Anti‐herpesvirus prophylaxis versus placebo, no treatment or pre‐emptive treatment in hemato‐oncological malignancies

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

We will assess the effects of anti‐herpes drugs in hemato‐oncological patients comparing prophylaxis versus placebo, no treatment or pre‐emptive treatment.

Background

Description of the condition

Viral infections caused by herpesviruses are a major cause of morbidity and mortality in hemato‐oncologic patients (patients diagnosed with a blood/bone marrow or lymph node‐related malignancy) (Gratwohl 2005). Prophylaxis using anti‐viral drugs against herpesviruses are used increasingly and it is important to question if the available data support such recommendation.

Herpesviruses represent a family of DNA viruses that include herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV), Epstein‐Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus (HHV) 6 and 7 and Kaposi sarcoma–associated herpesvirus (HHV‐8). These viruses have several common exclusive characteristics. Primary infections usually occur during infancy or childhood. All herpesviruses become latent following primary infection, residing in the host nervous or hematopoietic systems (Whitley 1998). Latency is identified by serum antibodies and the antibody positivity rate among adults (seroprevalence) of 65% for HSV1 (Xu 2002) and 54% (by age 40) for CMV (Staras 2006) in the United States and reflects the acquisition rates of these viruses in childhood. During latency, reactivations are common and mostly asymptomatic but result in virus shedding in mucus membranes, which is the source of infection for contacts of asymptomatic shedders. Infections primarily acquired in adulthood tend to be more severe. Symptomatic reactivations are rare among immunocompetent people except for VZV reactivations (zoster or shingles), but are very common among immunocompromised patients (Arduino 2008; Bruggeman 1993; Kawa 2000; Weaver 2009).

Herpesvirus infections in immune deficient patients and especially among patients undergoing hematopoietic cell transplantation (HCT) will lead to a severe disease with high rates of dissemination, complications and mortality (Boeckh 2003; Nguyen 2001; Styczynski 2009). The herpesviruses most commonly affecting hematological cancer patients are HSV 1, VZV, CMV and HHV6 and occur most commonly following reactivation among seropositive (IgG positive) patients. The incidence and outcomes of herpesvirus infections are dependent mainly on the intensity and duration of T‐cell–mediated immune suppression, which is the hallmark of immune suppression following allogeneic hematopoietic cell transplantation (allo‐HCT), especially with graft‐versus‐host disease (GVHD), a syndrome appearing when transplanted cells recognize recipients' cells and attack them (Centers for Disease Control and Infections 2000). Among allo‐HCT recipients, the incidence and presentation of herpesviridae infection are dependent on the antibody status of the recipient and the donor. Allo‐HCT recipients are at high risk for herpesviridae disease all seropositive recipients and seronegative recipients with a seropositive donor (Zaia 2009). Finally, herpesvirus infection rates are dependent on the time after transplantation. We recognize three phases of immune recovery following allo‐HCT (Dykewicz 2001).

Phase 1: pre‐engraftment phase ‐ up to 30 days post‐transplantation. Patients are mostly at risk due to prolonged neutropenia and breaks in the mucocutaneous barrier. HSV reactivations can occur during this phase.

Phase 2: post‐engraftment phase ‐ from 30 to 100 days post‐transplantation. This phase is known for the impairment in cell‐mediated immunity exposing recipients to all herpesviruses, especially CMV.

Phase 3: late phase ‐ more than 100 days post‐transplantation. In this phase, allogeneic transplantation still imposes cell‐mediated and humoral immunity defects leading to a continued risk for herpesvirus infections dependent on the existence of GVHD.

Apart from allo‐HCT, other hematological malignancies may lead to an increase risk for herpesvirus infections. For example, multiple myeloma (MM) is a progressive disease characterized by neoplastic proliferation of a single clone of plasma cell. Immune deficits caused by the disease as well as its treatments increase the risk for herpesvirus infections. For example, bortezomib (a proteasome inhibitor) ‐treated patients had a higher incidence of herpes zoster compared with MM patients treated with high‐dose dexamethasone (13% versus 5%) (Chanan‐Khan 2008).

HSV type 1 and 2 cause mainly localized mucocutaneous lesions and esophagitis (Bustamante 1991) in the immunocompromised cancer patients. The reported incidence of HSV reactivation among HSV‐seropositive allo‐HCT recipients reaches 80% (Flowers 2013). Other unusual manifestation of HSV disease are pneumonitis, hepatitis, meningitis, encephalitis, myelitis and retinitis (Cohen 2015). Primary VZV infection induces varicella in healthy persons, but in immunocompromised patients it can lead to visceral disseminated infection with diffuse cutaneous lesions, conjunctivitis, retinitis, pneumonitis, hepatitis, meningitis and bone marrow suppression (Cohen 2015). Attack rates of 13% to 55% symptomatic VZV reactivations have been described in the first year post‐transplantation (Locksley 1985; Schuchter 1989). CMV in hematological patients may lead to retinitis, esophagitis, pneumonitis, hepatitis, encephalitis and bone marrow suppression (Cohen 2015). About 75% of CMV‐seropositive recipients develop CMV reactivation, and 20% to 30% of these patients will further develop CMV disease if no intervention is applied (Ljungman 2002). The frequency of CMV pneumonia was reviewed among 2136 hospitalized adults with leukemia and revealed 61 patients (2.9%) had CMV pneumonia (Nguyen 2001). The most significant clinical syndrome related to EBV infection in HCT recipients is post‐transplant lymphoproliferative disease (PTLD) (Zaia 2009) and oral hairy leukoplakia (white linear papules on the tongue). HHV‐6 can induce fever and rash, bone marrow suppression and encephalitis with the latter described in HHV‐7 infection as well (Cohen 2015).

