Download Treatment of Ganciclovir-Resistant Cytomegalovirus in Adult Solid

Treatment of Ganciclovir-Resistant Cytomegalovirus in
Adult Solid Organ Transplant Recipients
Caught Between a Rock and a Hard Place?
Emily Gordon, Pharm.D.
PGY-1 Pharmacy Resident
Department of Pharmacy, University Health System, San Antonio, Texas
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center,
University of Texas Health Science Center at San Antonio
November 1, 2013
Learning Objectives:
1. Describe the impact of cytomegalovirus infection and disease following solid organ transplantation
and the current practice methods for prophylaxis and treatment.
2. Define the mechanisms and risk factors associated with the development of antiviral-resistant
cytomegalovirus.
3. Explain when antiviral resistance should be suspected in the clinical setting and what diagnostic
tests can be used for confirmation.
4. Evaluate the treatment options for ganciclovir-resistant cytomegalovirus infection and disease.
Cytomegalovirus
1-7
I. Epidemiology
a. Cytomegalovirus (CMV) is a member of the human herpesviruses
i. Transmitted from infected individuals to others through direct contact with bodily fluids
b. Evidence of prior exposure to CMV is present in about two-thirds of the United States population
i. Immunocompetent individuals
Primary
Infection
Life-long
Latency
• First time patient is infected with the virus
• Asymptomatic or non-specific viral illness
• Easily overcome by the host immune system
• Established in individuals following primary infection
• Latency of virus maintained primarily via cell-mediated immunity
• Reservoirs for reactivation and spread of infection when immune
system impaired
Figure 1. Stages of initial CMV infection in immunocompetent host
8
ii. Solid organ transplant (SOT) recipients
1. CMV is the most common infection leading to major complications after
transplantation
a. Rate is highly variable on type of transplantation, presence of associated risk
factors, and the use of prolonged prophylaxis
2. CMV is a major cause of morbidity and mortality
a. Increased incidence of rejection and crude mortality among SOT recipients who
have CMV disease compared to those who do not
3. Growing rates of CMV antiviral resistance becoming an increased concern
a. Association with poor clinical outcomes
b. Lack of alternate antiviral treatment options
1,3,5,9
II. Definitions
a. CMV infection
i. Evidence of CMV replication regardless of symptoms
b. CMV disease (see Table 1)
i. Evidence of CMV infection with attributable symptoms
1. CMV syndrome
2. Tissue invasive disease
a. Most severe form of CMV disease
b. Transplanted allograft is commonly involved
c. Biopsy required for diagnosis
c. Latent CMV
i. Virus exists as closed circular DNA
ii. Virus reactivation induced by many factors present in the transplant recipient
1. Therapy with antilymphocyte antibodies and cytotoxic drugs
2. Allogeneic reactions
3. Systemic infection and inflammation
2
1,4,6
III. Manifestations
(see Table 1)
a. Direct effects
i. Caused by viral infection itself
b. Indirect effects
i. Viral infection results in modification of the host immune system
1. Immunosuppressive, immunomodulatory, and inflammatory changes
2. Cytokine and growth factor response to viral replication
Table 1. Direct and Indirect Effects of Cytomegalovirus Infection
Direct Effects
CMV Syndrome
Tissue Invasive Disease
Fever
Colitis
Malaise
Pneumonitis
Weakness
Hepatitis
Myalgias/arthralgias
Nephritis
Leukopenia
Gastroenteritis
Thrombocytopenia
Retinitis
1,4
Indirect Effects
Acute rejection
Chronic rejection
Bacterial, viral, fungal
infections
Mortality
Assessing the Transplant Patient
I.
