1. Ocular Complications of AIDS: Learning from the Past John H. Kempen, M.D., Ph.D. Co-Founder and President, Sight for Souls Professor of Ophthalmology and Epidemiology

2. 2 Background The Acquired Immune Deficiency Syndrome (AIDS) Caused by the Human Immunodeficiency Virus Acquired sexually or parenterally Can be staged by the CD4+ T cell level in blood Primary treatments –Antiretroviral therapy Highly active antiretroviral therapy (HAART) –Prophylaxis for expected opportunistic complications –Specific therapy for diagnosed complications

3. Courtesy: Douglas A. Jabs, MD, MBA

4. 4

5. HIV Retinopathy Most common ocular complication of AIDS in most settings ~50% (pre-HAART) Cotton wool spots most common Telangiectasias, micro- aneurysms, dot-blot hemorrhage, capillary non-perfusion Cause is uncertain

6. CMV Disease in HIV/AIDS Caused by the Cytomegalovirus (CMV), a double-stranded DNA virus of the Herpesvirus type Caused by the Cytomegalovirus (CMV), a double-stranded DNA virus of the Herpesvirus type CMV is ubiquitous world-wide, with 40- 100% of adults seroprevalent worldwide 1 CMV is ubiquitous world-wide, with 40- 100% of adults seroprevalent worldwide 1 Nearly 100% of gay males infected 2 Nearly 100% of gay males infected 2 In HIV, CMV disease appears to result from reactivation of latent infection In HIV, CMV disease appears to result from reactivation of latent infection

7. CMV Disease in HIV/AIDS Late stage opportunistic complication of AIDS 3 Late stage opportunistic complication of AIDS 3 Occurred (pre-HAART) in up to 45% of patients 4 Occurred (pre-HAART) in up to 45% of patients 4 Reported to be much less common in Africa Reported to be much less common in Africa Retinitis is the most common manifestation, making up as many as 85% of CMV cases 5 Retinitis is the most common manifestation, making up as many as 85% of CMV cases 5 CMV retinitis is the most common ocular opportunistic infection and leading cause of blindness in AIDS in most of the world 6,7 CMV retinitis is the most common ocular opportunistic infection and leading cause of blindness in AIDS in most of the world 6,7 Much reduced incidence in the HAART era Much reduced incidence in the HAART era Can be controlled by immune reconstitution Can be controlled by immune reconstitution

8. Natural History of CMV Retinitis

9. 9 Progression of Retinitis

10. 10 Progression of CMVR Progression in trials defined as: 750µm advancement over a front at least 750µm long, or a new lesion 1/4 DD Absent anti-CMV treatment, such progression occurred in ~14 days In pre-HAART anti-CMV therapy trials, progression meeting this definition did not generally occur before regression of activity However, progression occurred 2-4 months later (low levels or resistance)

11. Progression is Uncommon with HAART-induced Immune Recovery 11 Ophthalmology, 117:2152-61

12. 12 Progression of CMVR with HAART Numerous early reports indicated remission of unrecognized CMVR with immune recovery US Public Health Service guidelines for removal of suppressive anti-CMV therapy: –Increase in CD4+ to >100 cells/µL for 3-6 months and not active Patients managed in this manner have similar outcomes to patients continuing anti-CMV Rx –Reported 3% relapse rate with discontinuation Guidelines are probably overly conservative for resource-limited settings.

13. Fulminant, Indolent, Atrophic

14. Reactivations under Suppression

15. Recovery in Seemingly Hopeless Cases

16. Morbidity from CMV Retinitis Vision Loss The primary mechanisms of vision loss include: The primary mechanisms of vision loss include: retinal necrosis from viral replication, and retinal necrosis from viral replication, and rhegmatogenous retinal detachment rhegmatogenous retinal detachment Immune Recovery Uveitis is a new cause of vision loss in the HAART era Immune Recovery Uveitis is a new cause of vision loss in the HAART era ■However, the overall effect of HAART, on average, is to preserve vision. Arch Ophthalmol 2003; 121:466-476

17. Symptoms of CMV Retinitis Floaters Floaters Photopsia Photopsia Visual Field Changes Visual Field Changes May be completely asymptomatic May be completely asymptomatic

18. Treatment of CMV Retinitis Systemic Therapy Systemic Therapy Local Therapy Local Therapy [Immune reconstitution with HAART] [Immune reconstitution with HAART]

