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Ocular Involvement in HIV infection and AIDS

Meenken, C.

2011

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CChapter 1

Introduction and Outline of the Thesis

IIntroduction Background: Natural course of HIV infection

Figure 1: schematic representation of course of plasma HIV RNA load and CD4 T-cell decline in HIV infection.

Note the relatively long period of clinical latency.

Ocular involvement in HIV infection

fl

References 1. Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, et al. Pneumocystis carinii

pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 1981 Dec 10;305(24):1425-31.

2. Masur H, Michelis MA, Greene JB, Onorato I, Stouwe RA, Holzman RS, et al. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981 Dec 10;305(24):1431-8.

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5. Kaslow RA, Phair JP, Friedman HB, Lyter D, Solomon RE, Dudley J, et al. Infection with the human immunodeficiency virus: clinical manifestations and their relationship to immune deficiency. A report from the Multicenter AIDS Cohort Study. Ann Intern Med 1987 Oct;107(4):474-80.

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11. Palella FJ, Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998 Mar 26;338(13):853-60.

12. Accorinti M, Pirraglia MP, Corradi R, Corsi C, Fabiani C, Pivetti-Pezzi P. Changing patterns of ocular manifestations in HIV seropositive patients treated with HAART Eur J Ophthalmol 2006 Sep;16(5):728-32.

13. Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 2000 Apr;30 Suppl 1:S5-14.

14. Hirsch HH, Kaufmann G, Sendi P, Battegay M. Immune reconstitution in HIV-infected patients Clin Infect Dis 2004 Apr 15;38(8):1159-66.

15. Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV Curr Opin Infect Dis 2006 Feb;19(1):20-5.

16. Otiti-Sengeri J, Meenken C, van den Horn GJ, Kempen JH. Ocular immune reconstitution inflammatory syndromes. Curr Opin HIV AIDS 2008 Jul;3(4):432-7.

17. Kuppermann BD, Holland GN. Immune recovery uveitis Am J Ophthalmol 2000 Jul;130(1):103-6.

18. Holland GN, Vaudaux JD, Jeng SM, Yu F, Goldenberg DT, Folz IC, et al. Characteristics of untreated AIDS-related cytomegalovirus retinitis. I. Findings before the era of highly active antiretroviral therapy (1988 to 1994) Am J Ophthalmol 2008 Jan;145(1):5-11.

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21. Westeneng AC, Rothova A, de Boer JH, de Groot-Mijnes JD. Infectious uveitis in immunocompromised patients and the diagnostic value of polymerase chain reaction and Goldmann-Witmer coefficient in aqueous analysis. Am J Ophthalmol 2007 Nov;144(5):781-5.

22. Jabs DA, Newman C, de BS, Polk BF. Treatment of cytomegalovirus retinitis with ganciclovir. Ophthalmology 1987 Jul;94(7):824-30.

23. de Smet MD, Meenken C, van den Horn GJ. Fomivirsen - a phosphorothioate oligonucleotide for the treatment of CMV retinitis. Ocul Immunol Inflamm 1999 Dec;7(3-4):189-98.

24. Deayton JR, Wilson P, Sabin CA, Davey CC, Johnson MA, Emery VC, et al. Changes in the natural history of cytomegalovirus retinitis following the introduction of highly active antiretroviral therapy AIDS 2000 Jun 16;14(9):1163-70.

25. Deayton JR, Griffiths PD. When can cytomegalovirus prophylaxis and maintenance therapy be stopped in HIV disease? Curr Opin Infect Dis 2000 Dec;13(6):637-41.

26. Jabs DA, Ahuja A, Natta MV, Lyon A, Srivastava S, Gangaputra S. Course of Cytomegalovirus Retinitis in the Era of Highly Active Antiretroviral Therapy: Five-Year Outcomes. Ophthalmology 2010 Jul 27.

27. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy AIDS 2004 Aug 20;18(12):1615-27.

28. Manabe YC, Campbell JD, Sydnor E, Moore RD. Immune reconstitution inflammatory syndrome: risk factors and treatment implications J Acquir Immune Defic Syndr 2007 Dec 1;46(4):456-62.

29. Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy Clin Infect Dis 2006 Jun 1;42(11):1639-46.

30. Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC, Jr., et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy AIDS 2005 Mar 4;19(4):399-406.

31. Biswas J, Choudhry S, Kumarasamy, Solomon S. Immune recovery vitritis presenting as panuveitis following therapy with protease inhibitors Indian J Ophthalmol 2000 Dec;48(4):313-5.

32. Karavellas MP, Plummer DJ, Macdonald JC, Torriani FJ, Shufelt CL, Azen SP, et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy J Infect Dis 1999 Mar;179(3):697-700.

33. Kempen JH, Min YI, Freeman WR, Holland GN, Friedberg DN, Dieterich DT, et al. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis Ophthalmology 2006 Apr;113(4):684-94.

