Cidofovir: An overview
- Martin Rodriguez, MD
Martin Rodriguez, MD
- Professor of Medicine
- University of Alabama at Birmingham
- Kimon C Zachary, MD
Kimon C Zachary, MD
- Assistant Professor of Medicine
- Harvard Medical School
Cidofovir was the first nucleotide analogue approved for clinical use. The drug has been employed almost exclusively to treat cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS). However, cidofovir is also used as a therapeutic option against other viral infections. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis".)
MECHANISM OF ACTION
Cidofovir is a monophosphate nucleotide analogue. After undergoing cellular phosphorylation to its diphosphate form, it competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA by viral DNA polymerase. Incorporation of the drug disrupts further chain elongation . Unlike nucleoside analogues such as acyclovir or ganciclovir, cidofovir is not phosphorylated (and hence activated) by a viral kinase.
SPECTRUM OF ACTIVITY
Cidofovir demonstrates in vitro activity against a number of DNA viruses, including the herpesviruses, adenovirus, polyomavirus, papillomavirus, and poxvirus . Cidofovir also retains activity against thymidine kinase-negative herpes simplex virus (HSV) and UL97 phosphotransferase-negative CMV, which are mutant viruses resistant to acyclovir and ganciclovir. Clinical efficacy has been demonstrated rigorously only against CMV. Its clinical utility in infections caused by other viral pathogens remains to be determined [1,2].
MECHANISM OF RESISTANCE
Reduced susceptibility of CMV to cidofovir has been associated with mutations in the viral DNA polymerase gene [3,4]. Since its mechanism of action does not require phosphorylation, cidofovir is unaffected by mutations in CMV phosphotransferase which confer resistance to ganciclovir. However, prolonged therapy with ganciclovir in patients with CMV retinitis has been associated with the emergence of viral DNA polymerase mutations which confer cross resistance to cidofovir [4-8].
Administration of a single dose of cidofovir (3 to 5 mg/kg IV) yields peak plasma concentrations of 7.3 to 11.5 mg/L. Over 80 percent of the drug is excreted unchanged in the urine within 24 hours, with a half-life of 2.4 to 3.2 hours . However, cidofovir diphosphate, an active metabolite is eliminated more slowly with first and second phase intracellular half-lives of 24 and 65 hours, respectively . This property permits the drug to be dosed every two weeks.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Lea AP, Bryson HM. Cidofovir. Drugs 1996; 52:225.
- De Clercq E. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev 2003; 16:569.
- Cherrington JM, Fuller MD, Lamy PD, et al. In vitro antiviral susceptibilities of isolates from cytomegalovirus retinitis patients receiving first- or second-line cidofovir therapy: relationship to clinical outcome. J Infect Dis 1998; 178:1821.
- Erice A, Gil-Roda C, Pérez JL, et al. Antiviral susceptibilities and analysis of UL97 and DNA polymerase sequences of clinical cytomegalovirus isolates from immunocompromised patients. J Infect Dis 1997; 175:1087.
- Chou S, Marousek G, Guentzel S, et al. Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease. J Infect Dis 1997; 176:786.
- Piret J, Boivin G. Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management. Antimicrob Agents Chemother 2011; 55:459.
- Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 2010; 23:689.
- Drew WL. Cytomegalovirus resistance testing: pitfalls and problems for the clinician. Clin Infect Dis 2010; 50:733.
- VISTIDE prescribing information. Gilead Sciences, Inc., 1996.
- Vittecoq D, Dumitrescu L, Beaufils H, Deray G. Fanconi syndrome associated with cidofovir therapy. Antimicrob Agents Chemother 1997; 41:1846.
- Marty FM, Winston DJ, Rowley SD, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med 2013; 369:1227.
- Vandercam B, Moreau M, Goffin E, et al. Cidofovir-induced end-stage renal failure. Clin Infect Dis 1999; 29:948.
- Meier P, Dautheville-Guibal S, Ronco PM, Rossert J. Cidofovir-induced end-stage renal failure. Nephrol Dial Transplant 2002; 17:148.
- Naiman AN, Roger G, Gagnieu MC, et al. Cidofovir plasma assays after local injection in respiratory papillomatosis. Laryngoscope 2004; 114:1151.
- Bienvenu B, Martinez F, Devergie A, et al. Topical use of cidofovir induced acute renal failure. Transplantation 2002; 73:661.
- Davis JL, Taskintuna I, Freeman WR, et al. Iritis and hypotony after treatment with intravenous cidofovir for cytomegalovirus retinitis. Arch Ophthalmol 1997; 115:733.
- Friedberg DN. Hypotony and visual loss with intravenous cidofovir treatment of cytomegalovirus retinitis. Arch Ophthalmol 1997; 115:801.