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2017 European guidelines for the management of genital herpes Authors: RajulPatel1,OliverJohnKennedy2,EmilyClarke1,AnnaGeretti3,ArvidNilsen4,ElizabethFoley1,Stephan Lautenschlager5, John Green6, Gilbert Donders7, Willem van der Meijden8, Mikhail Gomberg9, Harald Moi10,11andElizabethFoley1 1. 2. 3. 4. 5. 6. 7. 8. 9. DepartmentofGenitourinaryMedicine,Southampton,UK SouthamptonMedicalSchool,Southampton,UK DepartmentofVirology,UniversityCollegeLondon,London,UK DepartmentofDermatovenerology,UniversityofBergen,Bergen,Norway DermatologischesAmbulatoriumTriemli,Zurich,Switzerland CentralandNorthWestLondonNHSTrust,London,UK DepartmentofObstetricsandGynecology,UniversityHospitalAntwerp DepartmentofDermatology,ErasmusMedicalCentre,Rotterdam,TheNetherlands DepartmentofDermatologyandVenereology,MoscowStateUniversityforMedicineandDentistry, Moscow,Russia 10. DepartmentofVenereology,theOlafiaClinic,OsloUniversityHospital 11. InstituteofClinicalMedicine,UniversityofOslo,Oslo,Norway Abstract: Genitalherpesisoneofthecommonestsexuallytransmittedinfectionsworldwide.Usingthebest availableevidence,thisguidelinerecommendsstrategiesfordiagnosis,managementandfollow-upof theconditionaswellasforminimisingtransmission.Earlyrecognitionandinitiationoftherapyiskey andmayreducethedurationofillnessoravoidhospitalisationwithcomplications,includingurinary retention,meningismorseveresystemicillness.Theguidelinecoversarangeofcommonclinical scenarios,suchasrecurrentgenitalherpes,infectionduringpregnancyandcoinfectionwithhuman immunodeficiencyvirus. Declarationsofinterest: Noneoftheauthorsoreditorshadanyconflictsofinterestforthecontentofthisguideline. Keywords: Herpessimplex,HSV,genitalherpes,Europe,treatment,antibiotic Revisiondate:05/12/2016 INTRODUCTION First infection with either herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) is termed primary infectionandresultsineithersymptomaticdiseaseatthesiteofviralentry(i.e.onthefaceorgenital area)orasymptomatic,andthusunrecognised,infection.Inadditiontheremaybesystemicsymptoms, as with other acute viral illnesses. Only a third of patients who acquire genital herpes have any recognised clinical features at the time of acquisition.Following infection, the virus becomes latent in the local sensory ganglion, periodically reactivating to cause symptomatic lesions, or undergo asymptomatic,butnonethelessinfectious,viralshedding.GenitalherpescanbecausedbyeitherHSV-1 –theusualcauseoforo-labialherpes–orbyHSV-2.Infectionwitheitherviruscancauseanidentical initial illness; however, the actual clinical presentation may depend upon previous HSV-1 or HSV-2 infection, and previous sites of infection. Subsequent recurrence frequency is greater for HSV-2 than HSV-1diseasewheninfectioninvolvesthegenitalarea. Transmissionrisk Risk of transmission appears to be greatest during lesional recurrences or prodrome, and patients shouldbeadvisedtoabstainfromsexualcontactduringthistime.Transmissioncanoccurintheabsence of lesional recurrence as a result of sub-clinical viral shedding. Efficacy of condoms to prevent sexual transmission has not been formally assessed; however, indirect evidence from failed vaccine trials providesstrongsupportfortheirconsistentusage(IIb,B).1,2 DIAGNOSIS Clinicaldiagnosis Although classical genital herpes can be recognised by the presence of typical papular lesions progressing to vesicle and ulcer formation, associated with local adenitis and in recurrent cases precededbyprodromalsymptoms,thefeaturesinmanypatientscanbehighlyvariable.Themajorityof patients will suffer from atypical lesions where signs may be easily confused with other genital dermatoses. In atypical cases, depending upon clinical diagnosis alone should be avoided, whenever possible. Laboratorydiagnosis Virusdetection • • • • • • Laboratory confirmation is recommended in all patients with suspected genital herpes, using methods that directly demonstrate the virus in genital specimens, typically swabs taken from thebaseofthelesion(vesiclesshouldbeunroofedwithaneedleorscalpelblade)andplacedin viraltransportmedium(Ib,A).3 HSV typing into HSV-1 and HSV-2 is recommended in all patients with first-episode genital herpestoguidecounsellingandmanagement(III,B).1 AsHSVsheddingisintermittent,testingswabsfromasymptomaticpatientsisnotrecommended forroutinediagnosissinceitisunlikelytoyieldconfirmationofcarrierstatus(Ib,A).1 HSVDNAdetectionisnowconsideredthegoldstandardfordiagnosis.Itisbothmoresensitive and specific than HSV cell culture (Ib, A).3-8 Cell culture may occasionally be required to determineanti-viralsensitivityandtogenerateenoughvirusfortransmissionstudies. HSVDNAdetectionbyreal-timePCRincreasesHSVdetectionratesinmuco-cutaneousswabsby 11-71% compared with virus culture and is recommended as the preferred diagnostic method (Ib,A).3,7,8Real-timePCRcantoleratelessstringentconditionsforsamplestorageandtransport than virus culture, and allows the rapid detection and typing of HSV with a lower risk of contaminationthantraditionalPCRassays. Viral antigen detection methods such as direct immunofluorescence assay (IFA), enzyme immunoassay(EIA)andTzanckandPapanicolaoustainingarenolongerrecommendedexceptin extremelylimitedresourcesettings(Ib,A).9-11 HSVtype-specificserology Serologicaltestingisnotroutinelyrecommendedinasymptomaticpatients(IV,C),butmaybeusefulin thefollowinggroups:1,12-17 • • • Historyofrecurrentoratypicalgenitaldiseasewhendirectvirusdetectionmethodshavebeen negative (III, B). HSV-2 antibodies are supportive of a diagnosis of genital herpes; HSV-1 antibodies do not differentiate between genital and oro-pharyngeal infection. Counselling of HSV-2 IgG negative, HSV-1 IgG positive patients should take into account that HSV-1 is an uncommoncauseofrecurrentgenitaldisease.1 First-episode genital herpes, where differentiating between primary and established infection guidescounsellingandmanagement(III,B).Attheonsetofsymptoms,theabsenceofHSVIgG against the virus type detected in the genital lesion is consistent with a primary infection.1 Seroconversionshouldbedemonstratedatfollow-up. Sexualpartnersofpatientswithgenitalherpes,whereconcernsareraisedabouttransmission. Serodiscordant couples can be counselled about strategies to reduce the risk of infection and disease(Ib,A). CaremustbetakenininterpretingnegativeresultssinceantibodiestobothHSV-1and2canbelostwith time. Testingofasymptomaticpregnantwomenisnotroutinelyrecommended,butisindicatedwhenthereis ahistoryofgenitalherpesinthepartner(IIb,B).18-20HSV-1and/orHSV-2seronegativewomenshouldbe counselledaboutstrategiestopreventanewinfectionwitheithervirustypeduringpregnancy. LimiteddatasuggestsanincreasedriskofperinatalHIVtransmissionamongHSV-2seropositiveHIVinfectedwomen.21,22Asevidenceisnotconsistent,testingofHIVpositivepregnantwomenisnot routinelyrecommended(IV,C).23 HSV serological assays should be used that detect antibodies against the antigenically unique glycoproteins gG1 and gG2.11, 24 Non type-specific HSV antibody assays are of no value in the managementofgenitalherpes. Westernblot(WB)isthediagnosticgold-standard.Itis>97%sensitiveand>98%specific,butislabourintensiveandnotcommerciallyavailable.25,26 The sensitivities and specificities of commercially available