Valganciclovir e CMV

Dr. Dino Sgarabotto

Unità Infezioni nel TrapiantatoMalattie Infettive e Tropicali

Azienda Ospedaliera di Padova

PRO-DRUG del GANCICLOVIR

valganciclovir HCl ganciclovir

HN

N

O

H2N

N

NO

HO O

O

H2N

HCl HN

N

O

H2N

N

NO

HO OH

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

PROFILI PK COMPARATIVI DI GANCICLOVIR

IV & Oral GCVGCV from Val-GCV

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 sites2:1 randomization

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)

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

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%)

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)

Studio VICTOR

MaintenanceDay 21 to 49

Follow-up PhaseMonth 3 to 12

InductionDay 0 to 20

Oral valganciclovir900 mg x 2

Oral valganciclovir900 mg x 1

No study medication

CMV disease

IV ganciclovir5 mg/kg x 2

Induction period: patients assessed twice weekly

Maintenance period: patients assessed once a week

Definizione di CMV disease

CMV-syndromeCMV antigenemia plus one of the following:

• fever ≥ 38.0oC (100.4oF)• malaise• leucopenia (< 3,500/μL) or atypical

lymphocytosis (≥ 5 %) or thrombocytopenia (< 100,000/μL)

Tissue-invasive CMV diseaseCMV antigenemia plus one of the following

• clinical diagnosis of organ disease• CMV in tissue specimen

Eradicazione della Viremia: populazione ITT

Response

Valganciclovir

(N=164)

Ganciclovir

(N=157)

Difference

(95%CI)

Viremia eradicationat day 21

74 (45.1%) 76 (48.4%)

-14% to +8%

Viremia eradicationat day 49

110 (67.1%) 110 (70.1%)

-13% to +7%

Sintomi clinici persistenti

Days of observation

Pers

iste

nt a

ctiv

e C

MV

dise

ase

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

Febbre persistente

Days of observation

Pers

iste

nt fe

ver

0.0

0.2

0.4

0.6

0.8

1.0Oral valganciclovir (n=158)

IV ganciclovir (n=152)

0 7 14 21 28 35 42 5649

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%)

Cinetica di clearance del Cytomegalovirus

Oral valganciclovirIntravenous ganciclovir

100000

10000

1000

100

100 7 14 21 28 35 42 49Days

CM

V lo

ad (c

opie

s/m

L)

Treatment phase

>50,000 (N=108)

10,000-50,000 (N=70)

<10,000 (N=81)

Days of observation

Cum

ulat

ive

prob

abili

ty o

f pe

rsis

tent

vire

mia

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

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

Probabilità di rimanere in remissione

Fattori predittivi di recidiva:1.Tipo di organo trapiantato2.Eradicazione virologica al 21° giorno3. CMV IgG negative all’inizio terapia

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

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

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

CMV Elispot e trapianto di rene

TRE MESI

CMV Elispot CMV DNAemia

CMV Elispot e trapianto di cuore

TRE MESI

CMV Elispot CMV DNAemia

CMV Elispot e trapianto di fegato

TRE MESI

CMV Elispot CMV DNAemia

Caso clinico 1: Strategia Pre-emptive

Caso clinico 2: Profilassi e late CMV

Caso clinico 3: Strategia Pre-emptive

Caso clinico 4: profilassi efficace

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

†

‡ 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.

IMPACT 200

Valganciclovir 900 mg od*

Valganciclovir 900 mg od* Valganciclovir 900 mg od*

Placebo

100 days 200 daysRandomisation 12 monthspost-transplant

VGCV-100 days:

VGCV-200 days:

* dose adjusted for renal function

CMV disease tardivaP

ropo

rtion

of p

atie

nts

with

con

firm

ed

CM

V d

isea

se a

t 12

mon

ths

(%)

p < 0.0001

* Patients without an assessable month 12 status are not assumed to have the event in this sensitivity analysis.

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

Even

t-fre

e pr

obab

ility

Study day

VGCV 200 days

VGCV 100 days

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