Cytomegalovirus and the Eye Marc D. de Smet

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11.1

Introduction

In immunosuppressed patients, or those having specifically lost their cellular immunity against the cytomegalovirus (CMV) virus, a retinal infection can develop. In the 1980s and early 1990s, CMV retinitis was a common cause of blindness in AIDS patients. Its incidence has dramatically decreased in the last few years in large part due to the introduction of highly active anti-retroviral therapy (HAART). HAART has also led to a new syndrome of HAART associated ocular inflammation which might be related to the presence of CMV antigens in the eye.

CMV is not only found in AIDS patients, but can be found in any immunosuppressed patients. Usually witnessed while the patient is under active immunosuppression, we have recent- ly become aware that even a history of past immunosuppresion may be compatible with the late occurrence of active CMV retinitis, without any overt signs of immunodeficiency.

11.2

Populations at Risk

Screening, treatment, and follow-up protocols are dependent on the origin and nature of the disease. CMV retinitis is seen in two particular settings as an AIDS related infection, or as a result of immunosuppression. Both populations present certain characteristics of incidence and risk.

11.2.1

HIV Associated Immunosuppression

CMV was among the most common oppor- tunistic infections in patients with AIDS. Prior to HAART, CMV retinitis accounted for 75–85 % of cytomegalovirus disease in patients with AIDS, with an estimated lifetime risk of CMV retinitis of 30 % [1]. Since the introduction of HAART, the incidence of CMV retinitis has dropped by 80 %, and has stabilized at about 15 % of the population at risk, mainly as an AIDS defining infection.

The only reported systemic factor significantly associated with CMV retinitis is a low CD4+ T-cell count. The prevalence rate of CMV

Cytomegalovirus and the Eye

Marc D. de Smet

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∑Cytomegalovirus (CMV) retinitis is less common than prior to the introduction of highly active anti-retroviral therapy (HAART) in AIDS patients. However, it remains an important AIDS defining infection

∑Choice of therapy and length of use is dependent on the response to HAART therapy, and time since its introduction

∑Elimination of maintenance therapy is possible when the CD4 count is above 100 cells/ml with a sustained increase and the patient is on HAART for at least 6 months

∑Some patients will develop recurrent disease despite high CD4 counts

∑CMV may be present in other immunosuppressive states and require sustained therapy

Core Messages

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retinitis in AIDS patients with a CD4+ T-cell count <50 cells/ml is estimated at 30 % and pa- tients with a CD4+ T-cell count >100 cells/ml are felt to be at very low risk [2]. In the setting of HAART therapy, screening and/or treatment should continue for 3–6 months after a rise in CD4 count, as the recovery of specific immunity lags behind the recovery of CD4+ T-cell counts.

Thereafter when the rise in CD4+ cells is sustained with a low HIV mRNA load, it is possible to consider withdrawal of anti-viral treatment [3, 4].

Withdrawal may be unsuccessful or risky in the following three settings. (1) Some patients have a persistent deficiency in specific anti- CMV CD4+ cells. These patients are at risk for persistent and recurrent ocular disease despite high CD4+ T-cell counts [5]. Frequent follow-up will be required. (2) Some patients will fail HAART therapy due to drug intolerance or the development of viral resistance. In these patients, if they were retinitis free for some time, the risk of retinitis recurrence is low but has been reported [6]. Systemic anti-CMV titres may be of some help in follow-up [7]. (3) In some patients, HAART treatment is insufficient to maintain an increased immunologic response. These patients are at high risk of persistent ocular disease. While ocular disease can be controlled by local means, survival will be significantly improved by systemic anti-CMV therapy [8].

Summary for the Clinician

∑ CD4+ counts below 50 cells/ml indicate a high risk for CMV

∑ CD4+ counts above 100 cells/ml indicate a low risk for CMV

11.2.2

Immunosuppression in Non-HIV Settings

Patients being immunosuppressed for organ transplantation are at a high risk of CMV infection. Initially, these patients are carefully followed for the development of systemic CMV antigenemia, and are given when needed pro- phylactic treatment with antivirals. In patients with increasing CMV titres, particularly those

at high risk for CMV infection, retinitis may develop in spite of these measures. Usually symp- tomatic, they may require prolonged treatment [9]. CMV may manifest itself at a later time, even 1–2 years after stopping immunosuppres- sives [10]. When CMV develops, its clinical course and manifestations are indistinguishable from early disease. It is not associated with tra- ditional risk factors. A female preponderance has been suggested due to a hormonal predis- position. Clinical awareness and adequate patient instructions are most commonly used to detect this late CMV manifestation. In some centers, an extended antigenemic surveillance program has allowed detection of late disease [10, 11].

Another group at increased risk are patients with autoimmune disease, particularly collagen vascular diseases requiring intensive immunosuppression. CMV may develop with any immunosuppressive, including cyclosporine or tacrolymus, but is particularly associated with the use of cyclophosphamide, which has a generalized action on T and B cells. Patients who are lymphopenic, with low CD4 and or CD8 counts, are at particular risk. While there is often a temporal relationship to recent cyclophosphamide use, this is not always the case as patients may develop an active retinitis even months later [12]. These patients usually present with a generalized reduction of their cellular immunity sometimes related to the use of other medications such as antiviral agents.

∑ Stop or reduce immunosuppression to recover specific immunity to CMV

∑ In post-transplant patients, and collagen vascular disease, late CMV may occur months after stopping severe immunosup- presive therapy.

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11.3

Appearance and Course

CMV retinitis has a fairly characteristic appearance which varies slightly depending on its location in the eye. Initially, infected retinal tissue is transparent, but as viral replication increases within infected cells, the translucency is lost and is replaced by a white lesion. This gives CMV its characteristic appearance: a white granular retinal infiltrate, often in the form of a brushfire border (Fig. 11.1). High levels of viral replication ultimately lead to cell death, leaving in its wake a zone of diaphenous thinned atrophic retina.

The retinal pigment epithelium (RPE) is also affected, resulting in a granular, speckled RPE.

Limited areas of fibrous proliferation, even calcification are occasionally seen within the area of atrophy. Invariably, the retinal vessels are attenuated in the atrophic areas, as the oxy- gen requirement in these areas is limited (Fig. 11.2).

11.3.1

Manifestation Prior to Initial Treatment

Often asymptomatic, CMV retinitis may be associated with a complaint of increasing floaters.

If the disease is present centrally, it will lead to a permanent noticeable decrease in vision. Most CMV lesions do not start in the fovea, but are initially found somewhere in the peripheral retina, or along the arcades. In AIDS patiens not receiving HAART, untreated CMV retinitis will progress at 750 mm/week [13]. In other immuno- suppressed patients, the progression rate is less, and is related to the level of immunocompe- tence. Bilaterality at presentation is common in AIDS patients, with one eye being more severe- ly affected. In young children, the first eye is often blind at presentation, unless these children were part of a well established screening program. The extent of initial disease appears to have some prognostic implications with regards to response to treatment and risk of recurrence [14].

Initially, CMV lesions present as small white infiltrates, which are often difficult to distin-

guish from a cotton wool spot (Fig. 11.3) [15].

However, with time the CMV lesion will grow centripetally, leaving in its wake atrophic retina.

When lesions develop close to, or within, the arcades, they are often associated with retinal haemorrhages, while in peripheral lesions these haemorrhages are absent (Fig. 11.4). Satellite or skip lesions at the leading edge of the active infiltrate are a common feature. This leading edge varies in diameter but can reach 500–700 mm.

Retinal edema, characteristic of zoster infection, is absent.

