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Cmv and valganciclovir
Valganciclovir is a prodrug of ganciclovir used for CMV prophylaxis and treatment. A key study (PV16000) found that valganciclovir prophylaxis for 100 days was as effective as oral ganciclovir for preventing CMV disease in high-risk transplant patients. Valganciclovir had a higher bioavailability than oral ganciclovir but was associated with a higher rate of neutropenia as an adverse effect. Long-term follow up of patients in the VICTOR study found rates of CMV disease recurrence after stopping prophylaxis of 15.1% at 1 year. Factors like viral load at baseline and
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Cmv and valganciclovir
- 1. Valganciclovir e CMV Dr. DinoSgarabotto Unità Infezioni nel Trapiantato Malattie Infettive e Tropicali Azienda Ospedaliera di Padova
- 2. PRO-DRUG del GANCICLOVIR valganciclovirHCl 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 • GCVesposizione (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 DIGANCICLOVIR IV & Oral GCV GCV from Val-GCV
- 5. Profilassi Ganciclovir Oralevs 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 Valganciclovirnello 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 Valganciclovirnello 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 Valganciclovirnello 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 PayaCV 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 21to 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 CMVdisease 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: populazioneITT 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 Daysof 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 ofobservation 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 piùfrequenti 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 clearancedel 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 diCMV 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 rimanerein 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 specificoper CMV Assay Predict viremia Predict disease QuantiFERON-CMV No data Yes ELISPOT No Yes ICS Yes Yes Tetramer No No
- 22. Prospective Assessment ofCMV 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 ofCMV 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 etrapianto di rene TRE MESI CMV Elispot CMV DNAemia
- 25. CMV Elispot etrapianto di cuore TRE MESI CMV Elispot CMV DNAemia
- 26. CMV Elispot etrapianto 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 TerapiaPreemptive : 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 totissue-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 900mg 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 CMVDisease 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 unfarmaco 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
Editor's Notes
- #32 Slide &lt;number&gt; The graph depicts the incidence of CMV infection during three separate randomized studies that compared the use of preemptive versus prophylactic treatment in renal transplant recipients. Khoury and colleagues evaluated the prophylactic use of valganciclovir 900 mg daily for 100 days compared with preemptive therapy using 900 mg twice daily for 21 days.1 Reischig and colleagues compared prophylaxis with valacyclovir 2 g four times daily versus preemptive treatment with valganciclovir 900 mg twice daily for at least 14 days.2 Kliem and colleagues studied the use of prophylaxis or preemptive therapy using ganciclovir.3 As shown in the graph, the incidence of CMV infection was significantly reduced across all studies in patients who received prophylaxis (29% in the Khoury et al. study, 59% in the Reischig et al. study, 18% in the Kliem et al. study) compared with those who received preemptive therapy (59% in the Khoury et al. study, 92% in the Reischig et al. study, 51% in the Kliem et al. study) (P=0.004; P&lt;0.001, and P&lt;0.0001, respectively, for the comparisons of prophylaxis vs preemptive therapy). Khoury JA, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant. 2006;6:2134-2143. Reischig T, et al. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant. 2008;8:69-77. Kliem V, et al. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized trial. Am J Tranplant. 2008;8:975-983.