Pharmaceutical Services Division requested a systematic review of intravenous ganciclovir and oral valganciclovir for preemptive therapy of cytomegalovirus (CMV) infection in allogeneic stem cell transplant patients.
Ganciclovir is indicated for treatment of CMV retinitis in immuno-compromised patient and prevention of CMV disease in transplant recipients. It inhibits viral DNA synthesis by interfering with DNA incorporation and termination of DNA elongation.
Recommended dose for CMV prevention is 5mg/kg every 12 hours for 7-14 days followed by 5mg/kg once per day (if on a seven day/week regimen) or 6mg/kg once per day (if on a five day/week regimen) continued until day 100-120 post bone marrow transplantation.
Valganciclovir is the prodrug of ganciclovir. It is currently indicated for the treatment of CMV retinitis in patients with AIDS and in the prevention of CMV disease in solid organ transplant recipients. There is no recommended dose for allogenic stem cell transplant
Primary CMV infection ranges from asymptomatic to fulminant and can remain latent for long periods of time. It can reactivate as pneumonia, gastritis, retinitis and encephalitis. CMV infection and pneumonia occur in 38% and 17% of stem cell transplant patients, respectively. The mortality associated with untreated CMV pneumonia is 85% (Meyers 1986). Antiviral treatment of CMV infection in stem cell transplant patients has been shown to reduce CMV related mortality by 30 to 50% (Emmanuel 1988, Reid 1988).
Different preventative strategies:
Prophylaxis treats patients continuously with an antiviral from the day of engraftment to 100 days post-transplant in order to prevent recurrence or reactivation of CMV infection.
Pre-emptive limits antiviral therapy to instances when primary or reactivated CMV infection is detected by positive CMV detection methods. The point at which reactivation occurs is when antivirals are started and then are continued until 100 days post transplant.
Research questions directed by PSD:
- Is there sufficient evidence to support the efficacy and safety of IV ganciclovir for the preemptive treatment of cytomegalovirus infection in patients who have undergone allogenic stem cell transplant?
- Does the evidence support equivalence/non-inferiority of oral valganciclovir instead of IV ganciclovir in allogenic stem cell transplant recipients who become positive for CMV; particularly given the increased patient visits, lab testing, and nursing costs associated with the IV drug?
We searched for prospective, randomized controlled trials (RCTs) of patients who have undergone allogenic stem cell transplant or bone marrow transplant that compared IV ganciclovir with placebo, IV ganciclovir with an active comparator, and oral valganciclovir to IV ganciclovir (when used as a preventative strategy) to assess the outcomes of death, non-fatal serious adverse events, CMV disease, secondary infection, withdrawal due to adverse events and total adverse events.
Search strategy and findings
Our search included the following electronic databases: Cochrane Central Register of controlled trials (Issue 1, 2009), EMBASE (1988-2009 week 7), and Medline (1996-February week 1 2009).
Key search words included – ganciclovir, valganciclovir, preemptive therapy, bone marrow transplant, stem cell transplant.
Research question 1: 6 RCTs met the inclusion criteria
3 RCTS comparing IV ganciclovir with a placebo for prophylaxis (Goodrich JM 1993; Goodrich JM 1991 and Winston DJ 1993)
1 RCT comparing preemptive ganciclovir to prophylactic ganciclovir (Boekch 1996)
2 RCTS comparing preemptive IV ganciclovir with foscarnet (Reusser P 2002; Moretti S 1998)
Research question 2: 2 RCTs met the inclusion criteria
2 RCTS comparing IV ganciclovir with oral valganciclovir (Lim ZY 2008; Einsele H.2006)
1 pharmacokinetic study comparing IV ganciclovir to oral valganciclovir (Winston DJ 2006)
Results and Overall summary
- In 3 RCTs (N = 221, follow-up 100-180 days) in bone marrow transplant recipients (Goodrich JM et al, 1991, 1995 and Winston D 1993), prophylaxis with intravenous ganciclovir significantly reduced CMV infection versus placebo (ARR with 95%CI 21% (12-30%), NNT=5, p<0.00001) and in one RCT (Goodrich JM et al 1991) in 72 patients who had marrow engraftment and were excreting virus with follow-up 180 days) IV ganciclovir significantly reduced overall mortality [(4/37 (10.8%) in ganciclovir vs. 11/35 (31.4%) in placebo group p = 0.05 ARR = 21.4%, NNT =5]
- Based on 1 RCT (N =226, follow-up 400 days) in bone marrow transplant patients (Boekch 1996), preemptive (day 0 to day 100 post-transplant) compared to a prophylaxis treatment strategy with IV ganciclovir did lead to statistically significant differences in invasive fungal infections (6% versus 16%, respectively), but did not lead to significant differences in any bacterial infection (40% versus 45%, respectively), late CMV disease (20.2% versus 16.1%, respectively), or survival at day 400 post-transplant (61% versus 59%, respectively).
