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Retinal Detachment Risk in Cytomegalovirus Retinitis Related to the Acquired Immunodeficiency Syndrome
John H. Kempen, MD, MPH, MHS;
Douglas A. Jabs, MD, MS;
James P. Dunn, MD;
Sheila K. West, PhD;
James Tonascia, PhD
Arch Ophthalmol. 2001;119:33-40.
ABSTRACT
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Objectives To compare the incidence of retinal detachment in patients treated with
the ganciclovir implant compared with those treated using systemic therapy
only, among 511 patients with the acquired immunodeficiency syndrome (AIDS)
and cytomegalovirus (CMV) retinitis and to describe the influence of highly
active antiretroviral therapy (HAART) on retinal detachment incidence.
Patients and Methods All patients with AIDS and CMV retinitis at 1 center were followed up
prospectively from CMV retinitis diagnosis for incidence of retinal detachment.
Patient- and eye-specific data regarding demographic and clinical characteristics
were collected at the time of CMV retinitis diagnosis. Use of anti-CMV and
antiretroviral treatments and the development of an immunologic response to
HAART during follow-up were recorded.
Results No significant difference in the rate of retinal detachment was found
between eyes treated with systemic therapy only and those treated with ganciclovir
implants, whether used as primary therapy or subsequent to using systemic
anti-CMV therapy. The use of HAART was associated with a 60% reduction in
retinal detachment rate (P<.001), with the greatest
benefit observed among patients who developed an immunologic response to HAART.
Conclusions Our results suggest that there is no substantial excess risk of retinal
detachment when patients with AIDS and CMV retinitis are treated with ganciclovir
implants as opposed to systemic anti-CMV therapy only. However, the use of
HAART in these patients appears to reduce the risk of retinal detachment substantially.
INTRODUCTION
CYTOMEGALOVIRUS (CMV) disease is one of the most common opportunistic
complications of the acquired immunodeficiency syndrome (AIDS).1
In 71% to 85% of cases, it presents as retinitis.2-3
Prior to the availability of highly active antiretroviral therapy (HAART),
estimates of CMV retinitis incidence rates among patients with AIDS ranged
from 24.8% to 44.9%.1, 3-5
Vision loss is common in patients with AIDS and CMV retinitis.6
Most vision loss results from either progressive retinal necrosis caused by
CMV replication or from retinal detachment. Retinal detachment is a common
complication of CMV retinitis, with a reported incidence rate of approximately
50% per patient per year or 33% per eye per year.6-8
The ganciclovir implant is a surgically implanted reservoir of ganciclovir
that provides higher intraocular levels of drug than systemically administered
ganciclovir9 and longer-lasting control of
retinitis.10-11 One question has
been whether the use of ganciclovir implant therapy alters the rate of retinal
detachment in eyes with CMV retinitis, possibly increasing risk because of
surgical disturbance of the posterior segment or perhaps decreasing risk because
of improved control of retinitis.
The introduction of HAART has reduced the incidence of CMV retinitis.12 In some patients with CMV retinitis, HAART restores
sufficient immunity to suppress retinitis without specific anti-CMV therapy.
After confirmation that an immunologic response to HAART has occurred, these
patients may safely discontinue specific anti-CMV therapy.13-16
In this study, we evaluated the effects of ganciclovir implant therapy
and of HAART on the incidence of retinal detachment in a large, prospectively
followed cohort of patients with AIDS and CMV retinitis. Although initially
we were interested in the effect of ganciclovir implant therapy, the near
simultaneous introduction of HAART seemed likely to confound the analysis,
leading us to evaluate the effects of both on retinal detachment risk.
PATIENTS AND METHODS
POPULATION
All patients with CMV retinitis and AIDS seen by the Division of Ocular
Immunology at the Wilmer Ophthalmological Institute, Baltimore, Md, were studied,
from the first case on August 8, 1983, through September 1, 1998. Diagnoses
of CMV retinitis were based on the characteristic clinical picture of necrotizing
retinitis seen by indirect ophthalmoscopy through a dilated pupil.5 Diagnoses of AIDS were made according to standard
Centers for Disease Control and Prevention criteria in effect at the time
of each diagnosis.17-21
Each patient's CMV retinitis management strategy was determined by the
best medical judgment of the treating physicians from among the therapeutic
options available at the time of illness. Ganciclovir implants became available
to our population in November 1995. Prior to that date, only systemic therapies
(intravenous ganciclovir sodium,22-23
foscarnet sodium,23-24 and/or
cidofovir25-26) were used for
primary management, except for 3 eyes (of 3 patients), which received implants
under study protocols in 1993.