seroassays can vary significantly across populations.27-36 The positive predictive value (PPV) in low prevalence settings can make results uninterpretable.Falsenegativeresultsaremorelikelytooccurinearlyinfectionandcanberesolvedby repeattesting. HSVseroprevalencerates,thepresenceofriskfactorsforgenitalherpes,andclinicalhistoryinfluence thepositivepredictivevalue(PPV)ofHSVtype-specificserologyandshouldguidetestingandresult interpretation(III,B).13,22-31ThespecificitiesofELISAtestscanbeimprovedbyraisingtheindexvaluefor interpretingpositivityandtestingallintermediatespecimenswithanalternateconfirmatorytest(IIa, B).26,27,29-31 IgMtestingisnotrecommendedinroutineclinicalpractice.Studiessuggestthat12-30%ofpatientslose theirHSVtypespecificantibodiesdependingontheirHSVtypesandthetestused.37 MANAGEMENT First-episodegenitalherpes Indicationsfortherapy Firstepisodesofgenitalherpesarefrequentlyassociatedwithaprolongeddiseasecourse.Untreated, many patients suffer general and local complications. Therapy can be highly effective and should be instigatedattheearliestopportunityandonclinicalsuspicionalone. Antivirals Patients presenting within 5 days of the start of the episode, or while new lesions are still forming, shouldbegivenoralantiviraldrugs.Aciclovir,valaciclovirandfamciclovirarealleffectiveinreducingthe severity and duration of episode (Ib, A).38, 39 No therapy alters the natural course of genital herpes infection. Topical agents are not recommended as they are less effective than oral agents and easily generate resistance(IV,C).40 The only indication for the use of intravenous therapy is when the patient is unable to swallow or tolerate oral medication because of vomiting. The recommended regimens – all for five to ten days – are: • • • • Aciclovir400mgthreetimesaday,or Aciclovir200mgfivetimesaday,or Famciclovir250mgthreetimesaday,or Valaciclovir500mgtwotimesaday Choice should be made by individual clinicians, taking cost of therapy and likely compliance into account.Anumberofpatientswillhaveextendedepisodesbeyondfivedays.Ifadecisiontoprovidefive days of therapy is made, the patient should have early review to ensure they have no further lesion development,systemicsymptomsordiseasecomplications–theyallwillrequireextendedtherapy. Supportivemeasures Saline bathing and the use of appropriate analgesia are recommended. Although the potential for sensitisation exists in the use of topical anaesthetic agents, lignocaine is a rare sensitiser and can be usedsafelyingenitalherpesintheformofgelorointment.41Benzocaine,however,isapotentsensitiser andshouldnotbeused(IV,C). Counselling Itisimportanttobefrankabouttransmissionrisksincludingsubclinicalsheddingandthelimitedimpact ofcondomsandantivirals.Adviceondisclosureshouldbepracticalandtailoredtothepatient’spersonal situation. The low physical morbidity and high population prevalence should be stressed. Clear information about pregnancy is important both to men and women. High distress at diagnosis is common, often persists with recurrences and may be reduced by antivirals (Ib, A).42-44 Most patients requireoneortwosessionsbutadjustmentisdifficulttopredictandcarefulfollowupisimportantwith moreintensiveinputforthosewhodonotadjustwithin3-6months. Managementofcomplications Hospitalisation may be required for urinary retention, meningism, severe constitutional symptoms, or adversesocialcircumstances.Ifcatheterisationisrequired,considerationshouldbegivenastowhether a suprapubic approach offers better symptom control to the individual patient. Super infection of lesions is rare, but may occur during the second week. This is characterised by the recrudescence of localsymptoms.Candidaismostoftenimplicatedandiseasilydiagnosedandtreated. Specialsituations–HIV-positivepatientswithfirst-episodegenitalherpes There are no controlled trials on duration and dose of treatment. Some clinicians advocate a 10-day courseoftreatmentattwicethestandarddoseofanyoftheusualagents(IV,C). Informationforpatients The following information should be discussed when counselling patients with first episode genital herpes: • • • • • • Thecourseofinfection,includingsubclinicalshedding Treatmentoptions Theriskoftransmission,andinterventionsthatmaylimitorreducetheriskoftransmission The risk of transmission to the infant at birth. The patient should be counselled to inform the obstetricianormidwife Thepossibilityofpartnernotificationandthepossiblesourceofinfection That transmissions can occur from an asymptomatic partner some years into a monogamous relationship Follow-up Patientsarefollowed-upuntiltheepisodehasresolvedandcounsellingisconsideredcomplete.Further follow-up may be required to exclude other causes of genital ulceration that may be co-existent. Patientsshouldbeinvitedtore-attendshouldrecurrencesbeproblematic. Recurrentgenitalherpes Indicationsfortherapy Genitalherpesrecurrencesareself-limitingandgenerallycauseminorsymptoms.Decisionsabouthow best to manage clinical recurrences should be made in partnership with the patient. Management strategies include supportive therapy only, episodic antiviral treatments, and suppressive antiviral therapy.Themostappropriatestrategyformanaginganindividualpatientmayvaryovertimeaccording torecurrencefrequency,symptomseverity,andrelationshipstatus.Formostpatients,managementwill needtobesupportiveonly,withsimplelocalmeasuressuchassalinebathingortopicalpetroleumjelly beingadequate. Episodicantiviraltreatment Oralaciclovir,valaciclovirandfamciclovirareeffectiveatreducingthedurationandseverityofrecurrent genital herpes. The reduction in duration is a median of 1-2 days (Ib, A).45-47 Head-to-head studies of their effects show no advantage of one therapy over another, or the advantage of extended 5-day treatment over ultra-short therapy. Prodrugs offer simplified twice-a-day dosing. Patient-initiated treatmentstartedwithin24hoursismostlikelytobeeffective.Abortedlesionshavebeendocumented inuptoonethirdofpatientswithearlytreatment.48Toensureprompttreatment,patientsshouldbe advisedtocarryasmallquantityofdrugsatalltimes. Shortcoursetherapiesshouldbetriedinthefirstinstance: • • • Aciclovir800mgthreetimesdailyfor2days,or49 Famciclovir1gramtwicedailyforoneday,or50 Valaciclovir500mgtwicedailyfor3days(Ib,A).49,51-54 • • • • Aciclovir400mgthreetimesdailyfor3-5days,or Aciclovir200mgfivetimesdaily,or Valaciclovir500mgtwicedailyor Famciclovir125mgtwicedaily. Alternativelonger5daycoursesinclude: Suppressivetherapy The majority of early trials of suppressive therapy were done in patients with a recurrence rate equivalent to ≥6 recurrences/annum. More recently, studies have been completed in patients with milderdiseaseincludingthosewithonlyserological evidenceofinfection.Theseindicatethatpatients across all spectrums of disease will benefit from a reduced rate of recurrence with treatment. The frequencyofrecurrenceatwhichitisworthstartingsuppressivetherapyisasubjectiveissueandneeds tobalancethefrequencyofrecurrence,theimpactofdiseaseontheindividualandtheneedtomanage transmissionriskagainstthecostandinconvenienceoftreatment. All patients are highly likely to experience a substantial reduction in recurrence frequency on suppressiveantiviraltherapy.However,themajorityofpatientsonsucharegimenwillstillexperience anoccasionalsymptomaticrecurrence. Experience with suppressive antiviral therapy is most extensive with aciclovir (Ib, A).55 Safety and resistance data on patients on long-term therapy now extends to over 18 years of continuous surveillance. Although not essential, it may be prudent to regularly assess the need for continuing therapy,sincepatientcircumstancesmayaltersignificantly.However,evenafterprolongedperiodsof suppression, many patients do not find a significant alteration in disease frequency or severity upon discontinuationandreassessment. Recommendedregimens Theoptimaltotaldailydoseofsuppressiveaciclovirtherapyis800mg.Theonlypublishedclinicaldoseranging study concluded that 200 mg 4 times a day was marginally superior to 400 mg twice daily (p<0.02) (IIb, B).56 However, ability to comply with a 4 times a day dosing regimen should determine prescribing decisions for individual patients. Twice-daily valaciclovir (250 mg twice daily) has been shown to be as effective as twice-daily aciclovir (400 mg twice daily). Once-daily aciclovir does not suppress genital herpes recurrences. There is some debate as to whether once daily therapy is as effective as twice daily therapy with valaciclovir. For those patients experiencing <10 recurrences per annum, a dose of 500 mg daily valaciclovir will be adequate; for those patients experiencing >10 recurrencesperannum,250mgb.d.or1gonceadayisrequired.57 Nomajorclinicallysignificantdifferencesbetweensuppressivetherapywithvalaciclovir(500mgdaily) and famciclovir (250 mg twice daily) have been documented (IV, C).8 In patients with an insufficient clinicalresponsethedailysuppressivedoseofvalaciclovirorfamciclovirmayhavetobedoubled(IV,C). Routine blood monitoring of standard dose therapy is not required. Occasionally a mild headache or nauseamayoccurwithvalaciclovir. Thedecisiontocontinuesuppressivetherapyshouldbereviewedatleastannually.Discontinuationof therapyatthistime,ifthepatientiswilling,willallowareassessmentofrecurrencefrequency.Asmall numberofpatientswillexperienceareductioninrecurrencefrequencycomparedwithpre-suppression symptomaticlevels.Theminimumperiodofassessmentshouldincludetworecurrencestoallowaview tobetakenbothonthefrequencyandseverity.Itissafeandreasonabletorestarttreatmentinpatients whocontinuetohavesignificantdisease(IV,C). Short courses of suppressive therapy to prevent clinical symptoms may be helpful for some patients (e.g. for holidays, exams, etc.). Clinicians need to note that full suppressive effect is usually only obtainedfivedaysintotreatment. Viralsheddingandtransmissiononsuppressivetherapy SubclinicalsheddingofinfectiousvirusoccursinmostindividualswithgenitalHSV-1and/orHSV-2.Viral shedding is more likely to occur in patients with genital HSV-2, in the first year after infection, or in individuals with frequent symptomatic recurrences. Aciclovir, valaciclovir and famciclovir all suppress symptomaticandasymptomaticviralshedding. Evenifitseemsbiologicallyplausible,partialsuppressionofviralsheddingdoesnotnecessarilyequate toreducedtransmission.However,suppressivetherapywithvalaciclovir500mgaday(inthosewith10 or fewer recurrent episodes per year) significantly reduced transmission – by nearly 50% - in serodiscordant couples (Ib, A).16 Twice daily aciclovir 400mg achieves similar levels of reduction in asymptomaticsheddingtooncedailyVACV.Suppressiveantiviraltherapymaybeconsideredinaddition totheuseofcondomsandselectivesexualabstinencewhentransmissionconcernsarepresent. SPECIALSITUATIONS ManagementofHSVintheimmunocompromisedandHIVpositivepatient There is epidemiological synergy between Herpes simplex virus (HSV) and HIV infections.58, 59 Herpes simplex infections activate HIV replication and may facilitate onward HIV transmission to sexual partners.60-67 Suppressive treatment of HSV-2 infection with valaciclovir has been shown to reduce genital HIV shedding in women (not on ARVs).68 In addition, both prevalent and incident HSV-2 infectionsareassociatedwithanincreasedriskofHIVacquisition.69,70 ThenaturalhistoryofgenitalherpesinuntreatedpeoplewithHIV(PWHIV)issignificantlydifferentfrom thatinHIV-negativeindividuals.Themostimportantriskfactorforherpesreactivationisthedegreeof HIVassociatedimmunosuppression.71-73 Standardsystemicantiviraldrugs,asusedtotreatgenitalherpesinHIV-uninfectedpatients,havebeen shown to successfully treat genital herpes in PWHIV.74-79 Resistance to anti-herpes drugs is more common in those with HIV co-infection and is associated with treatment failure of genital herpes.80 Suppressiveantiviraltherapywithcurrentlyavailableagentshasbeenshowninmultiplestudiestohave no impact on HIV acquisition or transmission risk. HSV treatment used only to manage or reduce HIV transmissionoracquisitionriskcannotberecommended(1b,A).81,82 MuchoftheevidenceonherpesmanagementinPWHIVcomesfromstudiesperformedbeforetheera ofcombinationantiretroviraltherapy;prospectivestudiesperformedearlyintheepidemicshowedthat clinicallesionsmightbepersistentandprogressiveinthosewithHIV.Genitalherpes,includingchronic erosive lesions may occur as a manifestation of the immune reconstitution inflammatory syndrome (IRIS) following combination antiretroviral therapy.83-87 HSV associated IRIS may be unresponsive to previously effective anti-herpes viral therapy in the absence of increased antiviral resistance. Managementisdifficultbuttopicalcidofovirmaybeeffective.88 ManagementofinitialepisodeHSV There is no trial data for any antiviral in initial episode genital HSV in HIV infected patients. The vast majority of adults with HIV have serological evidence of established HSV-1 and -2 infections making acquisitiontrialsextremelydifficulttoperform. Case studies report that acquisition of genital HSV may be associated with a prolonged and uncertain clinical course. Systemic symptoms may predominate and chronic lesions may become established if immunological clearance of the skin does not occur. In the absence of HIV therapy, primary genital herpesmaybesevereandprolongedwithriskofprogressive,multifocal,andcoalescingmucocutaneous anogenital lesions. Moreover, serious and potentially life-threatening systemic complications such as fulminanthepatitis,pneumonia,neurologicaldiseaseanddisseminatedinfection,havebeenreported. Intheabsenceofdatamostauthoritiesadvisethatmultiplesofthestandardlevelsoftreatmentforfirst episodeHSVbeusedintheimmunocompromised.However,forthosewithHIVthesemaynotalwaysbe requiredparticularlyforthosewithnormalCD4counts. In patients with advanced HIV double the standard dose of antiviral should be considered and if new lesionscontinuetoformatday3-5ahigherdoseshouldbeconsidered.Promptinitiationoftherapyis recommended. If new lesions are still forming after 3-5 days, a repeat viral isolation should be attempted and susceptibility testing arranged if possible. The dose of HSV therapy should also be increased. Recommendedinitialdoses:89 • Aciclovir400mgfivetimesdaily,for7-10days(IV,C) • Valaciclovir500-1gtwicedaily,for10days(IV,C) • Famciclovir250-500mgthreetimesdaily,for10days(IV,C) Treatmentshouldbegivenforatleast10daysoruntilalllesionshavere-epithelialized–thiswilloften exceedtheusual10daydurationoftreatmentthatisgiventoHIVnegativepatients. Iffulminantdiseaseensues,thenintravenousaciclovirbesubstitutedat5-10mg/kgbodyweightevery8 