Valganciclovir for the prevention and treatment of cytomegalovirus disease in immunocompromised hosts

References

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• •This open-label randomized study demonstrated the comparable efficacy of oral and intravenous ganciclovir as maintenance treatment for cytomegalovirus (CMV) retinitis in patients with AIDS. The mean time-to-progression of CMV retinitis was not significantly different between those who received maintenance therapy and those who were treated with oral or intravenous ganciclovir.
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• •Prospective, randomized, double—blind, placebo controlled study of HIV and CMV-coinfected people with a CD4+ lymphocyte counts of 50/mm3 (or 100/mm3 in those with a history of an AIDS defining opporunistic infection) established the efficacy of oral ganciclovir prophylaxis for the primary prevention of CMV disease, including retinitis in high-risk patients with AIDS. Compared to patients who received placebo, the risk of CMV disease among patients on oral ganciclovir prophylaxis was reduced by about 50%.
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• •Largest prospective study that established the efficacy and safety of oral ganciclovir prophylaxis for the prevention of CMV disease in solid organ transplant patients. In this multicenter, randomized, placebo-controlled trial, prophylaxis with oral ganciclovir significantly reduced the incidence of CMV disease in liver transplant patients from 19 to 5%.
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• •Prospective, randomized, placebo-controlled study demonstrates that oral ganciclovir, when administered preemptively to liver transplant patients upon the detection of asymptomatic CMV DNAemia, is effective in preventing the progression of subclinical CMV replication to CMV disease.
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• ••Study of 28 liver transplant recipientsdemonstrates that oral administration of valganciclovir results in a ten fold higher bioavailability of ganciclovir compared with oral ganciclovir. It also demonstrates that the systemic exposure to ganciclovir after 450 mg once daily of valganciclovir was comparable to standard dose of oral ganciclovir, and that the systemic exposure to ganciclovir after 900 mg once daily of valganciclovir was comparable to that of intravenous ganciclovir, at a dose of 5 mg/kg daily. This exploratory pharmacokinetic study served as the basis for the dose of valganciclovir that was utilized in the Phase III prophylactic trialin high-risk solid organ transplant patients.
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• •This viral kinetics study illustrates the limitation of oral ganciclovir as preemptive therapy for the prevention of CMV disease in high-risk patients with high levels of CMV replication. In patients with high CMV load, viral replication persisted during oral ganciclovir therapy and resulted in breakthrough CMV disease.
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• •This open-label, four way cross-over, dose-ranging pharmacokinetic study involving 39 HIV-infected patients indicated that valganciclovir, at a dose of 900 mg once daily, is expected to produce a daily ganciclovir exposure that is comparable to that following intravenous ganciclovir, at a dose of 5 mg/kg daily. Consequently, the 900-mg dose was used in the efficacy trials of valganciclovir in patients with AIDS (and also in solid organ transplant recipients).
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• •The structural modifications of ganciclovir, which led to the novel formulation valganciclovir, resulted in the ten fold higher bioavailability of ganciclovir after oral valganciclovir administration. In this in vitro study, the investigators demonstrated that the high bioavailability is due to the high affinity of valganciclovir to the intestinal peptide transporter PEPT1. In Caco-2 cells, the PEPT1-mediated transport of glycylsarcosine was reduced by valganciclovir through competitive inhibition.
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• ••This is the landmark study thatestablished the efficacy and safety of valganciclovir for the prevention of CMV disease in high-risk solid organ transplant patients. In this randomized, double-blind, active comparator-controlled study of 372 high-risk CMV D+/R-liver, kidney, heart, and kidney-pancreas transplant patients, valganciclovir, at a dose of 900 mg once daily, was non-inferior to oral ganciclovir, at a dose of 1 g three times daily, in preventing CMV infection and disease. The results of this study led to the approval of valganciclovir as prophylaxis for the prevention of CMV disease in CMV D+/R-kidney, heart and pancreas transplant patients.
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• ••This landmark trial, which was arandomized, nonblinded study of 160 patients with AIDS, demonstrated that oral valganciclovir, at a dose of 900 mg twice daily for 3 weeks followed by 900 mg once daily, was equally as effective in the treatment of newly diagnosed CMV retinitis as intravenous ganciclovir, at a standard induction dose of 5 mg/kg every 12 hours for 3 weeks followed by daily maintenance dose of 5 mg/kg. The results of this study led to the approval of valganciclovir for the induction and maintenance treatment of CMV retinitis in patients with AIDS.
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• ••This observational cohort of 212 HIV-infected patients with "treated" CMV retinitis who were followed for median maintenance treatment duration of 372 days demonstrated, the comparable safety of valganciclovir, intravenous ganciclovir, and oral ganciclovir as maintenance therapy for CMV retinitis. The most common adverse event rates were diarrhea, nausea, fever, neutropenia, and anemia.
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