Antiviral Therapy (5): Cidofovir
Mechanism of Action:
Cidofovir inhibits viral DNA synthesis. Cidofovir is metabolized intracellularly to its active diphosphate form by cellular enzymes, and the levels of phosphorylated metabolites are similar in infected and uninfected cells. The diphosphate acts both as a competitive inhibitor with respect to dCTP and as an alternative substrate for viral DNA polymerase. Incorporation of cidofovir slows chain elongation and abrogates it if two consecutive cidofovir molecules are introduced. The diphosphate has a prolonged intracellular half-life, averaging 17 to 65 hours depending on the cell type, and it competitively inhibits CMV and HSV DNA polymerase at concentrations 8- to 600-fold lower than those inhibitory for human DNA polymerases. An adduct with prolonged intracellular half-life (>2 days) may serve as a reservoir of drug. Alkoxyalkyl ester prodrugs of cidofovir have enhanced cellular uptake, are more potent poxvirus inhibitors than the parent, are well absorbed orally, and are not renally concentrated.
Resistance Mechanisms:
Resistance to cidofovir selected by in vitro passage of CMV, poxviruses, and adenovirus relates to point mutations in viral DNA polymerase. Highly gancyclovir-resistant clinical isolates of CMV that possess UL54 mutations show cross-resistance to cidofovir in vitro with 8- to 16-fold reductions in inhibitory concentrations. Foscarnet-resistant CMV and HSV isolates may retain susceptibility to cidofovir, but multidrug-resistant CMV variants with DNA polymerase mutations occur. The development of resistance to cidofovir as a result of cidofovir therapy appears to be uncommon and low level (less than eightfold change in susceptibility). In patients with CMV retinitis, reduced cidofovir susceptibility has been detected in about 5% before treatment and in 29% by 3 months of therapy. Poxviruses selected for resistance to cidofovir in vitro (8- to 27-fold reduced susceptibility) appear less virulent than wild-type viruses but are resistant to cidofovir in vivo.
Clinical Indications:
Intravenous cidofovir has been used to treat acyclovir- or foscarnet-resistant mucocutaneous HSV infection. Early treatment is often effective in controlling invasive adenoviral infections of transplant recipients, although altered dosage schedules (e.g., 1 mg/kg thrice weekly) may be needed to reduce nephrotoxicity. Low dosages (0.25 to 1.0 mg/kg every 2 to 3 weeks, without probenecid) have been used in treating refractory BK virus-associated nephropathy in renal transplant patients. The addition of intravenous cidofovir to highly active antiretroviral therapy (HAART) has inconsistent effects on neurologic outcomes and survival in HIV-associated progressive multifocal leukoencephalopathy. Cidofovir did not reduce human herpesvirus (HHV)-8 viral load in peripheral blood mononuclear cells or prevent progression in Kaposi's sarcoma in one small trial.
Topical cidofovir gel formulated in polyethylene glycol reduces pain, virus shedding, and lesion healing time in HIV-infected patients with acyclovir-resistant mucocutaneous HSV infections. Intralesional cidofovir induces remissions in respiratory papillomatosis, and topical cidofovir has been used for the treatment of recurrent genital herpes, anogenital warts, refractory condyloma in HIV-infected persons, and the orf poxvirus lesion. Topical and intravenous preparations have been used in recalcitrant molluscum contagiosum in immunosuppressed patients. Intravitreal cidofovir injection may be effective for treatment of CMV retinitis but is contraindicated because of toxicity. A 1% ophthalmic solution reduced the risk for corneal opacities in adenoviral keratoconjunctivitis but was associated with severe, dose-dependent local toxicity.
Toxicity:
Dose-related nephrotoxicity is the principal side effect of intravenous cidofovir. It is characterized by proximal tubular dysfunction including proteinuria, ureaemia, glycosuria, metabolic acidosis, and, uncommonly, Fanconi's syndrome.
Nephrotoxicity appears as a result of a cidofovir-avid renal organic anion transport protein that causes drug accumulation in the renal cortex. Concomitant oral probenecid & cidofovir is relatively contraindicated in those with CrCl <55 mL/min or with significant proteinuria (2+). Dosage reductions (3 mg/kg) are indicated for minor rises in serum creatinine (0.3 to 0.4 mg/dL), and cessation of administration for greater creatinine rises or development of proteinuria of 3+ or higher. and vigorous saline prehydration reduce, whereas prior foscarnet therapy and concurrent use of other nephrotoxic agents increase, the risk for renal toxicity. On maintenance dosing (5 mg/kg every other week), approximately 12% to 39% of patients develop proteinuria and 15% to 24% have elevated serum creatinine. Severe nephrotoxicity requiring dialysis sometimes occurs.
Initiation of neutropaenia develops in approximately 24%, and regular monitoring of neutrophil counts is necessary. Fever, nausea, vomiting, diarrhoea, headache, rash, iritis, uveitis, and ocular hypotony may occur during combined therapy with cidofovir and probenecid. Maintenance is withdrawn in approximately 25% to 35% of patients with AIDS because of intolerance. Mucosal application is associated with dose-related application site reactions (burning, pain, pruritus) in up to one third of patients, and occasionally with ulceration, but no evidence of systemic toxicity has been reported.
Intravitreal cidofovir may cause iritis, vitreitis, reduced intraocular pressure, and visual loss. Conjunctival application causes local irritation; persistent epiphora related to lacrimal canalicular blockade has developed in some patients. Preclinical studies indicate that cidofovir has mutagenic, gonadotoxic, embryotoxic, and teratogenic effects. Because cidofovir causes carcinomas in rats, this agent is considered a potential human carcinogen. Safety during pregnancy is uncertain, and it is classified in pregnancy category C.
AMH.