hours,for2-7daysoruntilclinicalimprovement,andfollowedbyoralantiviraltherapytocompletea minimumof10daystotaltreatment(IV,C). Managementofrecurrentdisease Both clinical and subclinical reactivations of genital herpes are more frequent in people with HIV and may lead to persistent and progressive anogenital mucocutaneous lesions, especially with CD4 cell counts<50permm3.Featurescanbeatypicalinnatureandhypertrophiclesionscanoccur.Optimising thecontrolofHIVreplicationwithcombinationantiretroviraltherapyisoffundamentalimportancefor the management of recurrent genital herpes. HAART will reduce the frequency of clinical recurrences buthaslesseffectuponasymptomaticviralshedding.Thereafter,specificantiviraldrugscanbeusedfor either episodic or suppressive treatment. A number of trials of antiviral therapy in the immunocompromisedhavebeenreported. Episodictherapy It is likely that 5 days of therapy will be adequate for most patients. It should be noted that with advanced HIV 13-17% of patients have been reported to havenew lesions developing at the end of a seven day course of treatment. Shorter courses of therapy may be adequate in those with good CD4 counts(>500cell/mm3)althoughonlyonetrialwithfamciclovirhasreportedthiseffect(1b,B).50 Standarddosesofantiviralsshouldsufficeinthosewithnoevidenceofimmunefailure(1b,A).Inthose withadvanceddiseaseitmaybenecessarytodoublethestandarddoseandtocontinuetherapybeyond 5 days (1b,B). Caution should be exercised in using ultrashort courses of episodic therapy since these havenotbeenevaluatedfullyintheimmunocompromised. Suppressivetherapy SuppressiveantiviraltherapyforHSVappearstobelesseffectiveinpeoplewithHIVthaninHIVnegative people,butremainswelltolerated.Allthreeagentshavebeentrialled.Standardsuppressivedosesof aciclovir are effective. Valaciclovir is more effective when given twice daily (500mg bid) compared to oncedailydosing(1000mg).Thevalaciclovir500mgoncedailydosehasnotbeenevaluatedintheHIV positivepatient.Trialdatafortheefficacyofhighdosefamciclovirisonlyavailableovermuchshorter durations. Itisrecommendedthatintermittentcessationofsuppressiveantiviraltherapyforgenitalherpesshould occur,especiallyinthoseinwhomthereisalsoadequateinhibitionofHIVreplicationandrisingCD4cell counts. In some PWHIV with less frequent outbreaks of genital herpes, episodic treatment may be substituted.Inothers,wherethepre-treatmentpatternofrecurrencesresumes,suppressivetreatment mayneedtorestart(IV,C). There is a considerable body of data on the safety of oral antivirals in the HIV positive immunocompromisedhost.Twostudiesinthepre-HAARTeralookedathighdoseaciclovir(400mgqid) andmorerecentlyatstandarddoseregimens.Forvalacicloviranumberofstudieslookedatthevalueof valaciclovir for the suppression of recurrent genital herpes. High dose valaciclovir (2g qid) has been studied and reported in HIV positive people, and those immunosuppressed and recovering from bone marrow transplants. Most recently a large number of studies looking at the efficacy of aciclovir and valaciclovir suppression and its impact on HIV transmission from co-infected patients have been reported.Thesetrialsindicatethatuseoforalacicloviratstandarddoseandvalaciclovirat1godand 500mgbdisassociatedwithlittleornoadverseeffectortoxicityascomparedtothenonHIVpositive. High dose valaciclovir (8g daily) has been associated with Microangiopathic Haemolytic Uraemic syndrome. Recommendeddrugregimensfordailysuppressivetreatment:89-91 • Aciclovir400mgorallytwicetothreetimesaday • Valaciclovir500mgorallytwiceaday. Iftheseoptionsdonotadequatelycontroldiseasethenthefirstoptionshouldbetodoublethedose.If controlisstillnotachievedthenfamciclovir500mgorallytwiceadaycanbetried(IIa,B). HSVsuppressiontolimitHIVprogression SuppressiveantiviraltherapywithaciclovirorvalaciclovirhasbeenshowntodecreasethelevelsofHIV viraemia in those patients with detectable HIV viral loads through a mechanism not yet fully elucidated.92 Such a strategy will impact on HIV progression, particularly for those individuals not on HAART. A large RCT in early HIV (those individuals not on HAART and with CD4 counts above 250 cells/mm3) has shown that standard doses of suppressive antiviral therapy (aciclovir 400mg bd) will sustainCD4countsabove250cell/mm3andthiseffectreducedtheneedforHAARTat2yearsby16%in the treatment group. However, benefits of suppressive antivirals have not been demonstrated in the presenceofeffectiveHAART.81,82 Managementofrecalcitrantherpesinimmunocompromisedindividuals Although rare in immunocompetent individuals, clinically refractory lesions due to genital HSV are a majorprobleminpatientswithsevereimmunodeficiency,includinglate-stageHIVdiseasesandpatients withimmunereconstitutioninflammatorysyndrome(IRIS)followingcombinationantiretroviraltherapy. Algorithms for treatment in such situations are shown in Figure 1. Systemic therapy with either foscarnet or cidofovir is generally preferred to treat drug resistant herpes in those with HIV. There is evidenceforalternatingcoursesoftreatmentwithaciclovirandcidofovirforsubsequentrecurrencesas a strategy that may reduce the development of cidofovir-resistant strains. The efficacy, safety, and durability of the therapeutic response of these agents have yet to be determined in prospective controlledtrials. Inprospectivestudies,aciclovir-resistantstrainshavebeenfoundinaround5-7%isolatesfromgenital herpeslesionsinHIV-infectedpersons.40,93,94Aciclovirresistanceisconfirmedifisolatesrequireaciclovir concentrations>1-3mg/lforinhibition.Aciclovirresistanceismostcommonlyrelatedtoamutationin thegeneencodingHSVthymidinekinase(TK),whichisresponsibleforinitialphosphorylationofaciclovir toitsactiveform,resultinginTKthateitherhasreducedaffinityforaciclovirorisnotsynthesised.TKdeficient strains are of reduced pathogenicity in immunocompetent individuals but may cause serious localandsystemicdiseaseinseverelyimmunocompromisedindividuals.95,96Theyappearlesslikelytobe associatedwiththedevelopmentoflatency;hence,subsequentclinicalreactivationsofgenitalherpes areoftencausedbyaciclovirsensitiveisolates.Partiallyresistantstrainsmaysometimesbesuccessfully treatedwithhighdoseintravenousaciclovirandothernucleosideanaloguesbutfullyaciclovir-resistant strainsareresistanttovalaciclovirandganciclovir,andthemajorityareresistanttofamciclovir.95-97TKdeficient strains are susceptible to foscarnet and cidofovir which do not depend upon TK but which inhibitviralDNApolymerase. Antiviral susceptibility testing for HSV has limited availability and therefore the clinical response to antiviraltherapyisoftenusedtoguidedecisions,Advicefromaclinicalvirologistaboutappropriatedrug dosagesanddurationmaybesoughtwhenclinicalresistanceissuspected. Figure1:Algorithmforthetreatmentofherpesinimmunocompromisedindividuals. *AllHSVstrainsresistanttoaciclovirarealsoresistanttovalaciclovir **Theseproductswilloftenhavetobemadeupinhouse Managementofpartners Thereisnoevidenceonwhichtobaserecommendationsforpartnernotification.Onanindividualbasis, itmaybeappropriatetooffertoseepartnerstohelpwiththecounsellingprocess.Partnernotification inrelationtopregnancyisdiscussedbelow.Itisworthconsideringthefollowingpointswhencounselling partners; • • Theuseofcondomsisadvisableespeciallywhentransmissionconcernsarepresent-evenwhen