Description of the intervention

Anti‐herpesvirus drugs are continuously studied and developed. Management strategies of herpesvirus infections among hematological cancer patients include treatment of established infections, monitoring and pre‐emptive treatment when infection is suspected and prophylaxis administered to all patients at risk.

Current recommendations regarding CMV suggest the use of either prophylaxis or pre‐emptive treatment for allo‐HCT recipients based on the risks and benefit of each strategy and the hospital's laboratory support (Tomblyn 2009). HCT recipients with high risk for CMV disease are encouraged to receive anti‐CMV prophylaxis (Zaia 2009). Furthermore, certain CMV‐seropositive autologous recipients may benefit from the pre‐emptive strategy (Tomblyn 2009). The guidelines recommend prophylaxis for HSV‐seropositive allo‐HCT recipients (as assessed by anti‐HSV IgG before transplantation) (Styczynski 2009; Tomblyn 2009). HSV‐seropositive patients with acute leukemia, treated with chemotherapy should be considered for such prophylaxis. Anti‐viral prophylaxis is recommended for VZV seropositive allo‐HCT recipients, but prophylaxis is controversial for autologous HCT (Styczynski 2009; Tomblyn 2009). Anti‐EBV IgG antibodies should be assessed in HCT donors and recipients, but prophylaxis or treatment of asymptomatic reactivations are not recommended (Zaia 2009). Patients with acute leukemia are not routinely given anti‐viral prophylaxis due to lack of evidence and weak recommendations (Styczynski 2009). However, several studies have shown reduced incidence of herpesvirus infection using anti‐viral prophylaxis in leukemia patients (Anderson 1984; Saral 1983). Anti‐viral agents have cross‐activity against multiple species of herpesviruses, thus a single drug will prevent or treat more than one herpesvirus depending on its spectrum of activity.

Other than anti‐herpesviruses agents, vaccines can be used as herpesvirus prophylaxis as well (only for VZV and varicella vaccines). These vaccines are not widely used in hemato‐oncological patients (Styczynski 2009).

How the intervention might work

Anti‐virals against herpesviruses have different modes of action, spectrum of activity against the different herpesviruses, bio‐availability, safety profile and efficacy. In addition, resistance of herpesviruses to these therapeutic regimens has been described through several mechanisms. The main characteristics of currently approved drugs are summarized (Table 1).

Table 1.