1,2,10
Pretransplant assessment
a. Risk factors for development of posttransplant CMV infection and disease
i. Donor/recipient CMV immunoglobulin G (IgG) serostatus
1. Greatest risk factor for development of CMV disease (see Table 2)
a. Overall rate of CMV infection and disease among CMV naïve recipients
receiving seropositive organs is approximately 56% to 68%
2. Measure anti-CMV IgG before transplantation
a. Indicates prior exposure to CMV
b. Performed on both the organ donor and recipient
c. Recorded as Donor +/Recipient + (D+/R+)
d. Determines pharmacologic prophylactic strategy
1,2
Table 2. Risk Stratification Based on Donor and Recipient Serostatus
Donor status
Recipient status
High risk
+
Moderate risk
+/+
Low risk
ii. Degree of immunosuppression
1. Small bowel/heart/lung > kidney/pancreas > liver
2. Lung and small bowel considered to be at highest risk
iii. Use of lymphocyte-depleting agents
1. Alemtuzumab, antithymocyte globulin, rituximab
iv. Host factors
1. Age, comorbidity, leukopenia and lymphopenia, genetic factors
v. Others
1. Cold ischemia time, critical illness, stress
3
1-3,11
II. Posttransplantation assessment and monitoring
a. Viral load testing
i. Important aid for diagnosing disease and monitoring response to therapy
ii. Antigenemia assay
1. Detects pp65 antigen in CMV-infected peripheral blood leukocytes
a. Reported as positive cells per 200,000 leukocytes
2. High specificity (99%)
3. Limitations
a. Poor sensitivity
b. Labor intensive
c. Limited utility in patients with leukopenia
i. Need an ANC ≥1000 cells/mL
d. Lack of standardization
4. Mostly replaced by polymerase chain reaction
iii. Quantitative nucleic acid testing (QNAT) by polymerase chain reaction (PCR)
1. Preferred method of diagnosis and monitoring of CMV infection and disease
a. Increased precision, faster turnaround time, and high sensitivity and specificity
(94% and 92%, respectively)
2. Measures viral load
a. Reported as copies per milliliter
b. Must be aware of institution-specific limit of detection (LOD) and limit of
quantification (LOQ)
i. LOD is defined as lowest concentration of DNA that can be detected in
95% of replicates
ii. Upper and lower LOQ are highest and lowest concentrations of DNA that
can be quantified with precision
c. Lack of standardization between institutions
3. World Health Organization International Reference Standard (2011)
a. Makes it possible for comparison of CMV PCRs across institutions
i. Reported as international units (IU) per milliliter
b. Not all institutions have adopted this standard
Prevention of CMV Infection and Disease Following Solid Organ Transplantation
I. Optimal prevention of CMV infection and disease after SOT can significantly improve outcomes
1,3,12
II. Prior to development of anti-CMV therapy
a. CMV infection occurred in up to 80% of transplant recipients with a mortality rate of those who
developed tissue invasive disease being about 80 to 90%
b. Development of prophylactic strategies have reduced the incidence of CMV disease during the
early posttransplantation period and minimized the effects of CMV disease
1,3,13-16,17
III. Prophylactic agents
a. Ganciclovir (GCV) and valganciclovir (vGCV)
i. Nucleoside analogues active against CMV and HSV
1. GCV
a. Developed in the mid-1980s
b. Indicated for the treatment of CMV retinitis in immunocompromised patients
and for the prevention of CMV in transplant recipients at risk for CMV disease
2. vGCV
a. Valyl ester prodrug of GCV
b. Enhanced bioavailability and comparable efficacy to GCV
c. Indicated for treatment of CMV retinitis in patients with AIDS, prevention of
CMV in high-risk patients (D+/R-) undergoing kidney, heart, kidney/pancreas
transplantation
4
ii. Mechanism of action (see Figure 2)
Drug
phosphorylation
by UL97 kinase
Further
phosphorylation
by cellular
kinases
Figure 2. Ganciclovir mechanism of action
Active nucleoside
analogue
triphosphate
Competitive
inhibition of viral
DNA polymerase
13
iii. Dosing
1. GCV 5 mg/kg IV daily, adjusted for renal dysfunction
2. vGCV 900 mg by mouth daily, adjusted for renal dysfunction
a. Improved bioavailability with decreased pill burden
iv. Monitoring
1. Complete blood count (CBC): neutropenia>anemia>thrombocytopenia
2. Renal function
b. CMV immunoglobulin (CMV Ig)
i. Immunoglobulin containing standardized amount of antibody to CMV
1. Reduce incidence of serious CMV in those exposed to the virus
ii. Indicated for prophylaxis of CMV disease after kidney, lung, liver, pancreas and heart
