CMV, CMV resistance, valganciclovir, CMV elispot

1. Valganciclovir
e CMV
Dr. Dino Sgarabotto
Unità Infezioni nel Trapiantato
Malattie Infettive e Tropicali
Azienda Ospedaliera di Padova

2. PRO-DRUG del GANCICLOVIR
valganciclovir HCl ganciclovir
HN
N
O
H2N
N
N
O
HO O
O
H2N
HCl
HN
N
O
H2N
N
N
O
HO OH

3. VALGANCICLOVIR
Caratteristiche chiave
• GCV esposizione (AUC) dopo 900 mg Val-GCV è simile a
GCV (5 mg/kg) ev.
• Biodisponibilità approx. 60% (10X più alta che GCV orale)
• < 2% della dose assorbita compare come valganciclovir in
plasma (t1/2 ≈ 1 hour)
• compresse da 450 mg

4. PROFILI PK COMPARATIVI
DI GANCICLOVIR
IV & Oral GCV
GCV from Val-GCV

5. Profilassi Ganciclovir Orale vs Valganciclovir
Nei pazienti trapiantati CMV D+/R-
No significant difference between 2 groups at 12 months
Paya CV Am J Transpl (2004): STUDIO PV16000
CMV disease by 6 months Valganciclovir 900 mg QD
until D+100 (n=239)
Ganciclovir 1 g TID
until D+100 (n=125)
Endpoint committee 12.1% (29) 15.2% (19)
Protocol definition 11.3% (27) 12.8% (16)
Investigator-treated
disease
23.0% (55) 21.6% (27)
372 D+/R- SOT (liver, kidney, heart, pancreas), >13 y, 57 sites
2:1 randomization

6. Profilassi con Valganciclovir nello
Studio PV16000: Analisi degli Endpoint Primari
*Tissue invasive disease: 16/118 (14%) VGCV vs 2/59 (3%) OGCV
Paya CV. Am J Transpl (2004): STUDIO PV16000
CMV disease by 6 months
(Endpoint Committee)
Valganciclovir
(n=239)
Ganciclovir
(n=125)
All organs (n=364) 12.1% (29) 15.2% (19)
Liver (n=177)* 18.6% (22) 11.9% (7)
Kidney (n=120) 6.2% (5) 23.1% (9)
Heart (n=56) 5.7% (2) 9.5% (2)
Kidney-pancreas (n=11) 0 16.7% (1)

7. Profilassi con Valganciclovir nello Studio
PV16000: Analisi degli Endpoint Secondari
• Compared to oral ganciclovir, valganciclovir prophylaxis is associated
with a lower incidence of CMV viremia during prophylaxis and a later
onset of CMV viremia after completion of prophylaxis (Category 1 statement)
Paya CV. Am J Transplant (2004)
Incidence and Time to CMV Viremia*
Valganciclovir (n=239)± Ganciclovir (n=125)
During prophylaxis* 2.5% 10.4%
By 6 months 39.7% 43.2%
By 12 months 48.5% 48.8%
Time to CMV viremia 357 days 282 days
* P=0.001; ±Trend towards reduced peak viral load at time of suspected CMV disease

8. Profilassi con Valganciclovir nello
Studio Study PV16000 : Eventi Avversi
Paya CV. Am J Transplant (2004)
• The incidence of neutropenia is higher during valganciclovir
compared to oral ganciclovir prophylaxis (Category 2 statement)
Hematologic adverse
event
Valganciclovir
(n=239)
Ganciclovir
(n=125)
P
Anemia 38 (15.5%) 25 (19.8%) 0.300
Leukopenia 40 (16.3%) 14 (11.1%) 0.172
Neutropenia 20 (8.2%) 4 (3.2%) 0.063
Thrombocytopenia 12 (4.9%) 7 (5.6%) 0.792
Pancytopenia 7 (2.9%) 2 (1.6%) 0.448
≥ One adverse event 93 (38.1%) 50 (39.7%)

9. Data from Paya CV Am J Transplant (2004)
CMV Disease in CMV D+/R-
Profilassi con Valganciclovir vs Ganciclovir Orale
• Valganciclovir prophylaxis for 100 days is as effective as
oral ganciclovir for the prevention of CMV disease in CMV
D+/R- SOT patients (Category 1 recommendation)

10. Studio VICTOR
Maintenance
Day 21 to 49
Follow-up Phase
Month 3 to 12
Induction
Day 0 to 20
Oral valganciclovir
900 mg x 2
Oral valganciclovir
900 mg x 1
No study
medication
CMV
disease
IV ganciclovir
5 mg/kg x 2
Induction period: patients assessed twice weekly
Maintenance period: patients assessed once a week

11. Definizione di CMV disease
CMV-syndrome
CMV antigenemia plus one of the following:
• fever 38.0≥ o
C (100.4o
F)
• malaise
• leucopenia (< 3,500/μL) or atypical lymphocytosis ( 5 %)≥
or thrombocytopenia (< 100,000/μL)
Tissue-invasive CMV disease
CMV antigenemia plus one of the following
• clinical diagnosis of organ disease
• CMV in tissue specimen

12. Eradicazione della Viremia:
populazione ITT
Respons
e
Valganciclovi
r
(N=164)
Ganciclovi
r
(N=157)
Difference
(95%CI)
Viremia
eradicatio
n
at day 21
74 (45.1%) 76 (48.4%)
-14% to
+8%
Viremia
eradicatio
n
at day 49
110 (67.1%) 110 (70.1%)
-13% to
+7%

