Ophthalmic manifestations of HIV infection KRISADA HANBUNJERD.

Ophthalmic Ophthalmic manifestationsmanifestations

ofofHIV infectionHIV infection

KRISADA HANBUNJERD

ophthalmic manifestation of HIV infection

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Ophthalmic manifestations

Incidence = 44.6%* consist of Noninfectious microangiopathy Opportunistic ocular infections Neoplasm of ocular adnexa Neuroophthalmic manifestation Drug-induced manifestation*epidemiology of ocular complication of HIV infection in ChiangMai


Noninfectious microangiopathy

Conjunctival vessel abnormalitiescapillaries dilatationisolated vascular fragmentirregular vessel calibergranular blood column

HIV retinopathy


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HIV retinopathyoverview

most common ophthalmic lesion characterized by

cotton wool spot

retinal hemorrhage

microaneurysm

telangiectatic vessel

indicate immune deteriolation


HIV retinopathymanifestations

Cotton Wool Spotoccur 28-92% of patient with AIDSare microinfarct of nerve fiber layer of retinaclinically white fluffy lesion with feathery bordercommon site is peripapillaresolved within 4-6 weeks

Retinal Hemorrhageoccur less than 20%

Perivascular Sheathingoccur less than 1%more common in AFRICA


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HIV retinopathypathogenesis

multifactorial may be immune complex deposition

HIV infection of retinal vascular endotheliumlocal release of cytotoxic factorsrhealogic abnormalities such as

RBC aggregation,elevated fibrinogen level

circulating immune complex,plasma viscosity


Differentiation

Diabetes Mellitus

Malignant Hypertension

Collagen Vascular Disease


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Differentiation

especially from early Cytomegalovirus Retinitis


Opportunistic ocular infections (COMMON)

Anterior segmentMicrosporidial keratoconjunctivitisHerpes zoster ophthalmicus eyelid Molluscum

contagiosum


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Opportunistic ocular infections (COMMON)

Posterior segment

Cytomegalovirus retinitis

Varicella zoster retinitis

Toxoplasma retinitis


Opportunistic ocular infections(UNCOMMON)

Anterior segmentBacterial keratitisHerpes simplex keratitis

Posterior segmentPneumocystic choroiditisFungal chorioretinitisOcular syphilisOcular tuberculosis


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Cytomegalovirus Retinitis overview

The most common of opportunistic ocular infection in patient with AIDS

occur in approximately 20-40% of these patient

progressive if left untreated potentially blinding disease ultimately developed bilateral


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Cytomegalovirus Retinitis High Risk

CD Count < 50 Associated with PCP, Extraocular

CMV ,Toxoplasmosis HLA B44 , B51 , DR7


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Cytomegalovirus Retinitis Symptoms

asymptomatic light flash floater visual field loss blurred or distorted vision red eye,eye pain,photophobia are rare


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Cytomegalovirus Retinitis Signs

no conjunctival hyperemia minimal anterior chamber inflammatory

reaction minimal vitreous inflammatory reaction typically yellow to white area of retinal

necrosis that follow a vascular distribution


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Cytomegalovirus Retinitis Diagnosis

based on clinical fundus appearance

vitreous and aqueous humor analysis for CMV DNA **

endoretinal biopsy **

** for atypical presentation or unresponsive to treatment (usually not be done in normal setting)


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Cytomegalovirus Retinitis Clinical Presentation

Spectrum of fundus appearance fulminant/edematous form indolent form frosted branch angiitis form atypical form


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Fulminant form dense confluent

area of retinal opacification location along vesseles no clear central atrophic area sufficient retinal hemorrhage inflammatory perivascular

sheathing


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Indolent form faint grainy opacification

or blush fire location not overlying vessel may have central clear

atrophic area no or minimal retinal hemorrhage no inflammatory vascular

sheathing


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Frosted branch angiitis form

usually neglected case indicate insufficient

control of disease ( practically seen in patient who lost follow up treatment)


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Cytomegalovirus Retinitis Systemic Treatment

FDA approved IV Gancyclovir Induction and Maintenance IV Foscarnet Induction and Maintenance IV Gancyclovir Induction and Oral

Gancyclovir Maintenance IV Cidafovir Induction and Maintenance Oral valgancyclovir for Induction and

