir/valacyclovir
x 3 mos
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Not needed - only if
clinically indicated
by symptoms
HYBRID Strategy:
Preemptive Therapy After Prophylaxis
• High Risk (D+R-) may be highest yield population (for late disease)
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Other high risk groups (potent immunosuppression)
• Guidelines experts use approach, not strongly evidence-based
CMV disease
CMV viral load assay: 0
Prophylaxis
+
+
+
+
4
+
8
+
+
-
-
12
months
Could have initiated preemptive therapy before
disease developed
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Stringent adherence to a CMV-prevention protocol is
associated with reduced overall costs in the first 6 months
after kidney transplantation, Matter-Walstra et al, TID 2015
• Standard prevention cost Swiss francs [CHF] 104,548
(mean) versus CHF 76,983 for stringent prevention (P
= 0.0005) (1 CHF = US$1.03)
– Largely due to less disease in stringent group
• Overall difference in CMV disease episodes did not
occur in the high-risk group, rather in intermediate
group with CMV seropositive recipients (R+)
• Incidence of CMV disease was significantly reduced
from 14 (15%) to 4 (5%)
– 11% down to 1% in pre-emptive therapy group
Conclusions: “The use of secondary prophylaxis was not significantly associated with
fewer episodes of CMV relapse, graft loss, or death.”
“Time to clearance of CMV viremia during treatment was significantly longer in those
who relapsed (mean, 30 days vs. 20 days; P = 0.037).”
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Transplant ID 2015
• 45 patients on low dose prophylaxis were evaluated:
– 6 developed CMV infection while on prophylaxis (P = 0.11)
– 1 developed ganciclovir (GCV)-resistant infection
• Late-onset CMV infection/disease: same
– 11 patients (24%) in the standard dose group
– 12 patients (27%) in the low dose group (P = 0.86)
• More patients in the standard dose group developed
leukopenia (75% vs. 44%, P < 0.01).
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Low dose:
-6/45 developed CMV infection while receiving prophylaxis (P = 0.11). 1/45 w/ confirmed GCV-resistant infection
-same rates of late CMV
standard dose PPx
lower dose PPx
180 days of prophylaxis
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Stevens et al, TID 2015
Diagnostics: Molecular & Immunology
Crough and Khanna, CMR, 2009
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CMV Viral Load & International Standard
• Inter-laboratory comparison: Variation observed in viral load
results for individual samples ranged from 2.0 log(10) to 4.3
log(10), Pang et al, AJT 2009
• Assays at 5 transplant centers in US and Europe were
compared, using international units, Hirsch et al, CID 2013
– COBAS AmpliPrep/COBAS TaqMan CMV Test superior to local
assays
– Results generally comparable w/ international units
• Must compare same specimen type
– Plasma < whole blood
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“We predict that the era when CMV-specific T-cell immune
assays are part of the standard of care for CMV at-risk SOT
populations is very near”.
Potential Clinical Scenarios for the Use of
Cellular Immune-based Assays
Clinical Scenarios
Assays studied
Potential clinical management*
CMV D+/R- and R+ at the end of
prophylaxis
QFT, ELISpot, ICS
For negative assay, prolong prophylaxis;
For positive assay, no further prophylaxis
CMV D+/R- and R+ during preemptive strategy
QFT, ELISpot, ICS
Result may help guide frequency of viral load
monitoring and thresholds for initiating antiviral
therapy
Post-therapy for acute rejection
ICS (small number,
not predictive)
For negative assay, restart prophylaxis or viral
load monitoring;
For positive assay, no further intervention
Recent completion of therapy for
CMV disease or viremia
(Prediction of relapse)
No studies
For negative assay, secondary prophylaxis;
For positive assay, no further therapy
Risk stratification in patients pretransplant
ICS, QFT
For positive assay, assume true positive CMV
status
Kotton CN et al. Updated International Consensus Guidelines on the Management of
Cytomegalovirus in Solid-Organ Transplantation. Transplantation. 2013;96(4):333-360.
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Ex vivo monitoring of CMV-specific T-cell responses
Modified from Crough & Khanna, CMR, 2009
T-SPOT®.CMV
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Assessment of CMV-Specific Cell-Mediated Immunity
for the Prediction of CMV Disease in High-Risk SOT
Transplant Recipients: A Multicenter Cohort Study
• D+R- on antiviral prophylaxis; Quantiferon CMV assay
• Test done at end of PPX, then at 1, 2 months
• 22% developed CMV disease
• 124 patients:
• 31 (25%) positive
• 81 (65.3%) negative
• 12 (9.7%) indeterminate result (negative mitogen)
Manuel O, et al. CID 2013 Mar;56(6)817-824.
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CMV-Specific Cell-Mediated Immunity for the
Prediction of CMV Disease in High-Risk SOT
Freedom from CMV Disease
positive
negative
indeterminate
Manuel O, et al. CID 2013 Mar;56(6)817-824.