transplantation
iii. Limited data to support its use for prophylaxis
1. Typically used only as an adjunct to antivirals
1,2,10,18,19
IV. Methods of prophylaxis
a. Universal prophylaxis
i. Prophylactic antivirals initiated immediately posttransplantation
1. Continued for three to twelve months
ii. Prevention rates from 58% to 80%
b. Preemptive therapy
i. Serial testing performed weekly or biweekly for the first few months posttransplantation
ii. Regardless of symptoms, treatment doses of antivirals are administered with any early
evidence of CMV replication
iii. No widely acceptable viral load threshold to guide therapy due to lack of standardization of
PCR results across centers
c. Hybrid approach
i. Short term prophylaxis followed by preemptive therapy
ii. Clinical utility and efficacy not validated
d. Advantages and disadvantages of prophylactic regimens (see Table 3)
i. Optimal preventive regimens are undefined due to the lack of randomized, controlled trials
4
Table 3. Comparison of Universal Prophylaxis and Preemptive Therapy
Universal Prophylaxis
Efficacy
Good
Late onset disease
Common
Drug costs
Cost
$7678 + 6486
Monitoring
Drug toxicity
Seroconversion benefit
May improve
Prophylaxis Against Other Herpes Viruses
HSV, VZV
Reduced indirect effects
Yes
Antiviral resistance
Yes
Preemptive Therapy
Good*
Rare
Monitoring costs
$7130 + 3748
PCR
-No
Unknown
Yes
*Less optimal in high risk populations; potential failure of weekly surveillance with rapid viral replication
HSV=herpes simplex virus; PCR=polymerase chain reaction; VZV=varicella zoster virus
5
e.
1-3
Consensus (see Table 4)
i. Universal prophylaxis is the preferred strategy for high risk D+/R- transplant recipients
ii. Preemptive therapy can be considered in moderate risk SOT patients
1. R+
2. Kidney, liver, and heart transplants
Table 4. Consensus on the Use of Cytomegalovirus Prophylaxis Regimens*
D+/RR+
Duration
Liver, heart
3-6 months
3 months
Kidney, pancreas
6 months
3 months
Lung
6-12 months
≥6 months
Medication Regimen
Kidney, pancreas
vGCV or GCV
Liver
vGCV or GCV
Lung, heart
vGCV or GCV, + CMV Ig
D-/R---Acyclovir
Acyclovir
Acyclovir
*See Appendix A for summary of major CMV prophylaxis trials
GCV= 5 mg/kg IV daily; vGCV= 900 mg by mouth daily
f.
Late-onset disease after prophylaxis discontinuation
i. Disease occurring after discontinuation of antiviral prophylaxis
1. Typically within 3 to 6 months of antiviral discontinuation
ii. Associated with higher rates of mortality and graft loss
iii. About 30% of D+/R- kidney, heart, pancreas, and liver recipients develop late-onset CMV
after completing three months of prophylaxis
Treatment of CMV Posttransplantation
1,2,CDVPI
I. Indications for treatment initiation
a. CMV viremia
i. All patients with CMV disease
ii. Asymptomatic viremia
1. Patient and provider-specific
25,26,13
II. Treatment regimen
a. Immunosuppressive dose reduction
b. Antiviral medications
Figure 3. Timeline of antiviral development
6
i. Foscarnet (FOS)
1. Pyrophosphate analogue indicated for:
a. Treatment of CMV retinitis in patients with acquired immunodeficiency
syndrome (AIDS)
b. Mucocutaneous acyclovir-resistant herpes simplex virus (HSV) infections in
immunocompromised patients
2. Directly inhibits viral DNA polymerase without prior phosphorylation (see Figure 4)
a. Forms a complex with the pyrophosphate binding site of viral DNA polymerase
i. Prevents the cleavage of pyrophosphate from deoxynucleotide
triphosphates
3. Limitations
a. Nephrotoxicity
i. Major dose-limiting side effect
ii. Adequate hydration for prophylaxis recommended
1. Prior to first infusion: 750 to 1000 mL NS or D5W
2. Then, 750 to 1000 mL with each 90 to 120 mg/kg dose of FOS
b. Electrolyte abnormalities
c. Neurotoxicity
d. Fever, nausea and vomiting, anemia, and diarrhea
4. Use limited to patients who experience treatment failure with GCV or for those who
have GCV contraindications due to neutropenia
Figure 4. Pharmacologic mechanisms of antivirals used for CMV
13
ii. Cidofovir (CDV)
1. Acyclic nucleoside phosphonate (ANP) derivative
a. Must be phosphorylated via cellular kinases to diphosphoryl derivative to exert
its antiviral activity (see Figure 4)
2. Potent inhibitor and alternate substrate for viral DNA polymerase
3. Indicated for treatment of CMV retinitis in patients with acquired immunodeficiency
syndrome (AIDS)
4. No data from randomized clinical trials to support its use in SOT recipients
5. Advantageous pharmacokinetic profile allows once weekly dosing
7
6.
