Herpes Eye Disease 2011

8/7/2019 Herpes Eye Disease 2011

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APAOSydney 2011

Herpetic Eye Disease

Mei-Ling Tay-Kearney

Lions Eye Institute

Perth

Western Australia



2

Virology

About 100 different herpesviruses have been described, 8 found in

humans

Linear double-stranded DNA, surrounded by an icosahedral capsidof 162 capsomeres, an amorphous tegument and an envelope

The lipid envelope is studded with glycoprotein spikes (peptomers),

these recognise receptors on the host cell membrane facilitating

viral entry into cell

These peptomers are particularly antigenic, forming primary

targets for both humoral and cell-mediated immunity

Only enveloped virions are infectious, infectivity easily destroyed

by physical or chemical agents

All establish latency after primary infection, the viral genomeexisting as closed loops with only a small number of viral proteins

expressed

The herpesviridae family is divided into 3 subfamilies according to

cell tropism, reproduction rate and host range



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Viruses of Humans Common name SubfamilyHuman herpesvirus 1 Herpes simplex type 1 alpha

Human herpesvirus 2 Herpes simplex type 2 alpha

Human herpesvirus 3 Varicella-zoster alpha

Human herpesvirus 4 Epstein-Barr gammaHuman herpesvirus 5 Cytomegalovirus beta

Human herpesvirus 6/7 Exanthum subitum

Roseola infantum

beta

Human herpesvirus 8 Kaposi‟s sarcoma gamma

Ocular HSV disease

HSV is probably the most common infective cause of visual impairment in

developed nations, largely as a result of its recurrent nature. About 400000 people in the USA have ocular HSV disease with 50 000 new and

recurrent episodes annually. Asymptomatic viral shedding is an important

source of transmission. HSV-1 is highly prevalent, with 60%-70% of

children by age 5 years seropositive for HSV increasing to 90% in

adulthood. Despite the widespread prevalence, only 20%-30% manifest

clinical disease and ocular disease is seen in less than 1%.

Most studies of HSV ocular disease were conducted many years ago, or

have looked at selected populations only.Two studies however have provided helpful data on the incidence of

different presentations of ocular HSV.1,2

Primary ocular HSV disease

Study Moorfields Eye

Hospital

Rochester Study

Year of study 1973-1980 1950-1982

Patients 108 122

Mean age (yrs) 35 37

M:F 1:1 1:1

Conjunctivitis (%) 84 25

Blepharitis (%) 38 46

Epithelial keratitis (%) 15 63

Stromal keratitis (%) 2 6

Uveitis (%) Not done 4

Unilateral disease (%) 81 88



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The Moorfields data may be more representative of the clinical picture

because of the prospective data collection and a higher suspicion for HSV

infection. The most common presentation of a primary infection appears

to be blepharoconjunctivitis, though only 1%-6% of primary infections

manifest clinically. Therefore, most presentations of ocular HSV arereactivations.

Recurrent ocular HSV

recurrences occur in over a third of patients, and more than half

of these will have more than 1 episode

recurrences of any form of ocular disease increase with time; 10%

at 1 year, 23% at 2 years, 36% at 5 years and 63% by 20 years

after the primary episode (Liesegang et al)3

most common form appears to be either blepharitis or HSVepithelial keratitis

Risk factors for HSV epithelial and stromal keratitis

largely ill-defined

in the Herpetic Eye Disease Study (HEDS),4 326 patients were

followed for 18 months, the risk of a recurrence of HSV epithelial

keratitis was not significantly affected by a previous episode of

epithelial keratitis. But a previous episode of stromal keratitis

increased the risk of a subsequent one 10 fold (P < 0.001) age, gender, race and non-ocular herpes were not risk factors in

HEDS,

Bilateral ocular HSV

frequency varies, 3%-19%

more frequent in persons with atopic disease, men and younger

patients

Ocular HSV in children tends to be more severe with a higher incidence of dendritic ulcers

31 eyes of 28 children in Dublin documented higher incidences of

astigmatism (78%), visual impairment (89%), and recurrences (87%)

than would be expected in adults5

Ocular HSV in Immunocompromised patients

recurrent HSV keratitis are more frequent

presentation may be atypical in transplant patients – marginal

multiple dendrites with subepithelial infiltrates in uninflamed eyes



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Pathogenesis

the major route of ocular infection is zosteriform, with a 2-step

process of infection and reactivation

the optic nerve, trochlear, oculomotor and trigeminal nerves are

important routes of transmission of virus into the eye

different strains may dictate type of disease and recurrence rates

infection with different strains possible, making vaccinationsdifficult

the ocular disease seen is due to a combination of a direct viral

cytopathic destruction with different degrees of

immunopathogenic involvement

Latency

some studies suggest that HSV can establish latency at peripheral

sites

in one PCR study of corneas from 110 patients (52 with known HSKand 58 with non-herpetic corneal disease), HSV-1 DNA was

detected in 82% of patients with HSK and in 22% in patients

without HSK6

D Kennedy et al reviews this issue in Cornea 2011,30:251-259.



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Classification

1. Infectious epithelial keratitis

- vesicles

- dendritic ulcer- geographic ulcer

- marginal ulcer

2. Neurotrophic

3. Stomal keratitis

- necrotizing

- immune

4. Endotheliitis

- disciform

- diffuse- linear

Manifestations

corneal vesicles earliest manifestations, these may be mistaken for

PEE

within 24 hrs, these vesicles coalesce to form dendritic or

geographical ulcers

the dendritic ulcer is a branching linear lesion with terminal

endbulbs, swollen borders containing live virus

it is a true ulcer extending beyond the basement membrane,

therefore staining positive for fluorescein, and Rose Bengal at the

borders

geographical ulcers are enlarged dendritic ulcers with swollen,

scalloped epithelial borders, unlike neurotrophic ulcers with smooth

borders

geographical ulcers may be associated with longer healing time of

dendritic ulcers and prior topical steroid use (Wilhelmus)7



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Dendritic ulcers

Marginal ulcer

marginal ulcers are uncommon, tend to be more symptomatic, with

an anterior stromal infiltrate, and accompanying blood vessels

it can be more difficult to treat and most often confused with

staphylococcal marginal keratitis

an epithelial defect is always present with an HSV marginal ulcer,

often associated with neovascularisation, progression is central,

can occur in any meridian and blepharitis is not prominent

a staphylococcal marginal infiltrate does not have an epithelialdefect, new vessels are not seen, progression is circumferential,



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blepharitis is prominent and typically occurs at the 2,4,8,10 o‟clock

meridians

Neurotrophic keratopathy

corneal sensation is impaired, with decreased tear production may be exacerbated by chronic use of topical medications

irregularity of corneal surface, lack of corneal lustre, punctate

erosions are early signs

stop all unnecessary topical medications, use preserve-free

ocular lubricants

in severe cases, gentle debridement of rolled epithelial borders

may be beneficial

also consider tarsorraphy, botox-induced ptosis,

improve ocular surface milieu with lid scrubs, massage, oraltetracyclines, vitamin C

autologous serum eye drops are very useful

Neurotrophic ulcers

Stromal disease

Whilst stromal disease accounts for 2% of primary disease, it is

responsible for 20%-48% of recurrent episodes.

primary stromal involvement may be from direct viral invasion

(necrotizing), or as a result of the host‟s immune reaction to viral

antigens within the stroma (interstitial keratitis)

necrotizing stromal keratitis is uncommon, and may resemble

bacterial/fungal keratitis



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necrosis, ulceration and a dense stromal infiltration with an

overlying epithelial defect is seen

corneal thinning and perforation can occur in a short period of time

on the other hand, immune stromal keratitis is common, accounting

fore 20% of patients with ocular HSV an antigen-antibody-complement(AAC) cascade in response to viral

antigens within stroma results in intrastromal inflammation

subepithelial haze, punctate stromal opacities, immune ring,

neovascularization and lipid keratopathy may be seen

Stromal keratitis with neovacularisation

Stromal keratitis with perforation Stromal disease with lipid keratopathy

Stromal disease with scarring



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Endotheliitis

Corneal stromal edema without stromal infiltrates, classified according to

the distribution of the KPs and configuration of the overlying edema.

KPs, overlying stromal and epithelial edema, anterior uveitis are

characteristic

in some cases, the KPs are not seen till the severe corneal edema

resolve

probably an immune reaction directed against the corneal

endothelial cells which may contain viral antigens

disciform endotheliitis is the most common with patients

complaining of ocular discomfort, photophobia and limbal injection

is not uncommon unlike disciform and diffuse forms, linear endotheliitis is difficult

to treat, therefore use of oral antivirals should be considered

Disciform endotheliitis with KPs

Diffuse endotheliitis



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Disciform endotheliitis

Treatment

1. Avoidance of trigger factors

2. Aciclovir (ACV)

- readily penetrates the cornea after topical application, and

achieves therapeutic concentrations in aqueous

- 5 doses of 400mg ACV orally taken 24 hours before cataract

surgery reached levels above ED50 range for HSV-1 (mean

3.26M)- oral ACV may be a useful adjuct in children who tend to have

a more severe clinical course (12-80mg/kg/day)

- oral ACV should be given to patients with high rates of HSV

stromal keratitis recurrences, rates reduced by half in

patients given 400 mg bd ACV compared to placebo (HEDS)

- similar prophylaxis applied to children with recurrent HSV

stromal keratitis (10-20mg/kg/day)

- there is no consensus as to which patients should receive

prophylaxis and for how long, but patients with atopy, HIV



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infection and other forms of immunosuppression are good

candidates

- prophylaxis for epithelial keratitis, blepharoconjunctivitis is

less clear

3. Topical steroids

- when a decision is made to use steroids, a significant

strength and frequency should be used to suppress the

inflammation

- customise dose according to level of inflammation

- avoid rapid tapering or abrupt cessation of drops to prevent

“rebound” inflammation

- concept of the „threshold‟ or „flare‟ dose – some patients mayneed steroids long term used at a frequency above their

threshold dose

- cover with topical antivirals – „drop for drop‟ , this may be

discontinued when a weak steroid eg prednisolone phosphate

0.1% is used once a day.

Corneal grafts and HSK

replication of HSV –1 accounts for early recurrences of HSV

keratitis after corneal grafts

there is a 10%-25% recurrence rate in the first year of follow-up

in patients on topical steroids and antiviral therapy

the higher recurrence rates in the first year may be due in part to

the more frequent use of topical steroids

HSV disease should be considered as a possible cause of graft

failure

HSV DNA have been detected in donor tissue of patients without a

history of ocular HSV8

graft-to host transmission of HSV is a rare event, but can have

serious ocular sequelae

in a retrospective analysis of 2398 PKPs performed between 1980

and 1995, 18 presented with HSV epithelial keratitis in their grafts

i.e. an incidence of 1.2/1000 person-years9

most cases of infections occur within 2 years of PKP

donor tissue is not routinely screened for HSV



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prophylactic oral antivirals should be used in patients with known

HSV keratitis and continued for at least a year after

transplantation10

Failed grafts

Excimer laser photoablation and ocular herpes

case reports in humans and animal studies suggest that HSV can be

re-activated by excimer laser keratectomy

prophylaxis with valaciclovir reduced viral shedding in animal

studies

at present, photoablation of corneas with herpes are discouraged



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Herpetic Anterior Uveitis

Herpetic anterior uveitis (HSV or VZV ) probably accounts for 5%-10% of

all uveitis cases seen at tertiary referral centers and which makes this

entity the most common cause of infectious anterior uveitis in developedcountries.

may or may not have a history of previous ocular HSV/VZV

(herpes sine herpete)

it is almost always unilateral

acute onset with pain, redness, photophobia and blurring of

vision

if severe, hypopyon and /or hemorrhage may be seen

if occurs with stromal keratitis or endotheliitis, anterior uveitisis mild

KPs may be small, large or stellate,

patchy iris pigment epithelial loss, pupil is mid-dilated,

unreactive, distorted, best seen on transillumination

IOP typically raised, presumed secondary to trabeculitis

corneal sensation often decreased

intact viral particles have been isolated in aqueous with

lymphocytic infiltration in iris stroma

in VZV uveitis, perineuritis and perivasculitis found withvasoocclusive disease responsible for sectorial iris atrophy



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Management

combination of topical steroids and oral antivirals often required,

particularly in patients with numerous recurrences11

topical steroids must be tapered slowly and for some patients, lefton low dose maintenance therapy

oral antiviral prophylaxis( eg 400mg bd acyclovir) is useful in

patients with tendency to flare when off medications

ocular hypotensives may be necessary in the acute stages when IOP

is high. Note latanaprost may cause reactivation of HSV

Always examine the posterior segment to exclude ocular

involvement as arteriolar sheathing only has been described12

Herpetic Retinitis

More commonly known as acute retinal necrosis (ARN), the clinical picture

was only described in 1971 by Urayama et al. ARN has a two-peak age

distribution, the first peaking at 20 years and the second at 50 years of

age. HSV is presumed responsible for the first peak and VZV the second.

CMV have been reported in rare cases.

Herpetic retinitis is also seen in certain clinical settings eg congenital

zoster, chickenpox in adulthood and in patients with HSV encephalitis.

ARN may affect individuals who are immunocompetent or

immunosuppressed.

Clinical features

classic symptoms & signs do not always occur in practice

best to regard all entities as herpetic retinitis, the clinical picturemodified by the immune status of the patient

retinal vasculitis (arteritis), disc edema and macula ischemia with a

„cherry redspot‟ may be seen

retinal lesions secondary to HSV/VZV tend to start in the far

periphery with „satellite‟ lesions along the posterior border

as retinal lesions regress and heal, vitreous inflammation and haze

intensifies, this is an immune response to dying retina and not due

to a viral cytopathologic effect

retinal detachment occurs in 75% of cases



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in patients with severe immunosuppression as seen in AIDS, the

retinal lesions occur in the outer retina sparing the retinal vessels,

with little vitreous reaction (PORN)

treatment with acyclovir reduces infection of fellow eye from 70%

to 13% in the first year13

Herpes retinitis

CMV

VZV HSV

VZV



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PORN

Management

intravitreal injections of foscarnet (1200mcg/0.1ml) as

effective for HSV, VZV and CMV

intravenous acyclovir 10-15mg/kg tds for 10 - 14 days, followed

by high dose oral antivirals for at least 6 weeks

topical and oral prednisolone (1mg/kg)

barrier laser, early vitrectomy

silicone oil for retinal detachments

if unsure of diagnosis or if lesions worsen despite treatment,

biopsy

CMV Retinitis

Most commonly seen in patients who are immune suppressed. Since the

introduction of highly active anti-retroviral therapy (HAART) in late

1996, the incidence of this opportunistic infection has dropped

dramatically. CMV retinitis is now more commonly seen in post-transplant

patients, those on immunosuppressive drugs and in HIV patients who havefailed or have no access to HAART.

lesions may be hemorrhagic and swollen in the posterior pole,

granular in the periphery or may resemble frosted-branch angiitis

complications include retinal detachments, silicone oil cataracts and

immune recovery phenomena



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CMV retinitis

ARN and CMV retinitis

Management immune restoration with HAART

if possible

intravitreal injections, systemic

ganciclovir or foscarnet

GCV implant

oral ganciclovir

CMV retinal detachment

Silicone oil



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Concept of immune restoration disease (IRD)

First described in patients with AIDS treated with HAART

there is initially a polyclonal expansion of memory CD4+ T-cell

numbers in conjunction with an increase of the T-receptorrepertoire, followed by an increase of naïve CD4 T-cells

improvement of T-cell function follows

immune restoration typically occurs 2-3 months after HAART

host response to infective antigens in tissues results in „relapses‟ in

conjunction with iritis, vitritis, macula edema which may lead to

epiretinal membrane formation and tractional retinal detachment

treatment includes anti-infective agents as well as anti-

inflammatory drugs ( usually steroids)

HLA linkage found for immune restoration to CMV

Herpes Zoster Ophthalmicus

Lifetime risk is 10-30%

2/1000 age 20; 10/1000 age 80+

Second only to thoracic zoster V-1 20 times more involved

50-70% suffer some form of visual morbidity



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Risk Factors

decreased cell mediated immunity to VZV

- age (immunosenescence)

- iatrogenic immunosuppression

- HIV- haematological cancers

if immunocompromised

- 12-25X prevalence

- tends to be more severe and prolonged

- dissemination

- iv treatment required

In children

uncommon in children < 12 yrs (1%)

greatest risk of HZO if child had varicella age 12 months or less

usually mild, much less post-herpetic neuralgia

can occur after zoster vaccination



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Mechanisms of complications

direct viral infection vasoocclusive vasculitis

immune reaction

neuropathic cornea

Ocular complications

most occur within the month of rash onset

corneal ( 60%) and anterior uveitis14 ( 40%) most common

ocular hypertension usually seen with anterior uveitis

epi/scleritis

retinitis

nerve palsies

others

Postherpetic neuralgia

seen in about 15% of cases of HZO

incidence increases with age, duration of acute pain & severity

of rash

use of amitriptyline advocated to reduce acute pain

topical capsaicin, lignocaine, ketamine also used with variable

success

gabapentin, 300-900 mg po tds for severe cases

Condi‟s crystals, 10% iodine topically for weeping skin lesions



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Do oral antivirals make a difference

found to decrease duration of acute pain

viral shedding decreased

time to crusting of skin lesions increased

there is a reduction of the severity of ocular complications ( Cobo et al,15 Harding 16 , Herbort 17 )

reduction in neurotrophic keratitis ( Severson 18 )

severity of ocular complications increase with delay of treatment

(Severson )

