Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients

Ljungman, Per; Deliliers, Giorgio Lambertenghi; Platzbecker, Uwe; Matthes‐Martin, Susanne; Bacigalupo, Andrea; Einsele, Hermann; Ullmann, J.; Musso, Maurizio; Trenschel, Rudolf; Ribaud, Patricia; Bornhäuser, Martin; Cesaro, Simone; Crooks, Bruce; Dekker, A.; Gratecos, N; Klingebiel, Thomas; Tagliaferri, Elena; Ullmann, Andrew J.; Wacker, Pierre; Cordonnier, Catherine

doi:10.1182/blood.v97.2.388

Cited by 196 publications

(43 citation statements)

References 29 publications

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“…Other authors have shown that this drug can be used safely with some precautions in kidney transplant and HSCT patients. 21,[39][40][41][42] In conclusion, we found a significant correlation in paediatric patients between BK virus replication in both urine and plasma with post-HSCT HC; moreover, a threshold with high specificity and PPV for HC was found by BK load determination. These data deserve further prospective investigation given the small sample size of our study and in view of the possible use of the BK load as a guide for a pre-emptive treatment strategy for HC.…”

Section: Discussionmentioning

confidence: 84%

A prospective study of BK-virus-associated haemorrhagic cystitis in paediatric patients undergoing allogeneic haematopoietic stem cell transplantation

Cesaro

Facchin

Tridello

et al. 2007

Bone Marrow Transplant

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We investigated the incidence, risk factors and outcome of haemorrhagic cystitis (HC) in paediatric patients undergoing HSCT and the predictive value of BK viruria and viraemia for developing HC. Over a period of 54 months, 74 patients were recruited. The cumulative incidence of HC was 22%. Among 15 patients prospectively monitored for BK viruria and viraemia, four patients developed HC of grade XII. This group, which had two consecutive BK positive samples, showed a sensitivity of 100%, a specificity of 82%, a positive predictive value of 67%, and negative predictive value of 100% for developing HC. Analysed by a receiver-operator characteristic curve (ROC), a urine BK load 49 Â 10 6 genomic copies/ml had a sensitivity of 95% and specificity of 90%; while a blood BK load 41 Â 10 3 genomic copies/ml had a sensitivity of 40% and a specificity of 93% for HC, respectively. In univariate analysis, BK positivity was the only factor significantly associated with HC. After a median follow-up of 1.8 years, patients with HC showed a lower overall survival, 40 vs 65%, P 0.01, and a lower event-free survival, 42 vs 62%, P 0.03, compared to patients without HC. We conclude that BK detection in urine and/or plasma is a specific predictor for developing HC.

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Section: Discussionmentioning

confidence: 84%

A prospective study of BK-virus-associated haemorrhagic cystitis in paediatric patients undergoing allogeneic haematopoietic stem cell transplantation

Cesaro

Facchin

Tridello

et al. 2007

Bone Marrow Transplant

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“…32 Other antiviral drugs, including foscarnet, cidofovir and valganciclovir are also being studied for prevention of CMV disease. [33][34][35][36] As prophylactic and early treatment strategies aimed at further reduction of CMV antigenemia and disease are developed and tested, consideration should be given to comparison with high-dose acyclovir or valacyclovir in study designs.…”

