Ophthalmic manifestations of HIV infection

1. Ophthalmic manifestationsofHIV infection KRISADA HANBUNJERD

2. 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 ophthalmic manifestation of HIV infection

3. Noninfectious microangiopathy • Conjunctival vessel abnormalities capillaries dilatation isolated vascular fragment irregular vessel caliber granular blood column • HIV retinopathy ophthalmic manifestation of HIV infection

4. HIV retinopathyoverview • most common ophthalmic lesion • characterized by cotton wool spot retinal hemorrhage microaneurysm telangiectatic vessel • indicate immune deteriolation ophthalmic manifestation of HIV infection

5. HIV retinopathymanifestations Cotton Wool Spot occur 28-92% of patient with AIDS are microinfarct of nerve fiber layer of retina clinically white fluffy lesion with feathery border common site is peripapilla resolved within 4-6 weeks Retinal Hemorrhage occur less than 20% Perivascular Sheathing occur less than 1% more common in AFRICA ophthalmic manifestation of HIV infection

6. HIV retinopathypathogenesis • multifactorial • may be immune complex deposition HIV infection of retinal vascular endothelium local release of cytotoxic factors rhealogic abnormalities such as RBC aggregation,elevated fibrinogen level circulating immune complex,plasma viscosity ophthalmic manifestation of HIV infection

7. Differentiation • Diabetes Mellitus • Malignant Hypertension • Collagen Vascular Disease ophthalmic manifestation of HIV infection

8. Differentiation • especially from early Cytomegalovirus Retinitis ophthalmic manifestation of HIV infection

9. Opportunistic ocular infections (COMMON) • Anterior segment Microsporidial keratoconjunctivitis Herpes zoster ophthalmicus eyelid Molluscum contagiosum ophthalmic manifestation of HIV infection

10. Opportunistic ocular infections (COMMON) • Posterior segment Cytomegalovirus retinitis Varicella zoster retinitis Toxoplasma retinitis ophthalmic manifestation of HIV infection

11. Opportunistic ocular infections(UNCOMMON) • Anterior segment Bacterial keratitis Herpes simplex keratitis • Posterior segment Pneumocystic choroiditis Fungal chorioretinitis Ocular syphilis Ocular tuberculosis ophthalmic manifestation of HIV infection

12. 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 ophthalmic manifestation of HIV infection

13. Cytomegalovirus Retinitis High Risk • CD Count < 50 • Associated with PCP, Extraocular CMV ,Toxoplasmosis • HLA B44 , B51 , DR7 ophthalmic manifestation of HIV infection

14. Cytomegalovirus Retinitis Symptoms • asymptomatic • light flash • floater • visual field loss • blurred or distorted vision • red eye,eye pain,photophobia are rare ophthalmic manifestation of HIV infection

15. Cytomegalovirus Retinitis Signs • no conjunctival hyperemia • minimal anterior chamber inflammatoryreaction • minimal vitreous inflammatory reaction • typically yellow to white area of retinal necrosis that follow a vascular distribution ophthalmic manifestation of HIV infection

16. 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) ophthalmic manifestation of HIV infection

17. Cytomegalovirus Retinitis Clinical Presentation Spectrum of fundus appearance • fulminant/edematous form • indolent form • frosted branch angiitis form • atypical form ophthalmic manifestation of HIV infection

18. Cytomegalovirus Retinitis Clinical Presentation Fulminant form • dense confluent area of retinal opacification • location along vesseles • no clear central atrophic area • sufficient retinal hemorrhage • inflammatory perivascular sheathing ophthalmic manifestation of HIV infection

19. Cytomegalovirus Retinitis Clinical Presentation 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 ophthalmic manifestation of HIV infection

20. Cytomegalovirus Retinitis Clinical Presentation Frosted branch angiitis form • usually neglected case • indicate insufficient control of disease ( practically seen in patient who lost follow up treatment) ophthalmic manifestation of HIV infection

21. 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) ophthalmic manifestation of HIV infection