19. Effects of HAART on the Clinical Course of CMV Retinitis

20. Systemic Therapy for CMV Retinitis

21. Treatment of CMV Retinitis Systemic Therapy Intravenous Ganciclovir: 5 mg/kg bid x2wk; then 5 mg/kg qd indefinitely Intravenous Ganciclovir: 5 mg/kg bid x2wk; then 5 mg/kg qd indefinitely Intravenous Foscarnet: 60 mg/kg tid or 90 mg/kg bid for 2wks; then 90-120 mg/kg qd Intravenous Foscarnet: 60 mg/kg tid or 90 mg/kg bid for 2wks; then 90-120 mg/kg qd Intravenous Cidofovir (with probenecid) : 5 mg/kg/wk x 2wk then 5mg/kg/2wks Intravenous Cidofovir (with probenecid) : 5 mg/kg/wk x 2wk then 5mg/kg/2wks Oral Valganciclovir 900 mg bid x 3 wk then 900 mg/day maintenance Oral Valganciclovir 900 mg bid x 3 wk then 900 mg/day maintenance Oral ganciclovir 1.5 gm po tid (maintenance therapy) Oral ganciclovir 1.5 gm po tid (maintenance therapy)

22. Advantages of Systemic Therapy CMV is a systemic disease; not treating it systemically results in higher rates of: CMV is a systemic disease; not treating it systemically results in higher rates of: second eye retinitis second eye retinitis systemic CMV syndromes systemic CMV syndromes probably mortality probably mortality Avoids surgical complications Avoids surgical complications One treatment covers both eyes One treatment covers both eyes

23. JHU CMV Retinitis Cohort Study: Mortality Results Anti-CMV Therapy

24. Why CMV Retinitis Progresses Inadequate drug penetration into the eye (close to suppressive dose-50%) Inadequate drug penetration into the eye (close to suppressive dose-50%) Progressive host immunodeficiency Progressive host immunodeficiency Non-compliance with treatment Non-compliance with treatment Cytomegaloviral resistance to anti-CMV therapy Cytomegaloviral resistance to anti-CMV therapy

25. Local Therapy for CMV Retinitis

26. Advantages of Local Therapy Highest vitreous levels of drug Highest vitreous levels of drug Avoid toxicities of systemic agents Avoid toxicities of systemic agents Low cost in areas with economic constraint Low cost in areas with economic constraint Ganciclovir implant (now rarely used) Ganciclovir implant (now rarely used) More convenient for patients in some cases (especially those poorly adherent to therapy) More convenient for patients in some cases (especially those poorly adherent to therapy) Much longer time-to-relapse w/ GCV implant Much longer time-to-relapse w/ GCV implant Implant often succeeds in cases recalcitrant to systemic therapy Implant often succeeds in cases recalcitrant to systemic therapy

27. Intravitreous Injections for CMV Retinitis Weekly intravitreal injections of: Weekly intravitreal injections of: Ganciclovir 2 mg in 0.1 cc, 2x/week for 2-3 weeks then weekly Ganciclovir 2 mg in 0.1 cc, 2x/week for 2-3 weeks then weekly Foscarnet 2400µg in 0.1 cc, 2- 3x/week for 2-3 weeks then weekly Foscarnet 2400µg in 0.1 cc, 2- 3x/week for 2-3 weeks then weekly Cidofovir (controversial): can be injected every several weeks Cidofovir (controversial): can be injected every several weeks Generally effective at controlling retinitis Generally effective at controlling retinitis Requires frequent injections in sick patients Requires frequent injections in sick patients Does not address systemic disease Does not address systemic disease

28. Immune Recovery Uveitis The first of a class of immune recovery inflammatory syndromes described in patients with AIDS treated with HAART The first of a class of immune recovery inflammatory syndromes described in patients with AIDS treated with HAART Occurs only in eyes with CMV retinitis Occurs only in eyes with CMV retinitis Immune recovery inflammatory syndromes for other pathogens, e.g. TB, now have been described. Immune recovery inflammatory syndromes for other pathogens, e.g. TB, now have been described.

