Efficacy of valganciclovir and ganciclovir for cytomegalovirus disease in solid organ transplants: A meta-analysis

Siavash Vaziri, Zohre Pezhman, Babak Sayyad, Feizolla Mansouri, Alireza Janbakhsh, Mandana Afsharian, Farid Najafi, Siavash Vaziri, Zohre Pezhman, Babak Sayyad, Feizolla Mansouri, Alireza Janbakhsh, Mandana Afsharian, Farid Najafi

Abstract

Background: Cytomegalovirus (CMV), a problematic virus in solid organ transplant recipients (SOTR) such as liver, can worsen overall mortality and transplant outcome, so its prevention and treatment is a key of success in such patients. This study is aimed to compare the efficacy of ganciclovir (GCV) and valganciclovir (VGC) for prevention and treatment of infection with CMV.

Materials and methods: After sensitive and systematic search in PubMed, EMBASE, Cochrane and other available databases, both prospective and retrospective studies on effect of VGC and GCV in prevention and treatment of CMV disease among SOTR, which had our study criteria, were included. The pooled risk estimates were calculated using random-effects models.

Results: Among 1324 title, 19 studies were included. In 11 prophylactic studies (2368 patients), the pooled risk of CMV disease (VGC relative to GCV) was 1.16, 95% confidence interval (CI): 0.91-1.49 and in studies of liver transplant recipients, 1.53, 95% CI: 0.86-2.70. Rate of viremia eradication in VGC to GCV was 1.05, 95% CI: 0.97-1.13. In 3 treatment studies (422 patients), rate of successful treatment in VGC to GCV was 0.98, 95% CI: 0.91-1.06 and viremia eradication 0.95, CI 95% 0.77-1.16. All these values did not show statistically significantly differences between GCV and VGC.

Conclusion: It can be concluded that VGC as an alternative to GCV can be used with equal efficacy in prevention and treatment of CMV disease in SOTR.

Keywords: Cytomegalovirus; meta-analysis; solid organs; valganciclovir.

Conflict of interest statement

Conflict of Interest: None declared.

Figures

Figure 1
Figure 1
Flowchart of study selection
Figure 2
Figure 2
Meta-analysis of 12 prophylaxis studies comparing cytomegalovirus disease in valganciclovir and ganciclovir
Figure 3
Figure 3
Meta-analysis of high risk group prophylaxis studies comparing cytomegalovirus disease in valganciclovir and ganciclovir