34. Easterbrook PJ. HIV immune reconstitution syndrome in sub-Saharan Africa AIDS 2008 Mar 12;22(5):643-5.

OOutline of the thesis

Chapter 2

Chapter 3

Chapter 4

Chapter 5

Chapters 6 and 7

Chapter 8

Chapter 9

CChapter 2 -1

Association of progressive outer retinal necrosis and varicella zoster encephalitis

in a patient with AIDS

Br J Ophthalmol 1996;80:982-985

Abstract Background:

Methods:

Results:

Conclusion:

AAssociation of progressive outer retinal necrosis and varicella zoster encephalitis in a patient with AIDS

Methods

CASE REPORT

Figure 1 Progressive outer retinal necrosis (left eye). Early in the disease, the posterior pole shows a pale oedemic area, with a cherry red spot appearance of the macula. In te mid periphery, multiple small yellowish infiltrates can be seen, that become confluent in the later stages

Figure 3 Progressive outer retinal necrosis (left eye), 10 days after the stage of Figure 1. Perivascular clearing: while the retinitis progresses, oedema is cleared in the peri-vasular areas.

Figure 2 Fluorescein angiography (left eye) shows infiltrations in the deep retinal layer. The vasculature is normal; no signs of vasculitis are present.

Figure 4 Progressive outer retinal necrosis (left eye). Ultimately, the retina becomes burned out: note atrophic areas and destruction of the vasculature. Optic disc pallor can be seen.

Results of diagnostic procedures and necropsy

T gondii

Figure 5 Coronal section of the right parietal lobe. Several large and small necrotic foci (arrows) in the white matter. Some lesions mimic laminar necrosis. The central white matter is mildly demyelinated.

Discussion

et al

References 1. Forster DJ, Dugel PU, Frangieh GT, Liggett PE, Rao NA. Rapidly progressive outer retinal necrosis in

the acquired immunodeficiency syndrome. Am J Ophthalmol 1990;110:341-9. 2. Margolis TP, Lowder CY, Holland GN, Spaide RS, Logan AG, Weissman SS, et al. Varicella-zoster virus

retinitis in patients with the acquired immunodeficiency syndrome. AmJ Ophthalmol 1991;112:119-31. 3. Kuppermann BD, Quiceno JI, Wiley C, Hesselink J, Hamilton R, Keefe K, et al. Clinical and

histopathologic study of varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J7 Ophthalmol 1994;118:589-600.

4. Luyendijk L, Van den Horn GJ, Visser OHE, Suttorp-Schulten MSA, Kijlstra A. Detection of locally

produced antibodies to herpes viruses in the aqueous humour of patients with acquired immunodefi-ciency syndrome (AIDS) or acute retinal necrosis syndrome (ARN). Curr Eye Res 1990;9(suppl):7-1 1.

5. De Boer JH, Luyendijk L, Rothova A, Baarsma GS, De Jong PVTM, Bollemeijer JG, et al. Detection of

intraocular antibody production to herpesviruses in acute retinal necrosis syndrome. AmJI Ophthalmol 1994;117:201-10.

6. Fox GF, Crouse CA, Chuang EL, Pflugfelder SC, Clearly TJ, Nelson SJ, et al. Detection of herpes virus

DNA in vitreous and aqueous specimens by the polymerase chain reaction. Arch Ophthalmol 1991; 109: 266-71.

7. Aouizerate F, Cazenave J, Poirier L, Verin P, Cheyrou A, Begueret J, et al. Detection of Toxoplasma

gondii in aqueous humour by the polymerase chain reaction. Br J Ophthalmol 1993;77: 107-9. 8. Frank Y, Lim W, Kahn E, Farmer P, Gorey M, Pahwa S. Multiple ischemic infarcts in a child with AIDS,

varicella zoster infection and cerebral vasculitis. Pediatr Neurol 1989;5:64-7. 9. Doyle PW, Gibson G, Dohman CL. Herpes zoster ophthalmicus with contralateral hemiplegia.

Identification of cause. Ann Neurol 1983;14:84-5. 10. Gray F, Belec L, Lescs MC, Chretien F, Ciardi A, Hassine D, et al. Varicella zoster virus infection of the

central nervous system in the acquired immune deficiency syndrome. Brain 1994;117:987-99. 11. Gray F, Mohr M, Rozenberg F, Belec L, Lescs MC, Dournon E, et al. Varicella zoster virus encephalitis

in acquired immunodeficiency syndrome. Report of four cases. Neuropathol Appl Neurobiol 1992;18: 502-14.

12. Rousseau F, Peronne C, Raguin G, Thouvenot D, Vidal A, Leport C, et al. Necrotizing retinitis and

cerebral vasculitis due to varicella zoster virus in patients infected with the human immunodeficiency virus. Clin Infect Dis 1993;17: 943-4.

13. Pinnolis MK, Foxworthy D, Kemp B. Treatment of progressive outer retinal necrosis with Sorivudine. Am

J Ophthalmol 1995;119:516. 14. Batisse D, Eliaszewicz M, Zazoun L, Baudrimont M, Pialoux G, Dupont B. Acute retinal necrosis in the

course of AIDS: study of 26 cases. AIDS 1996;10:55-60. 15. Galindez OA, Sabates NR, Whitacre MM, Sabates FN. Rapidly progressive outer retinal necrosis caused

by varicella zoster virus in a patient infected with human immunodeficiency virus. Clin Infect Dis 1996;22:149-51.

