Herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis in immunocompromised adults

Morbidity and mortality in patients with malignancies are increased by viral infections. 

This document is intended to provide guidance for both primary and secondary prophylaxis of viral infections among adult patients with haematological malignancies, solid tumours or undergoing blood and marrow transplant (BMT). However it is anticipated that individual units or practitioners will adopt local antiviral strategies.

Pathophysiology

Most viral infections in patients with haematologic malignancies, solid tumours or undergoing BMT result from reactivation of asymptomatic latent infections, predominantly of herpes viruses, such as herpes simplex virus (HSV) and varicella zoster virus (VZV).

Risk factors

The risk of viral reactivation is determined by baseline serostatus. HSV reactivation commonly occurs in the setting of mucositis and neutropenia, whereas VZV is common in therapies that are T cell depleting. Patients at highest risk of reactivation of both HSV and VZV are allogeneic stem cell transplant recipients, in particular those who have received T cell depleting conditioning regimens and who remain on long term immunosuppression for graft versus host disease. For those allogeneic transplant recipients, the pre-engraftment period during which mucositis occurs is the time of heightened disease risk. HSV prophylaxis may be extended beyond this time in patients who experience frequent HSV recurrences.^r

Herpes simplex virus (HSV)

Herpes simplex virus is an important pathogen in patients who develop neutropenia and mucositis. HSV infections are primarily reactivation of the latent virus. The presence of latent HSV can be determined by pre-treatment HSV serology. Reactivation and infections with HSV occur in 60 to 80% of BMT recipients and in acute leukaemia patients with no primary HSV prophylaxis undergoing induction or re-induction therapy who are seropositive for HSV. Once a patient has had a HSV reactivation infection requiring treatment, it is recommended that HSV prophylaxis be administered during all future active antineoplastic treatment and episodes of neutropenia induced by treatment.^r

Varicella zoster virus (VZV)

The principle risk factor for VZV is impaired cellular immunity. In allogeneic BMT recipients with a history of VZV infection, about 30% without antiviral prophylaxis have VZV disease reactivation. VZV seropositive patients pre transplant should receive prophylaxis for at least 12 months post allogeneic transplant, as this has been shown to significantly decrease the incidence of VZV disease compared to placebo (5% vs. 26% respectively).^r Continuation of prophylaxis beyond this time is recommended in patients with chronic graft versus host disease (cGvHD) who continue on immunosuppression. Prophylaxis may be discontinued when CD4 counts are greater than 200 cells/microL and immunosuppressive therapy ceased.

Grading

Risk categories^rr are based on several factors, including:

• underlying malignancy,
• disease remission status,
• presence of mucositis,
• duration of neutropenia,
• prior antineoplastic treatment, and
• intensity of immunosuppressive therapy.

* doses recommended differ from the eTG June 2019 edition, and are based on the clinical expertise of the eviQ haematology reference committee

Notes:

• In patients who are unable to tolerate oral therapy, use aciclovir IV 5mg/kg every 8 hours.^r
• In patients who are receiving antiviral prophylaxis for prevention of CMV reactivation, additional prophylaxis for HSV and VZV is not necessary.
• Once a patient has had HSV reactivation requiring treatment, HSV prophylaxis is recommended during all future active antineoplastic treatment and episodes of neutropenia induced by treatment.^r

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Bibliography

Chanan-Khan, A., P. Sonneveld, M. W. Schuster, et al. 2008. "Analysis of Herpes Zoster Events Among Bortezomib-Treated Patients in the Phase III APEX Study." J Clin Oncol. 26(29):4784-4790

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PURPOSE: The aim of this subset analysis was to determine if bortezomib treatment is associated with increased incidence of varicella-zoster virus (VZV) reactivation in patients with relapsed multiple myeloma (MM). PATIENTS AND METHODS: Incidence of herpes zoster was evaluated in 663 patients with relapsed MM from the phase III APEX trial comparing single-agent bortezomib with high-dose dexamethasone. RESULTS: Bortezomib was associated with a significantly higher incidence of herpes zoster compared with dexamethasone treatment (13%, 42 of 331 v 5%, 15 of 332; P = .0002). Most herpes zoster infections were grade 1/2; incidences of grade 3/4 events (1.8% v 1.5%) and infections considered serious adverse events (1.5% v 0.9%) were similar between treatment arms, and no herpes zoster-related deaths occurred. Neither the time to onset of the herpes event nor the patients' absolute lymphocyte counts at baseline differed significantly between arms. VZV reactivation was the only herpes viral event noted to be significantly elevated in the bortezomib treatment group compared with the dexamethasone treatment group (P = .0002). The incidence of non-VZV-related herpes viral infections was comparable between arms. No additional risk factors for herpes zoster reactivation were identified. CONCLUSION: Further studies are needed to explain these observations and their implications; however, for patients treated with bortezomib or bortezomib-containing regimens, the risk of VZV reactivation should be monitored and routine use of antiviral prophylaxis considered