References

    1. Eid AJ, Razonable RR. Cytomegalovirus disease in solid organ transplant recipients: Advances lead to new challenges and opportunities. Curr Opin Organ Transplant. 2007;12:610.
    1. Husain S, Pietrangeli CE, Zeevi A. Delayed onset CMV disease in solid organ transplant recipients. Transpl Immunol. 2009;21:1–9.
    1. Ticehurst E, Trofe-Clark J, Blumberg E, Bloom R. Valganciclovir for the prophylaxis and treatment of cytomegalovirus infection in solid organ transplantation. Transplant Res Risk Manag. 2010;2:29.
    1. Singh N, Paterson DL, Gayowski T, Wagener MM, Marino IR. Cytomegalovirus antigenemia directed pre-emptive prophylaxis with oral versus I.V. ganciclovir for the prevention of cytomegalovirus disease in liver transplant recipients: A randomized, controlled trial. Transplantation. 2000;70:717–22.
    1. Peleg AY, Husain S, Qureshi ZA, Silveira FP, Sarumi M, Shutt KA, et al. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: A matched case-control study. Clin Infect Dis. 2007;44:1307–14.
    1. Burak KW, Kremers WK, Batts KP, Wiesner RH, Rosen CB, Razonable RR, et al. Impact of cytomegalovirus infection, year of transplantation, and donor age on outcomes after liver transplantation for hepatitis C. Liver Transpl. 2002;8:362–9.
    1. Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89:779–95.
    1. Limaye AP, Bakthavatsalam R, Kim HW, Randolph SE, Halldorson B, Healey PJ, et al. Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis. Transplantation. 2006;81:1645–52.
    1. Gane E, Saliba F, Valdecasas GJ, O’Grady J, Pescovitz MD, Lyman S, et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The oral ganciclovir international transplantation study Group [corrected] Lancet. 1997;350:1729–33.
    1. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2004;4:611–20.
    1. Winston DJ, Young JA, Pullarkat V, Papanicolaou GA, Vij R, Vance E, et al. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood. 2008;111:5403–10.
    1. Winston DJ, Imagawa DK, Holt CD, Kaldas F, Shaked A, Busuttil RW. Long-term ganciclovir prophylaxis eliminates serious cytomegalovirus disease in liver transplant recipients receiving OKT3 therapy for rejection. Transplantation. 1995;60:1357–60.
    1. Winston DJ, Busuttil RW. Randomized controlled trial of sequential intravenous and oral ganciclovir versus prolonged intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in high-risk cytomegalovirus-seronegative liver transplant recipients with cytomegalovirus-seropositive donors. Transplantation. 2004;77:305–8.
    1. Razonable RR. Cytomegalovirus infection after liver transplantation: Current concepts and challenges. World J Gastroenterol. 2008;14:4849–60.
    1. Paya CV, Hermans PE, Smith TF, Rakela J, Wiesner RH, Krom RA, et al. Efficacy of ganciclovir in liver and kidney transplant recipients with severe cytomegalovirus infection. Transplantation. 1988;46:229–34.
    1. Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay PG, Kable K, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: A systematic review of randomised controlled trials. Lancet. 2005;365:2105–15.
    1. Winston DJ, Busuttil RW. Randomized controlled trial of oral ganciclovir versus oral acyclovir after induction with intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in cytomegalovirus-seropositive liver transplant recipients. Transplantation. 2003;75:229–33.
    1. Boivin G, Goyette N, Gilbert C, Roberts N, Macey K, Paya C, et al. Absence of cytomegalovirus-resistance mutations after valganciclovir prophylaxis, in a prospective multicenter study of solid-organ transplant recipients. J Infect Dis. 2004;189:1615–8.
    1. Limaye AP. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin Infect Dis. 2002;35:866–72.
    1. Limaye AP. Antiviral resistance in cytomegalovirus: An emerging problem in organ transplant recipients. Semin Respir Infect. 2002;17:265–73.
    1. Razonable RR, Emery VC 11th Annual Meeting of the IHMF (International Herpes Management Forum. Management of CMV infection and disease in transplant patients 27-29 February 2004. Herpes. 2004;11:77–86.
    1. Pescovitz MD, Rabkin J, Merion RM, Paya CV, Pirsch J, Freeman RB, et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother. 2000;44:2811–5.
