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

Treatment of Epstein-Barr Virus Infection

For most EBV infections, supportive care alone is sufficient, but in high-risk populations (transplant recipients, immunosuppressed patients) or severe complications like post-transplant lymphoproliferative disorder (PTLD), rituximab is the treatment of choice, while antiviral drugs like acyclovir are ineffective and should not be used. 1

Uncomplicated Primary EBV Infection (Infectious Mononucleosis)

• Management focuses on symptom relief, adequate hydration, and rest until the self-limiting infection resolves. 1
• Antiviral drugs including acyclovir, ganciclovir, foscarnet, and cidofovir are not effective against latent EBV because latently infected B cells do not express the EBV thymidine kinase enzyme required for drug activation. 2
• Despite in vitro activity, acyclovir shows minimal clinical benefit in infectious mononucleosis and is not recommended. 3, 4

High-Risk Populations (Post-Transplant, Immunosuppressed)

Prophylaxis

• All allogeneic hematopoietic stem cell transplant (HSCT) patients and donors should be tested for EBV antibodies before transplantation. 1
• High-risk patients require prospective monitoring of EBV DNA-emia by quantitative PCR. 1
• B-cell depletion with prophylactic rituximab might reduce the risk of EBV DNA-emia, though evidence is limited. 2, 1
• EBV-specific cytotoxic T lymphocytes (CTLs) should be considered as first-line prophylactic treatment when available. 2, 1
• Antiviral drugs, interferon, and IVIG are not recommended for EBV prophylaxis. 2

Preemptive Therapy for Significant EBV DNA-emia

• Significant EBV DNA-emia without clinical symptoms warrants preemptive therapy with rituximab 375 mg/m² once weekly for 1-4 doses until EBV DNA-emia negativity. 2, 1
• Rituximab should be combined with reduction of immunosuppression when possible (except in patients with uncontrolled severe acute or chronic GvHD). 2
• Donor or third-party EBV-specific CTLs should be considered if available. 2
• Antiviral drugs are not recommended for preemptive therapy. 2

Common pitfall: No specific universal threshold of EBV DNA-emia can be recommended for initiating preemptive therapy; thresholds ranging from 1,000 to 40,000 copies/mL have been used, and local experience should guide center-specific cut-off values. 2

EBV-Associated Post-Transplant Lymphoproliferative Disorder (PTLD)

First-Line Therapy

• Rituximab 375 mg/m² once weekly is the treatment of choice for EBV-PTLD, with positive outcomes in approximately 70% of patients. 2, 1
• Therapy should be started as soon as practicable due to risk of rapidly growing high-grade lymphoid tumor and multi-organ impairment. 2
• Reduction of immunosuppressive therapy should always be combined with rituximab when possible. 2, 1
• Cellular therapy with donor or third-party EBV-specific CTLs should be considered if available. 2, 1

Critical caveat: Reduction of immunosuppression alone is rarely successful as sole intervention in PTLD following HSCT and may increase risk of rejection or GvHD. 2, 1

Dosing consideration: Additional doses of rituximab beyond 4 doses might result in down-regulation of CD20 expression and decreased efficacy. 2, 1

Second-Line Therapy

• Cellular therapy (EBV-specific CTLs or donor lymphocyte infusion) is recommended. 2
• Chemotherapy ± rituximab is a potential option after failure of other methods. 2
• Surgery, IVIG, interferon, and antiviral agents are not recommended for therapy of PTLD. 2

CNS EBV-PTLD

• Therapeutic options include rituximab ± chemotherapy (based on primary CNS lymphoma protocols), systemic or intrathecal rituximab monotherapy, anti-EBV T-cell therapy, or radiotherapy. 2, 1
• CNS localization requires special consideration due to risk of neurocognitive dysfunction. 1

Chronic Active EBV Infection (CAEBV)

• Hematopoietic stem cell transplantation is the only curative treatment for severe CAEBV and should be pursued when available. 5, 6
• Manifestations are often self-limiting with supportive care or prednisolone and cyclosporine A with or without etoposide. 6
• The 3-year overall survival rate is 87.3% after planned allogeneic HSCT, but only 16.7% in patients with uncontrolled active disease. 6
• Earlier initiation and completion of treatment without watchful waiting is recommended to maximize survival rates. 6

EBV-Associated Hemophagocytic Lymphohistiocytosis (EBV-HLH)

Graded Intensity Approach

• For less severe disease, start with corticosteroids (prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m²) with or without IVIG (1.6 g/kg over 2-3 days). 7
• For rapidly deteriorating patients, initiate etoposide treatment without delay according to HLH-94 protocol. 7
• Add rituximab 375 mg/m² once weekly for 2-4 doses to clear the B-cell reservoir of EBV. 7

Important distinction: EBV-HLH involves infection of T cells and/or NK cells, so rituximab cannot replace anti-T-cell therapy with corticosteroids with/without etoposide. 7

Monitoring

• Regular monitoring of ferritin, soluble CD25 (IL-2 receptor), complete blood counts, and EBV DNA levels is essential to assess treatment response. 7
• Response to rituximab can be identified by a decrease in EBV DNA-emia of at least 1 log10 in the first week of treatment. 7

Critical consideration: The optimal treatment strategy consists of three steps: (1) control of cytokine storm including coagulopathy and multiple organ failure, (2) control of opportunistic infections, and (3) eradication of clonally proliferating EBV-containing T- or NK-cells. 8