22. Retinal Zone ophthalmic manifestation of HIV infection

23. Gancyclovir IV Dosage Induction 5mg/kg q 12 hours 14-21 days Maintenance 5mg/kg daily or 6mg/kg 5 out of 7 days Foscarnet IV Dosage Induction 60 mg/kg q 8 hours 14-21 days Maintenance 90-120 mg/kg daily Cytomegalovirus Retinitis Dosage ophthalmic manifestation of HIV infection

24. 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 ophthalmic manifestation of HIV infection

25. 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 ophthalmic manifestation of HIV infection

26. Cytomegalovirus Retinitis Dosage Cidofovir IV Dosage • Induction 5mg/kg weekly 2 weeks • Maintenance 5mg/kg every 2 weeks ophthalmic manifestation of HIV infection

27. 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 ophthalmic manifestation of HIV infection

28. 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 ophthalmic manifestation of HIV infection

29. Cytomegalovirus Retinitis Local Treatment • Intravitreal drugs Gancyclovir Foscarnet Cidofovir fomivirsen • Gancyclovir Intraocular Implant ophthalmic manifestation of HIV infection

30. Cytomegalovirus Retinitis Intravitreal Injection GancyclovirDosage • Induction :200-4000microgram 2-3times/week • Maintenance: same dose weekly FoscarnetDosage • Induction 1.2-2.4 mg 2 times/week • Maintenance 1.2-2.4 mg weekly CidofovirDosage • 20 microgram q 5-6 weeks ophthalmic manifestation of HIV infection

31. Cytomegalovirus Retinitis Intravitreal Injection ophthalmic manifestation of HIV infection

32. Cytomegalovirus RetinitisGancyclovir Implant ophthalmic manifestation of HIV infection

33. Cytomegalovirus RetinitisGancyclovir 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 ophthalmic manifestation of HIV infection

34. CYTOMEGALOVIRUS RETINITISLocal Treatment(advantages) • prevent systemic side effect • need less drug so less cost • improve quality of life • higher drug concentration ophthalmic manifestation of HIV infection

35. 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 ophthalmic manifestation of HIV infection

36. CYTOMEGALOVIRUS RETINITISLocal Treatment(disadvantages) • unability to protect contralateral eye • increase risk of extraocular CMVR • less survival ophthalmic manifestation of HIV infection

37. increase intraocular pressure increase risk of retinal detachment vitreous hemorrhage endophthalmitis CYTOMEGALOVIRUS RETINITISLocal Treatment(complications) • scarring of injected site,retinal toxicity? ophthalmic manifestation of HIV infection

38. 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 ophthalmic manifestation of HIV infection

39. 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) ophthalmic manifestation of HIV infection

40. 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 ophthalmic manifestation of HIV infection

41. Comparison of Valgancyclovir and IV,Oral Gancyclovir ophthalmic manifestation of HIV infection

42. CYTOMEGALOVIRUS RETINITISIN HAART ERA • 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 ophthalmic manifestation of HIV infection

43. From Progressive if lefted untreated To Ability to discontinue AntiCMV agent without progression CLINICAL COARSECHANGE ophthalmic manifestation of HIV infection

44. ophthalmic manifestation of HIV infection

45. ALTERED CLINICAL PRESENTATIONFROM IMMUNE RESTORATION • Immune Recovery Vitritis • Cystoid Macula Edema • Epiretinal Membrane • Vitreomacula traction syndrome • Disc Edema and Neovascularization ophthalmic manifestation of HIV infection

46. 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 ophthalmic manifestation of HIV infection

47. IMMUNE RECOVERY VITRITIS ophthalmic manifestation of HIV infection

48. D/D for CMVR • Progressive Outer Retinal Necrosis • Toxoplasma Retinitis • Intraocular Lymphoma • Ocular Syphilis ophthalmic manifestation of HIV infection

49. 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 ophthalmic manifestation of HIV infection

50. 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) ophthalmic manifestation of HIV infection