11.3 Appearance and Course 163

Fig. 11.1. This image depicts a typical active CMV lesion which consists of a peripheral atrophic retina, followed by a white active lesion, more or less confluent. Small satellite lesions are often found in normal retina ahead of the active frond

Fig. 11.2. Following treatment, there is a sharp de- marcation between normal and abnormal retina.

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11.3.2

Manifestations Under Therapy

Treatment will lead to a progressive decrease in the diameter of the leading edge, though exten- sion in the initial 2 weeks is to be expected as viral replication in already infected retina leads to opacification of the retinal tissue. A progression of 750 mm or more is not incompatible with an adequate response. Response to treatment will be visible only after 1–2 weeks of treatment.

Once the acute infection resolved, a sharp edge will appear between healthy and atrophic retina.

Recurrences in AIDS patients under maintenance therapy, or in the setting of a partially functional immune system, may show little evi- dence of activity. The leading edge creeps pro- gressively closer to the fovea (Fig. 11.5). Diagno- sis of such progression necessitates a sharp clinical acumen, or preferably a close comparison of the current clinical picture to fundus photos taken some time before. If photos can- not be taken, the chart should document the relationship between the leading edge of the lesion and neighbouring landmarks such as vessels.

Fig. 11.3. Initial small CMV lesions can be difficult to distinguish from cotton wool spots or small areas of atrophy.

However, without treatment, they increase in size over a few weeks.

Photographic documentation facilitates follow- up as in this case which demonstrates progression of a CMV lesion over a 3-week period

Fig. 11.4. a, b Central CMV retinitis (a)is often associated with more hemorrhage than peripheral lesions (b)

a b

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∑ In treated patients, CMV retinitis may remain active as a “brush fire” border

∑ The long-term follow-up is provided by photographic documentation with a panoramic set of photos of the whole retina

11.3.3

Differential Diagnosis

In its classical presentation, CMV retinitis is easy to diagnose. However, it may simulate (or be masked by) a number of ocular conditions from which it can be distinguished by its presentation, time course, or response to treatment.

When CMV retinitis starts adjacent to a blood vessel, it can either cause a vascular occlusion with the typical arcuate haemorrhages seen along the course of an occluded branch retinal vein (BRVO), or it may present as a frosted angiitis. In the latter case, the vessels show

extensive sheathing extending far into the pe- riphery [16]. There may be little associated retinitis, but in the course of the subsequent week, along the edge of the major vessels, the typical white leading edge of retinitis will appear. In BRVO, there is usually a distinguishable focus of retinitis close to the site of occlusion. Here on fluorescein angiogram, the central area of necrosis will be surrounded by a zone of hyper- fluorescence, and may help differentiate the lesion from a simple vein occlusion.

Patients may also present with a zone of active retinitis adjacent to the optic nerve. Differ- entiating this lesion from an optic neuritis may be difficult. The optic nerve head often will become hyperemic, but vision and visual fields are usually preserved until the optic nerve becomes infected with CMV [17]. Rapid initiation of therapy is required. Optic neuritis may be a manifestation of other viral infections such as zoster retinitis where rapid initiation of therapy is also required [18, 19]. Often these patients have a more significant visual impairment or have other manifestations of disease.

There is usually little difficulty in differenti- ating CMV retinitis from other ocular infections. Zoster retinitis presents as a confluent peripheral retinitis with considerable retinal edema. In immunocompetent patients, there is usually severe vitreous inflammation, an un- usual manifestation in AIDS patients. A more common diagnostic problem is the differentia- tion of toxoplasmosis from CMV, which in AIDS patients can present with a similar white granular lesion. This lesion is usually static, and will show no response to antiviral treatment. Note that some patients will present with several con- current infections, which all require treatment if vision is to be preserved [19]. Luckily such cases are rare. Diagnostic tests can be of some help in such cases.

