Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients

Abstract

Cross ResistanceCidofovir-resistant isolates selected in vitro following exposure to increasing concentrations of cidofovir were assessed for susceptibility to ganciclovir and foscarnet 4 . All were cross resistant to ganciclovir, but remained susceptible to foscarnet. Ganciclovir-or ganciclovir/foscarnet-resistant isolates that are cross resistant to cidofovir have been obtained from drug naive patients and from patients following ganciclovir or ganciclovir/ foscarnet therapy. To date, the majority of ganciclovir-resistant isolates are UL97 gene product (phosphokinase) mutants and remain susceptible to cidofovir 5 . Reduced susceptibility to cidofovir, however, has been reported for DNA polymerase mutants of CMV which are resistant to ganciclovir [6][7][8][9] . To date, all clinical isolates which exhibit high level resistance to ganciclovir, due to mutations in both the DNA polymerase and UL97 genes, have been shown to be cross resistant to cidofovir. Cidofovir is active against some, but not all, CMV isolates which are resistant to foscarnet [10][11][12] . The incidence of foscarnet-resistant isolates that are resistant to cidofovir is not known.A few triple-drug resistant isolates have been described. Genotypic analysis of two of these triple-resistant isolates revealed several point mutations in the CMV DNA polymerase gene. The clinical significance of the development of these cross-resistant isolates is not known. CLINICAL PHARMACOLOGY PHARMACOKINETICSVISTIDE must be administered with probenecid. The pharmacokinetics of cidofovir, administered both without and with probenecid, are described below.The pharmacokinetics of cidofovir without probenecid were evaluated in 27 HIV-infected patients with or without asymptomatic CMV infection. Dose-independent pharmacokinetics were demonstrated after one hr infusions of 1.0 (n = 5), 3.0 (n = 10), 5.0 (n = 2) and 10.0 (n = 8) mg/kg (See Table 2 for pharmacokinetic parameters). There was no evidence of cidofovir accumulation after 4 weeks of repeated administration of 3 mg/kg/ week (n = 5) without probenecid. In patients with normal renal function, approximately 80 to 100% of the VISTIDE dose was recovered unchanged in urine within 24 hr (n = 27). The renal clearance of cidofovir was greater than creatinine clearance, indicating renal tubular secretion contributes to the elimination of cidofovir.The pharmacokinetics of cidofovir administered with probenecid were evaluated in 12 HIV-infected patients with or without asymptomatic CMV infection and 10 patients with relapsing CMV retinitis. Dose-independent pharmacokinetics were observed for cidofovir, administered with probenecid, after one hr infusions of 3.0 (n = 12), 5.0 (n = 6), and 7.5 (n = 4) mg/kg (See Table 2). Approximately 70 to 85% of the VISTIDE dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When VISTIDE was administered with probenecid, the renal clearance of cidofovir was reduced to a level consistent with creatinine clearance, suggesting that probenecid blocks ac...

Selective embolization of the internal iliac arteries for the treatment of severe hemorrhagic cystitis following hematopoietic SCT

“…2,13 Encouraging results with antiviral agents have been published; however, there is no evident proof in a large number of patients and mainly improve clinical symptoms. [14][15][16][17] The use of formalin, alum, prostaglandin E1, estrogens, FVIIa, factor XIII, hyperbaric oxygen treatment, intravesicular sodium hyaluronate, recombinant human epidermal growth factor or recombinant human GM-CSF has been described, but their efficacy remains controversial. [18][19][20][21][22][23][24][25][26][27] Severe HC may also require surgical treatment with cystoscopy and cauterization, and even cystectomy when previous methods have failed, 28 but it is limited by the disadvantage of operation.…”

Treatment of post-hematopoietic stem cell transplantation hemorrhagic cystitis with intravesicular sodium hyaluronate

“…However, the efficacy of this antiviral agent against HC needs to be further investigated. 23,24 Hyperbaric oxygen therapy has been shown to be effective for HC due to chemotherapy and/ or radiation therapy, and two cases of life-threatening late-onset HC after allogeneic BMT in children, which resolved after treatment with hyperbaric oxygen have been reported. 25 Surgical interventions such as cystectomy, nephrostomy, ureterostomy are associated with high rates of morbidity and mortality and are indicated for life- 27,28 Sodium hyaluronate (a member of glycosaminoglycans), is a major component of the extracellular matrix of most tissues.…”

Acute Renal Failure Induced by Adenovirus After Stem Cell Transplantation

“…In adenovirus-induced hemorrhagic cystitis cases before acute renal failure, the most rapid and handy qualitative diagnosis kit is immunochromatography, for example, adenocheck (Santen, Osaka, Japan, or SA Scientific, Texas, U.S.) (Nagafuji et al, 2004). This kit enables us to detect more than 1x10 4 viral particles /ml in urine at the bedside, although it was developed for the diagnosis of adenovirus conjunctivitis.…”

“…Recent reports showed that 69-98% of patients with adenovirus disease were successfully treated with Cidofovir (Yusuf et al, 2006, Ljungman, 2003. Nagafuji et al reported that 71% of patients with adenovirusinduced hemorrhagic cystitis were successfully treated with Cidofovir (Nagafuji et al, 2004). Therefore, Cidofovir is recommended as the first line treatment for adenovirus-induced hemorrhagic cystitis.…”

“…If possible, immunosuppressive drugs should be tapered (Kampmann et al, 2005, Chakrabarti et al, 2002. Because of the marked nephrotoxicity of Cidofovir, hyperhydration together with oral Probenecid (2 g) given 3 h before Cidofovir administration is essential for nephroprotection (Nagafuji et al, 2004, Anderson et al, 2008, Hoffman et al, 2001). Viral load increases of more than 1 log /week or patient presentation of adenovirus disease symptoms is indicative of therapy failure and immunotherapy (described later) should be considered.…”