title: 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 microliters (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 < or = 1.5 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.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Polis
authors.forename: K M
authors.initials: KM
authors.lastname: Spooner
authors.forename: B F
authors.initials: BF
authors.lastname: Baird
authors.forename: J F
authors.initials: JF
authors.lastname: Manischewitz
authors.forename: H S
authors.initials: HS
authors.lastname: Jaffe
authors.forename: P E
authors.initials: PE
authors.lastname: Fisher
authors.forename: J
authors.initials: J
authors.lastname: Falloon
authors.forename: R T
authors.initials: RT
authors.lastname: Davey
authors.forename: J A
authors.initials: JA
authors.lastname: Kovacs
authors.forename: R E
authors.initials: RE
authors.lastname: Walker
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D000077404:Cidofovir; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014556:Urine / Q000382:microbiology
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir