Management of herpesvirus reactivations in patients with solid tumours and hematologic malignancies: update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) on herpes simplex virus type 1, herpes simplex virus type 2, and varicella zoster virus

Herpesviridae persist — after primary infection usually in childhood or adolescence — lifelong in their hosts and can reactivate in situations of immune deficiency, like malignant diseases. Rates of reactivation depend on several factors such as underlying disease [1, 2], disease activity [3], antineoplastic therapy [1, 2], co-medication, comorbid conditions, and age [1]. Reactivation can lead to localized disease, as stomatitis and genital ulcers in case of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) or herpes zoster in case of varicella zoster virus (VZV), but also to viral dissemination, cerebral or visceral disease contributing to significant morbidity and mortality [4, 5]. Different strategies to prevent symptomatic reactivation are possible: risk-adapted pharmacological prophylaxis, suppressive therapy (after severe complication or in case of multiple reactivations), and pre-emptive treatment (in asymptomatic patients after virus detection by screening methods) [6]. Additionally, to prevent herpes zoster vaccination has become available as general prophylaxis and is recommended for adults aged 50 years or older. The European Medicines Agency (EMA) has recently expanded the approval to adults ≥ 18 years who are at increased risk of herpes zoster.

Quantity of data as well as systematic reviews and present guidelines describe risks of herpesvirus reactivation and prophylactic interventions in patients undergoing allogeneic [6, 7] or autologous [8] hematopoietic stem cell transplantation (HSCT). However, systematic analyses and trials of herpesvirus reactivation in patients with solid tumours or hematologic malignancies who are not candidates for HSCT are limited [4] but increasing, acknowledging the variable risks in the era of new therapeutics. This guideline summarizes current evidence on herpesvirus reactivation in patients with solid tumours and hematologic malignancies not undergoing allogeneic or autologous HSCT or cellular therapy (CAR T cell therapy) and constitutes an update of the guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) of 2015 “Antiviral prophylaxis in patients with solid tumours and hematological malignancies” [9] focusing on HSV-1, HSV-2, and VZV.

In 2015, recommendations for antiviral prophylaxis in patients with solid tumours and hematologic malignancies were published by the AGIHO [9]. Meanwhile, many new antineoplastic drugs have been approved. Drug combinations are used frequently for the treatment of patients with solid tumours and hematological malignancies. Moreover, vaccination has become available as preventive strategy for VZV reactivation. Therefore, an update of the recommendations was deemed necessary. This article represents the update regarding HSV-1, HSV-2, and VZV; recommendations regarding Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus type 6 (HHV-6) will be updated in a separate article.

An expert panel of twelve oncologists, infectious disease specialists, and microbiologists — all members of the AGIHO — conducted independent literature search of the PubMed and Medline databases, using the following search terms: herpes simplex cancer prophylaxis, herpes simplex cancer therapy, varicella zoster cancer prophylaxis, and varicella zoster cancer therapy, restricted to adult patients. The literature search extended initially from January 2013 to August 2020, and was updated on 30 April 2021. Articles in English and German were included. References and other literature published before 2013 were included in the assessment process if relevant. Abstracts presented at the annual meetings of the DGHO, the European Hematology Association (EHA), the European Society of Medical Oncology (ESMO), the American Society of Hematology (ASH), and the American Society of Oncology (ASCO) from 2013 to 2020 were included if relevant. The expert panel weighed the search results in a stepwise consensus process consisting of personal meetings, video conferences, and e-mail discussions. Strength of recommendation (SoR) and quality of evidence (QoE) were graded according to the criteria applied by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) [10] (Table 1). A formal consensus meeting took place at the general assembly of the AGIHO, as video conference on 6 October 2020, to which all members of the AGIHO were invited. Recommendations were finally approved by discussion and online voting among the participating experts. This guideline provides an evaluation of present evidence (which is sparse in some fields) and the experts’ consensus interpretation. The recommendations intend to assist physicians in decisions on individual patients [8].

After primary infection, herpesviridae establish latency in sensory neural ganglia [11] (Table 2). Reactivation can occur by several triggers in the healthy population, but particularly in situations with reduced cell-mediated immunity [12]. Risk of symptomatic reactivation increases with intensity and duration of functional T cell suppression [4, 11].

Primary infection with HSV-1 occurs mainly in the oropharyngeal mucosa, but is unrecognized or asymptomatic in more than 80% of individuals [13, 14]. On the contrary, primary infection can be severe, manifesting as encephalitis, particularly in the immunocompromised individual. Although seroprevalence of HSV-1 reaches 90% in the general population by the age of 50 years [14, 15], only about one-third will suffer from symptomatic reactivation during lifetime [14]. Symptomatic reactivation typically occurs as herpes labialis (“coldsores”), but in the immunocompromised person, herpes stomatitis is often seen [12] (Table 2). Life-threatening reactivations are HSV encephalitis, HSV pneumonitis, and rarely other visceral manifestations [5, 16‐18] (Table 2). Besides, HSV-1 is increasingly found in genital herpes [19] (Table 2). HSV-1 can also be detected in oral swabs in asymptomatic or oligosymptomatic individuals [14, 20].

Acquisition of HSV-2 results in infection at genital, perigenital, or anal skin sites, with seeding to sacral ganglia [21]. Occurrence in the oropharyngeal mucosa is less frequent in HSV-2. Severe primary manifestations are meningitis or other organ disease, mainly at very young age or in the immunocompromised. Seroprevalence shows considerable variation in different populations and ranges from 15 to 25% in industrialized countries [22]. Symptomatic reactivations mostly lead to genital ulcerous lesions and occur frequently [19]. Asymptomatic viral shedding is also common [23]. Severe manifestations are similar to HSV-1 (Table 2).

Primary infection with VZV in the naïve population results in varicella disease (“chickenpox”). Besides the characteristic skin lesions of macules, which progress to papules and then vesicles, systemic symptoms, like fever, may be present and are more pronounced in adolescents or adults compared to children [11]. Primary infection with VZV can affect organs and be life-threatening if it occurs in the immunocompromised individual. VZV establishes latency in sensory neurons and commonly reactivates as herpes zoster (“shingles”) in the elderly (≥ 50 years old), due to waning T cell immunity [11, 24, 25] (Table 2). While the incidence rate of herpes zoster in the population is 3.2 cases per 1000 person-years [26], it increases with age to 9.1 per 1000 person-years among persons 50 years of age or older [27]. Likewise, other conditions of T cell suppression may lead to herpes zoster in the younger population [24]. The incidence rate of herpes zoster is reported to be between 12 per 1000 person-years in individuals with solid tumours receiving immunosuppressive chemotherapy and 31 per 1000 person-years in patients with hematological malignancies receiving treatment [28, 29]. Typical herpes zoster appears as vesicular lesions in the distribution of dermatomes, accompanied by neuropathic pain [11], which can become chronic, leading to post-herpetic neuralgia in 15% [24]. Herpes zoster affecting the cranial nerves V (zoster ophthalmicus) or VII/VIII (zoster oticus or Ramsay Hunt syndrome) can be followed by longterm visual or hearing dysfunction. Further manifestations of reactivation in immunocompromised people are disseminated herpes zoster, meningoencephalitis, cerebral vasculopathy, pneumonitis, hepatitis, pancreatitis, or visceral zoster, that might be misdiagnosed as acute abdomen [11, 24, 30‐32] (Table 2). Because VZV is highly contagious, > 90% of people have become infected before adolescence prior to widespread implementation of vaccination [24]. However, since vaccination against varicella during early childhood with a live attenuated varicella virus (vOka) has become universal practice in Germany in 2004 like in several countries [24, 25], the younger generation will not have experienced varicella disease, but the majority will have been vaccinated. Reactivation of the vaccine-type VZV (vOka) has been seen sporadically [24].

Studies on prophylactic strategies used different definitions of viral manifestation [33, 34] and focused on different endpoints: clinical manifestations (without virological confirmation) or clinical manifestations with virological findings or virus detection. Mortality is only reported in few studies. Whereas the terms disease, infection, and reactivation are not used consistently throughout literature, we will nominate primary manifestations as either infection (asymptomatic) or disease (symptomatic). Primary manifestations rarely occur during cancer treatment. By contrast, reactivations are frequent in cancer patients, particularly while on tumour treatment [35] and can be asymptomatic (viral shedding) or symptomatic, thus to be named here as disease by reactivation (clinical reactivation) (Table 2). In the immunocompromised patient, the clinical picture may be severe [5, 11, 21, 36] contributing to morbidity and mortality (Table 2). Risk-dependent prophylactic strategies are warranted to reduce the rate of clinical reactivation (e.g. stomatitis, herpes zoster, fever), complications (e.g. dissemination, post-herpetic neuralgia) and mortality. These are summarized in this guideline.

Acyclovir has for long been the mainstay for prophylaxis and treatment of HSV and VZV in immunocompromised patients [21].

