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European consensus-based (S2k) Guideline on the Management of Herpes zoster– guided by the EDF in cooperation with EADV [Part 2: Treatment]No recommendationwith respect to anintervention“We cannot makearecommendationwith respect to ”0At the moment, a recommendation in favour or againstan intervention cannot be made due to certain reasons(e.g. no reliable evidence data available, conflictingoutcomes, etc.)Weakrecommendationagainst the use of anintervention“Wesuggestagainst ” We believe that most informed people would make achoice against that intervention, but a substantialnumber would not.Strongrecommendationagainst the use of anintervention“We recommendagainst ” We believe that all or almost all informed people wouldmake a choice against that intervention. Thisrecommendation can be adopted as a policy in mostclinical situations.This second part of the guideline is devoted to the treatment of patients who present with HZ.It is divided into three sections:1) Antiviral medication [background texts and recommendations drafted by B. Marinović (leadauthor), A. F. Nikkels, A. M. Agius, Z. Bata-Csörgő, J. Breuer, G. E. Gross, R. Lapid-Gortzak,T. H. Lesser, U. Pleyer, P. Wutzler],2) Pain management [background texts and recommendations drafted by M. Schäfer (leadauthor), R. Lapid-Gortzak (co-lead author), Z. Bata-Csörgő, G. E. Gross], and3) Local therapy [background texts and recommendations drafted by M. Czarnecka-Operacz(lead author), A. F. Nikkels, A. M. Agius, R. Lapid-Gortzak, T. M. Lesser, U. Pleyer].The final recommendations were formally consented within the expert panel of the guideline.Antiviral medicationGeneral considerations for an antiviral medicationIn the absence of risk factors for complicated courses (see part 1 of the guideline), HZusually is a self-limiting disease. Goals of treatment are to improve the outcomes concerningquality of life (QoL) of the affected patients, extent and duration of cutaneous symptoms, andintensity and duration of acute zoster-associated pain (ZAP). Since postherpetic neuralgia(PHN) is the most frequent sequela of HZ, reducing its incidence is a major secondarytreatment goal. In immunosuppressed or otherwise susceptible patients, treatment goalsextend to reducing the incidence and intensity of accompanying complications.6

European consensus-based (S2k) Guideline on the Management of Herpes zoster– guided by the EDF in cooperation with EADV [Part 2: Treatment]In controlled trials, a reduced duration of skin symptoms and duration or severity of ZAPcould be demonstrated for the systemic application of aciclovir3-6, and famciclovir7 whencompared to placebo. A meta-analysis of four placebo-controlled trials of oral aciclovir coulddemonstrate statically significant superiority over placebo regarding time to cessation ofpain.8 Results from RCTs suggest superiority of valaciclovir over aciclovir consideringduration and/or severity of ZAP9,10. In these studies, no statistically significant differenceswere seen for the resolution of cutaneous symptoms. No statistically significant differencesregarding pain cessation and resolution of skin symptoms were seen in RCTs comparingfamciclovir with aciclovir11, 12, brivudin with aciclovir13, and valaciclovir with famciclovir14. OneRCT, contrary to the previously mentioned trials, demonstrated superiority of famciclovirwhen compared to aciclovir regarding cessation of pain. However this difference onlyoccurred in the 500mg famciclovir group and was of questionable clinical significance.15Another RCT, contrary to the previously mentioned trial on valaciclovir versus famciclovir,found a statistically significantly earlier reduction of pain with famciclovir.16QoL, as a central patient-reported outcome, was only addressed in a very limited number oftrials. Due to the reduction of the duration and intensity of acute ZAP, it is presumed that anantiviral therapy may positively affect QoL. This presumption, however, is not based onscientific observations.A systematic review demonstrated that neither aciclovir nor famciclovir statisticallysignificantly reduced the incidence of PHN four to six months after the onset of acute HZwhen compared to placebo.17 Brivudin was compared with aciclovir in a survey study followup of a previously conducted RCT13, which found a significantly lower incidence of PHN afterbrivudin than after aciclovir treatment.18 In an RCT comparing brivudin with famciclovir,however, no statistically significant between-group differences with respect to painprevalence and duration were seen.19Regarding ocular complications of HZ ophthalmicus, pain duration and resolution ofcutaneous symptoms, systemic application of aciclovir was favourable when compared totopical application of aciclovir in an RCT.20 No statistically significant differences were seen inRCTs of valaciclovir versus aciclovir21 and famciclovir versus aciclovir22.Controlled studies on antiviral medication have also been conducted in immunocompromisedpatients: One RCT compared the efficacy of intravenous aciclovir and placebo inimmunocompromised patients with localized or disseminated HZ; here, aciclovir was superiorconsidering a reduced incidence of complications (including cutaneous and visceraldissemination).23 Another RCT in 48 immunocompromised patients, comparing intravenous7

European consensus-based (S2k) Guideline on the Management of Herpes zoster– guided by the EDF in cooperation with EADV [Part 2: Treatment]aciclovir with oral brivudin did not find statistically significant differences regarding cutaneousor visceral dissemination.24 When compared to vidarabine, aciclovir was statisticallysignificantly superior in preventing cutaneous dissemination, time until cessation of pain andhealing of skin symptoms.25Based on consensus and in line with previous guidelines26, 27, the expert panel recommendsthe initiation of an antiviral medication in the presence of any of the conditions listed inrecommendation #18 (Table 2). Due to the relatively low risk of complications associatedwith an antiviral medication, the initiation of an antiviral medication should also be consideredin patients who are at low risk of sequelae or a complicated course (Table 2).Table 2: Health question 2, Antiviral medication, Recommendations #18 and #19Recommendation#18#19SupportingliteratureWe recommend treating the following patient subgroups withan antiviral medication:HZ of any localization in patients 50 years of ageHZ of the head and/or neck areaHZ of any localization witho moderate to severe zoster-associated paino haemorrhagic or necrotizing lesionso 1 segment involvedo aberrant vesicles / satellite lesionso involvement of mucous membranesZoster in immunocompromised patientsZoster in patients with severe predisposing skindiseases (e.g. atopic dermatitis)Zoster in children and adolescents under long-termtreatment with salicylic acid or corticosteroidsClinicalconsensus;Tyring et al.19957;McKendrick etal. 19863; Huffet al. 19884;Wood et al.19885; Beutneret al. 19959; Linet al. 200110;Shen et al.200411;Shafran et al.200412;Wassilew et al.200313; Tyringet al. 200014;In patients younger than 50 years of age who present with HZDegreef et al.of the trunk or extremities, without being at risk of or displaying 199415; Ono etsigns of a complicated course, we suggest initiating anal. 201216;antiviral medication.Balfour et al.198323; Wutzleret al. 199524;Shepp et al.198625StrengthConsensus 90 % 90 %Based on consensus, an antiviral therapy using intravenous aciclovir is suggested in patientswho present with complicated HZ or who are at risk of a complicated course (conditionsspecified in recommendation #20, Table 3).Table 3: Health question 2, Antiviral medication, Recommendation #20Recommendation#20We suggest using intravenous aciclovir in patients whopresent with complicated HZ or who are at risk of acomplicated course. This includes the following patient groups:HZ of the head and/or neck area, particularly sensus 90 %8

European consensus-based (S2k) Guideline on the Management of Herpes zoster– guided by the EDF in cooperation with EADV [Part 2: Treatment]--elderly patientsHZ with haemorrhagic/necrotizing lesions, 1segment involved, aberrant vesicles / satellitelesions, involvement of mucous membranes, orgeneralized zosterHZ in immunocompromised patientsHZ with signs of visceral or central nervous systeminvolvement (dosage escalation up to 15mg/kgbodyweight 3x/d possible, treatment for up to 21days)Allthough limited evidence suggests superior efficacy of valaciclovir, famciclovir and brivudinover orally administered aciclovir regarding different outcomes, this evidence was notconsistently reproduced. Brivudin offers the advantage of a reduced dosing frequency.However, other factors should also be considered in choosing among an antiviral medication(Table 4). Costs are the lowest for aciclovir. Brivudin is not available in all countries. It iscontraindicated for immunosuppressed patients and patients who have been treated with 5fluoropyrimidine drugs (e.g. 5-fluorouracil, flucytosin) within the last 4 weeks due to possiblelife-threatening drug-interactions.Table 4: Health question 2, Antiviral medication, Recommendation #21Recommendation#21In patients who do not present with an indication to initiate anintravenous treatment with aciclovir, we suggest shareddecision making with respect to using oral aciclovir,valaciclovir, famciclovir or brivudin, taking e.g. practicabilty(dosage frequency), costs, contraindications, comorbidity anddrug interactions into sClinicalconsensus 90 %Adaptation of dosages to the renal function according to the product information is necessaryfor aciclovir, valaciclovir and famciclovir. For these agents, creatinine should be checked inpatients with known or suspected renal insufficiency at the time of treatment initiation (Table5).Table 5: Health question 2, Antiviral medication, Recommendation #22Recommendation#22We suggest checking creatinine in patients with known orsuspected renal insufficiency at the time of initiation of anantiviral medication with aciclovir, famciclovir, or Clinicalconsensus 90 %Due to the lack of trials evaluating the initiation of a systemic antiviral medication more than72 hours after onset of the rash, there is no evidence basis to recommend the administrationof antivirals in this setting. Based on consensus and as recommended in guidelinespreviously26, 27, we suggest an initiation of an antiviral medication at a later point in time in the9

