Cidofovir: a new therapy for cytomegalovirus retinitis

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, formerly known as HPMPC, is the first antiviral nucleotide analogue available for the treatment of cytomegalovirus (CMV) retinitis. Because cidofovir does not require viral activation, it has two advantages over nucleoside analogues such as ganciclovir and acyclovir. Cidofovir is active in uninfected cells and may act preemptively, and it may retain activity against ganciclovir-resistant strains. Preclinical studies showed the major toxicity of cidofovir to be dose-, schedule-, and species-dependent nephrotoxicity. These studies also showed that concomitant administration of probenecid protects animal models against cidofovir-induced nephrotoxicity. Two phase I-II studies were undertaken in HIV-positive patients with asymptomatic CMV excretion to evaluate several dose-escalation regimens. Data from both phase I-II studies showed that in patients receiving cidofovir at > or =3 mg/kg, the virologic response rate (> or =2 log reduction in CMV titer) was 93% for urine and 74% for semen. In addition, four treatment modifications were indicated to reduce the incidence of cidofovir-related nephrotoxicity: (a) dose reduction or interruption for changes in renal function; (b) concomitant administration of probenecid; (c) administration of 1 L of normal saline 1 h before infusion of cidofovir; and (d) extension of the dosing interval.