theindexcaseisonsuppressiveantiviraltreatment.16 Asymptomatic shedding plays a major role in the transmission of HSV infection and selective abstinenceinitselfisnotaneffectivestrategyformangingtransmissionrisk. • • • Partner notification is an effective way of detecting uninfected or asymptomatic individuals especiallywhencombinedwithtype-specificantibodytesting. Up to 50% of asymptomatic HSV-2 seropositive women can be taught to recognise genital herpesrecurrencesaftercounselling. Virus transmission can be reduced either with suppressive antiviral treatment or by using condoms. Managementofpregnantwomenwithfirstepisodegenitalherpes Firstandsecondtrimesteracquisition Managementofthewomanshouldbeinlinewithherclinicalconditionandwillofteninvolvetheuseof eitheroralorintravenousaciclovirinstandarddoses. Providing that delivery does not ensue, the pregnancy should be managed expectantly and vaginal deliveryanticipated(IV,C). Dailysuppressiveaciclovir400mgt.i.d.from36weeksgestationmaypreventHSVlesionsattermand hencetheneedfordeliverybyCaesareansection(Ib,B).98-103 Thirdtrimesteracquisition(IV,C) Caesareansectionshouldbeconsideredforallwomen,particularlythosedevelopingsymptomswithin6 weeksofdelivery,astheriskofviralsheddinginlabourisveryhigh(Ib,B). Dailysuppressiveaciclovir400mgt.i.d.todeliveryshouldbeconsidered. Ifvaginaldeliveryisunavoidable,prolongedruptureofmembranesandinvasiveprocedures,including the use of scalp electrodes, should be avoided. Intrapartum IV aciclovir given to the mother and subsequentlytothebabymaybeconsideredandthepaediatricianshouldbeinformed.104 Managementofpregnantwomenwithrecurrentgenitalherpes(III,B) Womenwithrecurrentgenitalherpesshouldbeinformedthattheriskofneonatalherpesislow. Symptomatic recurrences of genital herpes during the third trimester will be brief; vaginal delivery is appropriateifnolesionsarepresentatdelivery. ForwomenwithahistoryofrecurrentgenitalherpeswhowouldoptforaCaesareansectioniftheyhad HSVlesionsattheonsetoflabour,dailysuppressiveaciclovir400mgtidfrom36weeksgestationmay preventHSVlesionsattermandhencetheneedfordeliverybyCaesareansection(Ia,A).105 If there are no genital lesions at delivery, there is no indication for a Caesarean section to prevent neonatalherpes. SequentialculturesorPCRduringlategestationtopredictviralsheddingattermarenotindicated.106 TheutilityoftakingculturesorPCRatdelivery,inordertoidentifywomenwhoareasymptomatically sheddingHSV,isunproven. ManagementofrecurrentHSVinearlypregnancy Althoughthesafetyofaciclovirinearlypregnancyisnotfullyestablishedjudicioususeofthisagentfor suspected acquisition episodes is widely advocated. The same cannot be said for recurrent disease. Continuous or episodic therapy is not recommended in early pregnancy and should be avoided. Cliniciansareonoccasionobligedtousetherapyforsevereandcomplicateddiseaseandacase-by-case assessmentshouldbemade.Newerantiviralsshouldbeavoidedandthedoseofaciclovirtitrateddown totheminimumeffectivelevel. ManagementofHIVpositivewomenwithrecurrentHSVinfection(IV,C) ThereissomeevidencethatHIVantibodypositivewomenwithgenitalHSVulcerationinpregnancyare morelikelytotransmitHIVinfectionindependentofotherfactors.21,23However,thisisnotaconsistent findingacrossallstudies.23 Women who are HIV antibody positive and have a history of genital herpes should be offered daily suppressive aciclovir 400mg t.i.d. from 32 weeks gestation to reduce the risk of transmission of HIV-1 infection especially in women where a vaginal delivery is planned. Starting therapy at an earlier gestationthanusualshouldbeconsideredinviewoftheincreasedpossibilityofpretermlabour(IV,C). There is currently no evidence to recommend daily suppressive treatment for HIV-1 antibody positive womenwhoareHSV1or2seropositivebuthavenohistoryofgenitalherpes.107 Managementofwomenwithgenitallesionsatonsetoflabour Caesareansectionmaybeconsideredforwomenwithrecurrentgenitalherpeslesionsattheonsetof labourbuttheriskofneonatalherpesfollowingvaginaldeliveryissmallandmustbesetagainstrisksto themotherofCaesareansection.EvidencefromtheNetherlandsshowsthataconservativeapproach, allowingvaginaldeliveryinthepresenceofananogenitallesion,hasnotbeenassociatedwitharisein numbersofneonatalHSVcases(III,B).108However,thisapproachcanonlybeadoptediffullysupported byobstetriciansandneonatologists,andifconsistentwithlocalmedico-legaladvice. ClinicaldiagnosisofgenitalherpesatthetimeoflabourcorrelatesrelativelypoorlywithHSVdetection fromgenitalsitesbyeithercultureorPCRandfailstoidentifywomenwithasymptomaticHSVshedding. Note:Noneoftheantiviraldrugsislicensedforuseinpregnancybuttheuseofaciclovirinpregnancy has not been associated with any consistent pregnancy or foetal/neonatal adverse effects other than transient neutropenia.108, 109 Safety data for aciclovir may be extrapolated to valaciclovir in late pregnancy, as it is the valine ester, but there is less experience with use of valaciclovir.110 Famciclovir shouldcurrentlybeavoided. Preventionofacquisitionofinfection(IV,C) Maternal risk of HSV acquisition in pregnancy varies geographically and local epidemiological surveillanceshouldguidestrategyforprevention.Anystrategyforpreventionofneonatalherpesneeds toinvolvebothparents. Allwomenshouldbeaskedattheirfirstantenatalvisitiftheyortheirpartnerhavehadgenitalororal herpes. Femalepartnersofmenwithgenitalherpes,butwithoutapersonalhistoryofgenitalherpesshouldbe advised about reducing their risk of acquiring herpes in pregnancy and of subsequent transmission to theirbaby.Strategiesincludeselectiveandcompleteabstinence(especiallyinthethirdtrimester)and conscientiouscondomuse. DailysuppressivetreatmenthasbeenshowntosignificantlyreducetheriskoftransmissionofHSVtoa seronegativepartner,howevertheeffectivenessofsuppressivetreatmentofthemalepartnertoreduce transmissiontoapregnantwomanhasnotbeenevaluatedsocancurrentlyonlyberecommendedwith caveats. Pregnant women should be advised of the risk of acquiring HSV-1 as a result of receptive orogenital contactespeciallyinthelasttrimesterofpregnancy. Identifyingsusceptiblewomenbymeansoftype-specificantibodytestinghasnotbeenshowntobecost effectiveandisnotindicatedinEurope. Allwomen,notjustthosewithahistoryofgenitalherpes,shouldundergocarefulvulvalinspectionat theonsetoflabourtolookforclinicalsignsofherpesinfection. Mothers, staff and other relatives/friends with active oral HSV lesions or herpetic whitlow should be advisedtoavoiddirectcontactbetweenlesionsandtheneonate. Managementoftheneonate Babiesborntomotherswithfirst-episodegenitalherpesattheonsetoflabour Thepaediatricianshouldbeinformed. HSVPCRofurineandstool,fromtheoropharynx,eyesandsurfacesites,shouldbetakentoallowearly identificationofinfectedbabies Thepotentialbenefitsandrisksofstartingintravenousaciclovirwithoutwaitingfortheresultsofthese culturesshouldbediscussed If aciclovir is not started immediately the neonate should be closely monitored for signs of lethargy, fever,poorfeedingorlesions. Babiesborntomotherswithrecurrentgenitalherpesattheonsetoflabour Althoughsomecliniciansfeelthattakingasetofspecimensforviralculturecollectedafterdeliverymay helpwithearlyidentificationofinfectionthereisnoevidencetosupportthispractice.Howeverhealth care workers and parents should be advised to consider HSV in the differential diagnosis if the baby showsanysignsofinfectionordevelopsskin,eyeormucousmembranelesions,particularlyinthefirst twoweeksoflife. Proposeddateforreview:2022 Acknowledgements: Compositionofeditorialboard: Pleaserefertodocumentat:http://www.iusti.org/regions/Europe/pdf/2014/Editorial_Board2014.pdf Listofcontributingorganisations: Pleaserefertotextat:http://www.iusti.org/regions/Europe/euroguidelines.htm References 1. CasperC,WaldA.Condomuseandthepreventionofgenitalherpesacquisition.Herpes. 