Section: Discussionmentioning

confidence: 99%

Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation

Burns

Miller

Kandaswamy

et al. 2002

Bone Marrow Transplant

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Summary:Cytomegalovirus (CMV) disease remains a major cause of morbidity following allogeneic stem cell transplantation (SCT). In a prospective randomized trial, we tested prophylactic therapy with ganciclovir or acyclovir for patients at high risk of disease. Ninety-one CMV seropositive recipients of related (n = 53) and unrelated (n = 38) donor transplants were enrolled. All patients received intravenous (i.v.) ganciclovir 5 mg/kg every 12 h days ؊7 to ؊2, followed by acyclovir 10 mg/kg i.v. every 8 h from day ؊1 until neutrophil engraftment. Patients were then randomly assigned to either ganciclovir (n = 45) or acyclovir (n = 46) until day 100 post transplant. Any degree of antigenemia was treated with ganciclovir 5 mg/kg i.v. twice a day for 2 weeks, followed by 5 mg/kg i.v. each weekday for 6 weeks. At day 100, the cumulative incidence of antigenemia was 31% (95% CI 17-45%) for ganciclovir and 41% (95% CI 26-56%) (P = 0.22) for acyclovir prophylaxis, respectively. The assigned prophylaxis cohort did not predict for CMV antigenemia. The cumulative incidence of CMV disease at 12 months was 13% (95% CI 3-23%) and 17% (95% CI 6-28%) (P = 0.59) for the ganciclovir-and acyclovir-treated groups, respectively. An absolute neutrophil count (ANC) р1500 ؋ 10 6 /l at randomization (P < 0.01) and grade II-IV acute graftversus-host-disease (P = 0.01), but not the assigned prophylaxis cohort (P = 0.62), were independent risk factors for CMV disease. The incidence of fungal infections and renal insufficiency was similar across treatment groups; however, bacterial infections and secondary neutropenia occurred more frequently in the ganciclovir group. With our study powered to detect a 60% reduction in antigenemia with ganciclovir prophylaxis, we did not find a statistically significant difference between ganciclovir and acyclovir when used as part of an overall strategy for prevention of CMV antigenemia and disease in SCT, although fewer side-effects occurred with acyclovir treatment. Cytomegalovirus (CMV) disease is a frequent complication following allogeneic stem cell transplantation (SCT). 1,2 CMV seropositive recipients are at a high risk of CMV disease, as reactivation of latent endogenous virus is the dominant mechanism of infection in immunocompromised patients. [1][2][3][4][5] Despite recent advances in therapy, the mortality from CMV disease, and particularly CMV pneumonia, remains quite high. Recent therapeutic strategies have focused on the prevention of CMV disease.Acyclovir and ganciclovir have each been shown to be effective prophylaxis for patients at high risk of CMV disease. Two prospective studies demonstrated a decrease in the occurrence of CMV disease as well as a survival benefit of high-dose acyclovir for allogeneic marrow transplant recipients. [5][6][7] Ganciclovir has been incorporated into various prophylactic strategies. [8][9][10][11][12][13][14][15] In each of three randomized studies, [8][9][10] ganciclovir prophylaxis decreased CMV infection and/or disease; however, there was no benefit in ov...

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“…Ljungman et al (55) performed a retrospective survey among 17 bone marrow transplantation centers and enrolled 82 patients who were treated with CDV for CMV disease (n ϭ 20) or for CMV reactivation (primary preemptive treatment, n ϭ 24; secondary preemptive treatment in patients who had failed or relapsed after previous preemptive treatment with another antiviral drug, n ϭ 38). The dosage was 1 to 5 mg/kg per week followed by maintenance treatment, and all patients received probenicid and prehydration.…”

Section: CDVmentioning

confidence: 99%

Prevention of Cytomegalovirus Disease in Recipients of Allogeneic Stem Cell Transplants

2003

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The main risk factors for cytomegalovirus (CMV) disease in recipients of allogeneic stem cell transplants (SCT) are recipient CMV seropositivity and acute graft-versus-host disease. Currently, two antiviral strategies, prophylactic or preemptive antiviral treatment, are used for prevention of CMV disease. Preemptive treatment is most favorable when short-term (14-day) treatment is applied. Several methods are available for monitoring of CMV reactivation. PCR-based CMV DNA detection assays are the most sensitive methods; however, the clinical benefit of this high sensitivity is unclear. Even more, there is lack of clarity whether PCR tests can better be performed with plasma, whole blood, or peripheral blood leukocyte samples. Recovery of a CMV-specific CD8+ cytotoxic-T-lymphocyte (CTL) response is necessary for preventing CMV reactivation and disease. Reconstitution of absolute CMV-specific CTL counts to values above 10 × 106 to 20 × 106 CTLs/liter is associated with protection from CMV disease. In the near future, preemptive therapy might be withheld in patients with CMV reactivation who are shown to have adequate CMV-specific cytotoxic T-cell levels. Antiviral therapy with (val)acyclovir has been studied only as prophylactic treatment for prevention of CMV infection. High-dose oral valacyclovir is more effective than acyclovir when used in addition to preemptive treatment of CMV reactivation with ganciclovir or foscarnet. Three antiviral drugs have been tested for preemptive therapy of CMV reactivation and/or treatment of CMV disease. Although intravenous ganciclovir is considered the drug of choice, foscarnet has similar efficacy and less toxicity, especially hematologic toxicity. Cidofovir has not been tested extensively, but so far the results are disappointing. Oral valganciclovir for preemptive treatment of SCT recipients is currently being studied. In addition to antiviral therapy, adoptive immunotherapy with CMV-specific cytotoxic T cells as prophylactic or preemptive therapy is a very elegant strategy; however, generation of these cells is expensive and time-consuming, and therefore the therapy is not available at every transplantation center. Magnetic selection of CMV-specific CD8+ T cells from peripheral blood by using HLA class I-peptide tetramers may be very promising, making this strategy more accessible

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Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients

Cited by 196 publications

References 29 publications

A prospective study of BK-virus-associated haemorrhagic cystitis in paediatric patients undergoing allogeneic haematopoietic stem cell transplantation

A prospective study of BK-virus-associated haemorrhagic cystitis in paediatric patients undergoing allogeneic haematopoietic stem cell transplantation

Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation

Prevention of Cytomegalovirus Disease in Recipients of Allogeneic Stem Cell Transplants

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