Anti‐herpesviridae agents

Drug name	Drug class	Mechanism of action	Viral activity	Route	Dependence on viral TK	Major side effects
Acyclovir	Purine nucleoside	Deoxyguanosine analogue Thus Inhibitor of viral DNA synthesis	HSV VZV	Topical, IV, PO	Yes	Injection site: inflammation, phlebitis and vesicular eruption Diaphoresis Hematuria Hypotension Headache Neurotoxicity (IV) Nephrotoxicity (IV)
Valacyclovir	Purine nucleoside	Pro‐drug of acyclovir	HSV VZV	PO	Yes	Confusion and hallucination in transplanted patients
Brivudin	Pyrimidine nucleosides	Thymidine nucleoside analogue Inhibitor of viral DNA synthesis	VZV	PO		As acyclovir Gastrointestinal Headache Dizziness Delirium Hepatitis Serious drug interactions
Cidofovir	Pyrimidine nucleosides	Deoxycytidine monophosphate analogue Inhibitor of viral DNA synthesis	HSV CMV EBV HHV‐6 HHV‐7 HHV‐8	IV, topical	No	Nephrotoxicity(IV) Neutropenia Mucosal application‐burning, pain, pruritus, ulceration. Intravitreal application‐ iritis, vitreitis, visual loss
Penciclovir	Purine nucleoside	Guanosine analogue Inhibitor of viral DNA synthesis	HSV VZV	Topical, IV, PO	Yes
Famciclovir	Purine nucleoside	Pro drug of penciclovir	HSV VZV	PO	Yes	Headache Nausea Fatigue Diarrhea Urthicaria Confusional states Neutropenia Elevated transaminase
Fomivirsen	Antisense drug	Phosphorothioate oligonucleotide‐inhibits regulation and viral gene expression	CMV	Intravitreal		Increased intraocular pressure
Foscarnet	Phosphono‐formates	Pyrophosphate analogue. Inhibits DNA polymerase	CMV HSV VZV	PO/IV		Nephrotoxicity Hypocalcemia Hypomagnesemia Hypokalemia Hypercalcemia Hypophosphatemia Hyperphosphatemia Neurotoxicity Fever Rash Diarrhea Nausea Abnormal liver function Fatigue Painful genital ulcers and hemorrhagic cystitis in transplanted patients
Ganciclovir	Purine nucleoside	Deoxyguanosine analogue Thus Inhibitor of viral DNA synthesis	CMV HSV HHV‐6 HHV‐8 EBV	PO/IV/intravitreal	Yes	Myelosuppression Neurotoxicity Nephrotoxicity Diarrhea Rash Fever Liver function abnormality Phlebitis Intravitreal‐ visual changes, hemorrhage, infections, retinal detachment
Valganciclovir	Purine nucleoside	Pro drug of ganciclovir	CMV HSV HHV‐6 HHV‐8 EBV	PO
Idoxuridine	Pyrimidine nucleosides	Thymidine nucleoside analogue Inhibitor of viral DNA synthesis	HSV	topical		Mild local burning Headache Nausea Dizziness Dermatitis
Letermovir	Inhibition of viral terminase enzyme complex subunit PUL56	3, 4‐dihydro‐quinozoline.	CMV	PO		Gastroenteritis Dyspnea Nephrotoxicity
Trifluridine	pyrimidine nucleoside	Inhibition of viral DNA synthesis.	HSV‐1 HSV‐2 CMV	topical		Discomfort Palpebral edema Hypersensitivity Keratopathy
Vidarabine	Purine nucleoside	Adenosine analogue. Inhibition of viral DNA synthesis.	HSV			Hypersensitivity Keratitis Photophobia
Maribavir	inhibition of an protein kinase enzyme	L‐ribofuranosyl benzimidazole.Inhibition of viral DNA synthesis.	CMV EBV	PO		Taste disturbance Diarrhea Rash Pruritus Headache Nausea Fever
Amenamevir	Inhibiting helicase‐primase	Oxadiazolephenyl derivate	HSV‐1 HSV‐2 VZV	PO
Pritelivir	Inhibiting helicase‐primase	Thiazolylamide	HSV‐1 HSV‐2	PO	No

IV: intravenous PO: by mouth

The most common anti‐herpesvirus agents are nucleoside analogues. Acyclovir was the first discovered anti‐herpes agent in 1977 (Elion 1977). Acyclovir is an inactive drug that becomes activated in cells infected with HSV or VZV and eventually inhibits viral DNA synthesis (Field 2013). It is activated by the viral thymidine kinase (TK) and resistance of HSV to acyclovir is frequently described due to a shift in the viral TK (Field 2013). The prevalence of acyclovir‐resistant HSV strains is higher in immunocompromised patients compared to immunocompetent hosts (Aoki 2015). Acyclovir is considered the agent of choice for the treatment of HSV and VZV infections (Whitley 1992). Its main toxicities are phlebitis, hypotension, nephrotoxicity and neurotoxicity, especially when administered parenterally (Aoki 2015). Other nucleoside analogues include valacyclovir, brivudin, cidofovir penciclovir, famciclovir, ganciclovir, valganciclovir, idoxuridine, trifluridine and vidarabine (Table 1). These agents possess variable activity for different herpesviruses notably differing in their anti‐CMV activity. Ganciclovir and valganciclovir (prodrug of ganciclovir) are the main treatments to date in CMV disease. Ganciclovir and valganciclovir, are initially phosphorylated by a specific virus protein kinase (PK), which will lead to further phosphorylations, thus they are effective only against viruses producing the specific kinase, such as CMV (Steininger 2007). The most notable toxicities of ganciclovir are myelosuppression, neurotoxicity and nephrotoxicity.

Foscarnet belongs to a different drug class, a pyrophosphate analogue, leading to reversible and incomplete DNA polymerase inhibition with good anti‐CMV activity (Balfour 1990; Chrisp 1991). Foscarnet, unlike ganciclovir does not require phosphorylation in order to become active, but has a poor toxicity profile with a need for intense electrolyte monitoring and renal failure (Jacobson 1992; Zaia 2009). In addition, foscarnet might lead to painful genital ulcers and hemorrhagic cystitis in transplanted patients (Steininger 2007). Foscarnet is commonly used as a second‐line treatment for CMV, following resistance or intolerance to nucleoside analogues, and is also the treatment of choice for acyclovir‐resistant HSV disease (Zaia 2009).

New drugs against herpesviruses have been developed with novel mechanisms of action. One approach is inhibition of the helicase‐primase complex and eventually blocking of HSV DNA synthesis (Kleymann 2002) with reduced adverse profile. An example is pritelivir, demonstrating good clinical response in genital HSV‐2 otherwise healthy adults with low toxicity (Wald 2014). A different approach is letermovir, a novel anti‐CMV agent that targets the viral terminase subunit pUL56 a component of the terminase complex involved in viral DNA cleavage and packaging (Goldner 2011).