Erard V, Guthrie KA, Varley C et al. 2007 . " One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood. Oct 15;110(8):3071-7

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No consensus exists on whether acyclovir prophylaxis should be given for varicella-zoster virus (VZV) prophylaxis after hematopoietic cell transplantation because of the concern of rebound VZV disease after discontinuation of prophylaxis. To determine whether rebound VZV disease is an important clinical problem and whether prolonging prophylaxis beyond 1 year is beneficial, we examined 3 sequential cohorts receiving acyclovir from day of transplantation until engraftment for prevention of herpes simplex virus reactivation (n = 932); acyclovir or valacyclovir 1 year (n = 1117); or acyclovir/valacyclovir for at least 1 year or longer if patients remained on immunosuppressive drugs (n = 586). In multivariable statistical models, prophylaxis given for 1 year significantly reduced VZV disease (P < .001) without evidence of rebound VZV disease. Continuation of prophylaxis beyond 1 year in allogeneic recipients who remained on immunosuppressive drugs led to a further reduction in VZV disease (P = .01) but VZV disease developed in 6.1% during the second year while receiving this strategy. In conclusion, acyclovir/valacyclovir prophylaxis given for 1 year led to a persistent benefit after drug discontinuation and no evidence of a rebound effect. To effectively prevent VZV disease in long-term hematopoietic cell transplantation survivors, additional approaches such as vaccination will probably be required.

Oshima K, Takahashi T, Mori T et al. 2010 " One-year low-dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group". Transpl Infect Dis. Oct;12(5):421-7.

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Varicella zoster virus (VZV) disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). We carried out a trial of 1-year low-dose valacyclovir (VCV) prophylaxis against VZV disease to evaluate its efficacy and safety. Patients received oral acyclovir (ACV) 1000mg/day until day 35 after HSCT. Oral VCV 500mg/day, 3 times a week, was started on day 36 and continued until 1 year after HSCT. The development of VZV disease was monitored until 2 years after HSCT. A total of 40 patients with a median age of 43 years were enrolled. VCV was well tolerated in all but 1 patient who discontinued it on day 224 because of thrombocytopenia of unknown cause. Seven patients developed VZV disease at a median of 479 days (range 145-651) after HSCT, with a cumulative incidence of 18.5%. Two patients developed breakthrough disease during VCV prophylaxis. The other 5 patients developed VZV disease after the discontinuation of VCV, and 3 of these had developed extensive chronic graft-versus-host disease. Visceral involvement and serious complications were completely eliminated. All patients responded to the therapeutic dose of VCV or ACV. One-year low-dose VCV can be safely and effectively administered for the prevention of VZV disease after allogeneic HSCT.

Liesveld JL, Abboud CN, Ifthikharuddin JJ et al. 2002 . " Oral valacyclovir versus intravenous acyclovir in preventing herpes simplex virus infections in autologous stem cell transplant recipients". Biol Blood Marrow Transplant. ;8(12):662-5.

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Patients who are seropositive for herpes simplex virus (HSV) and are undergoing autologous marrow or peripheral blood stem cell transplantation require prophylaxis for HSV infection. Most prophylaxis regimens have used intravenous acyclovir (ACY). Oral valacyclovir (VAL), the L-valyl ester of ACY, can be used to achieve plasma concentrations equivalent to levels achieved with intravenous ACY. In this study, adults undergoing autologous stem cell transplantation were randomized to receive ACY, 250 mg/m2 intravenously (IV) every 12 hours from day 0 to engraftment, or VAL, 1 g orally every 12 hours from day 0 to engraftment. The primary study objective was to compare cost of HSV prophylaxis between study groups. Thirty patients were randomized to receive either oral VAL (n = 14) or IV ACY (n = 16) prophylaxis. Mean pharmacy cost of HSV prophylaxis in the patient group randomized to IV ACY was $1080 versus $320 for the group randomized initially to VAL. This study demonstrates the feasibility and significant cost savings of using oral VAL for HSV prophylaxis.