11
Toxicity profile limits its use
a. Nephrotoxicity
i. Prophylaxis with fluids and probenecid recommended
1. 1000 mL NS over 1 to 2 hours prior to CDV infusion
2. Additional 1000 mL, infused over 1 to 3 hours, with start of CDV
infusion or immediately following infusion, if tolerable
3. Probenecid 2 g by mouth 3 hours prior to CDV
4. Probenecid 1 g by mouth at 2 hours and 8 hours after completion of
CDV infusion
b. Neutropenia
III. Monitoring
a. Response to treatment
i. PCR monitoring on day of treatment initiation and weekly thereafter
b. Adverse reactions
1
IV. Duration
a. Continue treatment until one to two consecutive negative samples are obtained
i. Minimum two weeks of treatment
ii. Minimizes risk of disease recurrence and antiviral resistance
1
V. Secondary prophylaxis
a. Treatment course followed by prophylactic dosing of antiviral medications to prevent recurrent
disease
i. Typically for one to three months
High Initial
Viral Load
Slow
Reduction in
Viral Load with
Treatment
Multiorgan
Disease
Primary CMV
Infection
Persistent
Viremia
Increased
Risk
Recurrent
CMV
Figure 5. Risk factors for CMV disease recurrence
Concurrent
Treatment of
Rejection
1
CMV Antiviral Resistance
I. Increasing or persistent viral load despite adequate antiviral therapy for greater than two weeks with
7
confirmed resistance on genotypic and/or phenotypic testing
7,20-22
II. Prevalence and outcomes
a. Estimates of antiviral resistance among SOT recipients varies greatly
i. D+/R- recipients have highest incidence
1. Rates of about 5% to 10% in D+/R- recipients being treated for CMV
ii. Lung transplant recipients have been observed to experience higher rates of antiviral
resistance than rates observed in other SOT recipients
1. 17.6% of viremic lung transplant recipients versus 6.2% of viremic kidney recipients
b. Clinical outcomes in SOT recipients after antiviral resistance development are poor
i. Mortality rates 19% to 100%
8
1,2,7,23
III. Risk factors for antiviral resistance development
a. Absence of preexisting CMV specific immunity prior to transplantation (D+/R-)
i. Most consistently identified risk factor
b. Prolonged or inadequate antiviral drug exposure
c. Ongoing active viral replication
d. High levels of immunosuppressive medications
e. Lung transplant
f. High peak viral load
5
i. Greater than 10 copies/mL in peripheral blood
7,13,20,24
IV. Mutations associated with antiviral resistance
a. UL97 mutation (see Figure 6)
i. Constitute greater than 95% of antiviral-resistant strains
ii. Mutations in UL97 gene
1. Prevents initial phosphorylation of GCV
2. Confer various degrees of GCV resistance
a. Zero to 15 fold over baseline
3. These mutants will remain susceptible to FOS and CDV
iii. No significant fitness cost to the virus has been observed
iv. Mechanisms of resistance
1. Modify substrate recognition
2. Modify ATP binding
Figure 6. Mutations associated with antiviral resistance to cytomegalovirus
b.