Why it is important to do this review

Anti‐viral agents are commonly used among hemato‐oncology with different treatment approaches. Management strategies are variable reflecting gaps or uncertainty in the evidence for different strategies and anti‐viral drugs for specific patient populations. Recommendations on anti‐viral prevention are based mostly on soft outcomes of morbidity, such as mucositis and viremia. Summarizing the evidence on more severe morbidity and mortality might provide a stronger base for guidelines and uniform patient management. Defining which outcomes are positively affected by anti‐viral prophylaxis, can help in prioritizing treatments in a patient when adverse events or interactions arise.

Many randomized, controlled trials (RCTs) have assessed the efficacy of anti‐viral prophylaxis in hemato‐oncologic patients. A previous meta‐analysis published in 2009 concluded that anti‐viral prophylaxis should be administered to all CMV‐seropositive HCT recipients post‐engraftment with consideration of treatment also in VZV‐seropositive as well as HSV‐seropositive (Yahav 2009). The type and duration of prophylaxis remained undetermined (Yahav 2009). In the last decade novel anti‐viral drugs were evaluated and several RCTs were published.

This systematic review and meta‐analysis aims to assemble the complete data to allow for updated evidence‐based treatment recommendations.

Objectives

We will assess the effects of anti‐herpes drugs in hemato‐oncological patients comparing prophylaxis versus placebo, no treatment or pre‐emptive treatment.

Methods

Criteria for considering studies for this review

Types of studies

We will include RCTs. We will include studies regardless of publication status (published as articles, conference proceedings or unpublished).

Types of participants

We will include adult patients with hematological malignancy receiving chemotherapy/targeted therapy, with or without radiotherapy. In addition, we will include patients undergoing hematopoietic cell transplantation (HCT).

We will include trials monitoring for infection and disease throughout prophylaxis/pre‐emptive treatment.

We will exclude trials in which all patients had evidence of active viral disease (clinical disease with documentation of the virus in culture, antigenemia or polymerase chain reaction (PCR)) at study entry, although we will allow inclusion of studies that did not test asymptomatic patients at study entry.

We will exclude studies assessing only children, but allow inclusion of studies describing mixed populations of children and adults. We will attempt to extract data for adults only and, if not possible, include the overall results if children constitute the minority of the study population. We will exclude studies assessing hematological patients not receiving therapy for their primary malignancy.

Types of interventions

We will include the following interventions and comparisons in this review.

1. Anti‐viral prophylaxis (prevention of infection) compared with placebo

2. Anti‐viral prophylaxis compared with no treatment

3. One anti‐viral agent compared to a different anti‐viral agent as anti‐viral prophylaxis

4. One anti‐viral agent compared to a different anti‐viral agent as pre‐emptive treatment

5. Pre‐emptive approach compared to prophylaxis with the same anti‐viral agent in both arms

The anti‐virals included and their spectrum of herpesvirus coverage are detailed in (Table 1). If we will identify trials of anti‐virals active against herpesviruses that we did not plan to include initially, we will add these to the review and this information will be added to the ‘Differences between protocol and review’ section in the review.

Types of outcome measures

Primary outcomes

The primary outcomes analyzed will be:

1. Overall mortality

2. HSV disease

3. CMV disease

We will analyze these outcomes based on the following time points:

1. For non‐allo‐HCT patients, we will extract data up to three months from the beginning of allocated treatment, at the latest time point reported. If reported only later, we will extract the closest time point to three months.

2. For allo‐HCT patients, we will extract data up to one year from the beginning of allocated treatment, at the latest time point reported. If reported only later, we will extract the closest time point to one year.

In all cases, we will document the time points reported in the studies.

We will base disease definitions on established criteria (Humar 2006).

Secondary outcomes

1. Cytomegalovirus (CMV) or herpes simplex virus (HSV) pneumonitis at the time points described in the primary outcomes based on prophylaxis/pre‐emptive anti‐viral regimen

2. Varicella zoster virus (VZV) disease at the time points described in the primary outcomes based on prophylaxis/pre‐emptive anti‐viral regimen

3. HSV, CMV, VZV and human herpesvirus (HHV‐6) infection at the time points described in the primary outcomes

4. Secondary bacterial infections

5. Primary malignant disease relapse among allogeneic HCT recipients

6. Adverse events

   1. Requiring study drug discontinuation

   2. Any adverse event

   3. Specific adverse events

      1. Nephrotoxicity

      2. Neurotoxicity

      3. Electrolyte disorders

      4. Myelosupression

      5. Hypotension

      6. Hepatotoxicity

7. Hospitalization duration

8. Quality of life assessment

We will not mandate testing to rule out viral infection at onset. We will include trials monitoring for infection and disease throughout prophylaxis/pre‐emptive treatment.

