What is the recommended treatment for Epstein Barr virus (EBV) infection?

Treatment of Epstein-Barr Virus (EBV) Infection

For immunocompetent patients with uncomplicated EBV infection, supportive care alone is the recommended treatment, while high-risk immunocompromised patients require rituximab-based therapy for EBV-related complications such as post-transplant lymphoproliferative disorders (PTLD). 1, 2

Immunocompetent Patients with Uncomplicated EBV Infection

Supportive care is the cornerstone of management for typical infectious mononucleosis and uncomplicated primary EBV infection. 1, 2 This approach focuses on:

• Symptom relief, adequate hydration, and rest until the self-limiting infection resolves 1
• No antiviral therapy should be prescribed—acyclovir and other antivirals are completely ineffective against EBV and should not be used 1, 3

The evidence is clear that while acyclovir can transiently suppress oropharyngeal EBV replication, it produces minimal clinical benefit in infectious mononucleosis. 4 Even combination therapy with acyclovir and prednisolone showed only modest effects on pharyngeal symptoms and fever, without addressing the underlying disease course. 4

High-Risk Immunocompromised Patients

Pre-Transplant Risk Stratification

All allogeneic hematopoietic stem cell transplant (HSCT) patients and donors must be tested for EBV antibodies before transplantation. 5, 1, 2 High-risk features include:

• T-cell depletion (in vivo or ex vivo) 5
• EBV serology donor/recipient mismatch 5
• Cord blood transplantation 5
• HLA mismatch 5
• Severe acute or chronic GvHD requiring intensive immunosuppression 5

Monitoring Strategy

High-risk patients require prospective monitoring of EBV DNA-emia by quantitative PCR for at least 4 months post-transplant. 1, 2, 3 However:

• HLA-identical family transplant recipients without T-cell depletion and without GvHD do not require routine EBV screening 5
• Auto-HSCT patients and conventional chemotherapy patients should not be routinely monitored for EBV 5

Prophylactic Approaches

EBV-specific cytotoxic T lymphocytes (CTLs) should be considered as first-line prophylactic treatment when available. 1, 3 Alternatively:

• Prophylactic rituximab (B-cell depletion) might reduce the risk of EBV DNA-emia 1, 2
• However, prophylactic rituximab has not shown statistically significant impact on PTLD incidence, treatment-related mortality, or overall survival compared to pre-emptive approaches 5
• Rituximab after allo-HSCT carries increased risk of life-threatening cytopenias and bacterial infections 5

Pre-emptive Therapy for EBV DNA-emia

Significant EBV DNA-emia without clinical symptoms warrants pre-emptive therapy with rituximab. 1, 2, 3 The regimen is:

• Rituximab 375 mg/m² once weekly (1-4 doses) until EBV DNA-emia negativity 1, 2, 3

Important caveat: Additional doses beyond 4 doses might result in down-regulation of CD20 expression and decreased efficacy. 1, 3

Treatment of EBV-PTLD

Rituximab (375 mg/m²) administered once weekly is the treatment of choice for EBV-PTLD, achieving positive outcomes in approximately 70% of patients. 1, 2, 3 The treatment algorithm is:

1. Reduction of immunosuppressive therapy should always be combined with rituximab when possible 1, 2, 3
2. Administer rituximab 375 mg/m² once weekly for 1-4 doses 1, 2, 3
3. Consider cellular therapy with donor or third-party EBV-specific CTLs if available 1, 3

Critical pitfall: Reduction of immunosuppression alone is rarely successful for PTLD following HSCT and may increase risk of rejection or GvHD. 1, 3 This approach should not be used as monotherapy. 1, 3

CNS EBV-PTLD

CNS localization of EBV-PTLD requires special consideration due to risk of neurocognitive dysfunction. 1 Therapeutic options include:

• Rituximab ± chemotherapy based on primary CNS lymphoma protocols 1
• Systemic or intrathecal rituximab monotherapy 1
• T-cell therapy with EBV-specific CTLs 1
• Radiotherapy may be considered 1

Chronic Active EBV Infection (CAEBV)

For chronic active EBV infection, allogeneic hematopoietic stem cell transplantation is the only curative option. 3, 6 Without HSCT, patients with CAEBV die within several years. 6

• Manifestations are often self-limiting with supportive care or prednisolone and cyclosporine A with or without etoposide 6
• Earlier initiation and completion of treatment without watchful waiting maximizes survival rates 6
• Patients with uncontrolled active disease have only 16.7% 3-year overall survival 6

Late-Onset EBV-Negative B-PTLD

EBV-negative B-PTLD presenting late (>5 years) after transplant should be regarded as malignant lymphoma, not PTLD, and treated with appropriate chemotherapy protocols. 1, 3

Key Clinical Pitfalls to Avoid

• Never prescribe antivirals (acyclovir, valacyclovir, ganciclovir) for EBV—they are completely ineffective against latent or active EBV 1, 3
• Do not use unselected donor lymphocyte infusions, as they can cause severe GvHD; previous GvHD is usually a contraindication to DLI 1, 3
• Do not rely on reduction of immunosuppression alone for post-transplant PTLD 1, 3
• Do not confuse past infection (positive VCA IgG and EBNA IgG with negative VCA IgM) with chronic active EBV infection, which requires persistent symptoms for >3 months 3