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.
2
Cytomegalovirus
I. Epidemiology1-7
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
Figure 1. Stages of initial CMV infection in immunocompetent host8
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
II. Definitions1,3,5,9
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
Primary Infection
• First time patient is infected with the virus
• Asymptomatic or non-specific viral illness
• Easily overcome by the host immune system
Life-long Latency
• 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
3
III. Manifestations1,4,6
(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 Infection1,4
Direct Effects Indirect Effects
CMV Syndrome
Fever
Malaise
Weakness
Myalgias/arthralgias
Leukopenia
Thrombocytopenia
Tissue Invasive Disease
Colitis
Pneumonitis
Hepatitis
Nephritis
Gastroenteritis
Retinitis
Acute rejection
Chronic rejection
Bacterial, viral, fungal infections
Mortality
Assessing the Transplant Patient
I. Pretransplant assessment1,2,10
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
Table 2. Risk Stratification Based on Donor and Recipient Serostatus1,2
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
4
II. Posttransplantation assessment and monitoring1-3,11
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 II. Prior to development of anti-CMV therapy
1,3,12
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
III. Prophylactic agents1,3,13-16,17
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
5
ii. Mechanism of action (see Figure 2)
Figure 2. Ganciclovir mechanism of action13
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 IV. Methods of prophylaxis
1,2,10,18,19
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
Table 3. Comparison of Universal Prophylaxis and Preemptive Therapy4
Universal Prophylaxis Preemptive Therapy
Efficacy Good Good*
Late onset disease Common Rare
Cost Drug costs
$7678 + 6486 Monitoring costs
$7130 + 3748
Monitoring Drug toxicity PCR
Seroconversion benefit May improve --
Prophylaxis Against Other Herpes Viruses HSV, VZV No
Reduced indirect effects Yes Unknown
Antiviral resistance Yes 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
Drug phosphorylation by UL97 kinase
Further phosphorylation
by cellular kinases
Active nucleoside analogue
triphosphate
Competitive inhibition of viral DNA polymerase
6
e. Consensus1-3
(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+/R- R+ D-/R-
Duration Liver, heart
Kidney, pancreas Lung
3-6 months
6 months 6-12 months
3 months 3 months
≥6 months
-- -- --
Medication Regimen Kidney, pancreas
Liver Lung, heart
vGCV or GCV vGCV or GCV
vGCV or GCV, + CMV Ig
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
I. Indications for treatment initiation1,2,CDVPI
a. CMV viremia
i. All patients with CMV disease ii. Asymptomatic viremia
1. Patient and provider-specific II. Treatment regimen
25,26,13
a. Immunosuppressive dose reduction b. Antiviral medications
Figure 3. Timeline of antiviral development
7
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 CMV13
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
8
6. 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. Monitoring11
a. Response to treatment
i. PCR monitoring on day of treatment initiation and weekly thereafter b. Adverse reactions
IV. Duration1
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 V. Secondary prophylaxis
1
a. Treatment course followed by prophylactic dosing of antiviral medications to prevent recurrent disease
i. Typically for one to three months
Figure 5. Risk factors for CMV disease recurrence1
CMV Antiviral Resistance
I. Increasing or persistent viral load despite adequate antiviral therapy for greater than two weeks with confirmed resistance on genotypic and/or phenotypic testing
