The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.

AIDS CLINICAL ROUNDS

J.#Tyler#Lonergan,#MD#Clinical#Professor#of#Medicine#UCSD#Health#Systems#April#24,#2015#

  60#yo#HIVHinfected#(CD4=264/13%,#VL<40#

on#ART)#man,#w/#hx#of#

anal#dysplasia/#

condyloma,#anogenital#

HSV,#and#squamous#cell#

carcinoma#of#lip#who#

presents#with#this#

enlarging,#painful,#

exophyUc#scrotal#lesion#

for#two#months#

1.  Condyloma#acuminatum##

2.  Squamous#cell#carcinoma#

3.  Lymphoma#

4.  Herpes#simplex#

5.  Syphilis#(Condyloma#lata)#

  1997:#HIV##  Nadir#CD4#=#10#(‘99),#MDR,#due#to#past#poor#

adherence,#suppressed#now#with#DRV/r/RAL/ETR#

  1999:#Cryptosporidiosis#  1999:#Cryptococcal#meningiUs##

  2000:#Primary#CNS#lymphoma,#s/p#whole#brain#

XRT#

  2003:#Squamous#cell#carcinoma#of#lower#lip,#s/p#

excision#and#XRT#

  Recurrent#oral,#anal#and#genital#HSV#on#acyclovir#suppression#

 Anal#dysplasia/condyloma#

 OHL# Oral#candidiasis#  Recurrent#C.#difficile#coliUs#

  CogniUve#impairment#related#to#HIV,#brain#

radiaUon#

 Depression/Anxiety# Hypertension#  LUTS#

  Legally#immigrated#from#Cuba#as#a#teenager#in#

1960s#

 Worked#for#US#postal#service#for#several#years#

unUl#became#ill#and#qualified#for#disability#in#

late#90s#

  Lives#alone#in#SecUon#8#apartment#in#Hillcrest,#

has#SW#and#IHSS#worker,#meals#on#wheels#

 MSM,#not#sexually#acUve#for#years#

  Former#smoker#

 No#history#of#substance#abuse#

  2001H2014:#Recurrent,#painful,#large#(2H5#cm),#

ulceraUve,#hypertrophic#lesions#on#scrotum#and#

R#chin/lower#lip#area#

  IniUally#episodes#infrequent#(once#every#1H2#years)#but#became#frequent#(new#lesions#within#

a#week#of#compleUng#therapy)#and#then#

refractory#to#treatment#and#persistent#

  20#hospital#admissions#for#treatment;#one#

lasted#over#4#months#

 MulUple#biopsies#from#chin/lip#and#scrotal#

lesions#at#different#Umes#to#confirm#previous#

diagnosis#and#rule#out#alternaUve#ones##

  Swabs#from#chin#and#genital#lesions#grew#HSV#

from#cultures##

 HSV#PCR#tesUng#idenUfied#HSV#type#2#from#chin#

and#scrotal#lesions#

 Oral#Acyclovir/Valacyclovir/Famciclovir:#

ineffecUve#for#hypertrophic#lesions#irrespecUve#

of#dose#or#duraUon.###Typical#HSV#ulcers#

remained#responsive.##Prescribed#acyclovir#for#

suppression#but#adherence#poor#unUl#recently#

 Hypertrophic#lesions#presumed#to#be#acyclovir#

resistant#based#on#lack#of#clinical#response.#

AnUviral#suscepUbility#tesUng#in#2012.##From#

same#HSV#culture:##

  ARUP#phenotypic#assay#demonstrated#HSV#

resistance#to#acyclovir#and#ganciclovir#and#

suscepUbility#to#foscarnet##

ViroMed#assay#showed#suscepUbility#to#acyclovir###

  Repeat#test#requested#but#not#done#  TK#genotypic#resistance#tesUng#ordered#but#never#done##