∑ Toxoplasmosis may mimic a CMV lesion in AIDS patients

∑ CMV may be associated with BRVO, optic neuritis

∑ Early CMV lesions can mimic a cotton wool spot

11.3 Appearance and Course 165

Fig. 11.5. Anti-viral therapy can allow progression to occur without any significant border activity. A thin zone of reactivation associated with a larger atrophic zone is the only sign of ongoing activity in these patients. Photographs were taken 1 month apart

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11.3.4

Investigations

It will generally not be necessary to confirm the diagnosis with diagnostic tests. The most useful approach is to combine the measurement of ocular antibody production with PCR for CMV genome [20, 21]. Ocular antibody production against CMV is compared to serum levels. A Goldman-Witmer coefficient above 3 is indica- tive of active antibody production. Several sub- types should be analysed simultaneously (IgM, IgG and IgA) as any one of them could be elevat- ed. While PCR is most likely to be positive in most CMV infections [22], if there is little inflammation present in the anterior chamber, it may be negative. The highest sensitivity is ob- tained by combining both techniques.

Viral CMV loads in serum do not appear to correlate with ocular disease progression, though its presence indicates the presence of active disease [23]. Subtyping can be of use if the lesions does not seem to respond well to treatment, or if drug resistance is common in your patient population. Subtyping to aimed at iden- tifying ganciclovir resistant strains which may indicate an increased risk for retinitis progression [24].

11.4

Therapeutic Agents

11.4.1 Ganciclovir

Ganciclovir is the antiviral drug most widely studied for the treatment of CMV retinitis and is effective when administered by intravenous, intravitreal, or oral routes, or when released in the pars plana from a slow release implant. The systemic route is associated with neutropenia, which limits its use. IV it is associated with local infections in a substantial number of patients (20 % of patients in one study), while the oral route has a low bioavailability, limiting it to maintenance therapy. Oral ganciclovir can lead to gastric intolerance, its main advantage at present is its ability to prolong survival in patients unresponsive to HAART, and in whom the eye is protected by local therapy [25]. Intravitre- al injections can lead to local control in a high number of patients with a low risk of endoph- thalmitis provided adequate antisepsic measures are taken at the time of injection [26, 27].As initial therapy, it should be given twice a week (standard dose of 200 µg). Maintenance is given on a weekly basis. By increasing the dose to 2 mg, it is possible to delay repeat injections to once every 2 weeks (Table 11.1) [28].

Table 11.1. Dosing requirements of anti-CMV drugs

Drug name Dose Frequency Major side effect

Ganciclovir [47] 5 mg/kg IV I-2¥/day Myelosuppression

5 mg/kg IV M-1¥/day

or [28] 200–2000 mg IO in 0.1 ml Weekly

or [30] Intraocular implant Every 8 months

or [48] 1,500 mg p.o. M-3¥/day

Valganciclovir [31] 900 mg p.o. I-2¥/day Myelosuppression

900 mg p.o. M-1¥/day

Foscarnet [13] 90 mg/kg IV I-3¥/daily Nephrotoxicity

60 mg/kg IV M-3¥/day

Cidofovir [49] 5 mg/kg IV I-1¥/week ¥2 Nephrotoxicity

3–5 mg/kg IV M–Q 2 weeks Hypotony, AC uveitis

Fomivirsen [41] 330 mg IO I-1¥/week Uveitis increased IOP

330 mg IO M-1¥/month

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The intravitreal implant capable of releasing drug for up to 8 months has been very popular in North America. It is associated with a high local response rate even in cases of systemic resistance to ganciclovir [29, 30].

11.4.2

Valganciclovir

Valganciclovir is a monovalyl ester prodrug of ganciclovir that when administered orally is rapidly hydrolysed to the active compound ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir is 60 %. With an oral valganciclovir dose of 900 mg, given twice daily the same systemic levels of ganciclovir are achieved as with IV administered ganciclovir. In a randomized controlled clinical trial, oral valganciclovir was found to be as effective as intravenous ganciclovir for induction and maintenance therapy without having the incon- venience of IV ganciclovir. The side effects due to valganciclovir are identical to those of ganciclovir [31]. It is now the drug of choice for first line therapy.

11.4.3 Foscarnet

Foscarnet is the second most common treatment for CMV retinitis. This agent is usually given intravenously. It is not metabolized intra- cellularly as is ganciclovir. Thus, dosing must be given fairly frequently to ensure steady state intraocular concentrations [13]. It is not myelotox- ic, but requires extensive hydration to prevent renal toxicity. As with ganciclovir, prolonged use can lead to the development of resistant strains, at a similar incidence rate [32].When effectivity drops, a switch to an alternate treatment is needed, or one can consider the combined use of foscarnet and ganciclovir. These act synergistically [33, 34]. Unfortunately, this is a temporizing measure rather than a long-term solution, as the patient will suffer from the tox- ic effects of both drugs. One might consider us- ing IV foscarnet combined with intraocular ganciclovir in this situation, if no other alterna-

tive is available.An intravitreal formulation also exists but requires frequent administrations to maintain effectivity [35].

11.4.4 Other Agents

Among the other drugs that can be used to treat CMV retinitis, one should mention cidofovir, and fomivirsen. Cidofovir is an acyclic nucleoside phosphonate which does not require a virus encoded phosphorylation step as does ganciclovir [36]. It is a very potent anti-CMV compound which can be given on a less frequent basis than ganciclovir or foscarnet. It is effective in cases of retinitis relapsing on either medication [37]. While the incidence of anterior uveitis is higher when given concomitantly with HAART, the induced anterior segment inflammation is easily controlled with drops [38]. Tox- icity, renal and ocular, resolve with discontinua- tion of therapy. While it can be used by intravitreal injection, its use can lead to severe hypotony and uveitis [39].

Fomivirsen is a phosphorothioate oligonucleotide which specifically binds to the mRNA encoding for the immediate – early activation proteins of the CMV virus [40]. In two randomized clinical studies, it was shown to inhibit CMV retinitis by intravitreal injections. In its maintenance regimen, it can be given once a month [41–43].

11.5

Screening and Treatment Algorithms

CMV retinitis develops in patients who are immunosuppressed. Since all antivirals to date are virostatic, unless one can restore the patient’s own immunity against CMV, antiviral treatment will have to be prolonged, possibly lifelong. If immune recovery is possible or can be induced, treatment can be discontinued and follow-up tailored to the observed response.

11.5 Screening and Treatment Algorithms 167

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11.5.1

CMV in HIV Infected Patients

A distinction should be made between patients receiving HAART treatment and those who do not. Patients diagnosed with HIV infection and with low CD4+ counts <100 cells/ml should be screened and instructed regarding the signs and symptoms of CMV retinitis. Patients with CD4+

counts under <50 cells/ml should be screened roughly every 3–6 months. Above 100 CD4+

cells/ml frequent screening is unnecessary. The same algorithm holds for patients on HAART treatment, expect that for the first 6 months after achieving a CD4+ count equal or above 100 cells µl, the same protocol holds as for patients without HAART and a low CD4+ count.

Treatment choices will depend on available medications, and observed response. The preferred choice is presently oral valganciclovir. If it is not tolerated, placement of an intraocular implant would be the next choice. Other options are kept for more recalcitrant cases, or when the first two named options are unavailable. Follow- up is weekly until response is seen. Once the lesion is quiescent, follow-up can be on a monthly to 3 monthly basis. HAART status is also important in the choice of therapy. If a patient is HAART naive, treatment will likely be required for 6–12 months, after which it can be stopped. If CMV has occurred while on HAART, or after stopping HAART, the patient should be followed as a non-HAART patient.

11.5.2

CMV in Other Immunosuppressive States

Well-established algorithms do not exist for these patients. In general, an effort is made to reduce or stop the immunosuppressant causing the drop in immunity.As the lymphocyte counts improve, CMV retinitis will resolve. Local treatment with intravitreal agents (ganciclovir or fomivirsen) is the preferred approach, as it min- imizes the potential immunosuppression which can be caused by systemic ganciclovir or valganciclovir.

If CMV retinitis develops as a late manifestation, months after stopping immunosuppressive agents, a ganciclovir implant, cidofovir, or fomivirsen are the preferred approaches.

11.6

Management of Complications

In addition to vision loss, CMV retinitis can lead to a number of complications ranging from cataract formation to the development of a retinal detachment. With the introduction of HAART, about 15 % of patients will develop uveitis as the immune system recovers.

11.6.1

Immune Recovery

With the introduction of HAART, a number of patients with quiescent CMV retinitis started to develop signs of significant intraocular inflammation. This inflammatory response can be controlled in most patients with topical corti- costeroids and is transient. However, in some patients it leads to the development of recalcitrant cystoid macular edema, the formation of epiretinal membranes, cataract or glaucoma [44]. The process is most likely due to an en- hanced humoral immune response to ocular antigens [45]. The possibility that active viral replication is present has been suggested though not proven.

11.6.2

Retinal Detachment

Vision loss in CMV infection is either due to the retinitis itself, or as a result of retinal detachment. In the pre-HAART era, the risk of detachment was about 33 % per affected eye per year.

Lesion size and anterior location of the lesion were both associated with an increased risk, particularly at the time of posterior hyaloid separa- tion. Introduction of HAART therapy has dramatically reduced this risk by about 60 % [46].

This reduction is most significant in patients that do not develop immune recovery uveitis, as

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this variable doubles the risk of detachment in HAART treated patients (but nevertheless repre- sents a significant reduction in incidence as compared to non-HAART patients). The incidence of retinal detachment in patients receiving an implant does not appear to be higher than in patients receiving only systemic therapy.

Treatment options are dependent on the location of the detachment and response to HAART treatment. More conservative approaches such as placing a laser barrier around the detachment are often successful if the detachment is of limited size. More extensive detachments will require a pars plana vitrectomy. In non- HAART patients the use of silicone oil is required in most cases. For HAART patients, it can often be avoided provided there is no significant proliferative vitreoretinopathy present.

References

1. Jabs DA, van Natta ML, Kempen JH, et al. (2002) Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 133:48–61

2. Jabs DA, Enger C, Bartlett JG (1989) Cytomegalo- virus retinitis and acquired immunodeficiency syndrome. Arch Ophthalmol 107:75–80

3. van den Horn GJ, Meenken C, Danner SA, et al.

(1998) Effects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte responses in HIV+ patients. Br J Ophthalmol 82:988–990

4. Lin DY, Warren JF, Lazzeroni LC, et al. (2002) Cy- tomegalovirus retinitis after initiation of highly active antiretroviral therapy in HIV-infected patients. Natural history and clinical predictors.

Retina 22:268–277

5. Lilleri D, Piccinini G, Baldanti F, et al. (2003) Mul- tiple relapses of human cytomegalovirus retinitis during HAART in an AIDS patient with reconsti- tution of CD4+ T cell count in the absence of HCMV-specific CD4+ T cell response. J Clin Virol 26:95–100

6. Torriani FJ, Freeman WR, Macdonald JC, et al.

(2000) CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy. AIDS 14:1041–1049 7. Salmon-Ceron D, Mazeron MC, Chaput S, et al.

(2000) Plasma cytomegalovirus DNA, pp65 antigenemia and a low CD4 cell count remain risk factors for cytomegalovirus disease in patients receiving highly active antiretroviral therapy.

AIDS 14:1041–1049

8. Kempen JH, Jabs DA, Wilson LA, et al. (2003) Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis 37:1365–1373

9. Fishburne BC, Micrani AA, Davis JL (1998) Cy- tomegalovirus retinitis after cardiac transplantation. Am J Ophthalmol 125:104–106

10. Shibolet O, Ilan Y, Kalish Y, et al. (2003) Late cytomegalovirus disease following liver transplantation. Transpl Int 16:861–865

11. Machado CM, Menezes RX, Macedo MC (2001) Extended antigenemia surveillance and late cytomegalovirus infection after allogeneic BMT.

Bone Marrow Transplant 28:1053

12. Agrawal A, Dick AD, Olson JA (2003) Visual symptoms in patients on cyclophosphamide may herald sight threatening disease. Br J Ophthalmol 87:122–123

13. Palestine AG, Polis MA, de Smet MD, et al. (1991) A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 115:665–673 14. Holbrook JT, Davis MD, Hubbard LD, et al. (2000)

Risk factors for advancement of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome.Arch Ophthalmol 118:1196–1204 15. de Smet MD, Nussenblatt RB (1991) Ocular manifestations of AIDS. J Am Med Assoc 266:3019–

3022

16. Spaide RF, Vitale AT, Toth IR, et al. (1992) Frosted branch angiitis with cytomegalovirus retinitis.

Am J Ophthalmol 113:522–528

17. Grossniklaus HE, Frank KE, Tomsak RL (1987) Cytomegalovirus retinitis and optic neuritis in acquired immune deficiency syndrome. Ophthal- mology 94:1601–1604

18. Meenken C, van den Horn GJ, van der Meer JTM, et al. (1998) Optic neuritis heralding varicella zoster virus retinitis in a patient with AIDS. Ann Neurol 43:534–536

19. de Smet MD, De Fen S, Pepose JS, et al. (2003) Mi- crodissection combined with the polymerase chain reaction to identify potentiating viral co- infection in patients with HIV/AIDS with ocular infection. Can J Ophthalmol 38:207–213

20. de Boer JH, Verhagen C, Bruinenberg M, et al.

(1996) Serologic and polymerase chain reaction analysis of intraocular fluids in the diagnosis of infectious uveitis. Am J Ophthalmol 121:650–658 21. Doornenbal P, Baarsma GS, Quint WGV, et al.

(1996) Diagnostic assays in cytomegalovirus retinitis: detection of herpes virus by simultaneous application of the polymerase chain reaction and local antibody analysis on ocular fluid. Br J Oph- thalmol 80:235–240

References 169

(10)

22. Ando Y, Terao K, Narita M, et al. (2002) Quantita- tive analyses of cytomegalovirus genome in aqueous humor of patients with cytomegalovirus retinitis. Jpn J Ophthalmol 46:254–260

23. Scholz M, Doerr HW, Cinatl J (2003) Human cytomegalovirus retinitis: pathogenicity, immune evasion and persistence. Trends Microbiol 11:171–

178

24. Jabs DA, Martin BK, Forman MS, et al. (2003) Cy- tomegalovirus resistance to ganciclovir and clinical outcomes of patients with cytomegalovirus retinitis. Am J Ophthalmol 135:26–34

25. Martin DF, Kuppermann BD, Wolitz RA, et al.

(1999) Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 340:1063–1070

26. Cochereau-Massin I, LeHoang P, Lautie-Frau M, et al. (1991) Efficacy and tolerance of intravitreal ganciclovir in cytomegalovirus retinitis in acquired immune deficiency syndrome. Ophthal- mology 98:1348–1353

27. Baudouin C, Gastaud P (1992) A modified proce- dure for intravitreal injections of ganciclovir in the treatment of cytomegalovirus retinitis. Oph- thalmology 99:1183

28. Young SH, Morlet N, Heery S, et al. (1992) High dose intravitreal ganciclovir in the treatment of cytomegalovirus retinitis. Med J Aust 157:370–373 29. Martin DF, Dunn JP, Davis JL, et al. (1999) Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of the In- ternational AIDS Society – USA Panel. Am J Ophthalmol 127:329–339

30. Martin DF, Parks DJ, Mellow SD, et al. (1994) Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant. Arch Ophthalmol 112:1531–1539

31. Martin DF, Sierra-Madero J, Walmsley S, et al.

(2002) A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis.

