1. Ophthalmic manifestations of HIV infection KRISADA HANBUNJERD

2. ophthalmic manifestation of HIV infection2 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

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

4. ophthalmic manifestation of HIV infection4 HIV retinopathy overview  most common ophthalmic lesion  characterized by cotton wool spot retinal hemorrhage microaneurysm telangiectatic vessel  indicate immune deteriolation

5. ophthalmic manifestation of HIV infection HIV retinopathy manifestations 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

6. ophthalmic manifestation of HIV infection6 HIV retinopathy pathogenesis  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

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

8. ophthalmic manifestation of HIV infection8 Differentiation  especially from early Cytomegalovirus Retinitis

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

10. ophthalmic manifestation of HIV infection10 Opportunistic ocular infections (COMMON)  Posterior segment Cytomegalovirus retinitis Varicella zoster retinitis Toxoplasma retinitis

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

12. ophthalmic manifestation of HIV infection12 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

13. ophthalmic manifestation of HIV infection13 Cytomegalovirus Retinitis High Risk  CD Count < 50  Associated with PCP, Extraocular CMV,Toxoplasmosis  HLA B44, B51, DR7

14. ophthalmic manifestation of HIV infection14 Cytomegalovirus Retinitis Symptoms  asymptomatic  light flash  floater  visual field loss  blurred or distorted vision  red eye,eye pain,photophobia are rare

15. ophthalmic manifestation of HIV infection15 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

16. ophthalmic manifestation of HIV infection16 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)

17. ophthalmic manifestation of HIV infection17 Cytomegalovirus Retinitis Clinical Presentation Spectrum of fundus appearance  fulminant/edematous form  indolent form  frosted branch angiitis form  atypical form

18. ophthalmic manifestation of HIV infection18 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

19. ophthalmic manifestation of HIV infection19 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

20. ophthalmic manifestation of HIV infection20 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)

21. ophthalmic manifestation of HIV infection21 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)

22. ophthalmic manifestation of HIV infection22 Retinal Zone

23. ophthalmic manifestation of HIV infection23 Cytomegalovirus Retinitis Dosage 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

24. ophthalmic manifestation of HIV infection24 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

25. ophthalmic manifestation of HIV infection25 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

26. ophthalmic manifestation of HIV infection26 Cytomegalovirus Retinitis Dosage Cidofovir IV Dosage  Induction 5mg/kg weekly 2 weeks  Maintenance 5mg/kg every 2 weeks

27. ophthalmic manifestation of HIV infection27 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

28. ophthalmic manifestation of HIV infection28 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

29. ophthalmic manifestation of HIV infection29  Intravitreal drugs Gancyclovir Foscarnet Cidofovir fomivirsen  Gancyclovir Intraocular Implant Cytomegalovirus Retinitis Local Treatment

30. ophthalmic manifestation of HIV infection30 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

31. ophthalmic manifestation of HIV infection31 Cytomegalovirus Retinitis Intravitreal Injection

32. ophthalmic manifestation of HIV infection32 Cytomegalovirus Retinitis Gancyclovir Implant

33. ophthalmic manifestation of HIV infection33 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

34. ophthalmic manifestation of HIV infection34 CYTOMEGALOVIRUS RETINITIS Local Treatment(advantages)  prevent systemic side effect  need less drug so less cost  improve quality of life  higher drug concentration

35. ophthalmic manifestation of HIV infection35 Intraocular Gancyclovir Level microgram/ml  intravenous induction0.78  intravenous maintenance0.63  oral gancyclovir0.83  implant4  intravitreal injection(24hr)143  intravitreal injection(72hr)23

36. ophthalmic manifestation of HIV infection36 CYTOMEGALOVIRUS RETINITIS Local Treatment(disadvantages)  unability to protect contralateral eye  increase risk of extraocular CMVR  less survival

37. ophthalmic manifestation of HIV infection37 CYTOMEGALOVIRUS RETINITIS Local Treatment(complications)  increase intraocular pressure  increase risk of retinal detachment  vitreous hemorrhage  endophthalmitis  scarring of injected site,retinal toxicity?

38. ophthalmic manifestation of HIV infection38 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

39. ophthalmic manifestation of HIV infection39 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 (t 1/2 ) of ganciclovir following oral administration of valganciclovir tablets was 4.08 +- 0.76 hours (n=73)

40. ophthalmic manifestation of HIV infection40 Dosage of Valgancyclovir  Dose Modifications for Patients with Impaired Renal Function  CrCl(mL/min)Induction DoseMaintenance Dose  > 60900 mg twice daily900 mg once daily  40 – 59450 mg twice daily450 mg once daily  25 – 39450 mg once daily450 mg every 2 days  10 – 24450 mg every 2 days450 mg twice weekly

41. ophthalmic manifestation of HIV infection41 Comparison of Valgancyclovir and IV,Oral Gancyclovir

42. ophthalmic manifestation of HIV infection42  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 RETINITIS IN HAART ERA

43. ophthalmic manifestation of HIV infection43 CLINICAL COARSE CHANGE  From Progressive if lefted untreated  To Ability to discontinue AntiCMV agent without progression

44. ophthalmic manifestation of HIV infection44

45. ophthalmic manifestation of HIV infection45 ALTERED CLINICAL PRESENTATION FROM IMMUNE RESTORATION  Immune Recovery Vitritis  Cystoid Macula Edema  Epiretinal Membrane  Vitreomacula traction syndrome  Disc Edema and Neovascularization

46. ophthalmic manifestation of HIV infection46 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

47. ophthalmic manifestation of HIV infection47 IMMUNE RECOVERY VITRITIS

48. ophthalmic manifestation of HIV infection48 D/D for CMVR  Progressive Outer Retinal Necrosis  Toxoplasma Retinitis  Intraocular Lymphoma  Ocular Syphilis

49. ophthalmic manifestation of HIV infection49 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

50. ophthalmic manifestation of HIV infection50 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)

51. ophthalmic manifestation of HIV infection51 Neoplasm of Ocular Adnexa  Kaposi sarcoma usually asymptomatic sites involved are eyelid, conjunctiva, orbit inferior fornix is most common site  non Hodkin’s lymphoma non tender anterior orbital mass proptosis, diplopia, ptosis, eyelid edema  Conjunctival squamous carcinoma

52. ophthalmic manifestation of HIV infection52 Neuroophthalmic Manifestations  Cranial nerve palsy: CN6 palsy Internuclear ophthalmoplegia CN 3 palsy  Visual field defects

53. ophthalmic manifestation of HIV infection53 Neuroophthalmic Manifestations  Optic nerve disorder Papilledema, optic atrophy retrobulbar optic neuritis papillitis  Cortical blindness

54. ophthalmic manifestation of HIV infection54 Cryptococcal Papilledema  cause increase intracranial pressure back to the eye  these picture show optic nerve head in various stage

55. ophthalmic manifestation of HIV infection55 Drug induced manifestations  Cidofovir anterior uveitis, hypotony,enopthalmos

56. ophthalmic manifestation of HIV infection56 Drug induced manifestations  Rifabutin anterior uveitis  Terbinafine anterior uveitis, iridodonesis phacodonesis, conjunctival hemorrhage

57. ophthalmic manifestation of HIV infection57 International Variation of Manifestations most 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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