Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy

Course of Cytomegalovirus Retinitis in the Era of Highly Active Antiretroviral Therapy 2. Second Eye Involvement and Retinal Detachment Douglas A. Jabs, MD, MBA,1,2,3 Mark L. Van Natta, MHS,3 Jennifer E. Thorne, MD,1,3 David V. Weinberg, MD,4 Travis A. Meredith, MD,5 Baruch D. Kuppermann, MD, PhD,6 Kent Sepkowitz, MD,7 Helen K. Li, MD,8 for the Studies of Ocular Complications of AIDS Research Group* Purpose: To describe the course of cytomegalovirus (CMV) retinitis in patients with AIDS in the era of highly active antiretroviral therapy (HAART). Design: Multicenter, prospective, observational study. Participants: Two hundred seventy-one patients with AIDS and CMV retinitis. Methods: Follow-up every 3 months with medical history, ophthalmologic examination, laboratory testing, and fundus photographs. Main Outcome Measure: Second (contralateral) eye involvement among patients with unilateral disease and retinal detachment (RD). Results: The overall rate of second eye involvement among patients with unilateral CMV retinitis was 0.07 per person-year (PY); among those with CD4⫹ T-cell counts of ⬍50/␮l it was 0.34/PY, compared with 0.02/PY among those with CD4⫹ T-cell counts of ⱖ200/␮l (P⬍0.0001). Risk factors for contralateral eye involvement included low CD4⫹ T-cell count and detectable CMV load. The overall rate of RD was 0.06/PY; among those with CD4⫹ T-cell counts of ⬍50/␮l it was 0.30/PY, compared with 0.02/PY among those with CD4⫹ T-cell counts of ⱖ200/␮l (P⬍0.0001). Risk factors for RD included a low CD4⫹ T-cell count and larger area of CMV retinitis. Conclusions: Compared with the rates reported in the pre-HAART era of second eye involvement (⬃0.40/ PY) and RD (⬃0.50/PY), the rates of these events were reduced among patients in the HAART era. However, among patients with CD4⫹ T-cell counts of ⬍50/␮l, the rates were more similar to those from the pre-HAART era. Ophthalmology 2004;111:2232–2239 © 2004 by the American Academy of Ophthalmology.

Highly active antiretroviral therapy (HAART), which consists of combination therapy, typically with ⱖ3 antiretroviral drugs, has altered substantially the management of patients with AIDS.1– 6 Highly active antiretroviral therapy can suppress human immunodeficiency virus (HIV) replication, and with suppression of HIV replication, the patient’s immune system

may reconstitute partially, a phenomenon known as immune recovery or immune reconstitution.7 Among patients with opportunistic infections, immune recovery of sufficient magnitude sustained for a sufficiently long time often results in the ability to discontinue secondary prophylaxis for opportunistic infections.8

Originally received: May 11, 2004. Accepted: May 18, 2004. Manuscript no. 240355. 1 Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 2 Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 3 Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. 4 Department of Ophthalmology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 5 Department of Ophthalmology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. 6 Department of Ophthalmology, University of California, Irvine, School of Medicine, Irvine, California. 7 Department of Medicine, Weill Medical College of Cornell University, New York, New York. 8 Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, Texas.

Supported by cooperative agreements from the National Eye Institute, Bethesda, Maryland, to The Johns Hopkins University School of Medicine, Baltimore, Maryland (grant no.: U10 EY08052); The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland (grant no.: U10 EY08057); and the University of Wisconsin, Madison, Wisconsin (grant no.: U10 EY08067). Additional support was provided by the National Center for Research Resources, Bethesda, Maryland (General Clinical Research Center grant nos.: 5MO1 RR00188 [Baylor College of Medicine, Houston, Texas], MO1 RR00052 [The Johns Hopkins University School of Medicine, Baltimore, Maryland], 5MO1 RR05096 [Louisiana State University, Baton Rouge, Louisiana], 5MO1 RR00865 [University of California, Los Angeles, California], 5MO1 RR05280 [University of Miami, Miami, Florida], 5M01 RR00046 [University of North Carolina, Chapel Hill, North Carolina], 5MO1 RR00043 [University of Southern California, Los Angeles, California], and 5MO1 RR00047 [Weill Medical College of Cornell University, New York, New York]). Correspondence and reprint requests to Douglas A. Jabs, MD, MBA, Wilmer Eye Institute, 550 North Broadway, Suite 700, Baltimore, MD 21205. E-mail: [email protected]. *Members of the Group can be found using Ref. 20.