At 12 months, patients
with a positive result had
a subsequent lower
incidence of CMV
disease (6.4%) than
patients with a negative
(22.2%) and an
indeterminate result
(58.3%, respectively;
P < .001).
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Pre-transplant CMV–specific interferon (IFN) γ–producing T-cell
responses were significantly lower among CMV IgG–seropositive (R+)
kidney transplant recipients with CMV disease and viremia
Disease
Yes
No
Yes No
Viremia
Yes
Non-commercial assay
Lúcia et al, Clin Infect Dis. 2014 Jul
No
Yes
No
Factors Related to the Development of CMV-Specific CD8+
T cell Response in CMV-Seropositive SOT Transplant
Candidates, Cantisán et al, AJT 2015
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CMV seropositive but lacking CMV-specific CD8+ T cell
response=higher incidence of CMV replication/disease
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Used QuantiFERON-CMV assay
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n=141: 90 (64%) QF-CMV reactive/51 (36%) nonreactive.
“Therefore, although the assessment of CMV-specific CD8+
response is recommended in all R+ candidates, it is essential
in those with a lower probability of being reactive, such as nonrenal candidates, candidates under 50 or those with non-HLAA1/non-HLA-A2 alleles.”
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Treatment of CMV
• Treat with ganciclovir or valganciclovir, test viral
load/antigenemia weekly, until 1-2 assays are negative (or
low results (<1,000 IU)), often 2-3 weeks of treatment
• VICTOR trial showed valganciclovir PO similar to
ganciclovir IV for mild-moderate disease in SOT (Asberg,
AJT 2009)
• Foscarnet used when bone marrow suppression an issue
• Concern for resistance: worsening disease or increasing
viral load
– Consider sending genotypic resistance testing
– Consider switching to foscarnet or using high dose ganciclovir
Suggested Algorithm for Managing
Suspected CMV Drug Resistance
Kotton CN et al. Updated International Consensus Guidelines on the Management of
Cytomegalovirus in Solid-Organ Transplantation. Transplantation. 2013;96(4):333-360.
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Optimal Dosing of GCV/VGCV
Kotton CN et al. Updated International Consensus Guidelines on the Management of
Cytomegalovirus in Solid-Organ Transplantation. Transplantation. 2013;96(4):333-360.
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Novel/Emerging Therapeutics
• Maribavir (Viropharma)
• Letermovir (AIC246) (Merck)
• Brincidofovir (CMX001) (Chimerix)
• HSCT data, limited SOT
• Compassionate use - challenging
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Vaccines under Development
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Astellas vaccine (ASP0113, TransVax™) w/ Vical
– Plasmids encoding cytomegalovirus glycoprotein B and phosphoprotein
65 formulated with poloxamer CRL1005 and benzalkonium chloride
– multinational Phase 3 trial in HSCT recipients, Phase 2 in SOT recipients
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Sanofi vaccine (enveloped virus-like particles, glycoprotein B/MF59
adjuvant) w/ VBI
– Kirchmeier et al, Clin Vaccine Immuno 2014, increased efficacy in animals
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GSK vaccine (glycoprotein B/AS01 adjuvant)
– HCMV gB (hgB) antigen, a recombinant fusion protein consisting of the
extracellular domain of the native gB (AD169 strain) and peptide
sequences from glycoprotein gD of Herpes Simplex virus 2 (HSV2)
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Novartis (AVX601) w/ AlphaVax
– single-cycle particle RNA vaccine encoding three antigens--
phosphoprotein 65, immediate early protein I, and glycoprotein B
*CMV-specific T cells from a donor bank
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Genetics & CMV: Influences of Recipients
and Donors
• Polymorphisms in the IFNL3/4 region influence
susceptibility to CMV replication in solid-organ transplant
recipients (Manuel et al, JID 2015)
• Killer immunoglobulin-like receptors (KIR) (genetically
polymorphic natural killer (NK) cell receptors) important in
antiviral response KIR genotype impacts primary control
of CMV infection after transplantation (Van Duin et al)
• Toll-like receptors(TLR)-2/-4 polymorphisms influence
CMV risk (Cervera et al 2007, Ducloux et al 2005,
Kijpittayarit et al, 2007)
• Mannan-binding lectin deficiency increases risk of CMV
infection (Manuel et al 2007, numerous others)
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Summary
• Prevention is key, in both high and moderate risk groups
• Novel diagnostics, therapeutics, and vaccines under active
development
• A better appreciation of the contribution of donor and
recipient genetics may be revealing
• Personalized medicine may be in the near future, via
immunodiagnostics and genetics
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Questions? [email protected]
Massachusetts General Hospital, Harvard Medical School,
Boston, Massachusetts, USA