Taplitz, R. A., E. B. Kennedy, E. J. Bow et al. 2018. "Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update." J Clin Oncol 36(30):3043-3054.

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PURPOSE: To provide an updated joint ASCO/Infectious Diseases Society of America (IDSA) guideline on antimicrobial prophylaxis for adult patients with immunosuppression associated with cancer and its treatment. METHODS: ASCO and IDSA convened an update Expert Panel and conducted a systematic review of relevant studies from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel. RESULTS: Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. RECOMMENDATIONS: Antibacterial and antifungal prophylaxis is recommended for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as < 100 neutrophils/microL for > 7 days or other risk factors. Herpes simplex virus-seropositive patients undergoing allogeneic hematopoietic stem-cell transplantation or leukemia induction therapy should receive nucleoside analog-based antiviral prophylaxis, such as acyclovir. Pneumocystis jirovecii prophylaxis is recommended for patients receiving chemotherapy regimens that are associated with a > 3.5% risk for pneumonia as a result of this organism (eg, those with >/= 20 mg prednisone equivalents daily for >/= 1 month or on the basis of purine analog usage). Treatment with a nucleoside reverse transcription inhibitor (eg, entecavir or tenofovir) is recommended for patients at high risk of hepatitis B virus reactivation. Recommendations for vaccination and avoidance of prolonged contact with environments that have high concentrations of airborne fungal spores are also provided within the updated guideline. 

Thursky, K. A., L. J. Worth, J. F. Seymour, et al. 2006. "Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab*." Br J Haematol 132(1):3-12.

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There is an increasing use of monoclonal antibodies in the treatment of haematological malignancies. Alemtuzumab (Campath-1H; Ilex Pharmaceuticals, San Antonio, TX, USA) is a monoclonal antibody reactive with the CD52 antigen used as first and second line therapy for two types of lymphoproliferative disorders: chronic lymphocytic leukaemia (CLL), and T-cell lymphomas [both peripheral (PTCL) and cutaneous (CTCL)]. With alemtuzumab therapy, viral, bacterial and fungal infectious complications are frequent, and may be life threatening. An understanding of the patients at highest risk and duration of risk are important in developing recommendations for empirical management, antimicrobial prophylaxis and targeted surveillance. This review discusses the infection risks associated with these lymphoproliferative disorders and their treatment, and provide detailed recommendations for screening and prophylaxis

Sandherr, M., M. Hentrich, M. von Lilienfeld-Toal et al. 2015. "Antiviral prophylaxis in patients with solid tumours and haematological malignancies--update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO)." Ann Hematol 94(9):1441-1450.

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Reactivation of viral infections is common in patients with solid tumour or haematological malignancy. Incidence and severity depend on the extent of cellular immunosuppression. Antiviral prophylaxis may be effective to prevent viral reactivation. In 2006, the Infectious Diseases Working Party of German Society for Hematology and Medical Oncology (DGHO) published guidelines for antiviral prophylaxis in these patient populations. Here, we present an update of these guidelines for patients with solid and haematological malignancies undergoing antineoplastic treatment but not allogeneic stem cell transplantation. Relevant literature for reactivation of different viruses (herpes simplex virus (HSV), varicella zoster virus (VZV), hepatitis B virus (HBV) and respiratory viruses) is discussed to provide evidence-based recommendations for clinicians taking care of this patient population. We recommend a risk-adapted approach with (val)acyclovir against HSV and VZV in patients treated with alemtuzumab, bortezomib or purine analogues. Seasonal vaccination against influenza is recommended for all patients with solid or haematological malignancies regardless of antineoplastic therapy. Hepatitis B screening is recommended in lymphoproliferative disorders, acute leukaemia, and breast cancer, and during treatment with monoclonal anti-B-cell antibodies, anthracyclines, steroids and in autologous stem cell transplantation. In those with a history of hepatitis B prophylactic lamivudine, entecavir or nucleotide analogues as adefovir are recommended to prevent reactivation.

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