European consensus-based (S2k) Guideline on the Management of Herpes zoster– guided by the EDF in cooperation with EADV [Part 2: Treatment]presence of any of the conditions listed in recommendation #23 (Table 6), if treatment within72 hours after the onset of cutaneous symptoms was not possible.Table 6: Health question 2, Antiviral medication, Recommendations #23 and #24SupportingliteratureStrengthConsensusWe suggest initiating antiviral medication as early as possible,within 72 hours after the onset of symptoms, or at a later timeas long as new vesicles appearin patients at risk of a complicated course or withmanifest complicationsin patients with signs of cutaneous, visceral orneurological disseminationin the case of HZ ophthalmicus or HZ oticusin all immunocompromised patientsClinicalconsensus 90 %We suggest against initiating an antiviral medication inpatients who have ‘uncomplicated’ HZ (classical, unilateralthoracic or lumbar HZ in patients younger than 50 years ofage, without signs of a complicated course) who present 72hours after the onset of skin symptoms.Clinicalconsensus 90 %Recommendation#23#24There are few trials evaluating whether an extended period of intake of antivirals providesbenefit over the standard administration for seven days. These trials found no clinicallyrelevant difference9 or a benefit of questionable clinical importance with prolonguedtreatment28. Antiviral medication should be prolongued until no more vesicular lesionsappear. If vesicle formation extends to more than seven days, the diagnosis should bereassessed and resistancy to the antiviral medication considered.Specific situationsRenal function impairmentFor HZ in patients with renal function impairment, we suggest initiating an antiviralmedication with brivudin in the case of indication for oral treatment or with intravenousaciclovir with dosage adaptation in the case of indication for intravenous treatment as definedabove (Table 7). This recommendation is based on consensus among the expert panel andon the reasoning that brivudin is relatively less dependent on renal excretion than otherantiviral agents and intravenous (in-patient) treatment with aciclovir allows for closeexaminations of the renal function during the course of treatment.Table 7: Health question 2, Antiviral medication, Recommendation nsus10

European consensus-based (S2k) Guideline on the Management of Herpes zoster– guided by the EDF in cooperation with EADV [Part 2: Treatment]#25In patients with renal function impairment, we recommendusing oral brivudin (if oral antiviral medication is indicated) orintravenous aciclovir with dosage adaptation (if intravenoustreatment is indicated as defined above).Clinicalconsensus 90 %Ophthalmic HZThe treatment strategy in case of HZ ophthalmicus and necessity for an ophthalmologicreassessment should be determined by an ophthalmologist. Generally, treatmentrecommendations as specified above apply. Acute retinal necrosis (ARN) as complication ofHZ ophthalmicus is an ophthalmic emergency that has to be managed under closesupervision of an ophthalmologist. Since ARN is rapidly progressive and may spread to thecontralateral eye, it requires immediate treatment with an intravenous induction and oraltreatment continuation of antivirals for 3–4 months (Table 8). The prolonged treatment isrecommended in order to prevent involvement of the second eye.29, 30 The additional use ofsystemic corticosteroid in these patients is still controversial in respect to its appropriateinitiation. A loading dose of 0.5-1.0 mg/kg/day of corticosteroids (prednisolone) for the first 7–10 days of treatment has been suggested30,31. We suggest using topical and systemiccorticosteroids as adjunctive anti-inflammatory treatment (Table 8). Caution should be takento use corticosteroids in the absence of antiviral medication, since this may promote viralreplication and even initiate ARN.Table 8: Health question 2, Antiviral medication, Recommendations #26 and #27SupportingliteratureStrengthConsensusIn patients who present with acute retinal necrosis (ascomplication of HZ ophthalmicus), we recommend inductiontreatment with intravenous aciclovir (10mg/kg bodyweight 3x/dfor 7-10 days)* followed by oral aciclovir (800mg 5x/d for 3-4months)*.*Dosage adaptation may be necessaryWong et al.201330; Pleyeret al. 201529 90 %In patients who present with acute retinal necrosis (ascomplication of HZ ophthalmicus), we suggest to use topicaland systemic corticosteroids as adjunctive anti-inflammatorytreatment.Wong et al.201330;Tibbetts et al.201031 75 %Recommendation#26#27Otic HZThe treatment strategy in case of HZ oticus with involvement of the facial nerve (i.e. RamsayHunt syndrome) or with severe pain and cranial nerve palsies should be determined by anotorhinolaryngologist. The expert panel suggests initiating a combination therapy ofintravenous aciclovir and oral corticosteroids (Table 9). Corticosteroids are still considered11