7
II. Prevalence and outcomes7,20-22
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%
Increased Risk
Recurrent CMV
Primary CMV Infection
Multiorgan Disease
High Initial Viral Load
Slow Reduction in
Viral Load with Treatment
Persistent Viremia
Concurrent Treatment of
Rejection
9
III. Risk factors for antiviral resistance development1,2,7,23
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
i. Greater than 105 copies/mL in peripheral blood
IV. Mutations associated with antiviral resistance7,13,20,24
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 cytomegalovirus13
b. 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
10
V. Laboratory diagnosis of antiviral resistance7,13,20,24
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 VI. Cross-resistance between antiviral therapies
20
Figure 7. Cross-resistance observed among antiviral therapies20
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
•GCV/vGCV resistance
•Cross-resistance with other antivirals not seen
UL97 Mutations
• Common: GCV and CDV cross-resistance
• Rare: GCV and FOS cross-resistance
• Rare: FOS and CDV cross-resistanceUL54 Mutations
11
b. Changes in therapy must consider potency, toxicity, and logistical complexity of the available alternative antiviral agents
III. Reduction of immunosuppressive therapy25
a. Retrospective review of patient population included in the VICTOR trial
25
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 IV. Antiviral therapy
13,26
Table 5. Comparison of Antiviral Agents Approved for Treatment of CMV13,26,27
GCV FOS CDV Mechanism of action Inhibit viral DNA polymerase
Indication -CMV retinitis
-CMV prophylaxis -CMV retinitis in AIDS
-HSVa
-CMV retinitis in AIDS
Doseb
5 mg/kg IV twice daily 90 mg/kg IV twice daily 5 mg/kg IV once weekly
Major adverse effects Neutropenia > anemia >
thrombocytopenia Nephrotoxicity, electrolyte
abnormalities Nephrotoxicity,
neutropenia Mutations that confer
resistance UL97 UL54
UL54 UL54
a Mucotaneous acyclovir-resistant herpes simplex virus infections in immunocompromised patients
b Adjusted for renal function
a. Foscarnet i. Case Reports
28,29
Table 6. Case Reports of Severe CMV Disease Treated with Foscarnet28,29
Patient 1 Patient 2 Patient 3 Patient 4
Age (years) 59 64 40 52
Type of transplant Kidney Kidney Kidney Heart
Serology D?/R- D?/R- D?/R- D-/R-
Induction -- -- -- ATG
IS regimen CsA + CCSa
CsA + CCSa
CsA + CCS
TAC, AZA, CCS
Rejection (day) 29 44 28, 74, 128 --
Rejection treatment CCS CCS CCS --
Type of CMV disease PNA, Renal CNS?, PNA? PNA GI?, Renal?
CMV symptoms (day)
48 50 <60 (not treated);
134 37
FOS initiation (day) 69 66 143 43
FOS dose 3.3 mg/kg/hr 3.3 mg/kg/hr 3.24 mg/kg/hr ?
Duration of FOS (days) 5 5 8 15
Clinical improvement during treatment
Y Y Y Y
Adverse events (SrCrBeg-SrCrEnd)
↑SrCrb,c
(3.17-4.63)
-- (2-1.38)
-- (3.17-3.17)
↑SrCrb,d
(7.12-3.39)
Outcome (day) Death (75)
Alive + graft (290)
Alive + graft (290)
Alive + graft (180)
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
Immunosuppression discontinued with symptom onset or initiation of FOS; b
Patient also received gentamicin; c FOS discontinued
due to nephrotoxicity; d
Patient required hemodialysis even before initiation of FOS or gentamicin
12
c. Recent use of foscarnet and cidofovir i. Single center, retrospective analysis
30
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+/R- b. Detected a median of 9 months posttransplantation
Table 7. 20 Patients with Resistant Strains30
16 UL97 1 UL54 3 UL97 and UL54
7 kidney 3 heart 3 lung 2 liver
1 kidney/pancreas
1 lung 3 lung
iv. Foscarnet and cidofovir therapy
Figure 8. Patient population in Perez et al.