16. Sellitti TP, Huang AJW, Schiffinan J, Davis JL. Association of herpes zoster ophthalmicus with acquired

immuno-deficiency syndrome and acute retinal necrosis. Am J Ophthalmol 1993;116 :297-301.

CChapter 2-2

Optic Neuritis Heralding Varicella Zoster Virus Retinitis in a Patient with Acquired

Immunodeficiency Syndrome

Ann Neurol 1998;43:534-536

Abstract

OOptic Neuritis Heralding Varicella Zoster Virus Retinitis in a Patient with Acquired Immunodeficiency Syndrome

CASE REPORT

Toxoplasma

gondii

Discussion

References 1. Kuppermann BD, Quiceno JI, Wiley C, et al. Clinical and histopathologic study of varicella zoster virus

retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1994; 118:589-600

2. Van den Horn GJ, Meenken C, Troost D. Association of progressive outer retinal necrosis and varicella zoster encephalitis in a patient with the acquired immunodeficiency syndrome. Br J Ophthalmol 1996; 80:982-985

3. Galindez OA, Sabates NR, Whittacre MM, Sabates FN. Rapidly progressive outer retinal necrosis

caused by varicella zoster virus in a patient infected with human immunodeficiency virus. Clin Infect Dis 1996; 22:149-151

4. Batisse D, Eliaszewicz M, Zazoun L, et al. Acute retinal necrosis in the course of AIDS: study of 26

cases. AIDS 1996;10:55- 60

5. Friedlander JM, Rahdal FM, Ericson L, et al. Optic neuropathy preceding acute retinal necrosis in acquired immunodeficiency syndrome. Arch Ophthalmol1996; 114: 1481-1485

6. Whitley RJ, Gnann JW Jr. Editorial response: herpes zoster in patients with human immunodeficiency

virus infection-an ever expanding spectrum of disease. Clin Infect Dis 1995; 21: 989-990

7. Glesby MJ, Moore RD, Chaisson RE. Clinical spectrum of herpes zoster in adults infected with human immunodeficiency virus. Clin Infect Dis 1995; 21:370-375

8. Veenstra J, van Praag RME, Krol A, et al. Complications of varicella zoster virus reactivation in HIV-

infected homosexual men. AIDS 1996;10:393-399

9. Margolis TP, Lowder CY, Holland GN, et al. Varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1991; 112:119-131

10. Sellitti TP, Huang AJW, Schiffman J, Davis JL. Association of herpes zoster ophthalmicus with acquired

immunodeficiency syndrome and acute retinal necrosis. Am J Ophthalmol 1993; 116:297-301

CChapter 3

Fomivirsen – a phosphorothioate oligonucleotide for the treatment of CMV retinitis

Ocular Immunol and Inflamm 1999; 7:189-198

Abstract

Key words: CMV retinitis; review; phosphorothioate; antisense; pharmacology; treatment; adverse events

FFomivirsen – a phosphorothioate oligonucleotide for the treatment of CMV retinitis Introduction

Basic principles of antisense therapeutics

Fig. 1. Steps in mRNA meta-bolism and potential interaction sites by antisense compounds.

Fig. 2. Molecular structure of phosphorothioate oligonucleotides.

Phosphorothioate oligonucleotides

Fomivirsen ocular pharmacodynamics and toxicology

Fomivirsen’

Fig. 3. Pharmacokinetics of fomivirsen in the rabbit eye after a single intra-vitreal injection of 165 g.

Fomivirsen clinical experience

Efficacy time to progression

Fig. 4. Kaplan-Meier curve obtained with a dose of 165 g fomivirsen B immediate treatment compared with delayed treatment (intent to treat analysis, primary endpoint).

Side effects

(n=119) (n=309)

Data source . company information (Ciba-Vision). 1Numbers given are percentages of total numbers of patients treated (in parentheses).

Conclusion

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CChapter 4

Effects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte

responses in HIV+ patients

Br J Ophthalmol 1998;82:988-990

Abstract Aim:

Methods:

Results:

Conclusions:

Key words: AIDS, cytomegalovirus retinitis, HAART, protease inhibitors

EEffects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte responses in HIV+ patients

Introduction

Patients and methods

Patient characteristics before and during protease inhibitor (PI) treatment.----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Before PI treatment During PI treatment --------------------------------------------- ------------------------------------------------------------ Duration No of Time to of CMVR induction progression Recurrence Patient (weeks) courses (weeks) (weeks) Follow up (weeks)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

----

----

----

--------------------

-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

t’s

Results

Figure 1 Top: CD4 responses to protease inhibitor (PI) treatment. Individual counts are given at baseline, at 6–8, and at 12–16 weeks. (A) Non-responders. (B) Biphasic responders: an initial increase is followed by a return back to initial values. (C) Sustained responders: after an initial increase, a higher level is reached at 16 weeks and maintained for a prolonged period (up to 52weeks). Bottom: Outcome with respect to CMVR: R=recurrence; S=smouldering; C=completely inactive. Patient 13, whose retinitis remained smouldering, was non-compliant with respect to his PI and anti-CMV medications, and died after 16 weeks of follow up. Vitritis is indicated by an asterisk.