2002;9(1):10-4. 2. WaldA,LangenbergAG,KrantzE,DouglasJM,Jr.,HandsfieldHH,DiCarloRP,etal.The relationshipbetweencondomuseandherpessimplexvirusacquisition.AnnInternMed. 2005;143(10):707-13. 3. GuptaR,WarrenT,WaldA.Genitalherpes.Lancet.2007;370(9605):2127-37. 4. KoutskyLA,StevensCE,HolmesKK,AshleyRL,KiviatNB,CritchlowCW,etal.Underdiagnosisof genitalherpesbycurrentclinicalandviral-isolationprocedures.NEnglJMed.1992;326(23):1533-9. 5. WaldA,HuangML,CarrellD,SelkeS,CoreyL.Polymerasechainreactionfordetectionofherpes simplexvirus(HSV)DNAonmucosalsurfaces:comparisonwithHSVisolationincellculture.JInfectDis. 2003;188(9):1345-51. 6. RamaswamyM,McDonaldC,SmithM,ThomasD,MaxwellS,Tenant-FlowersM,etal.Diagnosis ofgenitalherpesbyrealtimePCRinroutineclinicalpractice.SexTransmInfect.2004;80(5):406-10. 7. vanDoornumGJ,GuldemeesterJ,OsterhausAD,NiestersHG.Diagnosingherpesvirusinfections byreal-timeamplificationandrapidculture.JClinMicrobiol.2003;41(2):576-80. 8. GerettiAM.Genitalherpes.SexTransmInfect.2006;82Suppl4:iv31-4. 9. VeranoL,MichalskiFJ.Herpessimplexvirusantigendirectdetectioninstandardvirustransport mediumbyDuPontHerpchekenzyme-linkedimmunosorbentassay.JClinMicrobiol.1990;28(11):25558. 10. SlomkaMJ,EmeryL,MundayPE,MoulsdaleM,BrownDW.AcomparisonofPCRwithvirus isolationanddirectantigendetectionfordiagnosisandtypingofgenitalherpes.JMedVirol. 1998;55(2):177-83. 11. ConeRW,SwensonPD,HobsonAC,RemingtonM,CoreyL.Herpessimplexvirusdetectionfrom genitallesions:acomparativestudyusingantigendetection(HerpChek)andculture.JClinMicrobiol. 1993;31(7):1774-6. 12. MundayPE,VuddamalayJ,SlomkaMJ,BrownDW.Roleoftypespecificherpessimplexvirus serologyinthediagnosisandmanagementofgenitalherpes.SexTransmInfect.1998;74(3):175-8. 13. AshleyRL,WaldA.Genitalherpes:reviewoftheepidemicandpotentialuseoftype-specific serology.ClinMicrobiolRev.1999;12(1):1-8. 14. MalkinJE.Herpessimplexvirus:whoshouldbetested?Herpes.2002;9(2):31. 15. CopasAJ,CowanFM,CunninghamAL,MindelA.Anevidencebasedapproachtotestingfor antibodytoherpessimplexvirustype2.SexTransmInfect.2002;78(6):430-4. 16. CoreyL,WaldA,PatelR,SacksSL,TyringSK,WarrenT,etal.Once-dailyvalacyclovirtoreduce theriskoftransmissionofgenitalherpes.NEnglJMed.2004;350(1):11-20. 17. RamaswamyM,McDonaldC,SabinC,Tenant-FlowersM,SmithM,GerettiAM.The epidemiologyofgenitalinfectionwithherpessimplexvirustypes1and2ingenitourinarymedicine attendeesininnerLondon.SexTransmInfect.2005;81(4):306-8. 18. BrownZA,SelkeS,ZehJ,KopelmanJ,MaslowA,AshleyRL,etal.Theacquisitionofherpes simplexvirusduringpregnancy.NEnglJMed.1997;337(8):509-15. 19. RouseDJ,StringerJS.Anappraisalofscreeningformaternaltype-specificherpessimplexvirus antibodiestopreventneonatalherpes.AmJObstetGynecol.2000;183(2):400-6. 20. TitaAT,GrobmanWA,RouseDJ.Antenatalherpesserologicscreening:anappraisalofthe evidence.ObstetGynecol.2006;108(5):1247-53. 21. DrakeAL,John-StewartGC,WaldA,Mbori-NgachaDA,BosireR,WamalwaDC,etal.Herpes simplexvirustype2andriskofintrapartumhumanimmunodeficiencyvirustransmission.Obstet Gynecol.2007;109(2Pt1):403-9. 22. BollenLJ,WhiteheadSJ,MockPA,LeelawiwatW,AsavapiriyanontS,ChalermchockchareonkitA, etal.Maternalherpessimplexvirustype2coinfectionincreasestheriskofperinatalHIVtransmission: possibilitytofurtherdecreasetransmission?AIDS.2008;22(10):1169-76. 23. ChenKT,TuomalaRE,ChuC,HuangML,WattsDH,ZorrillaCD,etal.Noassociationbetween antepartumserologicandgenitaltractevidenceofherpessimplexvirus-2coinfectionandperinatalHIV1transmission.AmJObstetGynecol.2008;198(4):399e1-5. 24. AshleyRL.PerformanceanduseofHSVtype-specificserologytestkits.Herpes.2002;9(2):38-45. 25. AshleyR,BenedettiJ,CoreyL.HumoralimmuneresponsetoHSV-1andHSV-2viralproteinsin patientswithprimarygenitalherpes.JMedVirol.1985;17(2):153-66. 26. AshleyR.Type-specificantibodiestoHSV-1and-2:reviewofmethodology.Herpes.1998;5:33-8. 27. SmithJS,BaileyRC,WestreichDJ,MacleanI,AgotK,Ndinya-AcholaJO,etal.Herpessimplex virustype2antibodydetectionperformanceinKisumu,Kenya,usingtheHerpeselectELISA,KalonELISA, Westernblotandinhibitiontesting.SexTransmInfect.2009;85(2):92-6. 28. GopalR,GibbsT,SlomkaMJ,WhitworthJ,CarpenterLM,VyseA,etal.Amonoclonalblocking EIAforherpessimplexvirustype2antibody:validationforseroepidemiologicalstudiesinAfrica.JVirol Methods.2000;87(1-2):71-80. 29. MorrowRA,FriedrichD,KrantzE.PerformanceofthefocusandKalonenzyme-linked immunosorbentassaysforantibodiestoherpessimplexvirustype2glycoproteinGinculturedocumentedcasesofgenitalherpes.JClinMicrobiol.2003;41(11):5212-4. 30. vanDyckE,BuveA,WeissHA,GlynnJR,BrownDW,DeDekenB,etal.Performanceof commerciallyavailableenzymeimmunoassaysfordetectionofantibodiesagainstherpessimplexvirus type2inAfricanpopulations.JClinMicrobiol.2004;42(7):2961-5. 31. GoldenMR,Ashley-MorrowR,SwensonP,HogrefeWR,HandsfieldHH,WaldA.Herpessimplex virustype2(HSV-2)WesternblotconfirmatorytestingamongmentestingpositiveforHSV-2usingthe focusenzyme-linkedimmunosorbentassayinasexuallytransmitteddiseaseclinic.SexTransmDis. 2005;32(12):771-7. 32. MorrowRA,FriedrichD,MeierA,CoreyL.Useof"biokitHSV-2RapidAssay"toimprovethe positivepredictivevalueofFocusHerpeSelectHSV-2ELISA.BMCInfectDis.2005;5:84. 33. AshleyMorrowR,KrantzE,FriedrichD,WaldA.Clinicalcorrelatesofindexvaluesinthefocus HerpeSelectELISAforantibodiestoherpessimplexvirustype2(HSV-2).JClinVirol.2006;36(2):141-5. 34. NascimentoMC,FerreiraS,SabinoE,HamiltonI,ParryJ,PannutiCS,etal.Performanceofthe HerpeSelect(Focus)andKalonenzyme-linkedimmunosorbentassaysfordetectionofantibodiesagainst herpessimplexvirustype2byuseofmonoclonalantibody-blockingenzymeimmunoassayand clinicovirologicalreferencestandardsinBrazil.JClinMicrobiol.2007;45(7):2309-11. 35. LeGoffJ,MayaudP,GresenguetG,WeissHA,NzambiK,FrostE,etal.Performanceof HerpeSelectandKalonassaysindetectionofantibodiestoherpessimplexvirustype2.JClinMicrobiol. 2008;46(6):1914-8. 36. GamielJL,TobianAA,LaeyendeckerOB,ReynoldsSJ,MorrowRA,SerwaddaD,etal.Improved performanceofenzyme-linkedimmunosorbentassaysandtheeffectofhumanimmunodeficiencyvirus coinfectionontheserologicdetectionofherpessimplexvirustype2inRakai,Uganda.ClinVaccine Immunol.2008;15(5):888-90. 37. vanRooijenMS,RoestW,HansenG,KwaD,deVriesHJ.False-negativetype-specific glycoproteinGantibodyresponsesinSTIclinicpatientswithrecurrentHSV-1orHSV-2DNApositive genitalherpes,TheNetherlands.SexTransmInfect.2016;92(4):257-60. 38. CoreyL,BenedettiJ,CritchlowC,MertzG,DouglasJ,FifeK,etal.Treatmentofprimaryfirstepisodegenitalherpessimplexvirusinfectionswithacyclovir:resultsoftopical,intravenousandoral therapy.JAntimicrobChemother.1983;12SupplB:79-88. 39. FifeKH,BarbarashRA,RudolphT,DegregorioB,RothR.Valaciclovirversusacyclovirinthe treatmentoffirst-episodegenitalherpesinfection.Resultsofaninternational,multicenter,doubleblind,randomizedclinicaltrial.TheValaciclovirInternationalHerpesSimplexVirusStudyGroup.Sex TransmDis.1997;24(8):481-6. 