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© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.

ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2004.05.028

Jabs et al 䡠 Cytomegalovirus Retinitis Course in the HAART Era Table 1. Risk Factors for Contralateral Eye Involvement in Patients with Unilateral Cytomegalovirus (CMV) Retinitis at Enrollment Risk Factor

Rate (/PY)

n/N

Overall rate Retinitis status at enrollment Newly diagnosed Long-standing Age (yrs) ⬍41 ⱖ41 Gender Male Female Race White Nonwhite Risk factor for HIV infection Men having sex with men Other Date enrollment August 1998–July 1999 August 1999–July 2000 August 2000–July 2001 August 2001–July 2003 Time since AIDS diagnosis at enrollment (yrs) 0–3.0 3.1–6.0 6.1–9.0 ⬎9.0 Area of CMV retinitis ⱖ25% of retinal area in eye at enrollment No Yes Visceral CMV disease at enrollment No Yes Karnofsky score at enrollment 90–100 ⱕ80 Hemoglobin at enrollment (g/dl) ⬍10 10–13 ⬎13 Antiretroviral therapy at enrollment HAART No HAART Immune recovery* No Yes Anti-CMV therapy at enrollment Local therapy only† Systemic therapy‡ None CD4⫹ T-cell count at enrollment (/␮l) 0–49 50–99 100–199 ⱖ200 CD4⫹ T-cell count at visit before event (/␮l) 0–49 50–99 100–199 ⱖ200 HIV load at enrollment (copies/ml) ⬍400 400–10 000 10 001–100 000 ⬎100 000

0.07

25/177

0.20 0.03

13/47 11/127

0.08 0.05

15/93 10/83

0.06 0.07

20/142 5/34

0.07 0.06

14/92 11/84

0.07 0.06

17/116 7/58

0.03 0.09 0.17 0.09

7/76 9/46 7/26 2/29

0.06 0.06 0.06 0.13

8/54 10/72 4/39 2/10

P Value 0.0002 0.44 0.86 0.60 0.62 0.07

0.88

0.68 0.06 0.07

16/121 9/56

0.06 0.09

22/159 3/17

0.05 0.08

9/72 16/103

0.37 0.13 0.03

3/8 15/69 7/100

0.06 0.10

18/138 7/37

0.13 0.02

19/88 5/85

0.10 0.05 0.06 0.007 0.16 0.08 0.01 0.02

9/45 8/73 8/57 15/63 4/24 1/28 4/61

0.34 0.04 0.05 0.02

16/53 1/15 2/16 6/93

0.02 0.03 0.11 0.22

3/63 2/23 7/36 12/43

0.55 0.31 0.001

0.23 0.002 0.39

⬍0.0001

0.002

(continues)

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Ophthalmology Volume 111, Number 12, December 2004 Table 1. (Continued.) Risk Factor HIV load at visit before event (copies/ml) ⬍400 400–10 000 10 001–100 000 ⬎100 000 Cytomegalovirus viral load at enrollment (copies/ml) ⬍400 ⱖ400 Cytomegalovirus viral load at visit prior to event (copies/ml) ⬍400 ⱖ400

Rate (/PY)

n/N

P Value 0.008

0.03 0.02 0.15 0.23

6/83 1/23 7/29 11/40 0.005

0.06 0.28

21/161 4/10

0.05 0.66

18/161 7/13

⬍0.0001

HAART ⫽ highly active antiretroviral therapy; HIV ⫽ human immunodeficiency virus; n/N ⫽ no. of events/no. at risk; PY ⫽ person-year. *Increase in CD4⫹ T-cells from nadir by ⱖ50 cells/␮l to a level of ⱖ100 cells/␮l. † Ganciclovir implant or intravitreous injections. ‡ IV or oral ganciclovir, valganciclovir, IV foscarnet, or IV cidofovir.

Cytomegalovirus (CMV) retinitis is a common opportunistic infection among patients with AIDS.9 –11 Before the introduction of HAART, 30% of patients with AIDS developed CMV retinitis during their lifetime,12 but with the advent of HAART, there has been a 75% reduction in the number of new cases of CMV retinitis.1,13–15 However, with the decline in AIDS mortality there is an increasing prevalent population of patients with CMV retinitis. Numerous small case series have documented the ability to discontinue successfully specific anti-CMV therapy among patients who exhibit immune reconstitution to a level of ⱖ100 CD4⫹ T-cells/␮l, as long as the CD4⫹ T-cell count remains elevated.16 –19 In the accompanying article we report that the rate of retinitis progression is lower in the HAART era than that reported in the pre-HAART era, even among patients with low CD4⫹ T-cell counts.20 In the pre-HAART era, patients with unilateral CMV retinitis frequently developed bilateral disease, presumably due to hematogenous dissemination.21–25 Systemic antiCMV therapy reduced the rate substantially but did not eliminate the occurrence of what was termed second eye or contralateral ocular disease.20 Retinal detachments (RDs) were a frequent complication of CMV retinitis, occurring at a rate of ⬃0.50 per person-year (PY) or ⬃0.33 per eyeyear.9,26 –28 Although the rates of second eye disease and RD might be expected to be less than those in the preHAART era among patients with immune recovery, the rates might be lower than (as with progression) or similar to those from the pre-HAART era among patients with low CD4⫹ T-cell counts, as most, but not all, patients developing CMV retinitis in the era of HAART already have been diagnosed with AIDS; have been previously or are currently treated with HAART; and have been intolerant of HAART, noncompliant with HAART, or nonresponsive to HAART.29 To address these questions, we analyzed data from a prospective cohort study of 271 patients with AIDS and CMV retinitis.

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Patients and Methods The Longitudinal Studies of the Ocular Complications of AIDS are prospective, multicenter observational studies of patients with AIDS.20,29 Patients with a diagnosis of AIDS30 and who are 13 years or older are eligible. Patients are enrolled with and without CMV retinitis; this report focuses on patients with CMV retinitis at entry. Data collection and follow-up are detailed in the accompanying article.20 Cytomegalovirus retinitis was diagnosed by ophthalmologic examination by a studycertified ophthalmologist based upon its characteristic presentation either as a necrotizing retinitis among those patients with active retinitis or as an atrophic and gliotic scar among those with treated and quiescent retinitis or with immune recovery.20,29 Highly active antiretroviral therapy was defined as a combination antiretrovial regimen with ⱖ3 drugs, including at least one protease inhibitor or non-nucleoside reverse transcriptase inhibitor, or a triple-nucleoside reverse transcriptase inhibitor regimen (e.g., abacavir, zidovudine, lamivudine) with similar efficacy. A Karnofsky performance score was graded on a scale of 0 to 100 by 10-point decrements, with 100 being perfect health and 0 death.31 CD4⫹ T-cell counts and determinations of HIV load and CMV load were performed as described in the accompanying article.20,32 For these analyses, an immunologic definition of the response to HAART was used, as the immunologic response seems to be superior to the virologic response to HAART at predicting the ability to control CMV retinitis without specific anti-CMV therapy.8,16 –19,29 Immune recovery was defined as an increase in the CD4⫹ T-cell count by ⱖ50/␮l from the nadir CD4⫹ T-cell count to a level of ⱖ100/␮l at enrollment.8,20,29,33 Data collected and reported to the Studies of the Ocular Complications of AIDS Coordinating Center as of July 31, 2003 are included in this report.20 Patients with unilateral CMV retinitis at enrollment as assessed by the clinician were included in the analysis of second (contralateral) eye involvement. Eyes that never had an RD at enrollment were included in the analysis of RD in either eye. Time-dependent risk factors were defined as the values of the risk factors at either the visit before the event, for patients with the event, or the most recent visit, for patients without the

Jabs et al 䡠 Cytomegalovirus Retinitis Course in the HAART Era event. Rates were defined as the number of events divided by the total PYs at risk for the event. Relative risks were estimated using Cox regression.34 P values were nominal, 2-sided, and based on the Wald test from Cox regression. Multiple regressions used a stepwise procedure starting with all variables (except enrollment date, because it was highly associated with newly diagnosed or longstanding retinitis), with the cutoff for inclusion in the final model being P⬍0.05.35 Univariate analysis did not include patients with missing values. For multiple regression, observations with missing values were imputed with the value from the most frequent category. Analyses were performed with SAS 8.0 and Stata 6.0.36,37 This study was approved by institutional review boards at each participating center, and all patients gave written informed consent.

Results Characteristics of the Study Population The characteristics of the study population are listed in Table 1 of the accompanying article.20

event, the rate was 0.34/PY for patients with CD4⫹ T-cell counts of ⬍50/␮l, compared with a rate of 0.02/PY for patients with counts of ⱖ200/␮l (P⬍0.0001). Human immunodeficiency virus loads at enrollment and at the visit before the event both were associated with the risk of contralateral eye involvement. Cytomegalovirus loads at enrollment and at the visit before the event both were associated with the risk of contralateral eye involvement. For patients with a CMV viral load of ⬍400 copies/ml at enrollment, the rate was 0.06/PY, whereas for those with a CMV viral load of ⬍400 copies/ml it was 0.28/PY (P ⫽ 0.005); for patients with a CMV viral load of ⬍400 copies/ml at the visit before event the rate was 0.05/PY, whereas for those with a CMV viral load of ⱖ400 copies/ml it was 0.66/PY (P⬍0.0001). In the multivariate analysis of contralateral eye involvement (Table 2), only CD4⫹ T-cell count and CMV load were associated. CD4⫹ T-cell count was the strongest predictor, with a relative risk of 13.7 for those with ⬍50 CD4⫹ T-cells/␮l versus those with ⱖ200/␮l (P⬍0.0001). A CMV load of ⱖ400 copies/ml had a relative risk of 5.3 (P ⫽ 0.003). Cytomegalovirus load’s sensitivity for contralateral eye involvement was only 28%; its specificity, 96%; its positive predictive value, 54%; and its negative predictive value, 89%.

Retinal Detachment

Contralateral Eye Involvement in Patients with Unilateral Disease at Enrollment Risk factors for involvement of the contralateral eye in patients presenting with unilateral CMV retinitis are listed in Table 1. Overall, the rate was 0.07/PY. Patients with newly diagnosed CMV retinitis had a greater risk of involvement of the contralateral eye (0.20/PY) than those with previously diagnosed and long-standing retinitis (0.03/PY, P ⫽ 0.0002). There were no cohort effects on contralateral eye involvement. Anti-CMV treatment at enrollment was not associated significantly with contralateral eye involvement. Patients receiving only local therapy (implant or intravitreous injections) had a rate of 0.10/ PY, whereas those receiving any systemic therapy (regardless of concomitant local therapy) had a rate of 0.05/PY, and those on no anti-CMV therapy had a rate of 0.06/PY (P ⫽ 0.39). CD4⫹ T-cells at enrollment and at the visit before the event both were associated with the risk of contralateral eye involvement. For patients with a CD4⫹ T-cell count of ⬍50/␮l at enrollment, the rate was 0.16/PY, whereas for those with counts of ⬎200/␮l it was 0.02/PY (P ⫽ 0.007). At the visit before the

Risk factors for RD in either eye are shown as Table 3. The overall rate of RD was 0.06/PY. For patients with newly diagnosed CMV retinitis, the rate was 0.19/PY, whereas for those with previously diagnosed and long-standing retinitis it was 0.04/PY (P⬍0.0001). As a general health measure, a lower hemoglobin level was associated with a greater rate of RD. CD4⫹ T-cell counts at enrollment and at the visit before the event both were associated with the risk of RD. For patients with a CD4⫹ T-cell count at enrollment of ⬍50/␮l, the rate was 0.14/PY, whereas for those with a count of ⱖ200/␮l the rate was 0.02/PY (P ⫽ 0.004). An analysis at the visit before the event revealed that the rate was 0.30/PY for patients with a CD4⫹ T-cell count of ⬍50/␮l, whereas it was 0.02/PY for those with a count of ⱖ200/␮l (P⬍0.0001). Human immunodeficiency virus load and CMV load at both enrollment and the visit before the event were associated with the risk of RD. For a CMV load of ⬍400 copies/ml at enrollment, the rate was 0.05/PY, whereas for a CMV load of ⱖ400 copies/ml it was 0.22/PY (P ⫽ 0.003); for a CMV load of ⬍400 copies/ml at the visit before the event, the rate was 0.05/PY, whereas for a CMV load of ⱖ400 copies/ml it was 0.60/PY (P⬍0.0001).

Table 2. Multiple Regression of Risk Factors for Other Outcomes of Cytomegalovirus (CMV) Retinitis Contralateral Eye CMV Risk Factor CD4⫹ T-cells at visit before event (/␮l) ⬍50 50–99 100–199 ⱖ200 (reference) CMV load at enrollment (copies/ml) ⱖ400 ⬍400 (reference) Area of retina affected by CMV retinitis ⱖ25% ⬍25% (reference)

RR

95% CI

13.7 1.8 2.3 1.0

4.6–40.7 0.2–15.3 0.5–11.5

5.3 1.0

1.8–15.9

Retinal Detachment P Value

RR

95% CI

15.7 3.9 3.3 1.0

6.0–41.2 0.8–19.6 0.9–11.7

2.6 1.0

1.3–5.3

⬍0.0001

P Value ⬍0.0001

0.003 0.007

CI ⫽ confidence interval; RR ⫽ relative risk.

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Ophthalmology Volume 111, Number 12, December 2004 Table 3. Risk Factors for Retinal Detachment in Patients with Cytomegalovirus (CMV) Retinitis Risk Factor

Rate (/PY)

Overall rate of retinal detachment Retinitis status at enrollment Newly diagnosed Long-standing Age (yrs) ⬍41 ⱖ41 Gender Male Female Race White Nonwhite Risk factor for HIV infection Men having sex with men Other Date of enrollment August 1998–July 1999 August 1999–July 2000 August 2000–July 2001 August 2001–July 2003 Time since AIDS diagnosis at enrollment (yrs) 0–3.0 3.1–6.0 6.1–9.0 ⬎9.0 Bilateral CMV retinitis at enrollment No Yes Area of CMV retinitis ⱖ25% of retinal area in either eye at enrollment No Yes Visceral CMV at enrollment No Yes Karnofsky score at enrollment 90–100 ⱕ80 Hemoglobin (g/dl) at enrollment ⬍10 10–13 ⬎13 Antiretroviral therapy at enrollment HAART No HAART Immune recovery* No Yes Anti-CMV therapy at enrollment Ganciclovir implant Intravitreous injections Systemic ganciclovir† Other‡ None CD4⫹ T-cell count at enrollment (/␮l) 0–49 50–99 100–199 ⱖ200 CD4⫹ T-cell count at visit before event (/␮L) 0–49 50–99 100–199 ⱖ200 HIV viral load at enrollment (copies/ml) ⬍400 400–10 000 10 001–100 000 ⬎100 000

n/N

0.06

33/263

0.19 0.04

16/60 17/199

0.06 0.05

18/130 14/131

0.05 0.10

23/211 9/50

0.06 0.05

18/138 14/123

0.05 0.07

17/165 14/93

0.04 0.05 0.12 0.16

13/117 7/65 8/41 5/40

0.05 0.06 0.05 0.11

9/75 14/111 5/52 4/22

0.06 0.06

19/158 14/105

0.05 0.07

16/159 17/104

0.06 0.05

28/222 4/39

0.05 0.07

12/100 20/158

0.12 0.09 0.03

8/43 17/103 8/117

0.06 0.07

26/206 7/55

0.12 0.02

24/123 8/134

0.05 0.14 0.10 0.03 0.06

10/92 2/10 8/47 2/22 11/90

0.14 0.09 0.03 0.02

19/90 5/31 4/48 5/93

0.30 0.07 0.06 0.02

21/74 2/20 4/30 6/139

0.02 0.02 0.10 0.18

6/96 2/40 9/50 14/60

P Value ⬍0.0001 0.45 0.14 0.74 0.29 0.32

0.72

0.80 0.16 0.88 0.59 0.01

0.77 0.0005 0.66

0.004

⬍0.0001

0.001

(continues)

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Jabs et al 䡠 Cytomegalovirus Retinitis Course in the HAART Era Table 3. (Continued.) Risk Factor HIV load at visit before event (copies/ml) ⬍400 400–10 000 10 001–100 000 ⬎100 000 CMV load at enrollment (copies/ml) ⬍400 ⱖ400 CMV load at visit before event (copies/ml) ⬍400 ⱖ400

Rate (/PY)

n/N

0.01 0.04 0.10 0.24

5/124 3/31 8/45 15/59

0.05 0.22

26/231 7/23

0.05 0.60

27/242 6/17

P Value ⬍0.0001

0.003 ⬍0.0001

HAART ⫽ highly active antiretroviral therapy; HIV ⫽ human immunodeficiency virus; n/N ⫽ no. of events/no. at risk; PY ⫽ person-year. *Increase in CD4⫹ T-cells from nadir by ⱖ50 cells/␮l to a level of ⱖ100 cells/␮l. † IV or oral ganciclovir or valganciclovir. ‡ Foscarnet or cidofovir.

In the multivariate analysis of RD (Table 2), CD4⫹ T-cell count and area of retinitis affected by CMV were associated with RDs. For those with a CD4⫹ T-cell count of ⬍50/␮l, the relative risk for a detachment was 15.7, compared with those with a count of ⱖ200/␮l (P⬍0.0001). Large CMV lesions (affecting ⱖ25% of the retinal area) had a relative risk of RD of 2.6 (P ⫽ 0.007).

Discussion Cytomegalovirus retinitis is a common opportunistic infection among patients with AIDS,9 affecting an estimated 30% of patients with AIDS before their deaths in the preHAART era.12 Although the incidence of CMV retinitis has been reduced by an estimated 75% by the introduction of HAART,1,13–15 it remains among the most common opportunistic infections among patients with AIDS. As such, information on the behavior of CMV retinitis in the HAART era is important. Large AIDS ophthalmology clinics typically follow 2 types of patients with CMV retinitis: (1) those who have previously diagnosed and long-standing retinitis, often have experienced immune recovery as a consequence of HAART, and may have had anti-CMV therapy discontinued after immune reconstitution and (2) those who have newly diagnosed retinitis, typically have not responded to HAART, and will need long-term anti-CMV therapy.29 Information on the course of CMV retinitis must evaluate these 2 types of patients, as well as the effects of HAART and immune recovery. The rate of contralateral ocular involvement among patients with unilateral retinitis enrolled in the Longitudinal Studies of the Ocular Complications of AIDS was 0.07/PY. This rate is low relative to that seen in the pre-HAART era (⬃0.40/PY),21,22,33,38,39 which is, at least in part, due to the occurrence of immune reconstitution. The primary risk factor for contralateral eye involvement in patients with unilateral disease was a low CD4⫹ T-cell count, and among patients with CD4⫹ T-cell counts of ⬍50/␮l, the rate of contralateral eye involvement (0.34/PY) was similar to that among patients on systemic anti-CMV therapy in the preHAART era (⬃0.40/PY). Cytomegalovirus load also was