A systematic review of oral herpetic viral disease of the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) showed that acyclovir orally is effective in preventing oral herpetic viral disease in patients with solid tumours or hematologic malignancies [34]. A most recent network meta-analysis compared different acyclovir regimens, evaluated in thirteen randomized controlled trials (RCT) on prevention of oral HSV disease in patients undergoing cancer treatment, including allogeneic or autologous HSCT: oral acyclovir 400 mg four times daily (QID) or oral acyclovir 400 mg twice daily (BID) or intravenous acyclovir 250 mg/m² TID were identified as most effective regimens to prevent oral HSV disease [36]. Since oral acyclovir 400 mg BID had an almost similar activity to oral acyclovir 400 mg QID, clinicians might prefer prescribing acyclovir 400 mg BID in most patients, particularly if renal function is a concern [36]. Valacyclovir, the L-valyl ester of acyclovir, has better oral bioavailability [36, 59]. Valacyclovir has been shown to be non-inferior to acyclovir in preventing HSV stomatitis in patients with acute leukaemia and intensive chemotherapy [60]. However, due to the limited number of reported trials, evidence is low and a network meta-analysis was not possible [36].

We recommend oral acyclovir 400 mg BID or 400 mg QID as prophylaxis of oral HSV disease (AIIr). Oral valacyclovir can be used alternatively (BI), but the best regimen (250 mg BID or 500 mg BID) has not yet been defined. For patients not tolerating oral medication, intravenous acyclovir 250 mg/m² TID is suitable (AIIr).

Long-term (6 to 12 months) oral administration of acyclovir, valacyclovir, or famciclovir, a well-absorbed prodrug of penciclovir, suppresses genital herpes in patients who have frequent recurrences (suppressive therapy). In a Cochrane meta-analysis of 26 trials in patients with at least four recurrences of genital herpes per year, 6950 participants were randomly assigned to either of the antiviral drugs or placebo [22]. Patients with immunosuppression were excluded in most of the trials [22]. Clinical recurrence of genital herpes was reduced with acyclovir (nine trials, pooled RR 0.48), valacyclovir (four trials, pooled RR 0.41), or famciclovir (two trials, pooled RR 0.57) [22]. The network meta-analysis was unable to determine which of the drugs was most effective [22, 23].

Acyclovir has been shown to reduce clinical VZV reactivation and to increase survival in patients undergoing HSCT, for whom the reactivation risk of VZV is as high as 50% [35]. Thus, antiviral prophylaxis with acyclovir has become standard of care in allogeneic and autologous HSCT recipients [4, 6, 8, 38, 61]. VZV reactivation risk in non-HSCT patients undergoing tumour treatment is also elevated, particularly in patients with lymphoma or multiple myeloma and best described for patients with multiple myeloma treated with proteasome-inhibitors, being up to 15% without antiviral prophylaxis [62]. VZV reactivation has remarkable influence on morbidity and quality of life. Therefore, antiviral prophylaxis is standard of care in these patients (for recommendations see below). However, no randomized controlled trials have been performed to find the most effective regimen (acyclovir has been used as 400 mg orally once daily, BID or TID most widely) or to compare acyclovir to valacyclovir or famciclovir.

We recommend oral acyclovir to reduce clinical VZV reactivation; dosages from 400 mg once daily to 400 mg TID have been shown to be effective (AII). Valacyclovir may also be effective by mechanism of action and due to transferred evidence, but has rarely been systematically tested [63, 64] (CIIu). For patients not tolerating oral medication, intravenous acyclovir is suitable, but evidence on the most appropriate dosage is lacking (BIIt).

Of note, all three nucleoside analogues (acyclovir, valacyclovir, famciclovir) require dose adjustment in patients with renal impairment.

VZV is the only human herpesvirus for which highly effective vaccines are available [24]. Since the introduction of a live attenuated varicella virus (vOKA) during childhood as primary prophylaxis against VZV, varicella disease and severe primary manifestations have decreased [25]. Still, the adult population nowadays almost universally experienced varicella disease and is therefore at risk of VZV reactivations, and incidences of VZV reactivation are rising. Recently, two different types of herpes zoster vaccines have been studied and approved [26]: The live-attenuated zoster vaccine Zostavax® is contraindicated in the immunocompromised [26]. The adjuvanted recombinant (non-live) subunit zoster vaccine Shingrix® has recently been approved for the prevention of herpes zoster and post-herpetic neuralgia for adults 50 years of age or older and for adults of any age at increased risk of herpes zoster. It has been studied in specific groups of patients with malignancies and shown to be safe [26, 65‐68]. Nevertheless, immunogenicity [26, 66‐68] and efficacy rates [26] seemed lower in patients while on tumour treatment than in the general elderly population: For instance, the incidence rate of herpes zoster was reduced from 66.2 per 1000 patient-years (placebo group) to 8.5 per 1000 patient-years (vaccine group) in 562 adults (≥ 18 years old) with hematologic malignancies in the zoster-39 trial [26], whereas in the ZOE-50 trial, herpes zoster incidence per 1000 patient-years was reduced from 9.1 (placebo group) to 0.3 (vaccine group) in more than 13.000 persons of at least 50 years of age [27]. Considering herpes zoster, vaccination with the recombinant zoster vaccine Shingrix® is recommended due to safety and immunogenicity, although data on clinical efficacy in certain malignancies are preliminary [66, 67, 69] and long-term protection rates are sparse. Until more data are available, particularly of comparative trials for vaccination versus pharmacological prophylaxis, it is suggested to apply acyclovir additionally in high risk patient groups (for recommendations see below). Around 30% of participants of the zoster-39 trial (i.e. patients with hematologic malignancies) received antiviral prophylaxis [26]. Nevertheless, it is anticipated that an increased use of the recombinant zoster vaccine Shingrix® in immunosuppressed patients would — if clinically shown effective — lead to a decreased use of pharmacological prophylaxis [70].