40. ReyesM,ShaikNS,GraberJM,NisenbaumR,WetherallNT,FukudaK,etal.Acyclovir-resistant genitalherpesamongpersonsattendingsexuallytransmitteddiseaseandhumanimmunodeficiency virusclinics.ArchInternMed.2003;163(1):76-80. 41. WeightmanW,TurnerT.Allergiccontactdermatitisfromlignocaine:reportof29casesand reviewoftheliterature.ContactDermatitis.1998;39(5):265-6. 42. CarneyO,RossE,BunkerC,IkkosG,MindelA.Aprospectivestudyofthepsychologicalimpact onpatientswithafirstepisodeofgenitalherpes.GenitourinMed.1994;70(1):40-5. 43. PatelR,TyringS,StrandA,PriceMJ,GrantDM.Impactofsuppressiveantiviraltherapyonthe healthrelatedqualityoflifeofpatientswithrecurrentgenitalherpesinfection.SexTransmInfect. 1999;75(6):398-402. 44. GreenJ,KocsisA.Psychologicalfactorsinrecurrentgenitalherpes.GenitourinMed. 1997;73(4):253-8. 45. NilsenAE,AasenT,HalsosAM,KingeBR,TjottaEA,WikstromK,etal.Efficacyoforalacyclovirin thetreatmentofinitialandrecurrentgenitalherpes.Lancet.1982;2(8298):571-3. 46. SpruanceSL,TyringSK,DeGregorioB,MillerC,BeutnerK.Alarge-scale,placebo-controlled, dose-rangingtrialofperoralvalaciclovirforepisodictreatmentofrecurrentherpesgenitalis.Valaciclovir HSVStudyGroup.ArchInternMed.1996;156(15):1729-35. 47. SacksSL,AokiFY,Diaz-MitomaF,SellorsJ,ShafranSD.Patient-initiated,twice-dailyoral famciclovirforearlyrecurrentgenitalherpes.Arandomized,double-blindmulticentertrial.Canadian FamciclovirStudyGroup.JAMA.1996;276(1):44-9. 48. SpruanceSL,OverallJC,Jr.,KernER,KruegerGG,PliamV,MillerW.Thenaturalhistoryof recurrentherpessimplexlabialis:implicationsforantiviraltherapy.NEnglJMed.1977;297(2):69-75. 49. WaldA,CarrellD,RemingtonM,KexelE,ZehJ,CoreyL.Two-dayregimenofacyclovirfor treatmentofrecurrentgenitalherpessimplexvirustype2infection.ClinInfectDis.2002;34(7):944-8. 50. BodsworthN,BlochM,McNultyA,DenhamI,DoongN,TrottierS,etal.2-dayversus5-day famciclovirastreatmentofrecurrencesofgenitalherpes:resultsoftheFaSTstudy.SexHealth. 2008;5(3):219-25. 51. AokiFY,TyringS,Diaz-MitomaF,GrossG,GaoJ,HamedK.Single-day,patient-initiated famciclovirtherapyforrecurrentgenitalherpes:arandomized,double-blind,placebo-controlledtrial. ClinInfectDis.2006;42(1):8-13. 52. AbudaluM,TyringS,KoltunW,BodsworthN,HamedK.Single-day,patient-initiatedfamciclovir therapyversus3-dayvalacyclovirregimenforrecurrentgenitalherpes:arandomized,double-blind, comparativetrial.ClinInfectDis.2008;47(5):651-8. 53. LeonePA,TrottierS,MillerJM.Valacyclovirforepisodictreatmentofgenitalherpes:ashorter 3-daytreatmentcoursecomparedwith5-daytreatment.ClinInfectDis.2002;34(7):958-62. 54. StrandA,PatelR,WulfHC,CoatesKM.Abortedgenitalherpessimplexviruslesions:findings fromarandomisedcontrolledtrialwithvalaciclovir.SexTransmInfect.2002;78(6):435-9. 55. MertzGJ,JonesCC,MillsJ,FifeKH,LemonSM,StapletonJT,etal.Long-termacyclovir suppressionoffrequentlyrecurringgenitalherpessimplexvirusinfection.Amulticenterdouble-blind trial.JAMA.1988;260(2):201-6. 56. MindelA,FahertyA,CarneyO,PatouG,FrerisM,WilliamsP.Dosageandsafetyoflong-term suppressiveacyclovirtherapyforrecurrentgenitalherpes.Lancet.1988;1(8591):926-8. 57. Lebrun-VignesB,BouzamondoA,DupuyA,GuillaumeJC,LechatP,ChosidowO.Ameta-analysis toassesstheefficacyoforalantiviraltreatmenttopreventgenitalherpesoutbreaks.JAmAcad Dermatol.2007;57(2):238-46. 58. WasserheitJN.Epidemiologicalsynergy.Interrelationshipsbetweenhumanimmunodeficiency virusinfectionandothersexuallytransmitteddiseases.SexTransmDis.1992;19(2):61-77. 59. HookEW,3rd,CannonRO,NahmiasAJ,LeeFF,CampbellCH,Jr.,GlasserD,etal.Herpessimplex virusinfectionasariskfactorforhumanimmunodeficiencyvirusinfectioninheterosexuals.JInfectDis. 1992;165(2):251-5. 60. MoscaJD,BednarikDP,RajNB,RosenCA,SodroskiJG,HaseltineWA,etal.Activationofhuman immunodeficiencyvirusbyherpesvirusinfection:identificationofaregionwithinthelongterminal repeatthatrespondstoatrans-actingfactorencodedbyherpessimplexvirus1.Proceedingsofthe NationalAcademyofSciencesoftheUnitedStatesofAmerica.1987;84(21):7408-12. 61. OstroveJM,LeonardJ,WeckKE,RabsonAB,GendelmanHE.Activationofthehuman immunodeficiencyvirusbyherpessimplexvirustype1.Journalofvirology.1987;61(12):3726-32. 62. GoldenMP,KimS,HammerSM,LaddEA,SchafferPA,DeLucaN,etal.Activationofhuman immunodeficiencyvirusbyherpessimplexvirus.JInfectDis.1992;166(3):494-9. 63. MargolisDM,RabsonAB,StrausSE,OstroveJM.TransactivationoftheHIV-1LTRbyHSV-1 immediate-earlygenes.Virology.1992;186(2):788-91. 64. KoelleDM,AbboH,PeckA,ZiegweidK,CoreyL.Directrecoveryofherpessimplexvirus(HSV)specificTlymphocyteclonesfromrecurrentgenitalHSV-2lesions.JInfectDis.1994;169(5):956-61. 65. KreissJ,CaraelM,MeheusA.Roleofsexuallytransmitteddiseasesintransmittinghuman immunodeficiencyvirus.GenitourinMed.1988;64(1):1-2. 66. KreissJK,CoombsR,PlummerF,HolmesKK,NikoraB,CameronW,etal.Isolationofhuman immunodeficiencyvirusfromgenitalulcersinNairobiprostitutes.JInfectDis.1989;160(3):380-4. 67. SchackerT,RyncarzAJ,GoddardJ,DiemK,ShaughnessyM,CoreyL.FrequentrecoveryofHIV-1 fromgenitalherpessimplexviruslesionsinHIV-1-infectedmen.Jama.1998;280(1):61-6. 68. NagotN,OuedraogoA,FoulongneV,KonateI,WeissHA,VergneL,etal.ReductionofHIV-1 RNAlevelswiththerapytosuppressherpessimplexvirus.NEnglJMed.2007;356(8):790-9. 69. ToddJ,GrosskurthH,ChangaluchaJ,ObasiA,MoshaF,BaliraR,etal.Riskfactorsinfluencing HIVinfectionincidenceinaruralAfricanpopulation:anestedcase-controlstudy.JInfectDis. 2006;193(3):458-66. 70. FreemanEE,WeissHA,GlynnJR,CrossPL,WhitworthJA,HayesRJ.Herpessimplexvirus2 infectionincreasesHIVacquisitioninmenandwomen:systematicreviewandmeta-analysisof longitudinalstudies.Aids.2006;20(1):73-83. 71. ChenCY,BallardRC,Beck-SagueCM,DangorY,RadebeF,SchmidS,etal.Human immunodeficiencyvirusinfectionandgenitalulcerdiseaseinSouthAfrica:theherpeticconnection.Sex TransmDis.2000;27(1):21-9. 72. BagdadesEK,PillayD,SquireSB,O'NeilC,JohnsonMA,GriffithsPD.Relationshipbetween herpessimplexvirusulcerationandCD4+cellcountsinpatientswithHIVinfection.Aids. 1992;6(11):1317-20. 73. WrightPW,HoesleyCJ,SquiresKE,Croom-RiversA,WeissHL,GnannJW,Jr.Aprospectivestudy ofgenitalherpessimplexvirustype2infectioninhumanimmunodeficiencyvirustype1(HIV-1)seropositivewomen:correlationswithCD4cellcountandplasmaHIV-1RNAlevel.ClinInfectDis. 2003;36(2):207-11. 74. QuinnanGV,Jr.,MasurH,RookAH,ArmstrongG,FrederickWR,EpsteinJ,etal.Herpesvirus infectionsintheacquiredimmunedeficiencysyndrome.Jama.1984;252(1):72-7. 75. MaierJA,BergmanA,RossMG.Acquiredimmunodeficiencysyndromemanifestedbychronic primarygenitalherpes.AmJObstetGynecol.1986;155(4):756-8. 76. LeungDT,SacksSL.Currentrecommendationsforthetreatmentofgenitalherpes.Drugs. 2000;60(6):1329-52. 77. DrewWLBW,ErlichKSetal.Chapter34:Managementofherpesvirusinfection (cytomegalovirus,herpessimplexvirusandvaricellazostervirus).In:VolberdingP,GreeneW,JoepLet al.ThemedicalmanagementofAIDS.9thed.London:Saunders,2012,p.433-454. 78. AokiFY.ManagementofgenitalherpesinHIV-infectedpatients.Herpes.2001;8(2):41-5. 79. FoleyE,PatelR.TreatmentofgenitalherpesinfectionsinHIV-infectedpatients.JournalofHIV therapy.2004;9(1):14-8. 80. MarksGL,NolanPE,ErlichKS,EllisMN.Mucocutaneousdisseminationofacyclovir-resistant herpessimplexvirusinapatientwithAIDS.Reviewsofinfectiousdiseases.1989;11(3):474-6. 