We will define 'Disease' of the above herpesviruses as documentation of the virus along with tissue invasive disease (including mucocutaneous disease) or fever with no alternative cause. We will define 'Infection' as documentation of the virus in culture, antigenemia or PCR without clinical symptoms (asymptomatic reactivation most commonly). We will assess outcomes rates for infection and disease, addressing repeat episodes/ events.

Search methods for identification of studies

We will search the following databases using the search strategy defined in Appendix I. We will apply no language, year of publication or publication status restrictions.

Electronic searches

We will search the following electronic databases.

1. The Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library) to present (Appendix 1).

2. MEDLINE to present (Appendix 2).

3. Embase (Elsevier) to present (Appendix 3).

4. LILACS to present (Appendix 4).

Searching other resources

We will also search for unpublished trials, relevant conferences abstracts using the following database.

1. American Society of Hematology (ASH) 2012 to present

2. American Society of Clinical Oncology (ASCO) 2012 to present

3. European Hematology Association (EHA) 2012 to present

4. Annual Meetings of the European Society for Blood and Marrow Transplantation (EBMT) 2012 to present

5. European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2012 to present

6. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/ American Society for Microbiology (ASM) 2012 to present

In addition, we will search trial registries and new drugs application documents using the following registries.

1. National Institute of Health (NIH) Register http://clinicaltrials.gov

2. International Standard Randomised Controlled Trial Number (ISRCTN) register: www.controlledtrials.com(search)

3. EU Clinical Trials Register: www.clinicaltrialsregister.eu/ctr‐search/search

Data collection and analysis

Selection of studies

One review author (OBK) will screen titles and abstracts resulting from the above search. Two review authors (OBK and RB) will independently apply inclusion and exclusion criteria on all potentially eligible articles. We will document the number of articles identified and number of studies included and excluded according to the PRISMA guidelines (Liberati 2009), along with reasons for exclusion.

Data extraction and management

Two review authors (OBK an RB) will extract data independently and will document the information in a data extraction form. We will identify studies by the name of the first author and year of publication. We will extract the following data.

1. Study characteristics: trial dates, countries and number of centres, sponsor, funding, study setting (general department, specialized hematology department, intensive care unit).

2. Interventions:anti‐viral/s, control arm, dosing, schedule, duration route of administration.

3. Included patients: age (median, mean and range) and percentage of children, sex, hematological diseases defined for inclusion and percentage with acute myeloid leukemia (AML), acute lymphatic leukemia (ALL) and other hematological cancers, disease stage defined for inclusion, percentage of patients with HCT, type and percentage of patients with GVHD, percentage neutropenic at randomization, baseline CMV, HSV 1&2 and VZV serostatus defined for inclusion and percentage seronegative for each.

4. Trial flow: number of participants randomized per arm, follow‐up duration, number excluded and reasons for exclusion per outcome and time point, number lost to follow‐up.

5. Outcomes: as defined above, we will extract number of patients with outcome and number evaluated. We will document outcome definitions and surveillance and diagnosis methods. We will extract outcomes for the intention‐to‐treat (randomized) population.

Whenever studies have more than one publication, we will obtain data from all the manuscripts. We will discuss differences in data extraction and if necessary we will consult a third review author (MP) for disagreement resolution. One review author (OBK) will enter data into RevMan and the data will be further reviewed by RB for accuracy.

Assessment of risk of bias in included studies

Two review authors (OBK and RB) will independently estimate risk assessment for bias using domain‐based evaluation as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will classify each of the following domains as low, high and unclear risk based on the definitions provided in the Handbook.

1. Sequence generation (selection bias)

2. Allocation concealment (selection bias)

3. Blinding of participants and personnel (performance bias)

4. Blinding of outcome assessment (detection bias)

5. Incomplete outcome data (attrition bias)

6. Selective outcome reporting (reporting bias)

7. Other issues will include sample size calculation (high risk if not performed) and early termination (relevant for studies calculating a sample size and high risk if study terminated before target sample size attained without adhering to pre‐defined stopping rules).

Measures of treatment effect

Dichotomous outcomes: we will calculate from each trials the risk ratio (RR) with 95% confidence interval (CI).

Time‐to‐event data: We will extract hazard ratios(HRs) and 95% CIs for time‐to‐event‐analyses (survival analyses). If HRs and 95% CIs are not reported, we will use the methods described by Tierney and Parmar (Parmar 1998; Tierney 2007).

Continuous outcomes: we will extract the treatment effect reported in the study for duration of hospital stay and quality of life with precision measures (standard deviation, standard error, confidence interval or other). Based on the consistency in reporting, we will decide whether or not to include the data in the meta‐analysis.

Unit of analysis issues

We do not anticipate any unit of analysis issues. In the event that we encounter randomization of patients more than once into the trial, we will attempt to extract data for the first randomization only.

Infection and disease outcomes will be extracted as events.

Dealing with missing data

We will request missing data regarding the primary outcomes and 'Risk of bias' items from the authors. If data are unavailable, we will analyze the available data (Higgins 2011b).

