Agents to Treat Cytomegalovirus CMV Infections

AGENTS TO TREAT CYTOMEGALOVIRUS CMV INFECTIONS

CMV infections occur primarily in the setting of advanced immu-nosuppression and are typically due to reactivation of latent infec-tion. Dissemination of infection results in end-organ disease, including retinitis, colitis, esophagitis, central nervous system disease, and pneumonitis. Although the incidence in HIV-infected patients has markedly decreased with the advent of potent anti-retroviral therapy, clinical reactivation of CMV infection after organ transplantation is still prevalent.

The availability of oral valganciclovir and the ganciclovir intraoc-ular implant has decreased the use of intravenous ganciclovir, intra-venous foscarnet, and intravenous cidofovir for the treatment of end-organ CMV disease (Table 49–2). Oral valganciclovir has largely replaced oral ganciclovir because of its lower pill burden.

GANCICLOVIR

Ganciclovir is an acyclic guanosine analog (Figure 49–2) that requires activation by triphosphorylation before inhibiting the viral DNA polymerase. Initial phosphorylation is catalyzed by the virus-specified protein kinase phosphotransferase UL97 in CMV-infected cells. 

The activated compound competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation (Figure 49–3). Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, HHV-6, and HHV-8. Its activity against CMV is up to 100 times greater than that of acyclovir.

Ganciclovir may be administered intravenously, orally, or via intraocular implant. The bioavailability of oral ganciclovir is poor. Cerebrospinal fluid concentrations are approximately 50% of serum concentrations. The elimination half-life is 4 hours, and the intracellular half-life is prolonged at 16–24 hours. Clearance of the drug is linearly related to creatinine clearance. Ganciclovir is readily cleared by hemodialysis.

Intravenous ganciclovir has been shown to delay progression of CMV retinitis in patients with AIDS. Dual therapy with foscarnet and ganciclovir is more effective in delaying progression of retinitis than either drug alone (see Foscarnet), although adverse effects are compounded. Intravenous ganciclovir is also used to treat CMV colitis, esophagitis, and pneumonitis (the latter often treated with a combination of ganciclovir and intravenous cytomegalovirus immunoglobulin) in immunocompromised patients. Intravenous ganciclovir, followed by either oral ganciclovir or high-dose oral acyclovir, reduces the risk of CMV infection in transplant recipi-ents. Oral ganciclovir is indicated for prevention of end-organ CMV disease in AIDS patients and as maintenance therapy of CMV retinitis after induction. Although less effective than intrave-nous ganciclovir, the oral form carries a diminished risk of myelo-suppression and of catheter-related complications. The risk of Kaposi’s sarcoma is reduced in AIDS patients receiving long-term ganciclovir, presumably because of activity against HHV-8.

Ganciclovir may also be administered intraocularly to treat CMV retinitis, either by direct intravitreal injection or by intraoc-ular implant. The implant has been shown to delay progression of retinitis to a greater degree than systemic ganciclovir therapy. Surgical replacement of the implant is required at intervals of5–8 months. Concurrent therapy with a systemic anti-CMV agent is recommended to prevent other sites of end-organ CMV disease.

Resistance to ganciclovir increases with duration of usage. The more common mutation, in UL97, results in decreased levels of the triphosphorylated (ie, active) form of ganciclovir. The less common UL54 mutation in DNA polymerase results in higher levels of resistance and potential cross-resistance with cidofovir and foscarnet. Antiviral susceptibility testing is recommended in patients in whom resistance is suspected clinically, as is the substi-tution of alternative therapies and concomitant reduction in immunosuppressive therapies, if possible. The addition of CMV hyperimmune globulin may also be considered.

The most common adverse effect of systemic ganciclovir treat-ment, particularly after intravenous administration, is myelosup-pression. Myelosuppression may be additive in patients receiving concurrent zidovudine, azathioprine, or mycophenolate mofetil. Other potential adverse effects are nausea, diarrhea, fever, rash, headache, insomnia, and peripheral neuropathy. Central nervous system toxicity (confusion, seizures, psychiatric disturbance) and hepatotoxicity have been rarely reported. Ganciclovir is mutagenic in mammalian cells and carcinogenic and embryotoxic at high doses in animals and causes aspermatogenesis; the clinical signifi-cance of these preclinical data is unclear.

Levels of ganciclovir may rise in patients concurrently taking probenecid or trimethoprim. Concurrent use of ganciclovir with didanosine may result in increased levels of didanosine.

VALGANCICLOVIR

Valganciclovir is an L-valyl ester prodrug of ganciclovir that exists as a mixture of two diastereomers (Figure 49–2). After oral admin-istration, both diastereomers are rapidly hydrolyzed to ganciclovir by esterases in the intestinal wall and liver.

