Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria

Abstract

Cidofovir {HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine} is a nucleotide analog with activity against human cytomegalovirus (CMV).A phase I/II dose escalation trial was conducted with asymptomatic human immunodeficiency virus (HIV)-infected patients with CMV viruria to determine its pharmacokinetics, maximally tolerated dose, and preliminary antiviral activity against CMV. Qualitative CMV blood and urine cultures were monitored weekly to assess anti-CMV activity. Twenty-one HIV-infected persons with CD4 counts from 0 to 389 cells per l (median, 39) were enrolled in six dose-ranging groups. The first five groups enrolled four patients each to receive cidofovir infusions either weekly or biweekly for 4 weeks or every 3 weeks for 12 weeks. The sixth group enrolled one patient who received infusions of 5 mg/kg of body weight every other week. Patients receiving 0.5 or 1.5 mg/kg twice weekly experienced no serious toxicity. The first two patients who received 5 mg/kg twice weekly developed glycosuria and 2؉ proteinuria. Subsequent patients received concomitant probenecid to attempt to ameliorate renal toxicity. Seventeen patients experienced proteinuria on one or more occasions; 6 of them experienced at least 2؉ proteinuria. Four patients did not complete the study as planned because of renal toxicity. Positive CMV urine cultures reverted to negative in 2 of 8 patients receiving doses of Յ1.5 mg/kg twice weekly and 11 of 13 patients receiving higher doses. Cidofovir has in vivo anti-CMV activity demonstrated by prolonged clearing of CMV viruria, although this observation is tempered by the fact that clearance of viremia could not be demonstrated. The dose-limiting toxicity is renal; however, concurrent administration of probenecid may be protective. The maximally tolerated weekly intravenous dose with probenecid is approximately 5 mg/kg. Efficacy trials with CMV disease will define the therapeutic utility and optimal dosing interval for cidofovir.

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

“…78 The major adverse effect observed thus far for CDV is nephrotoxicity. 79 In the clinical setting, the very long intracellular half-life (448 hours) of CDV metabolites is advantageous since it allows infrequent dosing (i.e. every week or every 2 weeks).…”

Treatment of Cowpox Virus Respiratory Infections in Mice with Ribavirin as a Single Agent or Followed Sequentially by Cidofovir

“…Both ribavirin and cidofovir have side-effects that may limit their utility. The compounds have been extensively used in humans and have tolerable safety profiles when used to treat chronic infections caused by other unrelated viruses (Polis et al, 1995;Moradpour & Blum, 1999). Short-term treatments with these drugs should be sufficient to combat orthopoxvirus infections in immunocompetent individuals and limit potential toxicity.…”

“…Its main side-effect in humans is renal toxicity in some patients (Polis et al, 1995), which can be moderated by coadministration of probenecid. This drug is remarkably potent against vaccinia (Neyts et al, 1993) and cowpox virus infection in mice when given either subcutaneously or intraperitoneally.…”

Inhibition of Ganciclovir-Susceptible and -Resistant Human Cytomegalovirus Clinical Isolates by the Benzimidazole l -Riboside 1263W94

“…Organ transplant recipients suffer from retinitis, gastrointestinal disease, hepatitis, and pneumonia caused by HCMV infections, whereas AIDS patients suffer from HCMV-induced retinitis and other complications (1). The current Food and Drug Administration-approved chemotherapies for HCMV infections consist of ganciclovir, foscarnet, cidofovir, and fomivirsen (5,16,17,20). These antiviral drugs are effective against infections caused by HCMV; however, they are not ideal because of their toxicity and poor bioavailability.…”