13. Sintomi clinici persistenti
Days of observation
PersistentactiveCMVdisease
0.0
0.2
0.4
0.6
0.8
1.0 Oral valganciclovir (n=158)
IV ganciclovir (n=152)
0 7 14 21 28 35 42 5649

14. Febbre persistente
Days of observation
Persistentfever
0.0
0.2
0.4
0.6
0.8
1.0
Oral valganciclovir (n=158)
IV ganciclovir (n=152)
0 7 14 21 28 35 42 5649

15. Eventi avversi più frequenti
Adverse event Valganciclovir Ganciclovir
Leucopenia 21 (16.7%) 23 (18.4%)
Diarrhea 13 (10.3%) 25 (20.0%)
Other gastrointestinal 17 (13.6%) 20 (16%)
Urinary tract
infection
17 (13.5%) 19 (15.2%)
Anemia 20 (15.9%) 11 (8.8%)
Respiratory disorders 23 (18.2%) 17 (13.6%)
Other 15 (13%) 10 (8%)

16. Cinetica di clearance del
Cytomegalovirus
Oral valganciclovir
Intravenous ganciclovir
100000
10000
1000
100
10
0 7 14 21 28 35 42 49Days
CMVload(copies/mL)
Treatment phase

17. >50,000 (N=108)
10,000-50,000 (N=70)
<10,000 (N=81)
Days of observation
Cumulativeprobabilityof
persistentviremia
0.0
0.2
0.4
0.6
0.8
1.0
0 7 14 21 28 35 42 49
Baseline viral loads (copies/mL):
La carica virale al giorno 0 è un fattore predittivo
per la eradicazione virologica di CMV

18. Recidive Cliniche di CMV
dopo il completamento della terapia
Recidive Cliniche: 15.1%
Recidive virologiche: 30.0%
Mortalità 6.2% (20/321)
Infezioni opportunistiche 7.5% (24/321)
Resistenza a ganciclovir 2,4% (8/321)
The VICTOR Study: One Year Follow-Up; Am J Transpl 2009; 9: 1205–1213

19. Probabilità di rimanere in remissione
Fattori predittivi di recidiva:
1.Tipo di organo trapiantato
2.Eradicazione virologica al 21° giorno
3. CMV IgG negative all’inizio terapia

21. Monitoraggio immunologico cellulare
specifico per CMV
Assay
Predict viremia Predict disease
QuantiFERON-CMV No data Yes
ELISPOT No Yes
ICS Yes Yes
Tetramer No No

22. Prospective Assessment of CMV Specific Immunity with
Preemptive Therapy vs Prophylaxis in High Risk
D+R- OLT Recipients
Limaye AP et al: Abstract 202 ATC Boston 2009

23. Prospective Assessment of CMV Specific Immunity with
Preemptive Therapy vs Prophylaxis in High Risk
D+R- OLT Recipients
Limaye AP et al: Abstract 202 ATC Boston 2009

24. CMV Elispot e trapianto di rene
TRE MESI
CMV Elispot CMV DNAemia

25. CMV Elispot e trapianto di cuore
TRE MESI
CMV Elispot CMV DNAemia

26. CMV Elispot e trapianto di fegato
TRE MESI
CMV Elispot CMV DNAemia

27. Caso clinico 1: Strategia Pre-emptive

28. Caso clinico 2: Profilassi e late CMV

29. Caso clinico 3: Strategia Pre-emptive

30. Caso clinico 4: profilassi efficace

31. Profilassi vs Terapia Preemptive :
Incidenza di Infezione da CMV dopo KTx
OGCV=oral ganciclovir; VACV=valacyclovir; VGCV=valganciclovir.
Khoury JA, et al. Am J Transplant. 2006;6:2134-2143.
Reischig T, et al. Am J Transplant. 2008;8:69-77.
Kliem V, et al. Am J Tranplant. 2008;8:975-983.
*22% >100 days following transplant
*
†
12-month incidence
†
†
12-month incidence
†

32. ‡
Mean time to tissue-invasive
disease, 135 days
*All symptoms occurred >100 days
after SOT
†
12-month incidence
Profilassi vs Terapia Preemptive :
Incidenza di Malattia da CMV dopo KTx
Khoury JA, et al. Am J Transplant. 2006;6:2134-2143.
Reischig T, et al. Am J Transplant. 2008;8:69-77.
Kliem V, et al. Am J Tranplant. 2008;8:975-983.

33. IMPACT 200
Valganciclovir 900 mg od*
Valganciclovir 900 mg od* Valganciclovir 900 mg od*
Placebo
100 days 200 daysRandomisation 12 months
post-transplant
VGCV-100 days:
VGCV-200 days:
* dose adjusted for renal function

34. CMV disease tardivaProportionofpatientswithconfirmed
CMVdiseaseat12months(%)
p < 0.0001
* Patients without an assessable month 12 status are not assumed to have the event in this
sensitivity analysis.

35. Incidenza di CMV Disease tardiva
Number of patients left
VGCV-100 days 163 161 161 157 151 125 110 104 102 101 95 94 83 4
VGCV-200 days 155 154 152 150 149 147 145 143 136 130 125 122 120 7
0
0.4
0.2
0
0.8
0.6
18060 120 240 360
1.0
300
Event-freeprobability
Study day
VGCV 200 days
VGCV 100 days

36. Ma con un farmaco come il Bactrim disponibile per
la prevenzione del CMV, ci sarebbe discussione?
• Poco costoso: a quando????
• Per via orale una volta al dì 
• Altamente biodisponibile 
• Relativamente non tossico 
• Efficace 
• Relativemente scarsa resistenza 
Conclusioni