Why is this patient experiencing recurrent Cytomegalovirus (CMV) infections and would introducing vedolizumab be beneficial, how to manage CMV resistance in this case?

Management of Recurrent CMV Infection and Treatment of Resistance

For patients with recurrent CMV infection, tapering steroids and considering vedolizumab is recommended, while ganciclovir-resistant CMV should be treated with foscarnet along with careful monitoring of renal function and electrolytes. 1

Causes of Recurrent CMV Infection

• Recurrent CMV infections are commonly associated with immunosuppressive therapy, particularly corticosteroids and azathioprine, which are independent predictive factors for CMV reactivation in the colon 1
• T-cell exhaustion, which occurs in chronic infections and certain disease states, contributes to impaired immune control of CMV, allowing for viral reactivation 1
• Inadequate duration of initial antiviral therapy or suboptimal dosing may lead to incomplete viral suppression and subsequent recurrence 2
• Exposure to less than fully therapeutic levels of ganciclovir (oral or intermittent IV) is commonly associated with development of resistance 3

Role of Vedolizumab in CMV Infection

• Vedolizumab may be considered for treatment of steroid-resistant colitis with CMV reactivation, as suggested by case reports, although its efficacy has not been demonstrated in large cohorts 1
• Vedolizumab has gut-selective mechanism of action that may provide a safer immunosuppressive option compared to systemic immunosuppressants in patients with opportunistic infections 4
• Unlike thiopurines or corticosteroids, vedolizumab is considered to have a lower risk of CMV reactivation, making it potentially beneficial for patients with recurrent CMV infection 1
• Vedolizumab can be maintained for control of IBD disease activity even in the presence of CMV infection 1

Management of CMV Resistance

Diagnosis of Resistance

• Persistent viral shedding or progressive CMV disease after several weeks of antiviral therapy suggests drug resistance, though laboratory confirmation is required 5
• Genotypic assays for specific mutations in the viral UL97 phosphotransferase or UL54 DNA polymerase genes can be used to detect resistance and predict cross-resistance to other drugs 5

Treatment of Ganciclovir-Resistant CMV

• Foscarnet is the treatment of choice for ganciclovir-resistant CMV infection 1, 3
• When administering foscarnet, strict monitoring of renal function and bivalent electrolytes is required 1
• Concomitant administration of normal saline may reduce the risk of irreversible renal damage 1
• High levels of foscarnet are excreted in the urine and may cause significant irritation and ulceration in the genital area; careful hygiene can mitigate this risk 1
• In some cases, cidofovir may be used as an alternative for ganciclovir-resistant CMV, though it also carries significant nephrotoxicity 2

Optimizing Treatment Approach

• Intravenous ganciclovir 5 mg/kg twice daily for 5-10 days, followed by valganciclovir 900 mg daily until completion of a 2-3 week course, is the standard treatment for initial CMV infection 1
• For recurrent infection, tapering steroids is recommended as they are a significant risk factor for CMV reactivation 1
• Immunosuppressive therapy may need to be continued for control of underlying IBD, as many case series have shown that immunosuppressants can be maintained while treating CMV infection 1
• CMV clearance may parallel the achievement of remission induced by immunosuppressants, even without antivirals, particularly in patients with low viral load 1
• In cases of severe disseminated CMV infection (characterized by mononucleosis-like syndrome with fever, malaise, leukopenia, thrombocytopenia, and elevated liver enzymes), discontinuation of immunosuppressive therapy is recommended 1

Prevention of Future Recurrences

• Optimization of host immunity by reducing overall immunosuppression when possible 5
• Use of potent antiviral drug regimens at adequate doses to fully suppress viral replication 5
• Adherence to proper dosing regimens to maintain therapeutic drug levels 5
• Regular monitoring for early signs of recurrence, particularly in high-risk patients 1

Common Pitfalls and Caveats

• Ganciclovir-resistant CMV is associated with high mortality even with foscarnet therapy, particularly in CMV D+/R- transplant recipients 3
• The common side effects of ganciclovir (neutropenia and thrombocytopenia) can complicate management as they are also manifestations of systemic CMV infection 1
• Delayed recognition of drug resistance can lead to progression of disease and worse outcomes 2
• Maintaining therapeutic drug levels is crucial, as subtherapeutic exposure is a major risk factor for developing resistance 3