Varicella Vaccine19,20

live attenuated Oka strain ( Varilix, Varivax)

single dose for infants, booster required for individuals 13 yrs andolder

zoster can still occur but is a milder disease

as exposure to varicella reduces the risk of zoster, consider

vaccination on individuals older than 60 yrs

Antiviral agents

Compounds with antiviral activity against the herpes viruses and mode ofadministration:

Acyclic guanosine nucleoside thymidine kinase dependant DNA polymerase

inhibitors

Aciclovir topical, oral, intravenous intravitreal

Valaciclovir oral prodrug of aciclovir

Ganciclovir topical, oral, intravenous, intravitreal

Valganciclovir oral prodrug of ganciclovir

Penciclovir topical, intravenous



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Famciclovir oral prodrug of penciclovir

Direct nucleoside DNA polymerase inhibitors

Cidofovir intravenous, intravitreal

Foscarnet topical, oral, intravenous, intravitreal inorganicpyrophosphate analogue

Antisense Oligonucleotide DNA chain terminator

Fomivirsen intravitreal antisense oligonucleotide prevents DNA

chain elongation

Other

Trifluridine topical fluorinated pyrimidine nucleoside inhibits viralDNA synthesis. More effective than idoxuridine and equivalent to

vidarabine. May be useful in aciclovir resistance. Trifluridine

resistance and hypersensitivity can occur

Idoxuridine topical iodinated thymidine analogue interferes with

various viral enzymes. Resistance is common

Vidarabine topical and previously intravenous adenine nucleoside

inhibits viral DNA synthesis

Docosanol topical long chain alcohol inhibits viral assembly and cell

entryBrivudine - not yet available in Australia

The very first antiviral drug, idoxuridine, became available in 1963. In

1977 vidarabine , the first topical and parenterally administered anti-

herpes-viral agent was released. The introduction of acyclovir in 1988

marked a major breakthrough because of its high efficacy and low

toxicity which will be discussed further. The landmark Herpes Eye

Disease Study provided evidence for the effectiveness of prophylactictreatment with oral acyclovir in reducing the recurrence of epithelial

disease. The study‟s approach to stromal disease was flawed in not

separating necrotic from interstitial / endotheliitis related stromal

disease. However results suggested that there probably is a benefit to

acute and prophylactic use of oral aciclovir in stromal necrotic disease.

Insufficient numbers were recruited to determine the benefit of

treatment for herpetic uveitis. Again the trend was towards

effectiveness of oral antiviral treatment and it is our experience that

this is definitely helpful, particularly in more severe cases.



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Therapy for HSV and VZV:

Acyclic guanine nucleoside analogues: Aciclovir / Valaciclovir,

Penciclovir / Famciclovir

These agents are phosphorylated intracellularly by viral kinase tobecome active inhibitors of viral DNA synthesis. The active

nucleoside triphosphate is present in 40-100 fold increased

concentrations in virally infected cells compared with non-infected

cells. It has minimal effects on cellular function of non-infected

mammalian cells. Valaciclovir is converted rapidly to aciclovir by

first pass hepatic and intestinal enzymatic hydrolysis. Famciclovir is

converted to penciclovir following intestinal absorbtion. Penciclovir

is 100 fold more potent against viral DNA polymerase than aciclovir

and is present in cells for longer and in higher concentrations. Theprodrugs valaciclovir and famciclovir have higher bioavailability than

their active metabolites, aciclovir and penciclovir. Because of these

features famciclovir and valacyclovir are administered at lower

systemic doses than aciclovir and are less toxic. Similar

concentrations of these drugs are found in all body fluids including

aqueous, CSF, breast milk and fetal circulation. They are excreted

mainly through the kidneys. Side effects are rare but include

nausea, reversible nephrotoxicity, neurotoxicity, diarrhoea and

headache. (famciclovir may be mutagenic and decreasespermatogenesis). Aciclovir is not thought to be teratogenic. Drug

interactions are few. Mycophenolate Mofetil potentiates the

effects of aciclovir by depleting deoxyguanosine (for which aciclovir

triphosphate competes). Famciclovir and penciclovir have no known

drug interactions. Bioavailability of aciclovir is 10-30% compared

with its prodrug, valaciclovir’s bioavailability of 70%. Bioavailability

of penciclovir is 5% compared with 65-77% for its prodrug

famciclovir.