Decision for treatment is made after considering the diagnosis on clinical grounds, before (and sometimes without) it is confirmed by virus detection (see Diagnostics). Treatment modalities depend on (a) type and severity of HSV or VZV reactivation, (b) the clinical condition of the patient, and (c) severity of immunosuppression. Oral administration can be used if disease is localized, symptoms are minor, and the immunosuppression can be considered as mild. In these cases, valacyclovir (1000 mg TID) and famciclovir (500 mg BID or TID respectively for herpes genitalis or herpes zoster) may be alternatives to oral acyclovir (400 mg five times per day for localised HSV disease or 800 mg five times per day for herpes zoster), with the limitation that data are deduced from the immunocompromised cohort of patients with human immunodeficiency virus (HIV). Therapy lasts 7 to 10 days in most cases. While on therapy, close clinical monitoring is essential to switch early to intravenous acyclovir when signs of cutaneous dissemination, involvement of the central nervous system, or other organs occur [139]. In patients with severe immunosuppression and thus a high risk for complications, upfront intravenous therapy should be considered [11, 52]. Careful clinical decision making is necessary as early effective therapy is important to reduce complication rate. For intravenous therapy, acyclovir is used with 5 mg/kg body weight TID for HSV reactivation by localized disease [38] and 10 mg/kg body weight TID for disseminated, cerebral or visceral disease of HSV and VZV and for herpes zoster. Disseminated disease as well as cerebral and visceral disease requires treatment for at least 14 days.

At large, treatment recommendations for patients with malignancies are consistent with recommendations and guidelines for the general population [19, 24, 52, 140‐143] as trials specific for patients with malignancies have not been performed. It has to be noticed, though, that brivudin is not approved in the immunocompromised patients and most importantly contraindicated in patients treated with 5-fluoruracil or its prodrugs (like capecitabine, tegafur) due to potential lethal hematologic toxicity [25, 38, 144]. Further information about treatment in the immunocompromised patient can also be derived from the AGIHO guideline on infections of the central nervous system in patients with hematological disorders [49] and from the S2-consensus-based guideline, referring to patients after solid organ transplantation or allogeneic HSCT [38].

This guideline updates our recommendations on antiviral prophylaxis in patients with solid tumours and hematological malignancies of 2015 [9]. As it is relevant for some strategies and an often raised question in clinical practice, we included recommendations on diagnostics.

HSV stomatitis (in patients with leukaemia treated with intensive chemotherapy) and herpes zoster (in patients with lymphoma and multiple myeloma) are the most frequent clinical herpesvirus reactivations and affect a considerable number of patients. Prophylaxis with acyclovir (or valacyclovir) has been successfully implemented to reduce these reactivations in different situations, while insufficient data still exist about the effect of antiviral prophylaxis on severe HSV or VZV disease and mortality. Since the previous publication of our guideline, only few prospective randomized studies have been published on prophylaxis of HSV und VZV. But evidence originating from retrospective trials and registries has increased substantially. Recent developments in herpes zoster vaccination strategies have led attention on VZV reactivation rates and clinical sequelae of herpes zoster. Incidence rates from large population groups are now available to better assess relative risk in different groups of patient with malignancies. We therefore update our recommendations from 2015 with regard to different patient groups. Because increasing data show the considerable risk of disease by reactivations of HSV or VZV in specific patient populations, the recommendation was often upgraded. Vaccination strategies will most likely influence the risk of VZV reactivations in the future. Up to now, some data exist on clinical outcomes, mainly in patients with hematologic malignancies, and immunological efficacy (with variable results). Further research is necessary on vaccination efficacy (short- and long-term) in different anticancer treatments.