What is the treatment for severe Cytomegalovirus (CMV) infection?

Treatment of Severe Cytomegalovirus (CMV) Infection

For severe CMV infection, initiate combination therapy with intravenous ganciclovir 5 mg/kg every 12 hours plus foscarnet 60 mg/kg every 8 hours (or 90 mg/kg every 12 hours) for 3 weeks, followed by maintenance therapy, as this regimen has demonstrated improvement or stabilization in 74% of patients with CMV encephalitis or myelitis. 1

Initial Treatment Approach

Combination Therapy (Preferred for Severe Disease)

• Ganciclovir 5 mg/kg IV every 12 hours PLUS foscarnet 60 mg/kg IV every 8 hours (or 90 mg/kg every 12 hours) for 3 weeks is the recommended regimen for severe CMV disease, particularly CNS involvement, as monotherapy with either agent has not improved survival 1

• This combination approach led to success in HIV-infected patients with improvement or stabilization in 74% of 31 patients with either CMV encephalitis or myelitis 1

• Following the 3-week induction period, transition to maintenance therapy to prevent relapse 1

Monotherapy Options (For Less Severe Disease)

• Ganciclovir 5 mg/kg IV every 12 hours for 2-3 weeks can be used as monotherapy for severe CMV infections outside the CNS, though therapeutic failures are common 1

• After 3-5 days of IV ganciclovir with clinical improvement, transition to oral valganciclovir 900 mg twice daily to complete the 2-3 week course 1, 2

• Foscarnet 60 mg/kg IV every 8 hours for 2-3 weeks is an alternative first-line agent, particularly when ganciclovir cannot be tolerated due to myelosuppression 1

Critical Treatment Considerations

Immunosuppression Management

• Discontinue or reduce immunosuppressive therapy whenever possible, as CMV encephalitis almost always develops in the context of profound suppression of cell-mediated immunity 1

• Prompt antiviral treatment combined with discontinuation of immunosuppressants is associated with clinical improvement and decreased mortality 1

CNS Penetration Issues

• Effective concentrations of ganciclovir and foscarnet may be difficult to achieve in the CSF, which is why combination therapy is preferred for CNS disease 1

• Drug resistance can develop even with combination therapy in severely immunocompromised patients (e.g., bone marrow transplant recipients) 1

Alternative and Second-Line Agents

• Cidofovir is not recommended for CNS disease because its ability to penetrate the blood-brain barrier is poorly studied 1

• Cidofovir may be considered as a third-line agent for non-CNS severe disease, though it carries substantial risk of nephrotoxicity 1

• Letermovir 480 mg/day orally or IV (or 240 mg/day with concurrent ciclosporin) is approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients but not for treatment of active severe disease 1

Monitoring Requirements

During Treatment

• Monitor renal function closely, especially with foscarnet or cidofovir, as foscarnet causes decreased renal function in up to 30% of patients 1

• Monitor for hematologic toxicity with ganciclovir, including severe leukopenia, neutropenia, anemia, and thrombocytopenia 3

• Foscarnet infusion should be administered slowly over 2 hours (no faster than 1 mg/kg/minute) with saline fluid loading to minimize renal toxicity 1

• Monitor electrolytes with foscarnet, as it binds to divalent metal ions causing metabolic abnormalities (calcium, phosphorus, magnesium, potassium) in approximately one-third of patients 1

Response Assessment

• Weekly CMV viral load by PCR is essential to assess treatment response 4

• Continue treatment until CMV is no longer detected in blood by PCR 4

Maintenance Therapy

• Maintenance therapy is required following induction to prevent relapse, particularly in patients who remain immunocompromised 1

• Options for chronic suppression include oral valganciclovir, parenteral ganciclovir, or parenteral foscarnet 1

• In HIV-infected patients with CD4+ counts <50 cells/µL, lifelong maintenance therapy is recommended unless immune reconstitution occurs 1

Common Pitfalls to Avoid

Dosing Errors

• Do not use standard dosing in renal impairment—dose reduction is mandatory when administering valganciclovir to patients with renal impairment 3

• For patients on hemodialysis (CrCl <10 mL/min), valganciclovir tablets should not be used; use IV ganciclovir with appropriate dose reduction instead 3

Premature Discontinuation

• Do not stop therapy prematurely—therapeutic failures are common with ganciclovir monotherapy, and even prophylaxis at maintenance doses does not guarantee protection against CMV encephalitis 1

• Maintenance therapy should continue until adequate immune function recovery occurs 1

Drug Resistance

• Be aware that rapid emergence of resistant mutants can occur with letermovir when treatment is interrupted, underdosed, or in patients with other risk factors 1

• Ganciclovir-resistant CMV strains can emerge with long-term therapy 1

Special Populations

HIV-Infected Patients

• In HIV-infected infants with CMV encephalitis, combination ganciclovir and foscarnet along with HAART has shown efficacy in some patients 1

• Maintenance therapy can be discontinued in patients whose CD4+ counts have increased to >100-150 cells/µL and whose HIV plasma RNA levels have been suppressed in response to HAART for >3-6 months 1

Pediatric Patients

• For pediatric patients, ganciclovir 5 mg/kg IV every 12 hours is the drug of choice for initial treatment of disseminated CMV disease 1

• Foscarnet 60 mg/kg IV every 8 hours is an alternative for pediatric patients with ganciclovir-resistant CMV infections 1

Toxicity Management

Hematologic Toxicity

• Dose reduction or interruption may be necessary in up to 40% of patients due to hematologic toxicity 1

• Granulocyte colony-stimulating factor (G-CSF) can be used to ameliorate marrow suppression 1

Renal Toxicity

• Adequate hydration should be maintained throughout treatment 3

• Dose modifications are required for elevated serum creatinine 1