:

HSV1 : HSV2 : VZV / EBV = 1 : 0.5 : 0.1. It has little activity against

CMV or HHV6

Although aciclovir is ineffective in established CMV it may be used for

prophylaxis. It does not have any clinical effect in infectious

mononucleosis but may help with EBV related oral hairy leucoplakia

Dosages:



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HSV VZV Necrotising retinitis Prophylaxis

Aciclovir 400mg 5x/d 800mg 5x/d 500mg/m2IV 400mg bd

or 10-15 mg/kg tds

for 10-14d, then

600mg 5x/d for6-12 w

Valaciclovir 500mg tds 1000mg tds 500mg bd

Famciclovir 250mg tds 500mg tds 250mg bd

In VZO acyclovir 800mg 5x/d for 7d reduces pain, healing time, keratitis

& uveitis if given within 72h

Valaciclovir 1000mg tds for 7d provides faster pain relief than aciclovir

in adults >50years oldGanciclovir gel is effective for HSV keratitis.

HSV Resistance occurs by the following mechanisms in order of

importance:

1. Absence / partial production of viral thymidine kinase

2. Altered thymidine kinase substrate specificity

3. Altered viral DNA polymerase

VZV resistance occurs by the following mechanisms in order of

importance:1. Decreased thymidine kinase activity

2. Rarely DNA polymerase resistance

Resistance is defined as in vitro inhibitory concentrations > 2-3 μg/ml

which predicts failure of therapy in immunocompromised patients.

Resistant viruses exist in normal wild virus isolates

Intravenous foscarnet is usually effective in progressive aciclovir

resistant disease

Ganciclovir may be ineffective against thymidine kinase deficient HSV.

Therapy for CMV:

Ganciclovir

This drug undergoes intracellular phosphorylation by viral UL97 gene

encoded phosphotransferase following which it inhibits viral DNA

polymerase. Ganciclovir’s bioavailability is 6-9% compared with its

prodrug, valganciclovir, at 61%. Valgangiclovir bioavailability increases if

taken with food. Excretion is predominantly renal. Side effects include



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myelosuppression, GIT & CNS toxicity as well as teratogenesis. Oral

ganiclovir 1000mg tds in addition to intravitreal treatment reduces time

to progression of CMV retinitis

Resistance is conferred by impaired phosphorylation or DNA polymerase

mutation. These strains may be cross resistant to foscarnet andcidofovir.

Dose: Ganciclovir IV induction5mg/kg bd x 2-3/52 then 5mg/kg daily or

6mg/kg 5d/wk or ganciclovir 1000mg po tds, or valganciclovir 900mg po

bd WITH ganciclovir 2mg/0.1ml intravitreal weekly

Cidofovir ( not used much now)

This drug has 8-600 fold greater activity on viral than human DNA

polymerase. It is phosphorylated to its active form by cellular rather

than viral enzymes and is hence effective against resistant viruses withthymidine kinase mutation induced resistance and UL97 mutations but not

those with DNA polymerase mutation induced resistance. Prior ganciclovir

treatment may lead to cidofovir resistance. Cidofovir is administered

intravenously with probenecid. It is excreted by the kidneys and is

nephrotoxic, teratogenic and possibly carcinogenic. Uveitis and hypotony

are common ocular side effects.

Dose: Induction 5mg/kg IV weekly x 3 wks then 3-5mg/kg biweekly.

Intravitreal 20ug every 5-6wk

Foscarnet Because foscarnet‟s effect is on DNA polymerase it is useful for

resistant strains with thymidine kinase mutations. Viral resistance may

occur through DNA polymerase mutation

Side effects include renal impairment, neurotoxicity, GIT upset,

neutropaenia, anaemia and hypocalcaemia.

Dose: Induction: 90mg/kg bd x 2wk then 120mg/kg IV daily. Intravitreal

1200ug in 0.1ml weekly

Fomivirsen ( not used much now)

Although in principle fomivirsen’s function as an antisense oligonucleotideis of benefit in the treatment of viruses with common mechanisms of

resistance its side effects severely limit its usefulness. These include

uveitis, vitritis, cataracts and IOP rise. Prior cidofovir treatment worsens

uveitis.

Dose: 330ug on day 1 & day 15, then monthly.



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Herpes Eye Disease 2011