29. Immune Recovery Uveitis Reports of the risk of IRU among “HAART responders” vary widely Reports of the risk of IRU among “HAART responders” vary widely Karavellas (UCSD): incidence=83%/person-year Karavellas (UCSD): incidence=83%/person-year Nguyen (JHU): incidence=11%/person-year Nguyen (JHU): incidence=11%/person-year Whitcup (NEI): prevalence=90% (patients with immune recovery referred for a trial) Whitcup (NEI): prevalence=90% (patients with immune recovery referred for a trial) SOCA (19 centers): prevalence=17.6% (95% CI: 12.3-24.1%) of those who had immune recovery SOCA (19 centers): prevalence=17.6% (95% CI: 12.3-24.1%) of those who had immune recovery

30. Clinical Features of IRU Vitreous cells/haze Vitreous cells/haze Cystoid macular edema Cystoid macular edema Epiretinal membrane Epiretinal membrane Optic nerve edema Optic nerve edema Cataract (mostly posterior subcapsular) Cataract (mostly posterior subcapsular) Anterior chamber cells/Posterior synechiae Anterior chamber cells/Posterior synechiae Occasional severe complications have been reported: Occasional severe complications have been reported: Neovascularization with vitreous hemorrhage Neovascularization with vitreous hemorrhage Angle closure glaucoma Angle closure glaucoma Proliferative vitreoretinopathy Proliferative vitreoretinopathy

31. Outcomes Limited available information suggests: Limited available information suggests: The uveitis is usually, but not always, chronic The uveitis is usually, but not always, chronic Vision loss usually is mild to moderate, often caused by CME Vision loss usually is mild to moderate, often caused by CME Severe vision loss occurs occasionally, usually from complications of neovascularization Severe vision loss occurs occasionally, usually from complications of neovascularization Partial improvement may result from treatment with periocular steroids; retinitis progression after such treatment is rare. Partial improvement may result from treatment with periocular steroids; retinitis progression after such treatment is rare.

32. Overview: Non-CMV Posterior Segment Infections Retinal/choroidal pathogens (uncommon) Retinal/choroidal pathogens (uncommon) Varicella zoster virus Varicella zoster virus Herpes simplex virus Herpes simplex virus Toxoplasma gondii Toxoplasma gondii Cryptococcus neoformans Cryptococcus neoformans Pneumocystis carinii Pneumocystis carinii Treponema pallidum Treponema pallidum Mycobacterium tuberculosis Mycobacterium tuberculosis

33. Acute Retinal Necrosis

34. Acute Retinal Necrosis: Treatment IV acyclovir 10-15 mg/kg every 8 hours IV acyclovir 10-15 mg/kg every 8 hours Reduces risk of second eye involvement Reduces risk of second eye involvement Oral valacyclovir is probably adequate: 2 gm 3x/day Oral valacyclovir is probably adequate: 2 gm 3x/day Prophylactic laser retinopexy: triple barricade Prophylactic laser retinopexy: triple barricade Prompt repair of retinal detachment (Si oil often indicated) Prompt repair of retinal detachment (Si oil often indicated) HAART HAART

35. Progressive “Outer Retinal” Necrosis Caused by VZV Occurs in the setting of very advanced AIDS High risk of RD High risk of blindness Treated with intravitreous foscarnet and ganciclovir, (val)acyclovir maintenance, HAART

37. Toxoplasmic Retinochoroiditis Requires suppressive SMZ/TMP in HIV/AIDS with low CD4 or other immunodeficient states

38. Candida Retinitis Commonly occurs with intravenous contamination/drug use Best treated with intravitreous amphotericin + oral fluconazole

39. Pneumocystis Choroidopathy Occurs most commonly with inhaled PCP prophylaxis Indicates disseminated Pneumocystosis with high mortality risk Treat with systemic anti- Pneumocystis therapy Usually does not affect vision

40. Syphilitic Retinitis Common co-infection with HIV Common co-infection with HIV Treat with neurosyphilis regimen of penicillin Treat with neurosyphilis regimen of penicillin

41. Corneal and External Complications

42. Herpes Zoster Often an early sign of HIV infection Often an early sign of HIV infection Severe and prolonged manifestations with AIDS Severe and prolonged manifestations with AIDS Cutaneous lesions Cutaneous lesions Keratitis (including late neurotrophic keratitis) Keratitis (including late neurotrophic keratitis) Anterior uveitis Anterior uveitis Necrotizing retinitis (Acute Retinal Necrosis and Progressive “Outer Retinal” Necrosis syndromes) Necrotizing retinitis (Acute Retinal Necrosis and Progressive “Outer Retinal” Necrosis syndromes)

43. Extensive Herpes Zoster Ophthalmicus

44. Treatment of Herpes Zoster Ophthalmicus Intravenous therapy recommended in HIV+ Intravenous therapy recommended in HIV+ 10-15 mg/kg every 8 hours until lesions crusted 10-15 mg/kg every 8 hours until lesions crusted Follow with oral acyclovir 800 mg 5x/day Follow with oral acyclovir 800 mg 5x/day Oral valganciclovir may be an adequate substitute for IV Oral valganciclovir may be an adequate substitute for IV Follow patients weekly until healed to rule out posterior segment disease Follow patients weekly until healed to rule out posterior segment disease