13
UL54 mutation (see Figure 6)
i. UL54 gene encodes the viral DNA polymerase
ii. Antiviral resistance depends of the site of the mutation of the viral DNA polymerase
1. Can confer resistance to GCV, vGCV, FOS, and/or CDV
iii. Isolated UL54 mutations uncommon
1. Typically evolve after UL97 mutations
2. Dual UL97/UL54 mutations present with high-grade GCV resistance (IC50≥30μM)
iv. Mechanisms of resistance
1. Reduced antiviral affinity
a. Proposed mechanism for FOS resistance
2. Reduced DNA chain incorporation
3. Increased antiviral excision out of the DNA chain
9
7,13,20,24
V. Laboratory diagnosis of antiviral resistance
a. Rapid laboratory confirmation of antiviral resistance is important
i. Increasing viral loads or disease progression may be due to host factors rather than antiviral
resistance
1. Empiric changes in antiviral treatment may therefore lead to unnecessary toxicity
through exposure to other drug therapies
2. Antiviral resistance should be confirmed before altering antiviral treatment regimens
a. Except in life or sight-threatening disease
b. Phenotypic assay
i. Reference standard for assessing antiviral susceptibility
1. Labor intensive
2. Four to six week turnaround time for results
3. Rarely used in clinical practice
ii. Determination of drug concentration required to inhibit 50% or 90% (IC50 or IC90) of viral
growth
1. Specific sequence of clinical strain is transferred to a reference laboratory CMV strain
iii. Proposed cutoffs for antiviral susceptibilities
1. GCV IC50>6 to 12 μM
2. FOS IC50>300-500 μM
3. CDV IC50 ≥2 μM
c. Genotypic testing
i. More commonly used in the clinical setting to test for CMV antiviral resistance
1. Produces results in as quick as a few hours or up to three days
ii. PCR amplification and sequencing of resistance loci from clinical specimens
1. Compared to known resistant or wild-type strain to categorize mutation sensitivity to
antivirals
2. IC50 ratio = IC50 of mutant/IC50 of wild type
a. IC50 ratio>3 is classified as resistance
b. IC50 ratio>5 is classified as major resistance
iii. Disadvantage
1. Resistance mutations cannot be distinguished from sequence polymorphisms without
confirmation with phenotypic assays
20
VI. Cross-resistance between antiviral therapies
UL97 Mutations
•GCV/vGCV resistance
•Cross-resistance with other antivirals not
seen
UL54 Mutations
• Common: GCV and CDV cross-resistance
• Rare: GCV and FOS cross-resistance
• Rare: FOS and CDV cross-resistance
Figure 7. Cross-resistance observed among antiviral therapies
20
Treatment of GCV-Resistant CMV
I. No controlled clinical trials to support the use of specific treatment regimens in cases where drug resistance
is suspected or proven
II. Standardized approach to the treatment of antiviral-resistant CMV infection and disease is difficult
a. Diversity of host factors affect clinical outcome in SOT recipients
10
b.
Changes in therapy must consider potency, toxicity, and logistical complexity of the available
alternative antiviral agents
25
III. Reduction of immunosuppressive therapy
25
a. Retrospective review of patient population included in the VICTOR trial
i. Significantly greater proportion of patients treated with dual versus triple
immunosuppressive therapy eradicated CMV DNAemia by day 21 (71.3% vs. 52%)
ii. No effect on risk of recurrence
13,26
IV. Antiviral therapy
13,26,27
Table 5. Comparison of Antiviral Agents Approved for Treatment of CMV
GCV
FOS
Mechanism of action
Inhibit viral DNA polymerase
-CMV retinitis
-CMV retinitis in AIDS
Indication
a
-CMV prophylaxis
-HSV
b
Dose
5 mg/kg IV twice daily
90 mg/kg IV twice daily
Neutropenia > anemia >
Nephrotoxicity, electrolyte
Major adverse effects
thrombocytopenia
abnormalities
Mutations that confer
UL97
UL54
resistance
UL54
a
b
CDV
-CMV retinitis in AIDS
5 mg/kg IV once weekly
Nephrotoxicity,
neutropenia
UL54
Mucotaneous acyclovir-resistant herpes simplex virus infections in immunocompromised patients
Adjusted for renal function
a.
Foscarnet
28,29
i. Case Reports
Table 6. Case Reports of Severe CMV Disease Treated with Foscarnet
Patient 1
Patient 2
Age (years)
59
64
Type of transplant
Kidney
Kidney
Serology
D?/RD?/RInduction
--a
a
IS regimen
CsA + CCS
CsA + CCS
Rejection (day)
29
44
Rejection treatment
CCS
CCS
Type of CMV disease
PNA, Renal
CNS?, PNA?
CMV symptoms
48
50
(day)
FOS initiation (day)
69
66
FOS dose
3.3 mg/kg/hr
3.3 mg/kg/hr
Duration of FOS (days)
5
5
Clinical improvement
Y
Y
during treatment
b,c
Adverse events
↑SrCr
-(SrCrBeg-SrCrEnd)
(3.17-4.63)
(2-1.38)
Death
Alive + graft
Outcome (day)
(75)
(290)
28,29
Patient 3
40
Kidney
D?/R-CsA + CCS
28, 74, 128
CCS
PNA
<60 (not treated);
134
143
3.24 mg/kg/hr
8
Patient 4
52
Heart
D-/RATG
TAC, AZA, CCS
--GI?, Renal?
