Download 2017 European guidelines for the management of genital herpes

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
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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
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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:
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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:
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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:
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Aciclovir800mgthreetimesdailyfor2days,or49
Famciclovir1gramtwicedailyforoneday,or50
Valaciclovir500mgtwicedailyfor3days(Ib,A).49,51-54
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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
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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