associated with the occurrence of contralateral eye disease, but it was a poor predictor, with a relatively low sensitivity and positive predictive value. Because CMV retinitis occurs via hematogenous dissemination to the eye,38,40,41 CMV load might have been a reasonable predictor of the occurrence of contralateral eye disease. However, in the era of HAART, it does not seem to be a particularly powerful predictor of the occurrence of contralateral eye disease. In the era before HAART, systemic anti-CMV therapy reduced the risk of contralateral eye involvement from approximately 50% at 6 months to approximately 20%.21,39,42 However, among patients on HAART, immune benefits reduce the risk of contralateral eye involvement, and the benefit of systemic anti-CMV therapy for contralateral eye involvement is no longer apparent. A similar result was observed in a clinical trial of oral ganciclovir combined with the ganciclovir implant.42 Nevertheless, despite the success of immune reconstitution at reducing the risk of second eye disease, it did not eliminate it, as the rate among patients with CD4⫹ T-cell counts of ⱖ200/␮l still was 0.02/PY. In the era before HAART, rates of RD in patients with CMV retinitis were approximately 0.50/PY for the occurrence of RD in either eye of a patient with retinitis and 0.33/PY for the occurrence of a detachment in an eye with CMV retinitis.9,22,27 The rate of RDs among our patients was reduced, with an observed rate of 0.06/PY. The rate was higher among patients with newly diagnosed retinitis (0.19/ PY), but still below that seen in the pre-HAART era. Even among patients with low CD4⫹ T-cell counts, the rate of RD remained lower than that seen in the pre-HAART era, although when the CD4⫹ T-cell count before the event was evaluated, those with CD4⫹ T-cell counts of ⬍50/␮l had a rate of 0.30/PY, a rate more similar to that seen in the pre-HAART era. Risk factors for RDs included a lower CD4⫹ T-cell count and larger CMV retinitis lesions. Work from the pre-HAART era also suggested that CMV lesion size was a risk factor for RD.9,22,27,28 In a cohort of patients spanning both the pre-HAART and HAART eras from The Johns Hopkins Medical Institutions, a substantially reduced rate of RDs among patients on HAART also was ob-

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Ophthalmology Volume 111, Number 12, December 2004 served.28 Despite the success of immune reconstitution at decreasing the rate of RD, it did not eliminate detachments, as evidenced by the detachment rate of 0.02/PY among patients with CD4⫹ T-cell counts of ⱖ200/␮l. Given the lower rate of RDs, some clinicians have repaired CMV retinitis–related RDs with approaches other than those using silicone oil (e.g., with vitrectomy and intraocular gas) and, in selected cases, have removed the silicone oil.43 Whether or not this approach will be as successful as silicone oil was in the pre-HAART era remains to be determined. In conclusion, our data suggest that in the HAART era the rates of contralateral eye involvement and RD are reduced from those seen in the pre-HAART era. This result largely is due to the occurrence of immune reconstitution, which can result in control of the retinitis without use of specific anti-CMV therapy. Among groups with immunologic function comparable to that seen in the pre-HAART era, as evidenced by low CD4⫹ T-cell counts, the rates of second eye involvement and RD seem to be more similar to those seen in the pre-HAART era. However, among those patients with immune reconstitution and CD4⫹ T-cell counts of ⱖ200/␮l, contralateral eye disease and RD occurred, suggesting the need for ongoing regular ophthalmologic examinations to detect these events. Our guideline has been to continue to see those patients with CMV retinitis and immune reconstitution (CD4⫹ T-cell counts of ⱖ100/ ␮l) for a dilated ophthalmologic examination every 3 months. Given the rates of ocular complications among patients with immune reconstitution, this guideline seems reasonable.

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