’

Discussion

eks’

et al.

References 1. Notermans DW, de Wolf F, Foudraine NA, et al .The effects of an antiretroviral triple combination

with ritonavir, AZT, and 3-TC. Third International Congress on Drug Therapy in HIV infection. Birmingham, UK, 1996. AIDS 1996;10(suppl 2): abstract OP9.1: S17.

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7. Benhamou Y, Bochet MV, Carriere J, et al. Effects of triple antiretroviral therapy including an HIV protease inhibitor on chronic intestinal cryptosporidiosis and microsporidiosis in HIV-infected patients. 4th Conference on Retroviruses and Opportunistic Infections, Washington, 1997 (abstract 357).

8. Carr A, Cooper DA (1997) Restoration of immunity to chronic hepatitis B infection in HIV infected patients on protease inhibitor. Lancet 349:995–996.

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11. Spector SA, Picher M, Lamy P, et al. PCR of plasma for cytomegalovirus DNA identifies HIV-infected persons most likely to benefit from oral ganciclovir prophylaxis. XIth International Conference on AIDS. Vancouver, 1996 (abstract Th.B. 302).

12. Dodt KK, Jacobsen PH, Hofman B, et al. (1997) Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS 11:21–28.

CChapter 5

Fulminant Ocular Leishmaniasis in an HIV-1-positive patient

AIDS 2004; 18:1485-1486

FFulminant Ocular Leishmaniasis in an HIV1-positive Patient

Leishmania

Leishmania donovani

Leishmania

Leishmania

Leishmania

Toxoplasma gondii

L. donovani

Mycobacteriae T. gondii

Leishmania et al

Leishmania major et al

Leishmania

braziliensis

Leishmania

et al Leishmania

Leishmania

References 1. El Hassan AM, Khalil EAG, El Sheikh EA, Zijlstra EE, Osman A, Ibrahim ME. Post kala-azar ocular

leishmaniasis. Trans R Soc Trop Med Hyg 1998, 92:177–179.

2. Blanche P, Gombert B, Rivoal O, Abad S, Salmon D, Brezin A. Uveitis due to Leishmania major as part of HAART-induced immune restitution syndrome in a patient with AIDS [Letter]. Clin Infect Dis 2002, 34:1279–1280.

3. Gontijo CMF, Pacheco RS, Orefice F, Lasmar E, Silva ES, Melo MN. Concurrent cutaneous, visceral

and ocular leishmaniasis caused by Leishmania (Viannia) braziliensis in a kidney transplant patient. Mem Inst Oswaldo Cruz, Rio de Janeiro 2002, 97:751–753.

4. Prasad LS, Sen S. Migration of Leishmania donovani amastigotes in the cerebrospinal fluid. Am J

Trop Med Hyg 1996, 55:652–654.

5. Garcia-Alonso M, Nieto CG, Blanco A, Requena JM, Alonso C, Navarrete I. Presence of antibodies in the aqueous humour and cerebrospinal fluid during Leishmania infections in dogs. Pathological features at the central nervous system. Parasite Immunol 1996; 18:539–546.

6. Henderson HW, Mitchell SM. Treatment of immune recovery vitritis with local steroids. Br J

Ophthalmol 1999, 83:540–545.

CChapter 6

Ocular immune reconstitution inflammatory syndromes

Current Opinion in HIV and AIDS 2008, 3:432–437

Abstract Purpose of review

Recent findings

Summary

Keywords: cytomegalovirus retinitis, HAART, HIV, immune recovery uveitis, ocular diseases

OOcular immune reconstitution inflammatory syndromes

Introduction

reaction’omes’).

RIS’

Immune recovery uveitis

Defining immune recovery uveitis

overy’

Epidemiology and pathophysiology of immune recovery uveitis

Risk factors

Clinical features

Diagnosis

et al

Treatment

et al

Ocular forms of immune reconstitution inflammatory syndrome in resource- limited settings

Prevention of ocular forms of immune reconstitution inflammatory syndrome

Conclusion

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: *of special interest **of outstanding interest

1. Mocroft A, Lederrgerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA

study: an observational study. Lancet 2003; 362:22–29. 2. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory

syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002; 81:213–227.

3. Murdoch DM, Venter WD, VanRie A, Feldman C. Immune reconstitution inflammatory syndrome

(IRIS): review of common infectious manifestations and treatment options. AIDS Research and Therapy 2007; 4:9.

4. French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of

immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000; 1:107–115.

5. Hirsch HH, Kaufmann G, Sendi P, et al. Immune reconstitution in HIV infected patients. Clin Infect

Dis 2004; 38:1159–1166.

6. Shelbourne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers,

more questions. J Antimicrob Chemother 2006; 57:167–170.

7.** Lawn SD, French MA. Immune reconstitution disease: recent developments and implications for antiretroviral treatment in resource limited settings. Current Opinion in HIV and AIDS 2007; 2:339–345. [In this recent overview the implications for the near future concerning IRD in resource limited countries are summarized.]