    1. Díaz-Pedroche C, Lumbreras C, San Juan R, Folgueira D, Andrés A, Delgado J, et al. Valganciclovir preemptive therapy for the prevention of cytomegalovirus disease in high-risk seropositive solid-organ transplant recipients. Transplantation. 2006;82:30–5.
    1. Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2007;7:2106–13.
    1. Levitsky J, Singh N, Wagener MM, Stosor V, Abecassis M, Ison MG. A survey of CMV prevention strategies after liver transplantation. Am J Transplant. 2008;8:158–61.
    1. Jain A, Orloff M, Kashyap R, Lansing K, Betts R, Mohanka R, et al. Does valganciclovir hydrochloride (valcyte) provide effective prophylaxis against cytomegalovirus infection in liver transplant recipients? Transplant Proc. 2005;37:3182–6.
    1. Aigner C, Jaksch P, Winkler G, Czebe K, Taghavi S, Marta G, et al. Initial experience with oral valganciclovir for pre-emptive cytomegalovirus therapy after lung transplantation. Wien Klin Wochenschr. 2005;117:480–4.
    1. Montejo M, Montejo E, Gastaca M, Valdivieso A, Fernandez JR, Testillano M, et al. Prophylactic therapy with valgancyclovir in high-risk (cytomegalovirus D+/R-) liver transplant recipients: A single-center experience. Transplant Proc. 2009;41:2189–91.
    1. Parreira L, Bruges M, Gaspar A, Weigert A, Machado D. Prevention of cytomegalovirus disease in renal transplantation: Single-center experience. Transplant Proc. 2009;41:877–9.
    1. Fernández A, Amezquita Y, Fernández-Tagarro E, Escuin F, Jiménez C, Sánchez Villanueva R, et al. Prophylaxis and treatment of cytomegalovirus infection postrenal transplantation in two Madrid units. Transplant Proc. 2009;41:2416–8.
    1. Singh N, Wannstedt C, Keyes L, Mayher D, Tickerhoof L, Akoad M, et al. Valganciclovir as preemptive therapy for cytomegalovirus in cytomegalovirus-seronegative liver transplant recipients of cytomegalovirus-seropositive donor allografts. Liver Transpl. 2008;14:240–4.
    1. Fellay J, Venetz JP, Aubert JD, Seydoux C, Pascual M, Meylan PR. Treatment of cytomegalovirus infection or disease in solid organ transplant recipients with valganciclovir. Transplant Proc. 2005;37:949–51.
    1. Díaz-Pedroche C, Lumbreras C, Del Valle P, San Juan R, Hernando S, Folgueira D, et al. Efficacy and safety of valgancyclovir as preemptive therapy for the prevention of cytomegalovirus disease in solid organ transplant recipients. Transplant Proc. 2005;37:3766–7.
    1. Wéclawiak H, Kamar N, Mengelle C, Guitard J, Esposito L, Lavayssière L, et al. Cytomegalovirus prophylaxis with valganciclovir in cytomegalovirus-seropositive kidney-transplant patients. J Med Virol. 2008;80:1228–32.
    1. Helanterä I, Lautenschlager I, Koskinen P. Prospective follow-up of primary CMV infections after 6 months of valganciclovir prophylaxis in renal transplant recipients. Nephrol Dial Transplant. 2009;24:316–20.
    1. Ciancio G, Burke GW, Mattiazzi A, Leibovici Z, Dowdy L, Roth D, et al. Cytomegalovirus prophylaxis with valganciclovir in kidney, pancreas-kidney, and pancreas transplantation. Clin Transplant. 2004;18:402–6.
    1. Taber DJ, Ashcraft E, Baillie GM, Berkman S, Rogers J, Baliga PK, et al. Valganciclovir prophylaxis in patients at high risk for the development of cytomegalovirus disease. Transpl Infect Dis. 2004;6:101–9.
    1. Devyatko E, Zuckermann A, Ruzicka M, Bohdjalian A, Wieselthaler G, Rödler S, et al. Pre-emptive treatment with oral valganciclovir in management of CMV infection after cardiac transplantation. J Heart Lung Transplant. 2004;23:1277–82.
    1. Babel N, Gabdrakhmanova L, Juergensen JS, Eibl N, Hoerstrup J, Hammer M, et al. Treatment of cytomegalovirus disease with valganciclovir in renal transplant recipients: A single center experience. Transplantation. 2004;78:283–5.
    1. Gruber SA, Garnick J, Morawski K, Sillix DH, West MS, Granger DK, et al. Cytomegalovirus prophylaxis with valganciclovir in African-American renal allograft recipients based on donor/recipient serostatus. Clin Transplant. 2005;19:273–8.