- In 2 RCTs (N=252, follow up 180 days) in stem cell transplant patients, preemptive treatment with IV ganciclovir compared to foscarnet did not show any statistically significant differences with respect to CMV disease rates (4.5% vs. 4.9%, respectively), non-viral infection rates (33% versus 35%, respectively), and overall mortality at 180 days post transplant (22% versus 26 %, respectively). Fewer patients who received foscarnet, discontinued therapy due to neutropenia or thrombocytopenia versus IV ganciclovir (ARR 6%, 95%CI 1% to 11%, p=0.02). (Reusser P 2002; Moretti S 1998)
- Based on 1 RCT (N=27, follow up 84 days) in stem cell transplant patients (Lim ZY 2008) preemptive treatment with IV ganciclovir and oral valganciclovir had similar pharmacokinetics. No virologic, serologic or clinical outcomes were evaluated.
- One randomized cross-over study (Winston et al, n=22) compared the pharmacokinetics of oral valganciclovir and IV ganciclovir. The primary endpoint of the study was the area-under-the-curve. Authors concluded that a single dose of 900 mg of oral valganciclovir was non-inferior to a single dose 5 mg/kg of IV ganciclovir.
Research question 1
There were no studies of IV ganciclovir versus placebo for preventative CMV treatment in stem cell transplant patients. In bone marrow transplant patients, IV ganciclovir prophylaxis provides a therapeutic advantage versus placebo in terms of mortality and in the incidence of CMV disease. In addition, IV ganciclovir preemptive and prophylatic treatment leads to similar rates of bacterial infections, late CMV disease, and survival rates. The preemptive strategy leads to lower rates of invasive fungal infections but higher rates of early CMV disease.
Research question 2
There is sufficient evidence to support the pharmacokinetic equivalence of oral valganciclovir and IV ganciclovir.
- Boeckh M, Gooley TA, et al. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation : a randomized double-blind study. Blood 1996; 88:4063-4071.
- Boeckh M, Zaia JA, Jung D, et al. A study of the pharmacokinetics, antiviral activity, and tolerability of oral ganciclovir for CMV prophylaxis in marrow transplantation. Biology of Blood and Marrow Transplantation 1998;4:13-19.
- Boeckh M, Nichols WG, Papanicolaou G et al. Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known challenges, and future strategies. Biology of Blood and Marrow Transplantation 2003;9: 543-558.
- Burns LJ, Miller W, Kandaswamy C, et al. Randomized clinical trial of ganciclovir vs. acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation. Bone Marrow Transplantation 2002;30: 945-951.
- Einsele H. et al. Oral valganciclovir leads to higher exposure to ganciclovir than intravenous ganciclovir in patients following allogeneic stem cell transplantation. Blood 2006; 107: 3002-3008.
- Emanuel, D., I. Cunningham, K. Jules-Elysee, J et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann. Intern. Med.1988; 109:777–782.
- Goodrich JM, Mori M, Gleaves CA, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. NEJM 1991;325(23):1601-1607.
- Goodrich, J. M., R. A. Bowden, L. Fisher, C. Keller, G. Schoch, and J. D.Meyers. Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann. Intern. Med. 1993 118:173–178.
- Lim ZY. et al. Results of a phase І/ІІ British Society of Bone Marrow Transplantation study on PCR-based preemptive therapy with valganciclovir or ganciclovir for active CMV infection following alemtuzumab-based reduced intensity allogeneic stem cell transplantation. Leukemia research 2008.
- Ljungman P. Review: prevention and treatment of viral infections in stem cell transplant recipients. British Journal of Hematology 2002; 118:44-57.
- Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clinical Infectious Diseases 2002; 34:1094-7.
- Mcgavin JK, Goa KL. Ganciclovir an update of its use in prevention of cytomegalovirus infection and disease in transplant recipients. Drugs 2001; 61(8): 1153-1183.
- Meyers, J. D., N. Flournoy, and E. D. Thomas. Risk factors for cytomegalovirus infection after human marrow transplantation. J. Infect.Dis.1986 153:478–488.
- Moretti S. et al. Foscarnet versus ganciclovir for CMV antigenemia after allogeneic hemopoietic stem cell transplantation: a randomized study. Bone Marrow Transplantation 1998;22: 175-180.
- Prentice HG, GLuckman E, Poweles RL, et al. Impact of long-term acyclovir on cytomegalovirus infectiono and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV prophylaxis Study Group. Lancet 1994; 343:79.
- Reed, E. C., R. A. Bowden, P. S. Dandliker, K. E. Lilleby, and J. D. Meyers. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann. Intern. Med.1988; 109:783–788.
- Reusser P. et al. Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood 2002; 99(4):1159-1164.
- Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid organ transplant recipients. Clinical Microbiology Reviews Jan 2000:83-121.
- Sullivan KM, Dykewicz CA, Longworth DL et al. Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America and American Society for Blood and Marrow Transplantation practice guidelines and beyond. Hematology 2001:392-421.
- Winston, D. J., W. G. Ho, K. Bartoni, C. Du Mond, D. F. Ebeling, W. C. Buhles, and R. E. Champlin. Ganciclovir prophylaxis of cytomegalovirus infection in allogeneic bone marrow transplant recipients. Ann. Intern.Med. 1993 118:179–184.
- Winston DJ. Et al. Pharmacokinetics of Ganciclovir after oral valganciclovir versus intravenous ganciclovir in allogeneic stem cell transplant patients with graft-versus host disease of the gastrointestinal tract. Biology of Blood and Marrow Transplantation 2006;12: 635-640.