8. Zamir E, Hudson H, Ober RR, Kumar SK, et al. Massive mycobacterial choroiditis during highly active antiretroviral therapy: another immune-recovery uveitis? Ophthalmology 2002; 109:2144–2180.

9. Hoover DR, Peng Y, Saah A, et al. Occurrence of cytomegalovirus retinitis after human immunode-

ficiency virus immunosuppression. Arch Ophthalmol 1996; 114:821–827. 10.* Holland GN, Vaudaux JD, Jeng SM, Yu F, et al. Characteristics of untreated AIDS-related

cytomegalo -virus retinitis. I. Findings before the era of highly active antiretroviral therapy (1998 to 1994) Am J Ophthalmol 2008; 145:5–11. [This article describes the nearly absent inflammation in patients with CMV retinitis before HAART was available, a similar finding in patients who fail on HAART. HAART responders, however, are predisposed to IRU.]

11. Van den Horn GJ, Meenken C, Danner SA, et al. Effects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte responses in HIV positive patients. Br J Ophthalmol 1998; 82:988–990.

12. Zegans ME, Walton RC, Holland GN, O’Donnell JJ, et al. Transient vitreous inflammatory reactions

associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis. Am J Ophthalmol 1998;125:292–300.

13. Karavellas MP, Plummer DJ, MacDonald JC, et al. Incidence of immune recovery vitritis in

cytomegalo-virus retinitis patients following institution of successful highly active antiretroviral therapy. J infectious Dis 1999;179:697–700.

14*. Schrier RD, Song MK, Smith IL, et al. Intraocular viral and immune pathogenesis of immune recovery

uveitis in patients with healed cytomegalovirus retinitis. Retina 2006; 26:165–169. [This paper explains the pathogenesis of IRU, the role of pathogenic antigens in development of IRU.]

15. Kempen JH, Min YI, Freeman WR, et al. Risk of immune recovery uveitis in patients with AIDS and

cytomegalovirus retinitis. Ophthalmology 2006;113:684–694. 16. Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active

antiretroviral therapy. Lancet 1997; 349:1443–1445. 17. Van den Horn GJ, Meenken C, DeSmet MD. Enhanced ocular inflammation can be due to other

cause than immune recovery [abstract]. In: Proceedings of Seventh European Conference on Clinical Aspects and Treatment of HIVinfection; 23–27 October 1999; Lisbon. Paris: European AIDS Clinical Society; 1999. Abstract 737.

18. Nguyen QD, Kempen JH, Bolton SG, et al. Immune recovery uveitis in patients with AIDS and

cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000; 130:49–56.

19. Masur H, Kaplan JE, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons: 2002. Recommendations of the US Public Health Service and the Infectious Diseases Society of America. Ann Intern Med 2002; 137:435–478.

20. Kuo IC, Kempen JH, Dunn JP, et al. Clinical characteristics and outcomes of cytomegalovirus retinitis

in persons without human immunodeficiency virus infection. Am J Ophthalmol 2004; 138:338–346.

21. Sinclair E, Tan QX, Sharp M, Girling V, et al. Protective immunity to cytomegalovirus retinitis in AIDS is associated with CMV specific T cells that express interferon-gamma and inerleukin-2 and have CD8+ cell maturational phenotype. J Infect Dis 2006; 194:1537–1546.

22. Multimer HP, Akatsuka Y, Manely T, et al. Association between immune recovery uveitis and a

diverse intraocular cytomegalovirus-specific cytotoxic T cell response. J infectious Dis 2002; 186:701–705.

23** Jabs DA, Van Natta ML, Holbrook JT, et al. Longitudinal study of the ocular complications of AIDS.

Ocular examination results at enrollment. Ophthalmology 2007; 114:787–793. [A detailed study reported on a large number of patients with AIDS: CMV retinitis and IRU were common in this population.]

24. Modorati G, Miserocchi E, Brancato R. Immune recovery uveitis and human leucocyte antigen typing:

a report on four patients. Eur J Ophthalmol 2005;155:607–609. 25. Manabe YC, Campbell JD, Sydnor E, Moore R. Immune reconstitution inflammatory syndrome. Risk

factors and treatment implications. J Acquir Immune Defic Syndr 2007; 46:456–462. 26. French MA. The immunopathogenesis of mycobacterial immune restoration disease. Lancet Infect

Dis 2006; 6:461–462. 27. Ortega-Larrocea G, Espinosa E, Reyes-Teran G. Lower incidence and severity of cytomegalovirus-

associated immune recovery uveitis in HIV-infected patients with delayed highly active antiretroviral therapy. AIDS 2005; 19:735–738.

28. Robinson MR, Reed G, Csaky KG, et al. Immune recovery uveitis in patients with cytomegalovirus

retinitis taking highly active antiretroviral therapy. Am J Ophthalmol 2000; 130:49–56. 29* Thorne JE, Jabs DA, Kempen JH, et al. Incidence of and risk factors for visual acuity loss among

patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology 2006; 13:1423–1440. [This paper reveals risk factors for visual loss in AIDS patients with CMV retinitis on HAART an important clinical significance of IRU.