    1. Molina Perez E, Fernández Castroagudín J, Seijo Ríos S, Mera Calviño J, Tomé Martínez de Rituerto S, Otero Antón E, et al. Valganciclovir-induced leukopenia in liver transplant recipients: Influence of concomitant use of mycophenolate mofetil. Transplant Proc. 2009;41:1047–9.
    1. Dupuis R, Harris M, Gillis K, Gerber D, Fair J, Watson R, et al. Experience with low-dose valganciclovir prophylaxis in adult liver transplant recipients. Transplant Proc. 2007;39:3266–70.
    1. Weclawiak H, Kamar N, Mengelle C, Esposito L, Mohamed AO, Lavayssiere L, et al. Pre-emptive intravenous ganciclovir versus valganciclovir prophylaxis for de novo cytomegalovirus-seropositive kidney-transplant recipients. Transpl Int. 2010;23:1056–64.
    1. Khoury JA, Storch GA, Bohl DL, Schuessler RM, Torrence SM, Lockwood M, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant. 2006;6:2134–43.
    1. Guirado L, Rabella N, Díaz JM, Facundo C, Maderuelo A, Margall N, et al. Prophylactic and pre-emptive therapy for cytomegalovirus infection in kidney transplant patients using oral valganciclovir. Nefrologia. 2008;28:293–300.
    1. Arthurs SK, Eid AJ, Pedersen RA, Dierkhising RA, Kremers WK, Patel R, et al. Delayed-onset primary cytomegalovirus disease after liver transplantation. Liver Transpl. 2007;13:1703–9.
    1. Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR. Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: Therapeutic implications and outcomes. Clin Transplant. 2008;22:162–70.
    1. Cervera C, Pineda M, Linares L, Marcos MA, Esteva C, Antón A, et al. Impact of valganciclovir prophylaxis on the development of severe late-cytomegalovirus disease in high-risk solid organ transplant recipients. Transplant Proc. 2007;39:2228–30.
    1. Donnelly C, Kennedy F, Keane C, Schaffer K, McCormick PA. Late-onset CMV disease following CMV prophylaxis. Ir J Med Sci. 2009;178:333–6.
    1. Lamoth F, Manuel O, Venetz JP, Faouzi M, Meylan P, Pascual M. What is the impact of late-onset cytomegalovirus disease after valganciclovir prophylaxis in kidney transplantation? Transplantation. 2008;86:1323–4.
    1. Boutolleau D, Deback C, Bressollette-Bodin C, Varnous S, Dhedin N, Barrou B, et al. Resistance pattern of cytomegalovirus (CMV) after oral valganciclovir therapy in transplant recipients at high-risk for CMV infection. Antiviral Res. 2009;81:174–9.
    1. Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010;10:1228–37.
    1. Akalin E, Bromberg JS, Sehgal V, Ames S, Murphy B. Decreased incidence of cytomegalovirus infection in thymoglobulin-treated transplant patients with 6 months of valganciclovir prophylaxis. Am J Transplant. 2004;4:148–9.
    1. San Juan R, Yebra M, Lumbreras C, López-Medrano F, Lizasoain M, Meneu JC, et al. A new strategy of delayed long-term prophylaxis could prevent cytomegalovirus disease in (D+/R-) solid organ transplant recipients. Clin Transplant. 2009;23:666–71.
    1. Palmer SM, Limaye AP, Banks M, Gallup D, Chapman J, Lawrence EC, et al. Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: A randomized, controlled trial. Ann Intern Med. 2010;152:761–9.
    1. Len O, Gavaldà J, Aguado JM, Borrell N, Cervera C, Cisneros JM, et al. Valganciclovir as treatment for cytomegalovirus disease in solid organ transplant recipients. Clin Infect Dis. 2008;46:20–7.
    1. Potena L, Holweg CT, Chin C, Luikart H, Weisshaar D, Narasimhan B, et al. Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection. Transplantation. 2006;82:398–405.
    1. Freeman RB, Paya C, Pescovitz MD, Humar A, Dominguez E, Washburn K, et al. Risk factors for cytomegalovirus viremia and disease developing after prophylaxis in high-risk solid-organ transplant recipients. Transplantation. 2004;78:1765–73.
    1. Asberg A, Humar A, Jardine AG, Rollag H, Pescovitz MD, Mouas H, et al. Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. Am J Transplant. 2009;9:1205–13.
    1. Boivin G, Goyette N, Gilbert C, Humar A, Covington E. Clinical impact of ganciclovir-resistant cytomegalovirus infections in solid organ transplant patients. Transpl Infect Dis. 2005;7:166–70.
    1. Moro JA, Almenar L, Martínez-Dolz L, Blanes M, Agüero J, Sánchez-Lázaro I, et al. Utility of oral valganciclovir for cytomegalovirus prophylaxis: Does it improve treatment compliance? Transplant Proc. 2008;40:3063–4.