ARUP%

ViroMed%

1.  Intravenous#Acyclovir#2.  Intravenous#Foscarnet#3.  Intravenous#Cidofovir#4.  Topical#Imiquimod#

5.  Topical#Cidofovir#6.  Surgery#

 Acyclovir:#high#dose#parenteral#@10#mg/kg/

Q8hr#used#twice;#once#x#8#days#and#other#for#2+#

weeks#without#response###

Foscarnet:#IniUally#responsive#to#2H3#weeks#of#

therapy#but#over#Ume#less#effecUve.##As#

outbreaks#became#more#frequent,#a#lower#dose#

of#daily#foscarnet#prescribed#for#suppression#

but#strategy#ineffecUve#due#to#logisUcal#issues,#

poor#adherence,#line#infecUons#

  IV#cidofovir#discussed#but#considered#too#nephrotoxic#(pt#had#chronic#CKD#with#Cr#

1.4H2.0)#

  Topical#cidofovir:#unable#to#get#as#outpaUent#because#of#cost#(~$900/2#weeks#of#therapy)#and#

not#covered#by#insurance.##Used#as#inpaUent#

twice#for#several#weeks#with#IV#foscarnet;#

parUal#response##

  Thalidomide:#considered#but#determined#too#

risky#with#his#underlying#cogniUve#impairment#

and#mental#illness#

Cryotherapy#used#twice#on#lip#lesions#but#

ineffecUve#

  Surgery:#scrotal#lesions#refractory#to#medical#

therapy#excised#in#OR#three#Umes.##Last#surgery#

June#2014.##Wound#dehisced#but#eventually#

healed#without#recurrence#of#lesions#

Imiquimod:#tried#twice#as#inpaUent#in#2012#but#

disconUnued#aner#brief#periods#because#

thought#to#be#irritaUng#lesions.##Used#as#

outpaUent#in#September#’14#when#he#

developed#new#chin#lesion.##Aner#a#month#

lesion#started#to#respond#and#within#3#months#

resolved#

1.  40%#2.  80%#3.  20%#4.  60%##

  Leading#cause#of#genital#ulcer#disease#worldwide#

 Higher#prevalence#in#HIVHinfected#persons#  In#a#prospecUve#cohort#of#700#HIVHinfected#persons#in#the#US,#60%#of#HIV#infected#paUents#were#HSVH2#

seroposiUve#compared#to#20%#in#general#US#

populaUon*#

*Patel#et#al.#Sex#Transm#Dis#2012;39:154#

 As#HIV#progresses#and#CD4#counts#decline#HSV#infecUons#more#severe#and#frequent,#with#

delayed#healing#and#prolonged#shedding#

 Not#clear#whether#ART#reduces#HSV#outbreaks#and#shedding#because#of#conflicUng#results#from#