45. Molluscum Contagiosum DNA poxvirus DNA poxvirus Typical (small, white, waxy, umbilicated) or atypical (large, necrotic, coalescent) lesions Typical (small, white, waxy, umbilicated) or atypical (large, necrotic, coalescent) lesions Can cause Can cause Cosmetic disfigurement Cosmetic disfigurement Cicatrical ectropion Cicatrical ectropion Follicular conjunctivitis Follicular conjunctivitis

46. Molluscum: Differential Diagnosis Cryptococcus neoformans Cryptococcus neoformans Bacillary angiomatosis Bacillary angiomatosis Histoplasma capsulatum Histoplasma capsulatum Verrucae Verrucae Sebaceous cysts Sebaceous cysts

47. Cryptococcus neoformans Optic neuropathy associated with meningitis that is hard to treat Optic neuropathy associated with meningitis that is hard to treat Occasional choroidopathy similar to Pneumocystis, but less yellow-looking Occasional choroidopathy similar to Pneumocystis, but less yellow-looking Skin lesions Skin lesions

48. Molluscum Contagiosum Molluscum  cryptococcus

49. Herpes Simplex Keratitis May not occur with higher frequency in HIV/AIDS patients However, clinical course is worse More peripheral corneal involvement More frequent recurrences Greater treatment resistance (consider oral and topical)

50. Microsporidial Keratoconjunctivitis Rare complication of HIV/AIDS Diagnosis sometimes possible from conjunctival swab Literature review suggests albendazole may be an effective (and inexpensive) treatment JOII 2011; 1:105-10

51. Infectious Keratitis: Local Risk Factors Dry eye Dry eye Use of topical corticosteroids Use of topical corticosteroids Exposure keratopathy Exposure keratopathy Drug-induced stupor Drug-induced stupor Bell’s palsy Bell’s palsy Corneal hypesthesia/anesthesia Corneal hypesthesia/anesthesia Crack cocaine Crack cocaine Previous HSV keratitis Previous HSV keratitis

52. Infectious Keratitis

53. Neuro-ophthalmic Lesions Papillaedema, cryptococcal meningitis Papillaedema, cryptococcal meningitis Visual field defects Visual field defects Optic neuropathy Optic neuropathy Cranial nerve palsies Cranial nerve palsies Intracranial lesions Intracranial lesions

54. Neuro-ophthalmic Lesions

55. AIDS-associated Neoplasms Kaposi’s Sarcoma (associated with HHV-8) Kaposi’s Sarcoma (associated with HHV-8) Conjunctiva Conjunctiva Eyelid Eyelid

56. AIDS-associated Neoplasms Squamous Cell Carcinoma of the conjunctiva (especially in Southern Africa) Squamous Cell Carcinoma of the conjunctiva (especially in Southern Africa) Lymphoma Lymphoma Orbit Orbit CNS CNS Courtesy, O. Nkomazana, MD

57. Squamous Cell CA of Conj Although reported around the world, seems to be common only (or primarily) in Sub-Saharan Africa (South Africa to Ethiopia) Although reported around the world, seems to be common only (or primarily) in Sub-Saharan Africa (South Africa to Ethiopia) Likely due to some pathogenic strain(s) of HPV; studies to date have found mixtures, which are likely to be seen in poly-infected patients Likely due to some pathogenic strain(s) of HPV; studies to date have found mixtures, which are likely to be seen in poly-infected patients Treatment: Surgical excision (wide margin “no touch” w cryo) plus topical interferon alpha 2b (, m itomycin C 0.04%, or b eta irradiation Treatment: Surgical excision (wide margin “no touch” w cryo) plus topical interferon alpha 2b ( 1 million units/mL), m itomycin C 0.04%, or b eta irradiation Orbital exenteration for invasive disease Orbital exenteration for invasive disease

58. HIV/AIDS and Ocular Complications Now primarily a global disease Now primarily a global disease In the US, an opportunity for compassion for those who suffer the consequences of lifestyle decisions or just bad “luck” In the US, an opportunity for compassion for those who suffer the consequences of lifestyle decisions or just bad “luck” Many opportunities for international engagement, although primary focus is on prevention and antiretroviral treatment not eye disease Many opportunities for international engagement, although primary focus is on prevention and antiretroviral treatment not eye disease Ocular complications might vary with the local infectious ecosystem Ocular complications might vary with the local infectious ecosystem