Y
Y
-(3.17-3.17)
Alive + graft
(290)
↑SrCr
(7.12-3.39)
Alive + graft
(180)
37
43
?
15
b,d
Alive + graft=patient alive with functioning graft; ATG=antithymocyte globulin; AZA=azathioprine; CCS=corticosteroid;
CNS=encephalitis; CsA=cyclosporine; FOS=foscarnet; PNA=pneumonitis; SrCrBeg-SrCrEnd=serum creatinine (mg/dL) at beginning and
end of FOS therapy; TAC=tacrolimus
a
b
c
Immunosuppression discontinued with symptom onset or initiation of FOS; Patient also received gentamicin; FOS discontinued
d
due to nephrotoxicity; Patient required hemodialysis even before initiation of FOS or gentamicin
11
c.
Recent use of foscarnet and cidofovir
30
i. Single center, retrospective analysis
ii. 1549 SOT recipients who all received vGCV universal prophylaxis
iii. 284 (18.3%) patients tested positive for CMV infection
1. 20/56 recipients genotypically tested had resistance mutations
a. 80% D+/Rb. Detected a median of 9 months posttransplantation
30
Table 7. 20 Patients with Resistant Strains
16 UL97
1 UL54
7 kidney
1 lung
3 heart
3 lung
2 liver
1 kidney/pancreas
3 UL97 and UL54
3 lung
iv. Foscarnet and cidofovir therapy
20 patients with resistant strains
14 recipients treated
with CDV
6 recipients treated
with FOS
-2 UL97
All UL97
mutations
-1 UL54
-3 UL97 and UL54
2 responded
(relapsed once FOS
discontinued)
1 maintained
low level viremia
CDV added and
viremia cleared
Figure 8. Patient population in Perez et al.
1 patient still on
FOS
2 deaths
13 achieved
CMV clearance
1 death
30
v. Toxicity
1. No significant changes in renal function were observed
vi. Take-home points
1. FOS appears useful for the treatment of severe, symptomatic CMV disease
2. Cases with known antiviral resistance were only presented in abstract form
a. Many details unknown
3. CDV appears useful for the treatment of CMV containing UL97 mutations
12
b.
31
High-dose GCV
i. Case series
1. To assess the utility of high-dose GCV for the treatment of non-severe CMV
replication in patients with GCV-resistant strains
2. Clinical resistance
a. Persistent viral load or symptom development after 2 weeks GCV or vGCV
treatment
b. Patients 1, 2, 3, and 5 had mutations conferring high grade resistance
31
Table 8. Use of High-Dose GCV in Patients with Asymptomatic CMV Posttransplantation
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Type of
KidneyKidney
Kidney
Kidney
Liver
transplant
pancreas
Induction
ATG
----IS regimen
T/M/S
T/M/S
T/M/S
T/M/S
T/M/S
CMV serology
D+/RD-/R+
D+/RD+/RD+/RProphylaxis
PT
PT
UP
UP
UP
Symptomatic
Y
CMV
N
N
N
N
(Colitis)
replication
b
b
b
b
Mutation
UL97
UL97
UL97
UL97
UL97
Treatment
Int GCV (14),
regimen
Int GCV (7),
Int GCV (12)
Int GCV (21)
Int GCV (28) Full GCV (14),
(duration in
Full GCV (21)
Int vGCV (14)
days)
Dose limiting
Y
N
N
N
N
neutropenia
(GCSF)
Outcome
Alive + graft
Alive + graft
Alive + graft
Alive + graft
Alive + graft
(time post(10 months)
(1 year)
(2 years)
(1 year)
(2 years)
infection)
Patient 6
a
Kidney
-T/M/S
D+/RUP
N
UL54
Full vGCV
(56)
N
Alive + graft
(2 years)
Alive + graft=patient alive with functioning graft; ATG=antithymocyte globulin; Full GCV=ganciclovir 10 mg/kg IV every 12 hours,
adjusted for renal function; Full vGCV=valganciclovir 1800 mg by mouth twice daily, adjusted for renal function;
6
GCSF=granulocyte colony-stimulating factor 30 x 10 for two doses; Int GCV=ganciclovir 7.5 mg/kg IV every 12 hours, adjusted
for renal function; Int vGCV=valganciclovir 1350 mg by mouth twice daily, adjusted for renal function; IS=immunosuppressive;
M=mycophenolate mofetil; N=no; PT=preemptive therapy; S=steroid; T=tacrolimus; UP=universal prophylaxis for 90 days with
vGCV; Y=yes
a
b
UL54 mutation detected, but patient refused foscarnet; High grade antiviral resistance
ii. Take-home points
1. Non-severe, asymptomatic disease with UL97 mutations
2. Dose-limiting neutropenia occurred in one of six patients
3. Increasing doses of GCV were effective despite mutations conferring high-grade
resistance
13
c.