small#observaUonal#studies#

#

 UlceraUve#disease:###

  Well#controlled#HIV:#

HSV#outbreaks#similar#

to#HIV#negaUve#

persons#

#

  Poorly#controlled#HIV#and#low#CD4#counts#

(<100):#ulcers#are#onen#

deeper,#larger,#more#

painful#and#can#be#

persistent##

  Hypertrophic#masses,#pseudotumors,#nodular#or#

plaqueHlike#lesions#and#most#with#superficial#

ulceraUons#

  Only#associated#with#HSVH2#  Rare;#most#cases#described#in#HIVHinfected#paUents#

but#also#cases#reported#in#other#immunoH

compromised#individuals#

 More#common#in#persons#with#current#or#previous#

diagnosis#of#AIDS#

  Most#have#history#of#typical#recurrent#ulceraUve#

anogenital#HSV#outbreaks#but#hypertrophic#form#can#

be#iniUal#presentaUon##

  Almost#all#cases#report#anogenital#lesions#but#few#

reports#of#ectopic#locaUons#(e.g.,#tongue,#tonsil,#face,#

endobronchial#tree)#

  Lesions#typically#large#  Single#lesion#at#one#site#most#commonly#reported#but#

mulUple#lesions#and#involvement#of#2#different#sites#

occurs##

  Usually#grow#slowly#over#months#but#a#few#reported#

rapidly#growing#over#a#couple#of#weeks#

#

#

  Case#reports#of#lesions#misdiagnosed#most#commonly#

as#condyloma#acuminata#or#squamous#cell#carcinoma#

  Possible#misdiagnosis#of#our#paUent’s#lip#lesion#as#squamous#

cell#carcinoma#in#situ#in#2003;#Derm#path#Bx#Report:##

  Clinical#History:#12#month#hx#of#enlarging#len#lower#lip#12#x#

13#mm#verrucous#plaque.##No#response#to#LN###

Dermatopath:#epidermis#irregularly#acanthoUc#and#

demonstrates#mild#papillomatosis.##Epithelium#covered#

with#densely#compacted#orthoH#and,#focally,#parakeratoUc#

scale.##Throughout#the#epithelium#there#is#evidence#of#

dysplasia,#with#many#mitoUc#figures#located#well#above#

the#basilar#layer##

  Plan#to#obtain#slides#stored#offsite#to#review##

  Some#but#not#all#paUents#exposed#to#acyclovir#prior#to#

development#of#hypertrophic#lesions#

  About#half#of#cases#reported#as#acyclovir#resistant#  Case#reports#with#longer#term#followHup#report#

recurrences#usually#within#a#year#

 Neoplasms:#squamous#cell#carcinoma,#

lymphoma#

  Bacteria:#Treponema#pallidum,#mycobacteria##

  Viruses:#HPV#

 HSV#PCR#of#lesion#surface# HSV#Culture#(if#PCR#unavailable)#  Biopsy#

  Epidermis:#foci#of#ulceraUon#with#epithelial#

hypertrophic#changes#(if#marked:#

pseudoepitheliomatous#hyperplasia)#

 Dermis:#dense#inflammatory#infiltrate#consisUng#

mostly#of#plasma#cells#mixed#with#lymphocytes,#

neutrophils#and#eosinophils#

 MulUnucleated#keraUnocytes#with#moulded#

ground#glass#nuclei#and#eosinophilic#inclusions#

typical#of#HSV##

 Underlying#mechanism#for#exaggerated#tumor#

like#response#to#HSV#has#not#been#elucidated#

  Polyclonal#lymphoplasmocyUc#B#cells#in#lesion#

infiltrate#supports#hypothesis#of#dysregulated#

anUgenHdriven#immune#reacUon,#likely#directed#

at#HSVH2##

  Scarcity#of#T#cells#in#the#lesional#mononuclear#

infiltrate#support#a#hypothesis#that#a#funcUonal#

deficit#of#HSVH2#specific#T#cells###

  IRIS#proposed#as#eUology#of#exaggerated#inflammatory#response#leading#to#epithelial#

hyperplasia#but#several#cases#described#in#

paUents#not#on#ART#and#others#presenUng#aner#

2#years#of#effecUve#ART.##Also#occurs#in#HIV#

negaUve#immunocompromised#paUents###

 Acyclovir#resistance#thought#to#play#a#role#but#some#lesions#are#responsive#and#suscepUble#to#

acyclovir##

  Some#respond#to#oral#or#intravenous#acyclovir#

  Those#refractory#to#acyclovir#had#mixed#

responses#to#topical#or#parenteral#foscarnet#or#

cidofovir#which#have#been#more#successfully#

used#for#acyclovir#resistant#ulcers#

 Other#cases#have#reported#beser#and#more#

sustained#response#to#immunomodulatory#

agents#such#as#imiquimod#and#thalidomide#

Imiquimod#,#a#TollHlike#receptor#7#agonist,#

boosts#both#innate#and#adapUve#anUviral#

immunity#and#may#overcome#deficiency#of#

anUherpeUc#immunity##

Imiquimod#advantage#of#low#adverse#effects,#

relaUvely#inexpensive,#topical,#no#risk#of#

resistance,#and#self#administered#

 Hypertrophic#HSV#is#a#rare#manifestaUon#of#

HSVH2#in#HIVHinfected#paUents#

  Include#in#differenUal#diagnosis#of#a#mass#lesion#

in#the#anogenital#or#oral#areas#

 Diagnosis#can#be#made#by#HSV#tesUng#of#

lesion’s#surface#but#may#require#a#biopsy#

(especially#at#iniUal#presentaUon)#to#confirm#

diagnosis#and#rule#out#other#mimicking#

condiUons##

 Acyclovir#should#be#tried#iniUally#but#if#lesion#is#unresponsive#then#test#for#acyclovir#resistance#

and#try#imiquimod##