Is antiviral prophylaxis required in patients at high risk of viral infections, such as Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) and Cytomegalovirus (CMV)?

Antiviral Prophylaxis in High-Risk Patients

Antiviral prophylaxis is required for specific high-risk populations, particularly allogeneic stem cell transplant recipients and patients receiving intensive T-cell depleting therapies, but is not universally indicated for all immunocompromised patients.

Risk-Based Stratification for Prophylaxis

The decision to initiate antiviral prophylaxis depends critically on the degree and duration of T-cell immunosuppression rather than neutropenia severity 1. The main risk factor for clinically relevant viral reactivation is profound disruption of cellular immune response 1.

Highest Risk Populations Requiring Prophylaxis

Allogeneic stem cell transplant recipients:

• HSV prophylaxis with acyclovir 400 mg three to four times daily is strongly recommended for all HSV-seropositive patients 1
• Prophylaxis should continue until granulocyte recovery or stomatitis healing, with prolonged prophylaxis (>30 days) considered for patients with acute or chronic GVHD 1
• CMV prophylaxis with letermovir (480 mg/day orally or IV) is recommended for CMV-seropositive recipients through day 100 post-transplant, with consideration for extension to day 200 in high-risk patients 2
• VZV prophylaxis with extended acyclovir for longer than one year after allogeneic transplant is recommended 1

Patients receiving alemtuzumab or intensive T-cell depleting therapies:

• These patients experience sustained suppression of T-cell function with significantly increased risk of viral complications 1
• CMV monitoring and preemptive therapy for minimum 2 months after alemtuzumab is required 2

Intermediate Risk Populations

Patients with chronic lymphocytic leukemia on BTK or BCL-2 inhibitors:

• Acyclovir or valacyclovir prophylaxis against HSV and VZV is recommended for all patients while receiving treatment 1
• Universal CMV prophylaxis is not recommended; instead, monitoring based on symptoms and clinical presentation is advised 1
• For patients with relapsed/refractory CLL and additional risk factors (prior alemtuzumab, purine analogue-based chemotherapy, or prolonged high-dose corticosteroids), consider PCP prophylaxis 1

Multiple myeloma patients receiving bispecific antibody therapy:

• Acyclovir or valacyclovir prophylaxis should be maintained throughout treatment and thereafter at physician discretion 1
• Prophylaxis should be maintained while the patient is still receiving treatment for MM 1

Lower Risk Populations NOT Requiring Routine Prophylaxis

Acute leukemia patients:

• Despite reduction in HSV reactivations with acyclovir prophylaxis, no effect on duration of febrile neutropenia, antibiotic consumption, or incidence of bacteremia has been demonstrated 1
• No recommendation for routine antiviral prophylaxis can be given for acute leukemia patients 1
• Duration and severity of chemotherapy-induced neutropenia are of lesser importance than T-cell function 1

Autologous stem cell transplant recipients:

• Lamivudine is recommended for prophylaxis of hepatitis B reactivation in HBsAg-positive patients 1
• Routine HSV/VZV prophylaxis recommendations are less stringent than for allogeneic transplant 1

Virus-Specific Prophylaxis Strategies

Herpes Simplex Virus (HSV)

• Acyclovir 400 mg three to four times daily or valacyclovir is the standard prophylactic regimen 1
• Prophylaxis is only recommended for HSV-seropositive patients; routine prophylaxis is not recommended for seronegative patients even with seropositive donors 1

Varicella-Zoster Virus (VZV)

• Acyclovir or valacyclovir prophylaxis is recommended for high-risk patients 1
• Extended acyclovir prophylaxis for longer than one year after allogeneic transplant effectively prevents herpes zoster 1
• Passive immunization with VZV hyperimmunoglobulin (1 mL/kg) post-exposure is recommended for at-risk patients 3
• Live-attenuated varicella vaccines are contraindicated during active treatment and within 24 months after completion of immunosuppressive therapy 3

Cytomegalovirus (CMV)

• Letermovir 480 mg/day (or 240 mg/day if taking cyclosporine) is preferred for prophylaxis in CMV-seropositive allogeneic HCT recipients 2
• Alternative approach: weekly quantitative CMV viral load monitoring by PCR for at least 3-6 months post-transplant with preemptive therapy using valganciclovir or ganciclovir upon detection of viremia 2
• Letermovir lacks HSV and VZV coverage, requiring concurrent HSV/VZV prophylaxis 2
• CMV-negative patients with CMV-negative donors should receive only CMV-negative and/or filtered blood products 2

Hepatitis B Virus (HBV)

• Lamivudine 100 mg daily is recommended for all HBsAg-positive patients undergoing chemotherapy 1
• Prophylaxis should be initiated prior to chemotherapy and continued for 2-8 weeks after completion 1
• The rate of HBV reactivation is approximately 20-50% in HBsAg-positive patients without prophylaxis, which can result in fulminant hepatitis 1
• For HBsAg-negative/HBcAb-positive patients, guidelines differ: some recommend monitoring only, while others recommend prophylaxis, particularly when combined with anti-CD20 therapy 1

Common Pitfalls and Caveats

Timing of prophylaxis initiation:

• Prophylaxis must be started at the onset of immunosuppressive treatment, not after viral reactivation is detected 1
• For HBV, initiating prophylaxis prior to chemotherapy significantly lowers the rate of reactivation 1

Duration considerations:

• Early termination of prophylaxis enhances the risk of viral reactivation 1
• For HBV prophylaxis with anti-CD20 therapy, continue at least 12 months after the last anti-CD20 administration 1
• Extended CMV prophylaxis may be considered in patients with severe chronic GVHD or intensive glucocorticoid therapy 2

Drug resistance:

• Rapid emergence of resistant mutants can occur with letermovir if treatment is interrupted or underdosed 2
• Excessively long lamivudine treatment for HBV may provoke resistance 1

Monitoring requirements:

• Letermovir lacks activity against HSV and VZV, necessitating concurrent prophylaxis for these viruses 2
• ALT and HBV-DNA monitoring should be performed during HBV prophylaxis and for at least 12 months after discontinuation 1
• Continue CMV monitoring until CD4+ cell counts reach ≥200 cells/mcL in high-risk patients 2

Drug toxicity:

• Ganciclovir and valganciclovir can cause bone marrow suppression 2
• Foscarnet can cause nephrotoxicity and electrolyte abnormalities 2
• Acyclovir and valacyclovir are only weakly active against CMV and not recommended for CMV prophylaxis 2