Assessment of heterogeneity

Heterogeneity will be assessed visually and statistically using the Chi‐squared (χ² or Chi²) test using a P value < 0.10 to denote significant heterogeneity and the I² measure of inconsistency that will be interpreted as follows (Deeks 2011):

1. 0% to 40%: not important;

2. 30% to 60%: moderate heterogeneity;

3. 50% to 90%: substantial heterogeneity;

4. 75% to 100%: considerable heterogeneity.

Whenever heterogeneity is identified, subgroup analysis will be conducted.

Assessment of reporting biases

Funnel plots will be used to assess small‐study effects, including publication bias. We will do this for analyses with more than 10 trials (Sterne 2001).

Data synthesis

We will compile RRs, HRs and mean difference (MD) if relevant with 95% CIs of individual trials using a random‐effects meta‐analysis for compilation. If enough trials report survival analyses, we will conduct an inverse variance meta‐analysis of hazard ratios. We will use an intention‐to‐treat analysis as far as possible. Data will be analyzed using Review manager 5.3 software (RevMan).

We will construct s'Summary of findings' tables using GRADEpro (gdt.guidelinedevelopment.org/app/) for all review outcomes.

The most important outcomes for patients that will be reported in the 'Summary of findings' tables are:

1. overall mortality;

2. HSV disease at end of prophylaxis/ pre‐emptive anti‐virals;

3. CMV disease at end of prophylaxis/ pre‐emptive anti‐virals;

4. VZV disease at end of anti‐viral therapy;

5. HSV infection at end of prophylaxis/ pre‐emptive anti‐virals;

6. CMV infection at end of prophylaxis/ pre‐emptive anti‐virals;

7. adverse events requiring study drug discontinuation.

Subgroup analysis and investigation of heterogeneity

We will examine outcomes separately for the following patient and intervention subgroups.

1. Hematological patients treated with aggressive chemotherapy (acute leukemia patients in induction, consolidation and salvage phase) and hematological patients undergoing allogeneic or autologous HCT‐pre‐engraftment

   1. Acute leukemia (1a) versus all other patients (1b), including‐ lymphoma, myeloma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML) , others

   2. Prophylaxis active against CMV versus that active only against human herpesvirus (HHV) 1, 2 and VZV

2. Hematological patients undergoing allo‐HCT‐post‐engraftment

   1. Seropositive recipients receiving the graft from a seropositive donor

   2. Prophylaxis active against CMV versus that active only against human herpesvirus (HHV) 1, 2 and VZV

Forest plots will be primarily subgrouped by population type (1a, 1b and 2). For each comparison we will examine the heterogeneity introduced by the spectrum of prophylaxis treatment. If significant, we will present separate analyses for CMV‐active and CMV non‐active anti‐virals. For the CMV‐related outcomes, we will present also a separate analysis of CMV‐active‐only anti‐virals. For the other herpesvirus infections and global outcomes (e.g. mortality), we will examine the combined effect of the different anti‐virals because of the cross‐effects of all anti‐virals against all herpesviruses.

Sensitivity analysis

We will examine the effect of selection risk of bias of results through sensitivity analyses, limiting the analysis to trials at low risk of bias. We will compare results from the fixed‐effect model to the main results reported using a random‐effects meta‐analysis.

Appendices

Appendix 1. CENTRAL (the Cochrane Library) search strategy

ID Search

#1 MeSH descriptor: [Antiviral Agents] explode all trees

#2 (antiviral* near/3 (drug* or agent*))

#3 MeSH descriptor: [Acyclovir] explode all trees

#4 (acyclovir* or aciclovir*)

#5 valac*clovir*

#6 valtrex*

#7 brivudin*

#8 cidofovir*

#9 vistide*

#10 penc*clovir*

#11 denavir*

#12 famic*clovir*

#13 famir*

#14 fomivirsen*

#15 foscarnet*

#16 foscavir*

#17 Ganc*clovir*

#18 cytovene* or nordexoguanosine DHPG sodium* or GCV sodium*

#19 valganc*clovir*

#20 MeSH descriptor: [Idoxuridine] explode all trees

#21 (idoxuridin* or dendrid herplex stoxil*)

#22 letermovir*

#23 MeSH descriptor: [Trifluridine] explode all trees

#24 (trifluridine* or lonsurf*)

#25 MeSH descriptor: [Vidarabine] explode all trees

#26 vidarabine*

#27 maribavir*

#28 amenamevir*

#29 pritelivir*

#30 BAY 57‐1293

#31 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30

#32 MeSH descriptor: [Hematologic Diseases] explode all trees

#33 MeSH descriptor: [Hematologic Neoplasms] explode all trees

#34 (hematolog* near/1 malignan*)

#35 (hematolog* near/1 neoplas*)

#36 (haematolog* near/1 malignan*)

#37 (haematolog* near/1 neoplas*)