30* Westeneng AC, Rothova A, De Boer JH, Groot-Mijnes JD. Infectious uveitis in immunocompromised

patients and the diagnostic value of polymerase chain reaction and Goldmann–Witmer coefficient in aqueous analysis. Am J Ophthalmol 2007; 144:781–785. [This paper explains the value of intraocular fluid PCR in the diagnosis of infectious uveitis, this paper is an important diagnostic work up in IRU.]

31. Henderson HW, Mitchell SM. Treatment of immune recovery vitritis with local steroids. Br J

Ophthalmol 1999; 83:540–545. 32. Karavellas MP, Azen SP, Macdonald C, et al. Immune recovery uveitis and uveitis in AIDS: Clinical

predictors, sequelae and treatment outcome. Retina 2001; 21:1–9. 33. El-Bradey M, Cheng L, Song M, et al. Long term results of treatment of macular complications in

eyes with immune recovery uveitis using a graded treatment approach. Retina 2004; 24:376–382.

34* Morrison VL, Kozak I, Labree LD, et al. Intravitreal triamcinolone acetonide for the treatment of immune recovery uveitis macula oedema. Ophthalmology 2007; 114:334–339. [This paper describes the useful effect of intravitreal steroids in treatment of IRU.]

35. Sirimaharaj M, Robinson MR, Zhu M, et al. Intravitreal injection of triamcinolone acetonide for

immune recovery uveitis. Retina 2006; 26:578–580. 36* Rothova A. Inflammatory cystoid macular oedema. Current Opinion Ophthalmol 2007; 18:487–492.

[This paper reviews recent developments in treatment of inflammatory cystoid macular oedema, a frequent complication of IRU.]

37. Ufret-Vincenty RL, Singh RP, Lowder CY, Kaiser PK. Cytomegalovirus retinitis after fluocinolone

acetonide implant. Am J Ophthalmol 2007; 143:334–335. 38. Kosobucki BR, Goldberg DE, Besshok et al. Valganciclovir therapy for immune recovery uveitis

complicated by macula oedema. Am J Ophthalmol 2004; 137: 636–638. 39. Kestelyn PG, Cunningham ET. HIV/AIDS and blindness. Bull World Health Organ 2001; 79:208–213. 40* Heiden D, Ford N, Wilson D, et al. Cytomegalovirus retinitis: the neglected disease of the AIDS

pandemic. PLoS Med 2007; 12:9–18. [This paper reveals recent findings on the situation of ocular diseases and CMV retinitis in resource-limited settings. More research is recommended in this region.]

41. Hoover DR, Saah AJ, Bacellar H, et al. Clinical manifestations of AIDS in the era of pneumocystis

prophylaxis. Multicenter AIDS Cohort Study. N Engl J Med 1993; 329:1922–1926.

CChapter 7

Ocular disease during HAART-induced immune reconstitution

Oogafwijkingen bij HAART-geïnduceerde immuunreconstitutie

Tijdschr Infect 2009; 4:3-10

Summary

Key words: CMV Retinitis, HAART, HIV immune recovery uveitis, IRU, Immune reconstitution, IRIS, ocular diseases

OOcular disease during HAART-induced immune reconstitution Introduction

I’s)

’s.

OI’s,

syndrome’, reconstitution’ disease’, syndrome’

n’syndrome’

Ocular immune reconstitution phenomena

’s

eitis’

Leishmania Major

Mycobacterium avium

Leishmania

syndrome’

’s,

munity’

yndromes’,

Risk factors

Clinical features

Diagnosis

’ ’s,

Borrelia

Treatment

Prevention of ocular forms of IRIS

’s. Prim’s

Conclusion

References 1. Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d'Arminio MA, Knysz B, Dietrich M, Phillips AN,

Lundgren JD: Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003; 362: 22-9

2. Murdoch DM, Venter WD, Van RA, Feldman C: Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res.Ther. 2007; 4: 9

3. Shelburne SA, III, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, Gathe JC, Jr., Visnegarwala F, Trautner BW: Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002; 81: 213-27

4. Shelburne SA, Montes M, Hamill RJ: Immune reconstitution inflammatory syndrome: more answers, more questions. J.Antimicrob.Chemother. 2006; 57: 167-70

5. Lawn SD, French MA: Immune reconstitution disease: recent developments and implications for anti-retroviral treatment in resource limited settings. Curr Opin HIV AIDS 2007; 2: 339-45

6. Haddow,LJ, Sahid, F, Moosa, M-Y,S: Cryptococcal breast abscess in an HIV-positive patient: Arguments for reviewing the definition of immune reconstitution inflammatory syndrome. Journal of Infection (2008) 57, 82-84

7. French MA, Lenzo N, John M, Mallal SA, McKinnon EJ, James IR, Price P, Flexman JP, Tay-Kearney

ML: Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV.Med. 2000; 1: 107-15

8. Hirsch HH, Kaufmann G, Sendi P, Battegay M: Immune reconstitution in HIV-infected patients. Clin.Infect.Dis. 2004; 38: 1159-66