Maintenance (non zone1CMVR)


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Retinal Zone


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Cytomegalovirus Retinitis Dosage

GancyclovirIV Dosage Induction 5mg/kg

q 12 hours 14-21 days

Maintenance 5mg/kg daily or 6mg/kg 5 out of 7 days

FoscarnetIV Dosage Induction

60 mg/kg q 8 hours 14-21 days

Maintenance 90-120 mg/kg daily


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SOCA1 234 patients with newly diagnosed CMVR

randomized to gancyclovir or foscarnet Time to progression :56 days for

gancyclovir V.S. 59 days for foscarnet (p=0.685)

Median survival 12.6 months for foscarnet V.S. 8.5 months for gancyclovir


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SOCA1 More neutropenia with gancyclovir More infusion related symptoms

genitourinary symptoms,nephrotoxic effect and electrolyte abnormality with foscarnet

Patient with foscarnet more likely to be switched to alternative treatment (46% V.S. 11%;p<0.00)

Toxicity resolved in 88% of cases after treatment switches


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Cytomegalovirus Retinitis Dosage

CidofovirIV Dosage Induction 5mg/kg weekly 2 weeks Maintenance 5mg/kg every 2 weeks


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Cytomegalovirus Retinitis General Consideration of Treatment

IV Antivirals are all effective for induction and maintenance

IV Antivirals have unique complications

gancyclovir-neutropenia

foscarnet-nephrotoxic

cidofovir-nephrotoxic,uveitis,hypotony


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Cytomegalovirus Retinitis General Consideration of Treatment(continue)

IV Treatment is associated with catheter’s complication

IV Treatment is costly IV Treatment needs hospitalization? Time consumed Systemic or Local Treatment


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Intravitreal drugs

Gancyclovir

Foscarnet

Cidofovir

fomivirsen Gancyclovir Intraocular Implant

Cytomegalovirus Retinitis Local Treatment


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Cytomegalovirus Retinitis Intravitreal Injection

Gancyclovir Dosage Induction :200-4000microgram 2-3times/week Maintenance: same dose weekly

Foscarnet Dosage Induction 1.2-2.4 mg 2 times/week Maintenance 1.2-2.4 mg weekly

Cidofovir Dosage 20 microgram q 5-6 weeks


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Cytomegalovirus Retinitis Intravitreal Injection


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Cytomegalovirus Retinitis Gancyclovir Implant


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Cytomegalovirus Retinitis Gancyclovir Implant

release drug 1 microgram/hour for 32 weeks

intravitreal drug level 4 fold higher than intravenous

median time to progress = 226 days retinal detachment 11-23% contralateral involvement 50% in 6 months


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CYTOMEGALOVIRUS RETINITIS Local Treatment(advantages)

prevent systemic side effect need less drug so less cost improve quality of lifehigher drug concentration


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Intraocular Gancyclovir Level

microgram/ml intravenous induction 0.78 intravenous maintenance 0.63 oral gancyclovir 0.83 implant 4 intravitreal injection(24hr) 143 intravitreal injection(72hr) 23


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CYTOMEGALOVIRUS RETINITIS Local Treatment(disadvantages)

unability to protect contralateral eye increase risk of extraocular CMVR less survival


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CYTOMEGALOVIRUS RETINITIS Local Treatment(complications)

increase intraocular pressure

increase risk of retinal detachment

vitreous hemorrhage endophthalmitis

scarring of injected site,retinal toxicity?


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Role of oral Gancyclovir

Low bioavailability Cause neutropenia Not indicate for induction therapy* Suitable for maintenance therapy in higher

dose (>4500mg/day)* May be combined with IV Gancyclovir or

Gancyclovir implant*due to low intraocular gancyclovir level


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valgancyclovir(valcyte)

is an L-valyl ester (prodrug) of ganciclovir absolute bioavailability was approximately 60% rapid conversion to ganciclovir elimination by renal excretion through glomerular

filtration and active tubular secretion.