#38 MeSH descriptor: [Bone Marrow Diseases] explode all trees

#39 MeSH descriptor: [Lymphoma] explode all trees

#40 MeSH descriptor: [Leukemia] explode all trees

#41 lymphom*

#42 leukem* or leukaem* or leucem*

#43 MeSH descriptor: [Multiple Myeloma] explode all trees

#44 myelom*

#45 sezary*

#46 #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45

#47 MeSH descriptor: [Bone Marrow Transplantation] explode all trees

#48 MeSH descriptor: [Stem Cell Transplantation] explode all trees

#49 (bone marrow* near/3 (transplantation* or grafting* or trasplant* or rescue*))

#50 (stem cell* or stem‐cell*)

#51 "progenitor cell*"

#52 (ASCT or ABMT or PBPC or PBSCT or PSCT or BMT or SCT or HSCT)

#53 MeSH descriptor: [Transplantation Conditioning] explode all trees

#54 myeloablat*

#55 (nonmyeloablat* or non‐myeloablat*)

#56 reduced intens*

#57 (mini‐transplant* or minitransplant* or mini‐trasplant* or minitrasplant*)

#58 #47 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57

#59 MeSH descriptor: [Transplantation, Homologous] explode all trees

#60 (allograft* or allo‐graft*)

#61 (allotransplant* or allo‐transplant*)

#62 (allotrasplant* or allo‐trasplant*)

#63 (allogen* or allo‐gen*)

#64 ((allogen* or allo‐gen*) near/5 (transplant* or trasplant* or graft* or rescue*))

#65 (homograft* or homo‐graft*)

#66 homolog*

#67 (homotransplant* or homo‐transplant*)

#68 (homotrasplant* or homo‐trasplant*)

#69 #59 or #60 or #61 or #62 or #63 or #64 or #65 or #66 or #67 or #68

#70 MeSH descriptor: [Myeloproliferative Disorders] explode all trees

#71 myeloproliferativ*

#72 MeSH descriptor: [Polycythemia Vera] explode all trees

#73 polycythemia*

#74 (osler vaquez near/3 diseas*)

#75 MeSH descriptor: [Thrombocythemia, Essential] explode all trees

#76 thrombocytos*

#77 (thrombocythem* or thrombocythaem* or thrombozyth*m*)

#78 #70 or #71 or #72 or #73 or #74 or #75 or #76 or #77

#79 #31 and (#46 or #58 or #69 or #78) in Trials

Appendix 2. Medline search strategy

#	Searches
1	exp ANTIVIRAL AGENTS/
2	(antiviral* adj3 (drug* or agent*)).tw,kf,ot.
3	exp ACYCLOVIR/
4	(acyclovir* or aciclovir*).tw,kf,ot.
5	Valac?clovir*.tw,kf,ot,fs,hw.
6	valtrex*.tw,kf,ot.
7	brivudin*.tw,kf,ot,fs,hw.
8	cidofovir*.tw,kf,ot,fs,hw.
9	vistide*.tw,kf,ot.
10	penc?clovir*.tw,kf,ot,fs,hw.
11	denavir*.tw,kf,ot.
12	famic?clovir*.tw,kf,ot,fs,hw.
13	famir*.tw,kf,ot.
14	fomivirsen*.tw,kf,ot,fs,hw.
15	foscarnet*.tw,kf,ot,fs,hw.
16	foscavir*.tw,kf,ot.
17	ganc?clovir*.tw,kf,ot,fs,hw.
18	(cytovene* or nordexoguanosine DHPG sodium* or GCV sodium*).tw,kf,ot.
19	valganc?clovir*.tw,kf,ot,fs,hw.
20	IDOXURIDINE/
21	(idoxuridin* or dendrid herplex stoxil*).tw,kf,ot.
22	letermovir*.tw,kf,ot,fs,hw.
23	TRIFLURIDINE/
24	(trifluridine* or lonsurf*).tw,kf,ot.
25	VIDARABINE/
26	vidarabine*.tw,kf,ot.
27	maribavir*.tw,kf,ot,fs,hw.
28	amenamevir*.tw,kf,ot,fs,hw.
29	pritelivir*.tw,kf,ot,fs,hw.
30	BAY 57‐1293.tw,kf,ot,nm.
31	or/1‐30
32	HEMATOLOGIC DISEASES/
33	exp HEMATOLOGIC NEOPLASMS/
34	(hematolog* adj1 malignan*).tw,kf,ot.
35	(hematolog* adj1 neoplas*).tw,kf,ot.
36	(haematolog* adj1 malignan*).tw,kf,ot.
37	(haematolog* adj1 neoplas*).tw,kf,ot.
38	exp BONE MARROW DISEASES/
39	exp LYMPHOMA/
40	exp LEUKEMIA/
41	lymphom*.tw,kf,ot.
42	leuk?em*.tw,kf,ot.
43	exp Multiple Myeloma/
44	myelom*.tw,kf,ot.
45	sezary.tw,kf,ot.
46	or/32‐45
47	exp BONE MARROW TRANSPLANTATION/
48	exp STEM CELL TRANSPLANTATION/
49	(bone marrow adj2 (transplant* or graft* or transplant* or rescue*)).tw,kf,ot.
50	(stem cell* or stem‐cell*).tw,kf,ot.
51	"progenitor cell*".tw,kf,ot.
52	(ASCT or ABMT or PBPC or PBSCT or PSCT or BMT or SCT or HSCT).tw,kf,ot.
53	TRANSPLANTATION CONDITIONING/
54	Myeloablat*.tw,kf,ot.
55	(nonmyeloablat* or non‐myeloablat*).tw,kf,ot.
56	reduced intens*.tw,kf,ot.
57	(mini‐tra?splant* or minitra?splant*).tw,kf,ot.
58	or/47‐57
59	exp TRANSPLANTATION, HOMOLOGOUS/
60	(allograft* or allo‐graft*).tw,kf,ot.
61	(allotransplant* or allo‐transplant*).tw,kf,ot.
62	(allotrasplant* or allo‐trasplant*).tw,kf,ot.
63	(allogen* or allo‐gen*).tw,kf,ot.
64	((allogen* or allo‐gen*) adj5 (transplant* or trasplant* or graft* or rescue*)).tw,kf,ot.
65	(homograft* or homo‐graft*).tw,kf,ot.
66	homolog*.tw,kf,ot.
67	(homotransplant* or homo‐transplant*).tw,kf,ot.
68	(homotrasplant* or homo‐trasplant*).tw,kf,ot.
69	or/59‐68
70	exp MYELOPROLIFERATIVE DISORDERS/
71	myeloproliferativ*.tw,kf,ot.
72	POLYCYTHEMIA VERA/
73	polycythemia*.tw,kf,ot.
74	(osler vaquez adj3 diseas*).tw,kf,ot.
75	exp THROMBOCYTHEMIA, ESSENTIAL/
76	thrombocytos*.tw,kf,ot.
77	(thrombocythem* or thrombocythaem* or thrombozyth#m*).tw,kf,ot.
78	or/70‐77
79	randomized controlled trial.pt.
80	controlled clinical trial.pt.
81	randomi?ed.ab.
82	placebo.ab.
83	clinical trials as topic.sh.
84	randomly.ab.
85	trial.ti.
86	or/79‐85
87	humans.sh.
88	86 and 87
89	31 and (46 or 58 or 69 or 78) and 88