9. van der Ende ME: Immuunreconstitutiesymdroom: een complicatie van antiretrovirale therapie bij hiv-positieve patiënten. Tijdschr Infect 2006; 1: 48-54

10. van den Horn GJ, Meenken C, DeSmet MD: Enhanced Ocular Inflammation can be due to other cause than immune recovery. Proceedings 7th European AIDS conference/EACS 1999

11. Meenken C, Danner SA, Ringens PJ, Mudiayi TK, van den Horn GJ: Clinical importance of ocular immune recovery syndromes. A prospective observational study in HIV+ individuals starting HAART in Botswana. Proceedings 8th International congress on Drug Therapy in HIV Infection 2006; 57-P165. www.aegis.org/conferences/hiv-glasgow/

12. Meenken C, Ringens PJ, Danner SA, Mudiayi TK, van den Horn GJ: Ocular Immune Recovery Syndrome; a prospective observational study in HIV+ individuals starting HAART in a resource limited country. Abstract Book 11th European AIDS conference/EACS 2007; 105-P9.9/01 http://www.eacs.eu/conference/madrid07/pdf2.php?pdf=P9.9-01_1

13. Hoover DR, Peng Y, Saah A, Semba R, Detels RR, Rinaldo CR, Jr., Phair JP: Occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression. Arch.Ophthalmol. 1996; 114: 821-7

14. van den Horn GJ, Meenken C, Danner SA, Reiss P, de S: Effects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte responses in HIV+ patients. Br.J.Ophthalmol. 1998; 82: 988-90

15. Zegans ME, Walton RC, Holland GN, O'Donnell JJ, Jacobson MA, Margolis TP: Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis. Am.J.Ophthalmol. 1998; 125: 292-300

16. Karavellas MP, Plummer DJ, MacDonald JC, Torriani FJ, Shufelt CL, Azen SP, Freeman WR: Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J.Infect.Dis. 1999; 179: 697-700

17. Kempen JH, Min YI, Freeman WR, Holland GN, Friedberg DN, Dieterich DT, Jabs DA: Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology 2006; 113: 684-94

18. Schrier RD, Song MK, Smith IL, Karavellas MP, Bartsch DU, Torriani FJ, Garcia CR, Freeman WR: Intraocular viral and immune pathogenesis of immune recovery uveitis in patients with healed cytomegalovirus retinitis. Retina 2006; 26: 165-9

19. Zamir E, Hudson H, Ober RR, Kumar SK, Wang RC, Read RW, Rao NA: Massive mycobacterial choroiditis during highly active antiretroviral therapy: another immune-recovery uveitis? Ophthalmology 2002; 109: 2144-8

20. Blanche, P, Gombert, B, Rivoal, O, Abad, S, Salmon, D, Brezin, A: Uveitis Due to Leishmania major as part of HAART-Induced Immune Restitution Syndrome in a patient with AIDS. Clin. Infect. Dis. 2002; 34:1279–80

21. Meenken C, van Agtmael MA, Ten Kate RW, van den Horn GJ: Fulminant ocular leishmaniasis in an HIV-1-positive patient. AIDS 2004; 18: 1485-6

22. Jacobson MA, Zegans M, Pavan PR, O'Donnell JJ, Sattler F, Rao N, Owens S, Pollard R:

Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443-5

23. Nguyen QD, Kempen JH, Bolton SG, Dunn JP, Jabs DA: Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am.J.Ophthalmol. 2000; 129: 634-9

24. Masur H, Kaplan JE, Holmes KK: Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann.Intern.Med. 2002; 137: 435-78

25. Otiti-Sengeri J, Meenken C, van den Horn GJ, Kempen JH: Ocular immune reconstitution inflammatory syndromes. Curr Opin HIV AIDS 2008; 3: 432-7

26. Jabs DA, Van Natta ML, Holbrook JT, Kempen JH, Meinert CL, Davis MD: Longitudinal study of the ocular complications of AIDS: 2. Ocular examination results at enrollment. Ophthalmology 2007; 114: 787-93

27. Price P, Mathiot N, Krueger R, Stone S, Keane NM, French MA: Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy. J.Clin.Virol. 2001; 22: 279-87

28. Modorati G, Miserocchi E, Brancato R: Immune recovery uveitis and human leukocyte antigen typing: a report on four patients. Eur.J.Ophthalmol. 2005; 15: 607-9

29. Manabe YC, Campbell JD, Sydnor E, Moore RD: Immune reconstitution inflammatory syndrome: risk factors and treatment implications. J.Acquir.Immune.Defic.Syndr. 2007; 46: 456-62

30. Thorne JE, Jabs DA, Kempen JH, Holbrook JT, Nichols C, Meinert CL: Incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology 2006; 113: 1432-40

31. Westeneng AC, Rothova A, de Boer JH, de Groot-Mijnes JD: Infectious uveitis in immunocompromised patients and the diagnostic value of polymerase chain reaction and Goldmann-Witmer coefficient in aqueous analysis. Am.J.Ophthalmol. 2007; 144: 781-5