81. CelumC,WaldA,HughesJ,SanchezJ,ReidS,Delany-MoretlweS,etal.Effectofacicloviron HIV-1acquisitioninherpessimplexvirus2seropositivewomenandmenwhohavesexwithmen:a randomised,double-blind,placebo-controlledtrial.Lancet.2008;371(9630):2109-19. 82. CelumC,WaldA,LingappaJR,MagaretAS,WangRS,MugoN,etal.Acyclovirandtransmission ofHIV-1frompersonsinfectedwithHIV-1andHSV-2.NEnglJMed.2010;362(5):427-39. 83. SacksSL,WanklinRJ,ReeceDE,HicksKA,TylerKL,CoenDM.Progressiveesophagitisfrom acyclovir-resistantherpessimplex.ClinicalrolesforDNApolymerasemutantsandviralheterogeneity? AnnInternMed.1989;111(11):893-9. 84. GateleyA,GanderRM,JohnsonPC,KitS,OtsukaH,KohlS.Herpessimplexvirustype2 meningoencephalitisresistanttoacyclovirinapatientwithAIDS.JInfectDis.1990;161(4):711-5. 85. EnglundJA,ZimmermanME,SwierkoszEM,GoodmanJL,SchollDR,BalfourHH,Jr.Herpes simplexvirusresistanttoacyclovir.Astudyinatertiarycarecenter.AnnInternMed.1990;112(6):41622. 86. RatnamI,ChiuC,KandalaNB,EasterbrookPJ.Incidenceandriskfactorsforimmune reconstitutioninflammatorysyndromeinanethnicallydiverseHIVtype1-infectedcohort.ClinInfect Dis.2006;42(3):418-27. 87. FoxPA,BartonSE,FrancisN,YouleM,HendersonDC,PillayD,etal.Chronicerosiveherpes simplexvirusinfectionofthepenis,apossibleimmunereconstitutiondisease.HIVmedicine. 1999;1(1):10-8. 88. LalezariJ,SchackerT,FeinbergJ,GatheJ,LeeS,CheungT,etal.Arandomized,double-blind, placebo-controlledtrialofcidofovirgelforthetreatmentofacyclovir-unresponsivemucocutaneous herpessimplexvirusinfectioninpatientswithAIDS.JInfectDis.1997;176(4):892-8. 89. CDC-2015SexuallyTransmittedDiseasesTreatmentGuidelines-GenitalHSVInfections. http://www.cdc.gov/std/tg2015/herpes.htm(accessed2ndSeptember2016). 90. DeJesusE,WaldA,WarrenT,SchackerTW,TrottierS,ShahmaneshM,etal.Valacyclovirforthe suppressionofrecurrentgenitalherpesinhumanimmunodeficiencyvirus-infectedsubjects.JInfectDis. 2003;188(7):1009-16. 91. WarrenT,HarrisJ,BrennanCA.Efficacyandsafetyofvalacyclovirforthesuppressionand episodictreatmentofherpessimplexvirusinpatientswithHIV.ClinInfectDis.2004;39Suppl5:S258-66. 92. DelanyS,MlabaN,ClaytonT,AkpomiemieG,CapovillaA,LegoffJ,etal.Impactofacicloviron genitalandplasmaHIV-1RNAinHSV-2/HIV-1co-infectedwomen:arandomizedplacebo-controlledtrial inSouthAfrica.AIDS.2009;23(4):461-9. 93. StranskaR,SchuurmanR,NienhuisE,GoedegebuureIW,PolmanM,WeelJF,etal.Surveyof acyclovir-resistantherpessimplexvirusintheNetherlands:prevalenceandcharacterization.JClinVirol. 2005;32(1):7-18. 94. HillEL,HunterGA,EllisMN.Invitroandinvivocharacterizationofherpessimplexvirusclinical isolatesrecoveredfrompatientsinfectedwithhumanimmunodeficiencyvirus.Antimicrobialagentsand chemotherapy.1991;35(11):2322-8. 95. SafrinS.Treatmentofacyclovir-resistantherpessimplexvirusinfectionsinpatientswithAIDS. Journalofacquiredimmunedeficiencysyndromes.1992;5Suppl1:S29-32. 96. GnannJ,DavisM,HardenE,etal.ResistanceTforceonH.acyclovir-resistantHSVfromHIVinfectedindividuals.Populationsurveillanceandinvitrocharacterizationofisolates(abstract).New Orleans,USA,38thAnnualInternationalDiseaseSocietyofAmerica(IDSA)Meeting,2000. 97. EngelJP,EnglundJA,FletcherCV,HillEL.Treatmentofresistantherpessimplexviruswith continuous-infusionacyclovir.Jama.1990;263(12):1662-4. 98. SheffieldJS,HollierLM,HillJB,StuartGS,WendelGD.Acyclovirprophylaxistopreventherpes simplexvirusrecurrenceatdelivery:asystematicreview.ObstetGynecol.2003;102(6):1396-403. 99. WattsDH,BrownZA,MoneyD,SelkeS,HuangML,SacksSL,etal.Adouble-blind,randomized, placebo-controlledtrialofacyclovirinlatepregnancyforthereductionofherpessimplexvirusshedding andcesareandelivery.AmJObstetGynecol.2003;188(3):836-43. 100. ScottLL,HollierLM,McIntireD,SanchezPJ,JacksonGL,WendelGD,Jr.Acyclovirsuppressionto preventrecurrentgenitalherpesatdelivery.InfectDisObstetGynecol.2002;10(2):71-7. 101. BrocklehurstP,KinghornG,CarneyO,HelsenK,RossE,EllisE,etal.Arandomisedplacebo controlledtrialofsuppressiveacyclovirinlatepregnancyinwomenwithrecurrentgenitalherpes infection.BrJObstetGynaecol.1998;105(3):275-80. 102. ScottLL,SanchezPJ,JacksonGL,ZerayF,WendelGD,Jr.Acyclovirsuppressiontoprevent cesareandeliveryafterfirst-episodegenitalherpes.ObstetGynecol.1996;87(1):69-73. 103. BraigS,LutonD,SibonyO,EdlingerC,BoissinotC,BlotP,etal.Acyclovirprophylaxisinlate pregnancypreventsrecurrentgenitalherpesandviralshedding.EurJObstetGynecolReprodBiol. 2001;96(1):55-8. 104. HollierLM,WendelGD.Thirdtrimesterantiviralprophylaxisforpreventingmaternalgenital herpessimplexvirus(HSV)recurrencesandneonatalinfection.CochraneDatabaseSystRev. 2008(1):CD004946. 105. GardellaC,BrownZA,WaldA,MorrowRA,SelkeS,KrantzE,etal.Poorcorrelationbetween genitallesionsanddetectionofherpessimplexvirusinwomeninlabor.ObstetGynecol. 2005;106(2):268-74. 106. ChenKT,SeguM,LumeyLH,KuhnL,CarterRJ,BulterysM,etal.Genitalherpessimplexvirus infectionandperinataltransmissionofhumanimmunodeficiencyvirus.ObstetGynecol. 2005;106(6):1341-8. 107. PoeranJ,WildschutH,GaytantM,GalamaJ,SteegersE,vanderMeijdenW.Theincidenceof neonatalherpesinTheNetherlands.JClinVirol.2008;42(4):321-5. 108. AcyclovirandValacyclovirinPregnancyRegistryfinalreport.April1999. http://pregnancyregistry.gsk.com/acyclovir.html(accessed2ndSeptember2016). 109. AndrewsWW,KimberlinDF,WhitleyR,CliverS,RamseyPS,DeeterR.Valacyclovirtherapyto reducerecurrentgenitalherpesinpregnantwomen.AmJObstetGynecol.2006;194(3):774-81. 110. SheffieldJS,HillJB,HollierLM,LaiblVR,RobertsSW,SanchezPJ,etal.Valacyclovirprophylaxis topreventrecurrentherpesatdelivery:arandomizedclinicaltrial.ObstetGynecol.2006;108(1):141-7. Appendices: SearchStrategy: AliteraturesearchwasperformedusingPubMed/MEDLINE,Google,TheCochraneLibraryandrelevant guidelinesfromJanuary1981toOctober2016.AMEDLINE/PubMedsearchwascarriedoutfrom January1981toOctober2016usingthefollowingsearchterms/MedicalSubjectHeadings(MeSH):“HSV ORherpes”,“genitalulcerORgenitalulcers”and“pregnancycomplications:infectious”.Thesearchwas limitedtohumansandtheEnglishlanguage.Forsomespecificrecommendations,anadditional MEDLINE/PubMedsearchwasperformedwhennecessary.AGooglesearchwasperformedinOctober 2016withthesearchterm“HSVguidelineORHSVguidelines”andallrelevantdocumentsofthefirst 150searchresultswerereviewed.AsearchofTheCochraneLibraryincludedtheCochraneDatabaseof SystematicReviews,DatabaseofAbstractsofReviewsofEffectsandCochraneCentralRegisterof ControlledTrials.Thefollowingguidelineswerereviewedindetail:2010Europeanguidelineforthe managementofgenitalherpes;2014BASHHguidanceonthemanagementofgenitalherpes;USA CentersforDiseaseControlandPrevention2015STDTreatmentGuidelines;2014BASHH/RCOGJoint Guidelineonthemanagementofgenitalherpesinpregnancy;andthe2016WHOguidelinesonthe treatmentofgenitalherpessimplexviruses.Themembersoftheguidelinedevelopmentgroupselected studiesrelevanttothescopeoftheguideline.Articletitlesandabstractswerereviewedandifrelevant thefull-textarticleobtained.Prioritywasgiventorandomisedcontrolledtrialandsystematicreview evidenceand,wherepossible,recommendationsweremadeandgradedonthebasisofthebest availableevidence.Inareaswhereevidenceislacking,recommendationsbasedonconsensusopinion withinthewritinggrouphavebeenmade. GradingofEvidence: FordetailsoftheTablesoflevelsofevidenceandgradingofrecommendationspleasesee: http://www.iusti.org/regions/Europe/pdf/2013/Levels_of_Evidence.pdf Statementondeclarationsofinterest: Nonetodeclare