Appendix 3. Embase search strategy

#	Searches
1	exp randomised controlled trial/
2	exp randomization/
3	exp double blind procedure/
4	exp single blind procedure/
5	random$.tw.
6	or/1‐5
7	Antiviral Agents/
8	Aciclovir/
9	(acyclovir or aciclovir).tw.
10	valaciclovir/
11	(valacyclovir or valaciclovir or valciclovir or valcyclor or valcyclovir).tw.
12	brivudin/
13	cidofovir/
14	Vistide/
15	Penc/
16	Denavir/
17	famciclovir/
18	(Famic or famir or fomivirsen). Tw.
19	Foscarnet/
20	Cytovene/
21	letermovir/
22	trifluridine/
23	lonsurf/
24	vidarabine/
25	maribavir/
26	amenamevir/
27	pritelivir/
28	7‐27
29	6 and 28

Appendix 4. LILACS search strategy

antiviral$ OR acyclovir$ OR aciclovir$ OR valac$ OR valtrex$ OR brivudin$ OR cidofovir$ OR vistide$ OR penc$ OR denavir$ OR famic$ OR famir$ OR fomivirsen$ OR foscarnet$ OR cytovene$ OR nordexoguanosine DHPG sodium$ OR GCV sodium$ OR valganc$ OR idoxuridin$ OR dendrid herplex stoxil$ OR letermovir$ OR trifluridine$ OR lonsurf$ OR vidarabine$ OR maribavir$ OR amenamevir$ OR pritelivir$ [Words]

and hematolog$ OR haematolog$ OR lymphom$ OR leukem$ OR leukaem$ OR myelom$ OR bone marrow$ OR hematolog$ OR haematolog$ OR lymphom$ OR leukem$ OR leukaem$ OR myelom$ OR transplantation$ OR grafting$ [Words]

and ((Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double‐blind method OR Mh single‐blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow‐up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal))) [Words]

Contributions of authors

OBK: drafting the protocol, trial searching and selection, data extraction, statistical analysis.

RB: trial searching and selection, data extraction.

TZ: interpretation of trial data, statistical analysis.

YO: interpretation of trial data, statistical analysis.

DY: interpretation of trial data, statistical analysis.

LL: interpretation of trial data, statistical analysis.

MP: guidance of the Cochrane review, drafting the protocol, trial searching and selection, data extraction, statistical analysis.

Sources of support

Internal sources

• Division of Infectious Diseases, Rambam Health Care Campus, Israel.

External sources

• No sources of support supplied

Declarations of interest

OBK:nothing to declare

RB: nothing to declare

TZ: nothing to declare

YO: nothing to declare

DY: nothing to declare

LL: nothing to declare

MP: nothing to declare

New