N Engl J Med 346:1119–1126

32. Weinberg A, Jabs DA, Chou S, et al. (2003) Muta- tions conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis 187:777–784

33. Cytomegalovirus Retreatment Trial (1996) Com- bination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. Arch Ophthalmol 114:23–33

34. Butler KM, de Smet MD, Husson RN, et al. (1992) Treatment of aggressive CMV retinitis with ganciclovir in combination with foscarnet in a child with human immunodeficiency virus infection. J Pediatr 120:483–485

35. Berthe P, Baudouin C, Garraffo R, et al. (1994) Toxicologic and pharmacokinetic analysis of intravitreal injections of foscarnet, either alone or in combination with ganciclovir. Invest Ophthal- mol Vis Sci 35:1038–1045

36. De Clercq E (2003) Clinical potential of the acyclic nucleoside phosphonates cidofovir, ade- fovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev 16:569–596

37. Lalezari JP, Holland GN, Kramer F, et al. (1998) Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 17:339–344

38. Berenguer J, Mallolas J, Spanish Cidofovir Study Group (2000) Intravenous cidofovir for compas- sionate use in AIDS patients with cytomegalovirus retinitis. Clin Infect Dis 30:182–184 39. Banker AS, Arevalo JF, Munguia D, et al. (1997) In-

traocular pressure and aqueous humor dynamics in patients with AIDS treated with intravitreal cidofovir (HPMPC) for cytomegalovirus retinitis. Am J Ophthalmol 124:168–180

40. de Smet MD, Meenken C, van den Horn GJ (1999) Fomivirsen: a phosphorothioate oligonucleotide for the treatment of cytomegalovirus retinitis.

Ocul Immunol Infl 7:189–198

41. Vitravene Study Group (2002) Randomized dose- comparison studies of intravitreous fomivirsen for treatment of cytomegalovirus retinitis that has reactivated or is persistently active despite other therapies in patients with AIDS. Am J Oph- thalmol 133:475–483

42. Vitravene Study Group (2002) A randomized controlled clinical trial of intravitreous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol 133:467–474

43. Vitravene Study Group (2002) Safety of intravitreous fomivirsen for treatment of cytomegalovirus retinitis in patients with AIDS. Am J Oph- thalmol 133:484–498

44. Goldberg DE, Wang H, Azen SP, et al. (2003) Long term visual outcome of patients with cytomegalovirus retinitis treated with highly active antiretroviral therapy. Br J Ophthalmol 87:853–

855

45. Stone SF, Price P, Tay-Kearney ML, et al. (2002) Cy- tomegalovirus (CMV) retinitis immune restoration disease occurs during highly active antiretroviral therapy – induced restoration of CMV- specific immune responses within a predominant Th2 cytokine environment. J Infect Dis 185:1813–

1817

(11)

46. Kempen JH, Jabs DA, Dunn JP, et al. (2001) Retinal detachment risk in cytomegalovirus retinitis related to the acquired immunodeficiency syndrome. Arch Ophthalmol 119:33–40

47. Holland GN, Buhles WC, Mastre B, et al. (1989) A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Arch Ophthalmol 107:1759–1766

48. Drew WL, Ives D, Lalezari JP, et al. (1995) Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. N Engl J Med 333:615–620

49. Studies of Ocular Complications of AIDS Re- search Group in Collaboration with the AIDS Clinical Trials Group (2000) Long-term follow- up of patients with AIDS treated with parenteral cidofovir for cytomegalovirus retinitis: the HP- MOC peripheral cytomegalovirus retinitis trial.

AIDS 14:1571–1581

References 171