Abstract & Commentary
Synopsis: Foscarnet and ganciclovir had similar efficacy in the preemptive treatment of CMV infection in recipients of allogeneic stem cell transplants.
Source: Reusser P, et al. Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood. 2002;99:1159-1164.
Twenty-three European and 3 US transplant centers, on behalf of the European Group for Blood and Bone Marrow Transplantation, evaluated the comparative efficacy and toxicity of ganciclovir and foscarnet in the preemptive therapy of cytomegalovirus (CMV) infection in patients who had received allogeneic stem cell transplantation (SCT). At each center, SCT patients were prospectively monitored at weekly intervals for the appearance of CMV antigenemia or of CMV DNA in blood leukocytes by PCR.
Randomization, which occurred at the time of detection of CMV and was stratified by center and relatedness of the allograft donor, yielded 213 evaluable patients who received assigned open-label therapy. If CMV was no longer detectable in blood after the end of 14 days of induction therapy, administration of the antiviral was discontinued. If, however, CMV remained detectable after 14 days of therapy, maintenance therapy with the originally assigned drug was administered for an additional 14 days.
Reasons for exclusions from the study included the presence of a neutrophil count < 500/mm3 and serum creatinine clearance < 60 ml/min. The primary study end point was event-free survival within 180 days after SCT, with an "event" defined as the occurrence of CMV disease or death from any cause. The study was designed to have a power of 80% to detect a difference of at least 15% in the primary end point within 180 days after SCT.
CMV remained detectable in the blood of 29% of foscarnet and 34% of ganciclovir recipients after completion of induction therapy (P = 0.4) and in 10% and 13%, respectively, after the end of maintenance therapy. Retreatment within 180 days after SCT because CMV, once having been cleared became detectable once again, was required in 43% of foscarnet and 28% of ganciclovir recipients (P = 0.06). There was no significant difference between groups in the incidence of development of HSV, VZV, or major nonviral infections.
Kaplan-Meier estimates of event-free survival to 180 days (66% for foscarnet, 73% for ganciclovir) did not differ significantly (P = 0.6). Five patients in each group developed CMV disease and 2 died of CMV pneumonia, both having been assigned to ganciclovir therapy. The overall mortality within the 180 days of interest was 26% in the foscarnet and 22% in the ganciclovir group.
Eleven percent of ganciclovir, but only 4% of foscarnet recipients (P = 0.04), had a decrease in neutrophil count to < 500/mm3 during antiviral therapy. Overall, a similar proportion in each group required hematopoietic growth factors. However, when only patients who remained exclusively on their assigned therapy during the first 100 days after SCT were considered, 25% of ganciclovir recipients and only 8% of foscarnet recipients (P = 0.007) were given such growth factors.
On the other hand, hypocalcemia occurred significantly more frequently in foscarnet recipients (22% vs 4%; P < 0.001), as did hypomagnesemia (18% vs 6%; P = 0.006), hypokalemia (17% vs 6%; P = 0.01), and hypophosphatemia (6% vs 0%; P = 0.01). Five percent of foscarnet assignees and 2% of those assigned ganciclovir developed impairment of renal function. During induction, 2% of the foscarnet and 5% of the ganciclovir group had their assigned antiviral therapy prematurely discontinued because of a drug-related adverse event, while this occurred in 0% and 3%, respectively, during maintenance. Overall, however, 6% of ganciclovir recipients, but no foscarnet recipients, required discontinuation of their assigned therapy because of neutropenia or thrombocytopenia.
Comment by Stan Deresinski, MD, FACP
Previous trials have demonstrated that both prophylactic and preemptive antiviral therapy are effective strategies in the prevention of CMV disease in transplant recipients. Prophylaxis is given to all at-risk patients in an attempt to prevent reactivation of CMV replication, while preemptive therapy is administered only when active CMV infection is documented. The latter approach prevents unnecessary exposure to potentially toxic antiviral drugs. The study reviewed here examined the relative efficacy and safety of 2 antivirals with potent activity against CMV which have different toxicity profiles.
Reusser and colleagues point out here that their choice of a relatively brief 14-day course of induction and, when necessary, maintenance therapy, is based on the prior observation that prolonged prophylactic administration of ganciclovir is associated with a potentially increased risk of late CMV disease after SCT as a consequence of diminished reconstitution of CMV-specific CD8+ cytotoxic T cell responses.1
Despite the brief courses of therapy, however, 3 of the 10 patients who developed CMV disease did so more than 100 days after SCT, indicating that patients with persistent severe immunosuppression may benefit from prolonged continued surveillance for CMV reactivation.
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The apparent trend toward a greater frequency of requirement for retreatment in the patients assigned foscarnet may have been the result of the use of a dose (60 mg/kg q12h) less than that generally recommended for the treatment of active CMV disease (60 mg/kg q8h). The lower dose, however, has the likely benefit of reduced toxicity. With either drug, however, the need for intravenous administration is an important drawback, in terms of both cost and convenience. In consequence, the recent demonstration that valganciclovir, an orally administered prodrug of ganciclovir, is as effective as intravenously administered ganciclovir in the treatment of CMV retinitis in AIDS patients,2 is welcome information that likely will be applicable to other forms in CMV disease in other types of immunocompromise.
One concern regarding both prophylactic and preemptive antiviral therapy in transplant recipients is the potential for the emergence of drug-resistant strains of CMV. In a recently presented study, ganciclovir-resistant CMV was isolated from 3 of 36 (8.3%) lung transplant recipients who received preemptive ganciclovir therapy for CMV infection and 1 of 8 (12.5%) who received it prophylactically (2001 ICAAC, Abstract #1120). All isolates contained the UL97 mutation. Such resistance could result in a lack of response to therapy. It may now be possible to detect such resistance more rapidly than heretofore considered. Thus, in solid organ transplant recipients given ganciclovir for their first episode of CMV viremia, a rise in CMV viral load as detected by a quantitative PCR assay heralded the presence of resistance in a number of patients, particularly in CMV-negative recipients receiving a CMV-positive organ (2001 IDSA, Abstract #438). Such a rise in viremia may also herald treatment failure in the absence of detectable antiviral resistance.
Dr. Deresinkski, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.
References
1. Li CR, et al. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood. 1994;83:1971-1979.
2. Martin DF, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med. 2002;346:1119-1126.
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