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
20 patients with resistant strains
6 recipients treated with FOS
-2 UL97
-1 UL54
-3 UL97 and UL54
2 responded
(relapsed once FOS discontinued)
1 maintained low level viremia
CDV added and viremia cleared
1 patient still on FOS
2 deaths
14 recipients treated with CDV
All UL97 mutations
13 achieved CMV clearance
1 death
13
b. High-dose GCV31
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
Table 8. Use of High-Dose GCV in Patients with Asymptomatic CMV Posttransplantation31
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6a
Type of transplant
Kidney Kidney Kidney Kidney-
pancreas Liver Kidney
Induction ATG -- -- -- -- --
IS regimen T/M/S T/M/S T/M/S T/M/S T/M/S T/M/S
CMV serology D+/R- D-/R+ D+/R- D+/R- D+/R- D+/R-
Prophylaxis PT PT UP UP UP UP
Symptomatic CMV
replication N N N
Y (Colitis)
N N
Mutation UL97b UL97
b UL97
b UL97 UL97
b UL54
Treatment regimen
(duration in days)
Int GCV (12) Int GCV (7),
Full GCV (21) Int GCV (21) Int GCV (28)
Int GCV (14), Full GCV (14), Int vGCV (14)
Full vGCV (56)
Dose limiting neutropenia
Y (GCSF)
N N N N N
Outcome (time post-infection)
Alive + graft (10 months)
Alive + graft (1 year)
Alive + graft (2 years)
Alive + graft (1 year)
Alive + graft (2 years)
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; GCSF=granulocyte colony-stimulating factor 30 x 10
6 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
UL54 mutation detected, but patient refused foscarnet; b 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
14
c. Combination therapy i. Synergy between GCV and FOS has been demonstrated in vitro
32
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 with another medication
33
iii. Case series34
1. Massachusetts General Hospital
a. Oral GCV prophylaxis for 3 months posttransplantation i. D+/R-
ii. 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)
Figure 9. Patient population in Mylonakis et al.34
d. Treatment i. Combination therapy
1. GCV 5 mg/kg IV daily 2. FOS titrated to max of 125 mg/day 3. CMV Ig
e. Secondary prophylaxis i. Oral GCV and monthly CMV Ig for 3 months
f. Adverse effects i. FOS-induced electrolyte abnormalities, specifically magnesium wasting
g. All patients had antigenemia levels of zero by 4 to 8 weeks h. No relapses observed after 12 to 36 month follow-up i. 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
6 SOT Recipients
•2 Lung, 2 liver, 1 kidney, 1 heart
•5 D+/R-, 1 R+
GCV Resistance
•Suspected based on persistent symptoms despite ≥3 weeks of GCV
•Confirmed with minimum inhibitory concentration (MIC) testing
Susceptibility Testing
•All isolates had high level ganciclovir resistance (MIC ≥3 μg/mL)
15
1. Patients required 10 g to 24 g of magnesium supplementation daily iii. Regimen did not lead to increased antiviral resistance
V. Adjunct therapy1,35,36
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
5. Retrospective chart review36
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
I. Hexadecyloxypropyl cidofovir conjugate (CMX001)37
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
II. Letermovir (AIC246)1
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
III. Maribavir1,7
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 IV. Vaccine
1
a. Currently under development, but none are available for clinical use
16
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
17
Figure 10. Suggested treatment algorithm for ganciclovir-resistant cytomegalovirus
Suspected Resistance
-Consider reducing immunosuppression
-Send for genotypic resistance testing
Asymptomatic or Non-Severe
CMV Disease
High-dose GCV
or
Combination low-dose GCV + FOS
Response?
Yes
Continue high-dose GCV
or
Combination therapy
No
FOS
Severe
CMV Disease
Life or sight-threatening disease
Immediate change in antiviral therapy
FOS
or
CDV
CDV=cidofovir; CMV=cytomegalovirus; FOS=foscarnet; GCV=ganciclovir
18
References
1. Kotton CN, Kumar D, Caliendo AM, et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013;96(4):333-60.
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Appendix
Appendix A. Summary of Major Cytomegalovirus Prophylaxis Studies19,38-40
Paya et al.38
IMPACT39
Palmer et al.19
Copeland et al.40
N 372 326 136 38
Study design P, R, DB, DD study MC, DB, R, PC trial P, MC, DB, PC, R trial Follow up of Palmer et al. study
Serostatus D+/R- D+/R- -D+/R- (33%) -D+/R+ (31%) -D-/R+ (36%)
-D+/R- (24%) -R+ (76%)
Type of transplant -Heart -Liver -Kidney -Multiorgan
-Kidney -Lung -Lung
Intervention vGCV 900 mg PO daily vs. GCV 1000 mg PO TID for prophylaxis
200 days vs. 100 days of vGCV 900 mg daily for CMV prophylaxis
vGCV 900 mg daily for 3 months vs. 12 months for prophylaxis
Mean follow up was 3.9 years
Outcome -vGCV found to be as clinically effective and of comparable safety to GCV in D+/R- recipients
-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
-Incidence of CMV was significantly greater in patients who received 3 months of prophylaxis versus 12 months
-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