What is the recommended treatment and dosage of Valganciclovir (valganciclovir) for preventing and treating cytomegalovirus (CMV) infections in immunocompromised adults, such as those with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), organ transplant recipients, or patients undergoing chemotherapy, with impaired renal function?

Valganciclovir Treatment and Dosing for CMV in Immunocompromised Adults with Renal Impairment

For immunocompromised adults with impaired renal function, valganciclovir dosing must be adjusted based on creatinine clearance, with induction therapy at 900 mg twice daily (if CrCl ≥60 mL/min) for 21 days followed by maintenance at 900 mg once daily, but dose reductions are mandatory for CrCl <60 mL/min, and the drug cannot be recommended for patients on hemodialysis. 1

Dosing Algorithm Based on Renal Function

For Treatment of CMV Retinitis in HIV/AIDS Patients

Induction Phase (21 days):

• CrCl ≥60 mL/min: 900 mg (two 450 mg tablets) twice daily 1
• CrCl 40-59 mL/min: 450 mg twice daily 1
• CrCl 25-39 mL/min: 450 mg once daily 1
• CrCl 10-24 mL/min: 450 mg every 2 days 1
• CrCl <10 mL/min (hemodialysis): Not recommended - no dose can be given 1

Maintenance Phase (after induction):

• CrCl ≥60 mL/min: 900 mg once daily 1
• CrCl 40-59 mL/min: 450 mg once daily 1
• CrCl 25-39 mL/min: 450 mg every 2 days 1
• CrCl 10-24 mL/min: 450 mg twice weekly 1
• CrCl <10 mL/min (hemodialysis): Not recommended 1

For CMV Prophylaxis in Solid Organ Transplant Recipients

Kidney transplant patients: 900 mg once daily (adjusted for renal function per table above) starting within 10 days of transplantation until 200 days post-transplant 1

Heart or kidney-pancreas transplant patients: 900 mg once daily (adjusted for renal function) starting within 10 days of transplantation until 100 days post-transplant 1

Treatment Strategy by Clinical Presentation

CMV Retinitis in HIV/AIDS

For sight-threatening lesions (adjacent to optic nerve or fovea): The CDC recommends ganciclovir intraocular implant plus oral valganciclovir 900 mg twice daily as preferred initial therapy, as this combination is superior to systemic therapy alone for preventing relapse 2, 3

For small peripheral lesions: Oral valganciclovir 900 mg twice daily alone is adequate 2, 3

Duration: Continue treatment for initial 3-6 months until ART induces immune recovery (CD4+ count >100 cells/µL sustained for 3-6 months), as anti-CMV therapy decreases mortality even in patients with small peripheral lesions 2

CMV Colitis or Esophagitis

Initial approach: Start with IV ganciclovir 5 mg/kg twice daily for 3-5 days to rapidly achieve therapeutic levels 4

Transition criteria: Switch to oral valganciclovir 900 mg twice daily (adjusted for renal function) when clinical improvement is observed after 3-5 days AND adequate gastrointestinal absorption is assured (no significant GI symptoms impairing absorption) 4

Duration: Continue for 21-28 days or until signs and symptoms have resolved 2

CMV in Transplant Recipients (Treatment of Active Disease)

Hematopoietic cell transplant recipients: Valganciclovir is highly acceptable for pre-emptive therapy in the absence of substantial gastrointestinal GVHD (grades 3-4) 2

Solid organ transplant recipients: Valganciclovir is effective, but avoid in liver transplant patients with hepatic dysfunction, as hepatic dysfunction decreases cleavage of the valine ester, limiting conversion to active ganciclovir 2

Pre-emptive therapy approach: Weekly monitoring by PCR for CMV reactivation, and on confirmation of CMV viremia (PCR positivity in ≥2 consecutive samples 1 week apart), initiate valganciclovir 2

Critical Monitoring Requirements

Hematologic Monitoring

Frequency during treatment: Complete blood counts with differential and platelet counts should be performed twice weekly during induction, then weekly during maintenance 3, 1

Contraindications to initiation: Avoid valganciclovir if absolute neutrophil count <500 cells/µL, platelet count <25,000/µL, or hemoglobin <8 g/dL 1

Expected toxicities: Severe neutropenia, anemia, and thrombocytopenia occur frequently; cytopenia may occur at any time and may worsen with continued dosing 1

Renal Function Monitoring

Frequency: Serum creatinine levels or creatinine clearance should be monitored regularly (at least weekly) during treatment, with dose adjustments as renal function changes 1, 5

Hemodialysis consideration: Hemodialysis removes 50% of ganciclovir, but no safe dosing regimen exists for patients on hemodialysis 5

Virologic Monitoring

For transplant recipients: Weekly monitoring of CMV viral load by PCR or pp65 antigenemia 4

Treatment endpoint: Continue until CMV is no longer detectable by plasma NAT or pp65 antigenemia 4

For CMV retinitis: Dilated indirect ophthalmoscopy at diagnosis, after completion of induction, at 1 month, then monthly while on treatment 3

Administration Requirements

Food requirement: Valganciclovir tablets must be taken with food to optimize bioavailability (60% with food) 1, 6

Tablet integrity: Tablets should not be broken or crushed due to teratogenic and carcinogenic potential 1

Handling precautions: Handle according to guidelines for antineoplastic drugs; avoid direct contact with broken tablets on skin or mucous membranes 1

Common Pitfalls and How to Avoid Them

Switching to oral therapy too early: Do not transition from IV ganciclovir to oral valganciclovir before 3-5 days of IV therapy and documented clinical improvement, especially in patients with severe disease or questionable GI absorption 4

Inadequate dose adjustment in renal impairment: Ganciclovir clearance is highly correlated with creatinine clearance (r=0.975), making dose adjustment mandatory; failure to adjust leads to severe toxicity 5, 6

Use in liver transplant patients: Avoid valganciclovir in liver transplant patients with hepatic dysfunction, as bioabsorption occurs but conversion to active drug is impaired 2

Premature discontinuation: Do not stop therapy before viral clearance is documented or before immune recovery occurs (CD4+ >100 cells/µL for 3-6 months in HIV patients) 2, 4

Failure to monitor for neutropenia: Neutropenia is common (occurs in 33.9% of patients) and may require dose reduction or temporary discontinuation; monitor CBC twice weekly during induction 2, 1

Use in severe gastrointestinal GVHD: Valganciclovir should not be used in transplant patients with grades 3-4 gastrointestinal GVHD due to impaired absorption; use IV ganciclovir instead 2, 4

Ignoring drug interactions: Concomitant use with zidovudine increases risk of neutropenia and anemia; probenecid may increase ganciclovir levels and toxicity 1

Refractory or Resistant CMV

Definition of resistance: Continued presence or recurrence of CMV viremia after at least 1 week of antivirals 2

Alternative agent: For refractory or resistant CMV infections, maribavir 400 mg twice daily has shown superior viremia clearance (56% vs 24%, P<0.001) compared to other anti-CMV agents, with less acute kidney injury than foscarnet (8.5% vs 21.3%) and less neutropenia than valganciclovir/ganciclovir (9.4% vs 33.9%) 2