European consensus-based (S2k) Guideline on the Management of Herpes zoster– guided by the EDF in cooperation with EADV [Part 2: Treatment]the best treatment in viral inflammatory processes of the facial nerve.32 In HZ oticus withsevere pain and cranial nerve palsies, intravenous aciclovir followed by oral treatment forone to two weeks has been used with success.33-35 Combination treatment is more effectivein restoring facial nerve function after HZ oticus36 and seems to offer better prognosis.37Table 9: Health question 2, Antiviral medication, Recommendation #28SupportingliteratureStrengthConsensusde Ru et al.201136;Coulson et al.201137 90 %Recommendation#28In patients with HZ oticus with involvement of the facial nerve(Ramsay-Hunt syndrome) or with severe pain and multiplecranial nerve palsies, we suggest combination therapy ofintravenous aciclovir with systemic corticosteroids.PregnancyDue to the lack of systematically assessed data on the safety of antiviral medications duringpregnancy, careful consideration of possible harms and benefits is recommended. In theabsence of the risk of complications (see part 1 of the guideline), we suggest againstinitiating an antiviral medication in pregnant women who present with HZ (Table 10). In alarge population-based retrospective controlled cohort study and in a study including datafrom registries, the risk of birth defects in children whose mothers had been exposed toaciclovir was not increased. For other antiviral agents (valaciclovir and famciclovir), thenumber of cases was too small to draw conclusions.38,39Therefore, the initiation of anantiviral medication in pregnant women using aciclovir may be suggested in the presence ofrisk factors for complicated courses of disease, if potential benefits to the mother outweighthe potential risks to the fetus (Table 10).Table 10: Health question 2, Antiviral medication, Recommendations #29 and nsusClinicalconsensus 90 % 90 %#29In the absence of the risk of complications, we suggestagainst initiating an antiviral medication in pregnant women.#30We suggest the initiation of an antiviral medication in pregnantClinicalconsensus,women in the presence of risk factors for complicated coursesPasternak et al.of disease, if potential benefits to the mother outweigh the201038; Reiffpotential risks to the fetus. In this case, aciclovir should beEldridge et al.used preferentially.200039ChildrenDue to the lack of data on the safety in children, we recommend careful consideration ofpossible harms and benefits of an antiviral medication. Generally, HZ in children presentswith less morbidity than HZ in adults.40, 41 In the absence of the risk of complications (see part12

European consensus-based (S2k) Guideline on the Management of Herpes zoster– guided by the EDF in cooperation with EADV [Part 2: Treatment]1 of the guideline), we suggest against initiating an antiviral medication in children (Table 11).The initiation of an antiviral medication in children is suggested in the presence of risk factorsfor complicated courses of disease, if potential benefits outweigh the potential risks (Table11).Table 11: Health question 2, Antiviral medication, Recommendations #31 and nsus#31In the absence of the risk of complications, we suggestagainst initiating an antiviral medication in children.Clinicalconsensus 90 %#32We suggest the initiation of an antiviral medication in childrenin the presence of risk factors for complicated courses ofdisease, if potential benefits of the treatment outweigh thepotential risks.Clinicalconsensus 90 %Therapy refractory / chronic HZ lesionsClinical resistance of VZV infections to aciclovir should be considered in case of treatmentfailure of drug therapy for at least 10 to 21 days42,43, particularly in patients presentingverrucous VZV infections44. When aciclovir resistance occurs, treatment with alternativemedications, e.g. with brivudin or another TK dependent antiviral agent (famciclovir) may berequired. In small retrospective case series of immunocompromised patients with aciclovirresistant HZ, a response to intravenous foscarnet therapy has been observed.42, 45 Anecdotalreports exist which demonstrate responses of aciclovir-resistant VZV-strains to cidofovir.46-48Both agents are not licensed for the treatment of HZ. They should only be used in verysevere cases, with caution due to the risk of severe adverse effects, and only followingdiscussion with virologists, pharmacists and intensive discussion of the risk-benefit balancewith the patient. In the case of chronic HZ lesions, we refer to a revie

Zagreb School of Medicine, Zagreb, Croatia 4. Department of Anesthesiology, Charité - Universitätsmedizin Berlin, Berlin, Germany 5. Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland 6. Department of Otorhinolaryngology, The Medical School, University of Malta, Msida, Malta 7. Department of Dermatology and .