32. Henderson HW, Mitchell SM: Treatment of immune recovery vitritis with local steroids. Br.J.Ophthalmol. 1999; 83: 540-5

33. Karavellas MP, Azen SP, MacDonald JC, Shufelt CL, Lowder CY, Plummer DJ, Glasgow B, Torriani FJ, Freeman WR: Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes. Retina 2001; 21: 1-9

34. Morrison VL, Kozak I, LaBree LD, Azen SP, Kayicioglu OO, Freeman WR: Intravitreal triamcinolone acetonide for the treatment of immune recovery uveitis macular edema. Ophthalmology 2007; 114: 334-9

35. Sirimaharaj M, Robinson MR, Zhu M, Csaky KG, Donovan B, Sutter F, Gillies MC: Intravitreal injection of triamcinolone acetonide for immune recovery uveitis. Retina 2006; 26: 578-80

36. El-Bradey MH, Cheng L, Song MK, Torriani FJ, Freeman WR: Long-term results of treatment of macular complications in eyes with immune recovery uveitis using a graded treatment approach. Retina 2004; 24: 376-82

37. Rothova A: Inflammatory cystoid macular edema. Curr.Opin.Ophthalmol. 2007; 18: 487-92

38. Ufret-Vincenty RL, Singh RP, Lowder CY, Kaiser PK: Cytomegalovirus retinitis after fluocinolone acetonide (Retisert) implant. Am.J.Ophthalmol. 2007; 143: 334-5

39. Zolopa, A, Andersen, J, Komarow, L, Sanchez, A, Suckow, C, Sanne, I, Hogg, E, Powderly, W, and ACTG A5164 Study Team. Immediate vs Deferred ART in the Setting of Acute AIDS-related Opportunistic Infection: Final Results of a Randomized Strategy Trial, ACTG A5164. CROI 2008 Abstract 142; www.retroconference.org/2008/Abstracts/32805.htm. 2008.

CChapter 8

Ocular Immune Reconstitution Inflammatory Syndromes and associated risk factors

submitted

Abstractt Background:

Methods:

Results:

Conclusions:

Keywords: IRIS, ocular immune recovery uveitis, HIV, sub-Saharan Africa, cART

Acknowledgements:

Ocular Immune Reconstitution Inflammatory Syndromes and associated risk factors

A cross-sectional study in 357 consecutive HIV+ patients on cART in a rural town in Botswana Introduction

Patients and methods

Statistical analysis

Results

Male Female

CI: confidence interval

Discussion

et al non

’s

et al

References 1. French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immuno-

deficient HIV-infected patients with highly active antiretroviral therapy. HIV Med. 2000; 1:107-15.

2. Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect.Dis. 2006; 19:20-5.

3. Dhasmana DJ, Dheda K, Ravn P, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients receiving antiretroviral therapy : pathogenesis, clinical manifestations and management. Drugs 2008; 68:191-208.

4. Henderson HW, Mitchell SM. Treatment of immune recovery vitritis with local steroids. Br.J.Ophthal-mol. 1999; 83:540-5.

5. van den Horn GJ, Meenken C, Danner SA, et al. Effects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte responses in HIV+ patients. Br.J.Ophthalmol. 1998; 82:988-90.

6. Zegans ME, Walton RC, Holland GN, et al. Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis. Am.J.Ophthalmol. 1998; 125:292-300.

7. Karavellas MP, Azen SP, MacDonald JC, et al. Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes. Retina 2001; 21:1-9.

8. Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005; 19:399-406.

9. Nguyen QD, Kempen JH, Bolton SG, et al. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am.J.Ophthalmol. 2000; 129:634-9.

10. Robinson MR, Reed G, Csaky KG, et al. Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy. Am.J.Ophthalmol. 2000; 130:49-56.

11. Kestelyn P. The epidemiology of CMV retinitis in Africa. Ocul.Immunol.Inflamm. 1999; 7:173-7.

12. Cunningham ET, Jr., Margolis TP. Ocular manifestations of HIV infection. N.Engl.J.Med. 1998; 339:236-44.

13. Golub JE, Pronyk P, Mohapi L, et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS 2009; 23:631-6.

14. Dandona L, Dandona R. Revision of visual impairment definitions in the International Statistical Classification of Diseases. BMC Med. 2006; 4:7.

15. Murdoch DM, Venter WD, Feldman C, et al. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008; 22:601-10.

16. Pathai S, Deshpande A, Gilbert C et al. Prevalence of HIV-associated ophthalmic disease among patients enrolling for antiretroviral treatment in India: a cross-sectional study. BMC.Infect.Dis. 2009;9:158.

17. Kempen JH, Min YI, Freeman WR, et al. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology 2006; 113:684-94.

18. Otiti-Sengeri J, Meenken C, van den Horn GJ, et al. Ocular immune reconstitution inflammatory syndromes. Curr Opin HIV AIDS 2008; 3:432-7.

19. Levinson RD, Vann R, Davis JL et al. Chronic multifocal retinal infiltrates in patients infected with human immunodeficiency virus. Am.J.Ophthalmol. 1998;125:312-24.