    1. Humar A, Kumar D, Preiksaitis J, Boivin G, Siegal D, Fenton J, et al. A trial of valganciclovir prophylaxis for cytomegalovirus prevention in lung transplant recipients. Am J Transplant. 2005;5:1462–8.
    1. Brady RL, Green K, Frei C, Maxwell P. Oral ganciclovir versus valganciclovir for cytomegalovirus prophylaxis in high-risk liver transplant recipients. Transpl Infect Dis. 2009;11:106–11.
    1. Shiley KT, Gasink LB, Barton TD, Pfeiffenberger P, Olthoff KM, Blumberg EA. Increased incidence of cytomegalovirus infection in high-risk liver transplant recipients receiving valganciclovir prophylaxis versus ganciclovir prophylaxis. Liver Transpl. 2009;15:963–7.
    1. Park JM, Lake KD, Arenas JD, Fontana RJ. Efficacy and safety of low-dose valganciclovir in the prevention of cytomegalovirus disease in adult liver transplant recipients. Liver Transpl. 2006;12:112–6.
    1. Weng FL, Patel AM, Wanchoo R, Brahmbhatt Y, Ribeiro K, Uknis ME, et al. Oral ganciclovir versus low-dose valganciclovir for prevention of cytomegalovirus disease in recipients of kidney and pancreas transplants. Transplantation. 2007;83:290–6.
    1. Akalin E, Sehgal V, Ames S, Hossain S, Daly L, Barbara M, et al. Cytomegalovirus disease in high-risk transplant recipients despite ganciclovir or valganciclovir prophylaxis. Am J Transplant. 2003;3:731–5.
    1. Keven K, Basu A, Tan HP, Thai N, Khan A, Marcos A, et al. Cytomegalovirus prophylaxis using oral ganciclovir or valganciclovir in kidney and pancreas-kidney transplantation under antibody preconditioning. Transplant Proc. 2004;36:3107–12.
    1. Avidan YP, Paul M, Rahamimov R, Bishara J, Samra Z, Edna S, et al. Selective low-dose valganciclovir for prevention of cytomegalovirus disease following kidney transplantation. J Infect. 2008;57:236–40.
    1. Gelone D, Cibrik D, Vogler S, Keichtman A, Lake K, Arbor MA. Comparative efficacy and safety of low dose valganciclovir vs. oral ganciclovir for the prevention cytomegalovirus diseases in renal allograft recipients. Am J Transplant. 2008;3(Suppl 5):89.
    1. Singh N, Wannstedt C, Keyes L, Gayowski T, Wagener MM, Cacciarelli TV. Efficacy of valganciclovir administered as preemptive therapy for cytomegalovirus disease in liver transplant recipients: Impact on viral load and late-onset cytomegalovirus disease. Transplantation. 2005;79:85–90.
    1. Kalpoe JS, Schippers EF, Eling Y, Sijpkens YW, de Fijter JW, Kroes AC. Similar reduction of cytomegalovirus DNA load by oral valganciclovir and intravenous ganciclovir on pre-emptive therapy after renal and renal-pancreas transplantation. Antivir Ther. 2005;10:119–23.
    1. Mattes FM, Hainsworth EG, Hassan-Walker AF, Burroughs AK, Sweny P, Griffiths PD, et al. Kinetics of cytomegalovirus load decrease in solid-organ transplant recipients after preemptive therapy with valganciclovir. J Infect Dis. 2005;191:89–92.
    1. Humar A, Siegal D, Moussa G, Kumar D. A prospective assessment of valganciclovir for the treatment of cytomegalovirus infection and disease in transplant recipients. J Infect Dis. 2005;192:1154–7.
    1. Luan FL, Chopra P, Park J, Norman S, Cibrik D, Ojo A. Efficacy of valganciclovir in the treatment of cytomegalovirus disease in kidney and pancreas transplant recipients. Transplant Proc. 2006;38:3673–5.
    1. Wiltshire H, Hirankarn S, Farrell C, Paya C, Pescovitz MD, Humar A, et al. Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. Clin Pharmacokinet. 2005;44:495–507.
    1. Wiltshire H, Paya CV, Pescovitz MD, Humar A, Dominguez E, Washburn K, et al. Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients. Transplantation. 2005;79:1477–83.
    1. Kalil AC, Freifeld AG, Lyden ER, Stoner JA. Valganciclovir for cytomegalovirus prevention in solid organ transplant patients: An evidence-based reassessment of safety and efficacy. PLoS One. 2009;4:e5512.
    1. Sun HY, Wagener MM, Singh N. Prevention of posttransplant cytomegalovirus disease and related outcomes with valganciclovir: A systematic review. Am J Transplant. 2008;8:2111–8.
    1. Hodson EM, Craig JC, Strippoli GF, Webster AC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2008 CD003774.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel