Treatment of Cytomegalovirus Infection or Disease in Solid Organ Transplant Recipients with Valganciclovir

To the Editor: We read with great interest the recently published American Society of Transplantation guidelines and the report of the Canadian Society of Transplantation consensus workshop on cytomegalovirus (CMV) management in solid organ transplantation (1American Society of Transplantation, Infectious Disease Community of Practice. Cytomegalovirus. Am J Transplant 2004; 4: 51–58.Google Scholar,2Preiksaitis JK Brennan DC Fishman J Allen U Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report..Am J Transplant. 2005; 5: 218-227Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar). Intravenous ganciclovir (GCV) is recommended as the preferred therapy for the treatment of post-transplantation CMV disease, and it is mentioned that valganciclovir (VGC) might be used in place of intravenous GCV, but that studies are lacking. Several arguments suggest that oral VGC may be as efficacious as intravenous GCV. First, VGC has a favorable pharmacokinetic profile, essentially similar to intravenous GCV, providing similar areas under curves after corresponding prophylactic or therapeutic doses (3Reusser P Oral valganciclovir: a new option for treatment of cytomegalovirus infection and disease in immunocompromised hosts..Expert Opin Investig Drugs. 2001; 10: 1745-1753Crossref PubMed Scopus (53) Google Scholar). Second, oral VGC proved as efficacious as intravenous GCV in the therapy of CMV retinitis in AIDS patients (4Martin DF Sierra-Madero J Walmsley S et al.A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis..N Engl J Med. 2002; 346: 1119-1126Crossref PubMed Scopus (326) Google Scholar). We present here our experience in using VGC for the treatment of documented CMV infection or disease in solid organ transplant recipients. Fourteen patients (9 kidney, 3 lung and 2 heart recipients) were treated, starting between 6 and 26 weeks after transplantation: 9 for CMV disease (CMV syndrome n = 4 and tissue-invasive disease n = 5) and 5 for asymptomatic CMV infection (i.e. viremia without signs or symptoms). The CMV antibody donor/recipient pattern was D+/R- (n = 10), D+/R+ (n = 3) and D-/R+ (n = 1). The induction immunosuppressive protocol consisted of methylprednisolone, associated with anti-interleukin-2 receptor antibodies in 12 patients, or anti-thymocyte globulin in 2 patients. The maintenance regimen included mycophenolate mofetil and prednisone, associated with ciclosporine A in 10 patients or tacrolimus in 4 patients. An acute rejection episode was observed in 2 patients. Three patients had received valacyclovir and 7 patients VGC prophylaxis during the first 3 months after transplantation, and all CMV infections occurred after prophylaxis discontinuation. Initial VGC dose was 900–1800 mg/day for 2–3 weeks, followed by maintenance therapy (450–900 mg/day), but the exact duration of therapy was left to the physician in charge (median duration of the whole treatment: 47 days). Doses of VGC were adapted to renal function according to the package insert table. In the 9 patients with CMV disease, all symptoms disappeared after a median of 7 days (range 4–18) after VGC initiation. Virologically, blood cultures (shell vial) turned negative within 2 weeks in all patients, and a ≥2 log decrease in blood CMV DNA, measured by real time PCR (for method used, see Ref. 5Muheim C Vogel G Seydoux C et al.Determinants of protracted cytomegalovirus infection in solid-organ transplant patients..Transplantation. 2002; 74: 226-236Crossref PubMed Scopus (31) Google Scholar), was observed within 3 weeks in all tested patients (8/8, see Table 1).Table 1Patients characteristics, CMV infection/disease and treatment with oral VGC (n = 14)PtAgeGenderOrganCMV antibody status (donor/recipient)CMV ProphylaxisTime to CMV from Tx (weeks)CMV clinical pictureLength of treatment (days)PCR viral load (copies/mio leucocytes)Recurrence (days after completion of treatment)InitialFollow-up (3 weeks)145FK+/-VAC12Syndrome2575 300664yes (24)251MK+/+No6Infection149570156yes (24)351MK+/+No8Infection3515 400130454FK+/-VAC18Infection17yes (16)569MK+/-VAC16Infection44yes (6)*New course of VGC treatment administered for recurrent CMV; recurrence consisted in a CMV syndrome only in one patient (patient 12).634FK+/-VGC19GI disease3114 5000750MK-/+VGC14Syndrome53852MK+/-VGC16Syndrome4846 100380929FK+/-VGC26Infection5616 500851057ML+/-VGC17GI disease811157ML+/-VGC20Syndrome531262ML+/-VGC18Pneumonia46yes (14)11366MH+/+No21Retinitis6812 70001457MH+/-No6GI disease7371 90051yes (37)Tx = transplantation, F = female, M = male, K = kidney, L = lung, H = heart, VAC = valacyclovir, VGC = valganciclovir, GI = gastro-intestinal.* New course of VGC treatment administered for recurrent CMV; recurrence consisted in a CMV syndrome only in one patient (patient 12). Open table in a new tab Tx = transplantation, F = female, M = male, K = kidney, L = lung, H = heart, VAC = valacyclovir, VGC = valganciclovir, GI = gastro-intestinal. With a follow-up of 6 months, asymptomatic recurrent CMV viremia was noted in 5/14 cases, and CMV syndrome in one case. In fact, recurrent CMV infection correlated nearly significantly with a shorter treatment (median 34.5 vs. 53 days, p = 0.1, Mann-Whitney test). Two patients received a second course of VGC treatment, which was again associated with a rapid clearance of the viremia. VGC was clinically well tolerated, while transient laboratory abnormalities were observed in 3 cases: increase in transaminases, thrombocytopenia and moderate pancytopenia. These abnormalities reversed after VGC dose reduction. VGC has recently been used pre-emptively for CMV infection, and there has been one single report of VGC as treatment of late symptomatic CMV infections after kidney transplantation (6Babel N Gabdrakhmanova L Juergensen JS et al.Treatment of cytomegalovirus disease with valganciclovir in renal transplant recipients: a single center experience..Transplantation. 2004; 778: 283-285Crossref Scopus (30) Google Scholar,7Mattes FM Hainsworth EG Hassan-Walker AF et al.Kinetics of cytomegalovirus load decrease in solid-organ transplant recipients after preemptive therapy with valganciclovir..J Infect Dis. 2005; 191: 89-92Crossref PubMed Scopus (94) Google Scholar). We present here the first description of successful treatment of CMV disease (some tissue invasive) with VGC in various solid organ transplant recipients. Our preliminary experience, together with these recent reports (6Babel N Gabdrakhmanova L Juergensen JS et al.Treatment of cytomegalovirus disease with valganciclovir in renal transplant recipients: a single center experience..Transplantation. 2004; 778: 283-285Crossref Scopus (30) Google Scholar,7Mattes FM Hainsworth EG Hassan-Walker AF et al.Kinetics of cytomegalovirus load decrease in solid-organ transplant recipients after preemptive therapy with valganciclovir..J Infect Dis. 2005; 191: 89-92Crossref PubMed Scopus (94) Google Scholar), indicates that VGC indeed represents an attractive option to treat active and potentially severe CMV in organ transplant recipients, frequently allowing treatment on an outpatient basis and thus eliminating the risks associated with intravenous lines. Optimal dosing of VGC, drug levels and toxicity as well as appropriate duration of therapy remain to be investigated in larger studies before VGC can be recommended as the standard therapy for CMV infection and disease.

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