Valganciclovir is well absorbed and rapidly metabolized in the intestinal wall and liver to ganciclovir; no other metabolites have been detected. The bioavailability of oral valganciclovir is 60%; it is recommended that the drug be taken with food. The AUC_0–24h resulting from valganciclovir (900 mg once daily) is similar to thatafter 5 mg/kg once daily of intravenous ganciclovir and approxi-mately 1.65 times that of oral ganciclovir. The major route of elimination is renal, through glomerular filtration and active tubular secretion. Plasma concentrations of valganciclovir are reduced approximately 50% by hemodialysis.

Valganciclovir is indicated for the treatment of CMV retinitis in patients with AIDS and for the prevention of CMV disease in high-risk kidney, heart, and kidney-pancreas transplant patients. Adverse effects, drug interactions, and resistance patterns are the same as those associated with ganciclovir.

FOSCARNET

Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog (Figure 49–2) that inhibits herpesvirus DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly without requiring activation by phosphorylation. Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV-1, and HIV-2.

Foscarnet is available in an intravenous formulation only; poor oral bioavailability and gastrointestinal intolerance preclude oral use. Cerebrospinal fluid concentrations are 43–67% of steady-state serum concentrations. Although the mean plasma half-life is 3–7 hours, up to 30% of foscarnet may be deposited in bone, with a half-life of several months. The clinical repercussions of this are unknown. Clearance of foscarnet is primarily renal and is directly proportional to creatinine clearance. Serum drug concentrations are reduced approximately 50% by hemodialysis.

Foscarnet is effective in the treatment of CMV retinitis, CMV colitis, CMV esophagitis, acyclovir-resistant HSV infection, and acyclovir-resistant VZV infection. The dosage of foscarnet must be titrated according to the patient’s calculated creatinine clear-ance before each infusion. Use of an infusion pump to control the rate of infusion is important to prevent toxicity, and large volumes of fluid are required because of the drug’s poor solubility. The combination of ganciclovir and foscarnet is synergistic in vitro against CMV and has been shown to be superior to either agent alone in delaying progression of retinitis; however, toxicity is also increased when these agents are administered concurrently. As with ganciclovir, a decrease in the incidence of Kaposi’s sarcoma has been observed in patients who have received long-term foscarnet.

Foscarnet has been administered intravitreally for the treat-ment of CMV retinitis in patients with AIDS, but data regarding efficacy and safety are incomplete.

Resistance to foscarnet in HSV and CMV isolates is due to point mutations in the DNA polymerase gene and is typically associated with prolonged or repeated exposure to the drug.

Mutations in the HIV-1 reverse transcriptase gene have also been described. Although foscarnet-resistant CMV isolates are typically cross-resistant to ganciclovir, foscarnet activity is usually main-tained against ganciclovir- and cidofovir-resistant isolates of CMV.

Potential adverse effects of foscarnet include renal impairment, hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, and hypomagnesemia. Saline preloading helps prevent nephrotox-icity, as does avoidance of concomitant administration of drugs with nephrotoxic potential (eg, amphotericin B, pentamidine, aminoglycosides). The risk of severe hypocalcemia, caused by chelation of divalent cations, is increased with concomitant use of pentamidine. Genital ulcerations associated with foscarnet therapy may be due to high levels of ionized drug in the urine. Nausea, vomiting, anemia, elevation of liver enzymes, and fatigue have been reported; the risk of anemia may be additive in patients receiving concurrent zidovudine. Central nervous system toxicity includes headache, hallucinations, and seizures; the risk of seizures may be increased with concurrent use of imipenem. Foscarnet caused chromosomal damage in preclinical studies.

CIDOFOVIR

Cidofovir (Figure 49–2) is a cytosine nucleotide analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses, and human papillomavirus. In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes (Figure 49–3); thus activity is maintained against thymidine kinase-deficient or -altered strains of CMV or HSV. Cidofovir diphosphate acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain. Cidofovir-resistant isolates tend to be cross-resistant with ganciclovir but retain susceptibility to foscarnet.

Although the terminal half-life of cidofovir is approximately 2.6 hours, the active metabolite cidofovir diphosphate, has a pro-longed intracellular half-life of 17–65 hours, thus allowing infre-quent dosing. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Cerebrospinal fluid penetration is poor. Elimination is by active renal tubular secretion. High-flux hemo-dialysis reduces serum levels of cidofovir by approximately 75%.

Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus, human papillomavirus, and poxvirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Before each infusion, cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity.

The primary adverse effect of intravenous cidofovir is a dose-dependent proximal tubular nephrotoxicity, which may be reduced with prehydration using normal saline. Proteinuria, azotemia, metabolic acidosis, and Fanconi’s syndrome may occur. Concurrent administration of other potentially nephrotoxic agents (eg, ampho-tericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, pentamidine, foscarnet) should be avoided. Prior administration of foscarnet may increase the risk of nephrotoxicity. Other poten-tial adverse effects include uveitis, ocular hypotony, and neutrope-nia (15–24%). Concurrent probenecid use may result in other toxicities or drug-drug interactions . Cidofovir is mutagenic, gonadotoxic, and embryotoxic, and caused mammary adenocarcinomas in rats.