Valganciclovir hydrochloride tablets are used for initial (induction) treatment and maintenance treatment (secondary prophylaxis) of cytomegalovirus (CMV) retinitis in adults with human immunodeficiency virus (HIV) infection, including those with acquired immunodeficiency syndrome (AIDS). The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) also recommend use of oral valganciclovir for treatment and secondary prophylaxis of CMV retinitis in HIV-infected older children and adolescents who can receive adult dosage. Safety and efficacy of oral valganciclovir have not been established for the treatment of congenital CMV disease.
The antiviral regimen used for initial treatment of CMV retinitis in HIV-infected patients should be selected based on the location and severity of CMV lesions, severity of underlying immunosuppression, concomitant drug therapy, and the patient's ability to adhere to the treatment regimen. Certain HIV specialists recommend use of oral valganciclovir in conjunction with an intraocular implant containing ganciclovir as the preferred regimen for initial treatment of CMV retinitis in HIV-infected adults or adolescents with immediate sight-threatening lesions (e.g., adjacent to the optic nerve or fovea), but state that oral valganciclovir may be adequate alone for the treatment of small peripheral lesions. CMV retinitis should be managed in consultation with an experienced ophthalmologist, and specialized references should be consulted for more specific information regarding initial treatment of CMV retinitis in HIV-infected individuals.
Because CMV disease is not cured with currently available antivirals, long-term suppressive or maintenance therapy (secondary prophylaxis) is recommended to prevent relapse in HIV-infected patients who have received initial treatment. The CDC, NIH, and IDSA state that the antiviral regimen used for secondary prophylaxis of CMV disease in HIV-infected individuals should be selected in consultation with a specialist. Although efficacy of valganciclovir as maintenance therapy has not been evaluated in comparative studies, use of the drug for this indication is supported by pharmacokinetic data in adults (i.e., the area under the concentration-time curve [AUC] for ganciclovir following oral administration of valganciclovir 900 mg daily is similar to that following IV administration of ganciclovir 5 mg/kg daily [the recommended IV dosage of ganciclovir for maintenance therapy of CMV retinitis in adults]).
Consideration can be given to discontinuing secondary prophylaxis against CMV in HIV-infected adults and adolescents with healed CMV retinitis who have had a sustained (e.g., 3-6 months) increase in CD4 T-cell counts to greater than 100/mm in response to antiretroviral therapy. The decision to discontinue such prophylaxis should be made in consultation with an ophthalmologist and in consideration of patient-specific factors (e.g., magnitude and duration of increase in CD4 T-cell count, anatomic location of retinal lesions, vision in the contralateral eye, feasibility of regular ophthalmologic monitoring). If secondary CMV prophylaxis is discontinued, the patient should continue to receive regular ophthalmologic monitoring (optimally every 3 months) to ensure early detection of CMV relapse or immune recovery uveitis. If CD4 T-cell counts decrease to less than 100/mm, secondary prophylaxis against CMV should be reinitiated.
In a randomized, open-label, comparative study (study WV15376) in HIV-infected adults (median age 39 years, baseline serum HIV-1 RNA levels of 4.9 log10, median CD4 T-cell count of 23/ mm, 91% male, 53% white, 31% Hispanic, 11% black) with previously untreated CMV retinitis, oral valganciclovir (900 mg twice daily for 21 days followed by 900 mg once daily for 7 days) was as effective as IV ganciclovir (5 mg/kg twice daily for 21 days followed by 5 mg/kg once daily for 7 days) in inhibiting CMV retinitis progression based on a masked evaluation of retinal photographs at week 4 of the study (the primary outcome measure).
All patients enrolled in study WV15376 received open-label valganciclovir after week 4; the median time to photographically determined first CMV retinitis progression in patients receiving induction therapy with oral valganciclovir or IV ganciclovir was 180 (mean: 226) or 126 (mean: 219) days, respectively.
Prevention of Cytomegalovirus Disease in Transplant Recipients
Valganciclovir hydrochloride tablets are used for prevention of CMV disease in adult kidney, heart, and kidney-pancreas transplant recipients considered at high risk for the disease (CMV-seronegative recipient of an organ from a CMV-seropositive donor).
Valganciclovir hydrochloride tablets or oral solution is used for prevention of CMV disease in pediatric kidney or heart transplant recipients 4 months to 16 years of age considered at high risk for the disease (CMV-seronegative recipient of an organ from a CMV-seropositive donor). Safety and efficacy have not been established for prevention of CMV disease in any other pediatric solid organ transplant recipients.
Based on poor clinical study results in adults (see Clinical Experience under Uses: Prevention of Cytomegalovirus Disease in Transplant Recipients), valganciclovir should not be used for prevention of CMV disease in adult or pediatric liver transplant recipients. In addition, safety and efficacy of the drug for prevention of CMV disease in other solid organ transplant recipients (e.g., lung transplant recipients) have not been established.
Safety and efficacy of valganciclovir for prevention of CMV disease in solid organ transplant recipients were evaluated in a double-blind, double-dummy, active comparator study (study PV16000) in heart, liver, kidney, and kidney-pancreas transplant patients at high risk (CMV-seronegative recipient of an organ from a CMV-seropositive donor). Patients were randomized to receive oral valganciclovir (900 mg once daily) or oral ganciclovir (1 g 3 times daily) initiated within 10 days of transplantation and continued until 100 days after transplantation. During the first 6 months following transplantation, 12% of those receiving valganciclovir and 15% of those receiving ganciclovir developed CMV disease (CMV syndrome and/or tissue-invasive disease). However, in liver transplant recipients, the incidence of CMV disease was greater in those receiving valganciclovir (19%) than in those receiving ganciclovir (12%); tissue-invasive CMV disease was reported most frequently.
Safety and efficacy of a longer duration (200 days) of valganciclovir prophylaxis against CMV disease were established in a double-blind, placebo-controlled trial in adult kidney transplant patients at high risk (CMV-seronegative recipient of an organ from a CMV-seropositive donor). Patients were randomized to receive valganciclovir prophylaxis (900 mg once daily) starting within 10 days of transplantation and continued for 200 days posttransplantation or for 100 days posttransplantation followed by placebo for 100 days. At 1 year posttransplantation, the incidence of CMV disease was about 17% in those who received 200 days of valganciclovir prophylaxis compared with 37% in those who received only 100 days of such prophylaxis. There was no overall difference in the safety profile between the 2 groups.
Safety and pharmacokinetics of oral valganciclovir in pediatric patients were established in an open-label study of 63 solid organ transplant (i.e., kidney, liver, heart, kidney and liver) recipients 4 months to 16 years of age. These pediatric patients received once-daily valganciclovir (tablets or oral solution) given in a dose calculated based on body surface area (BSA) and estimated creatinine clearance (modified Schwartz formula) and limited to a maximum dosage of 900 mg daily. Valganciclovir treatment was initiated within 2 days posttransplantation and was continued for a maximum of 100 days (median duration was approximately 92 days). Pharmacokinetics of valganciclovir in these pediatric solid organ transplant patients were comparable to that reported in adult solid organ transplant patients receiving the drug at a dosage of 900 mg once daily. Although CMV viremia was reported in 11% of patients in this study, CMV disease was not reported in any pediatric patient up to 26 weeks posttransplantation. Use of valganciclovir for the prevention of CMV disease in pediatric kidney or heart transplant recipients 4 months to 16 years of age at high risk for the disease is based on pharmacokinetic, safety, and efficacy data from this open-label study and efficacy extrapolated from a study in adults. Safety and efficacy have not been established for prevention of CMV disease in any other pediatric solid organ transplant recipients.