Combination therapy
32
i. Synergy between GCV and FOS has been demonstrated in vitro
ii. Other immunocompromised populations
1. Addition of FOS to failing GCV monotherapy, or addition of GCV to failing FOS, has
been shown to be superior to continuing monotherapy or switching to monotherapy
33
with another medication
34
iii. Case series
1. Massachusetts General Hospital
a. Oral GCV prophylaxis for 3 months posttransplantation
i. D+/Rii. R+ patients who receive antilymphocyte agents for induction or graft
rejection
b. CMV antigenemia assay monitored monthly
i. Persistently positive antigenemia
1. Treatment dose GCV IV and monthly CMV Ig
c. CMV Disease
i. Diagnosed 3 months to 2 years posttransplantation (median 5 months)
6 SOT
Recipients
GCV
Resistance
Susceptibility
Testing
•2 Lung, 2 liver, 1 kidney, 1 heart
•5 D+/R-, 1 R+
•Suspected based on persistent symptoms despite ≥3 weeks of GCV
•Confirmed with minimum inhibitory concentration (MIC) testing
•All isolates had high level ganciclovir resistance (MIC ≥3 μg/mL)
Figure 9. Patient population in Mylonakis et al.
d.
e.
f.
g.
h.
i.
34
Treatment
i. Combination therapy
1. GCV 5 mg/kg IV daily
2. FOS titrated to max of 125 mg/day
3. CMV Ig
Secondary prophylaxis
i. Oral GCV and monthly CMV Ig for 3 months
Adverse effects
i. FOS-induced electrolyte abnormalities, specifically magnesium wasting
All patients had antigenemia levels of zero by 4 to 8 weeks
No relapses observed after 12 to 36 month follow-up
Take-home points
i. Low-dose combination therapy of GCV and FOS can be beneficial in SOT
recipients infected with GCV-resistant CMV
1. Unknown which mutation was being treated
ii. Magnesium wasting was the major adverse effect observed
14
1,35,36
1. Patients required 10 g to 24 g of magnesium supplementation daily
iii. Regimen did not lead to increased antiviral resistance
V. Adjunct therapy
a. Immunosuppressive drugs with anti-CMV activity
i. Leflunomide
1. Prodrug indicated for the treatment of rheumatoid arthritis
2. Immunosuppressive and antiviral properties
a. Novel mechanism of action compared to currently used antivirals for CMV
i. Inhibits B-cell and T-cell proliferation
ii. Interferes with viral capsid assembly
3. Dosing
a. 100 mg/day by mouth for 3 days , followed by 20 mg/day
b. Therapeutic monitoring
i. Target range 50-80 mcg/mL
4. Adverse reactions
a. Diarrhea, anemia, hepatotoxicity
b. Viral clearance delayed when compared to IV GCV
36
5. Retrospective chart review
a. 15 SOT recipients who received leflunomide after failure of other antivirals
i. 13 D+/R-, 1 D-/R-, 1 unknown
ii. 3 kidney, 1 pancreas, 5 kidney/pancreas, 2 heart, and 2 lung
b. Patients receiving a calcineurin inhibitor, mycophenolate mofetil (MMF), and
corticosteroid for immunosuppression
i. Dose of MMF was typically reduced or removed from the regimen due to
antirejection effects of leflunomide
c. 53% of patients achieved long-term suppression of CMV recurrences
d. Testing form UL97 and UL54
i. Via genotyping in 16 patients
ii. Mammalian target of rapamycin (mTOR) inhibitor
1. Both immunosuppressive and antiviral properties
2. Some evidence that switching recipients’ immunosuppressive therapy to an mTOR
inhibitor may lead to a lower incidence of CMV infection and disease
Future Options
37
I. Hexadecyloxypropyl cidofovir conjugate (CMX001)
a. Orally bioavailable cidofovir derivative
i. Not concentrated in the renal tubules, so less likely to cause nephrotoxicity
b. Major adverse effect: diarrhea
c. Cross-resistance with CDV expected
1
II. Letermovir (AIC246)
a. Inhibits formation and release of infectious virus particles via targeting the UL56 viral terminase
complex
b. Currently undergoing phase II clinical trials
c. No cross-resistance with current antivirals expected
1,7
III.
Maribavir
a. Oral UL97 inhibitor with good bioavailability and low toxicity
b. Phase III trials in D+/R- liver SOT and hematopoietic stem cell transplant recipients
i. No antiviral efficacy observed
ii. Currently undergoing trials to investigate efficacy of maribavir at higher dose
c. Resistance involves UL27 and UL97 genes
1
IV. Vaccine
a. Currently under development, but none are available for clinical use
15
Summary and Recommendations
I. Summary
a. CMV incidence has decreased dramatically with the implementation of ganciclovir prophylaxis
b. When CMV does occur, it significantly impacts both patient and graft survival
c. Resistance to ganciclovir is a growing problem among adult solid organ transplant recipients
d. Inadequate literature to support treatment decisions when resistance is encountered
e. Furthermore, lack of alternative antivirals, antiviral cross-resistance, and drug toxicity makes
choosing an optimal treatment regimen difficult
II. Recommendations (see Figure 10)
a. Selection of an alternative treatment regimen for GCV-resistant CMV is highly patient-specific
b. Factors to consider
i. Severity of disease, degree of immunosuppression, presence of concurrent organ rejection,
viral load, mutations present, exposure and tolerability to previous antiviral medications
16
Figure 10. Suggested treatment algorithm for ganciclovir-resistant cytomegalovirus
Suspected Resistance
-Consider reducing immunosuppression
-Send for genotypic resistance testing
Asymptomatic or Non-Severe
Severe
CMV Disease
CMV Disease
High-dose GCV
or
Life or sight-threatening
disease
Combination low-dose
GCV + FOS
Immediate change in
antiviral therapy
Response?
FOS
Yes
No
or
CDV
Continue high-dose GCV
or
FOS
Combination therapy
CDV=cidofovir; CMV=cytomegalovirus; FOS=foscarnet; GCV=ganciclovir
17
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19
Appendix
19,38-40
Appendix A. Summary of Major Cytomegalovirus Prophylaxis Studies
38
39
Paya et al.
IMPACT
N
372
326
Study design
P, R, DB, DD study
MC, DB, R, PC trial
Serostatus
D+/RD+/R-
Type of transplant
Intervention
Outcome
-Heart
-Liver
-Kidney
-Multiorgan
vGCV 900 mg PO daily vs. GCV
1000 mg PO TID for prophylaxis
-vGCV found to be as clinically
effective and of comparable
safety to GCV in D+/Rrecipients
-Kidney
200 days vs. 100 days of vGCV
900 mg daily for CMV
prophylaxis
-Significantly fewer patients in
200 day group developed
confirmed disease at 12
months posttransplantation
without the cost of additional
safety concerns
-Incidence of allograft function,
graft loss, and survival were not
different between groups at 1
and 2 years
Palmer et al.
19
Copeland et al.
40
136
P, MC, DB, PC, R trial
-D+/R- (33%)
-D+/R+ (31%)
-D-/R+ (36%)
-Lung
38
Follow up of Palmer et al. study
-D+/R- (24%)
-R+ (76%)
vGCV 900 mg daily for 3
months vs. 12 months for
prophylaxis
-Incidence of CMV was
significantly greater in patients
who received 3 months of
prophylaxis versus 12 months
Mean follow up was 3.9 years
-Lung
-Long-term prophylaxis
prevents rather than simply
delays onset of CMV disease
without increasing GCV
resistance or adverse events
CMV=cytomegalovirus; DB=double blind; DD=double-dummy; D+/R+=donor/recipient serostatus; GCV=ganciclovir; MC=multicenter; N=number of patients; NS=not
significant; P=prospective; PC=placebo controlled; PO=by mouth; R=randomized; TID=three times a day; vGCV=valganciclovir