The half-life (t1/2) of ganciclovir following oral

administration of valganciclovir tablets was 4.08 +- 0.76 hours (n=73)


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Dosage of Valgancyclovir

Dose Modifications for Patients with Impaired Renal Function

CrCl(mL/min) Induction Dose Maintenance Dose > 60 900 mg twice daily 900 mg once daily 40 – 59 450 mg twice daily 450 mg once daily 25 – 39 450 mg once daily 450 mg every 2 days 10 – 24 450 mg every 2 days 450 mg twice weekly


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Comparison of Valgancyclovir and IV,Oral Gancyclovir


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Decrease incidence From 21.9 Per 100 Person-Year To 3.7 Per 100 Person-Year

Change in the clinical course of the disease

Altered Clinical presentation

CYTOMEGALOVIRUS RETINITISIN HAART ERA


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CLINICAL COARSECHANGE

From Progressive if lefted untreated To Ability to discontinue AntiCMV

agent without progression


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Source,year No of Patients Median Time(Range) No of Patients CD4 Cell Count(Range)

(NoRx) Not Receiving Therapy With Reactivation When Therapy Stopped

month 10 /L

Whitcup,1997 4(1) 6(4-12) 0 0.24-0.28

Reed,1997 4(4) 5(4-7) 0 not available

Tural,1998 7(0) 9(9-12) 0 0.18-0.52

Macdonald,1998 11(0) 5(3-18.5) 0 0.06-0.41

Vrabec,1998 8(0) 13.5(3-16) 0 0.09-0.24

Whitcup,1998 2(2) 9.5(7-12) 1 0.06-0.11

Jabs,1998 15(0) 8(3-16) 0 0.09-0.65

Whitcup,1999 14(0) 16.4(8-22) 0 0.08-1.3

Reported Cases of Inactive Cytomegalovirus Retinitis Without Specific AntiCMV Therapy


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ALTERED CLINICAL PRESENTATIONFROM IMMUNE RESTORATION

Immune Recovery Vitritis Cystoid Macula Edema Epiretinal Membrane Vitreomacula traction syndrome Disc Edema and Neovascularization


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IMMUNE RECOVERY UVEITIS(IRU)

3 I Intraocular inflammation characterized by

vitritis ,disc edema , cytoid macula edema usually reversible , treated by local steroid if still unchanged

Inactive cytomegalovirus retinitis Immune recovery by CD4 rise >50 longer

than 3 months


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IMMUNE RECOVERY VITRITIS


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D/D for CMVR

Progressive Outer Retinal Necrosis Toxoplasma Retinitis Intraocular Lymphoma Ocular Syphilis


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Progressive Outer Retinal Necrosis caused by VZV , Herpes simplex

virus , CMV minimal anterior and vitreal

inflammatory reaction start at peripheral retina first

as deep multifocal opacification then progress rapidly to

posterior pole and cause secondary retinal detachment finally


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Toxoplasmic Retinitis usually acquired disease granulomatous anterior uveitis focal or multifocal retinitis +/- vitritis no previous toxoplasma retinochoroidal

scar approximately 50% of retinitis patient have

encephalitis (not vice verca)


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Neoplasm of Ocular Adnexa Kaposi sarcoma

usually asymptomatic sites involved are eyelid , conjunctiva , orbitinferior fornix is most common site

non Hodkin’s lymphomanon tender anterior orbital massproptosis , diplopia , ptosis ,eyelid edema

Conjunctival squamous carcinoma


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Neuroophthalmic Manifestations Cranial nerve palsy: CN6 palsy

Internuclear ophthalmoplegia CN 3 palsy

Visual field defects


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Neuroophthalmic Manifestations

Optic nerve disorder

Papilledema , optic atrophy

retrobulbar optic neuritis

papillitis Cortical blindness


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Cryptococcal Papilledema cause increase

intracranial pressure back to the eye

these picture show optic nerve head in various stage


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Drug induced manifestations

Cidofoviranterior uveitis , hypotony ,

enopthalmos


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Drug induced manifestations

Rifabutinanterior uveitis

Terbinafineanterior uveitis , iridodonesis

phacodonesis , conjunctival hemorrhage


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International Variation of Manifestationsmost common reported ocular conditions

Industrialized Countries

Subsaharan Africa

Latin America

South and Southeast Asia

CMVR

HZO

conjunctival squamous cell tumors

CMVR

ocular toxoplasmosis CMVR

HZO

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Ophthalmic manifestations of HIV infection KRISADA HANBUNJERD.

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