When available at the time of the patient's illness, antiretroviral
therapy and prophylaxis against specific opportunistic infections were used
according to the best medical judgment of treating physicians. HAART, defined as combination antiretroviral therapy including a protease
inhibitor and/or nonnucleoside reverse transcriptase inhibitor, has been widely
used in our population since early 1996. Prophylaxis for Pneumocystis carinii became widely used in our population in 1990,
whereas prophylaxis for Mycobacterium avium complex
infections became widely used in 1996.
DATA COLLECTION
A computerized database was kept prospectively for all patients with
CMV retinitis seen at our center. Demographic data collected included age
at the time of CMV retinitis diagnosis, race, gender, and risk factor(s) for
human immunodeficiency virus infection. Data regarding clinical status at
the time of CMV retinitis diagnosis included the date of diagnosis (for each
affected eye), current absolute CD4+ T-lymphocyte count (when available),
location of the CMV lesion(s), and lesion size. Location was characterized
according to whether each of the following zones was involved: zone 1, which
includes the area within 3000 µm of the foveal center plus the area
within 1500 µm of the optic disc; zone 2, which extends from zone 1
to the equator; and zone 3, anterior to the equator.5, 27
Lesion size was classified as involving "24% or less" or "25% or more" of
the retina.5
Follow-up data regarding treatment and outcomes were collected over
time, including the date at which each specific anti-CMV therapy was initiated,
dates of all surgerical procedures, and date of most recent visit. Date(s)
of retinal detachment diagnosis by ophthalmoscopy or ultrasonography was also
recorded.
Ganciclovir implant placement was performed using standard surgical
techniques.9 The anti-CMV treatment status
of each eye was classified into 1 of 3 categories: (1) systemic anti-CMV therapy
only, with no ganciclovir implant surgery ever performed; (2) primary implant,
placed within 30 days after diagnosis of CMV retinitis in the ipsilateral
eye; or (3) secondary implant, placed more than 30 days after diagnosis of
CMV retinitis in the ipsilateral eye. In the primary implant group, none received
treatment with intravenous therapy prior to implantation. In the secondary
implant group, all but 2 eyes of 2 patients received systemic treatment prior
to ganciclovir implant therapy. Two other eyes developed retinal detachment
during treatment with systemic therapy and subsequently received a ganciclovir
implant more than 30 days after CMV retinitis diagnosis. Because these eyes
developed retinal detachment prior to ganciclovir implant exposure, they were
included with the systemic therapy group, censoring follow-up at the time
of retinal detachment occurrence.
Patients were considered as treated with HAART if at any visit they
were taking combination antiretroviral therapy including a protease inhibitor
and/or a nonnucleoside reverse transcriptase inhibitor. Those receiving HAART
were further classified as "HAART responders" if an immunologic response was
observed during follow-up; otherwise, they were classified as "HAART nonresponders."
For the purposes of this analysis, a HAART response
was defined as an increase in CD4+ T-lymphocyte count by 50 or
more cells/µL above the level at the time of CMV retinitis diagnosis
to an absolute level of at least 100 cells/µL.
The data set was closed September 1, 1998. Logical inconsistencies and
outliers were investigated and adjudicated based on chart review. Missing
data were investigated by chart review and entered into the data set unless
unavailable.
STATISTICAL ANALYSIS
Demographic and clinical characteristics at the time of CMV retinitis
diagnosis were compared among subgroups by calculating odds ratios (ORs) and
applying the  2 test or Fisher exact test when expected counts
in a category were less than 5. Direct comparisons of time to retinal detachment
by demographic and clinical characteristics were performed by constructing
Kaplan-Meier curves and applying the log-rank test.28
For each characteristic, risk ratios with 95% confidence intervals were generated
using the Cox proportional hazards model,28
using indicator variables when necessary to make pairwise comparisons. Cox
models were also used for multiple regression analyses of time to retinal
detachment. Final multiple regression models were generated by sequentially
removing demographic and clinical characteristic variables found not to be
significantly associated with retinal detachment by likelihood ratio testing.
Robust variance estimation and methods to adjust for correlation between eyes
of the same patient were used for all Cox models.29
STATA 5.0 software30 was used to perform statistical
analyses.
Eyes receiving ganciclovir implants more than 30 days after diagnosis
of CMV retinitis were not included in the secondary implant group if retinal
detachment occurred prior to implant placement. Therefore, the risk of retinal
detachment for this group was calculated from the time of implant placement.
For all other factors and for the systemic therapy and primary implant groups,
the reported retinal detachment risk was calculated from the time of CMV retinitis
diagnosis. As a result, 2 different follow-up time denominators were used
for risk calculations, making it necessary to create 2 Cox models for calculation
of adjusted risk ratios. The "from implant" model excludes the time between
CMV retinitis diagnosis and ganciclovir implant placement in the secondary
implant group, providing the best means of assessing the adjusted risk ratio
for the secondary implant group with respect to the systemic therapy group.
The "from diagnosis" model includes all follow-up time in all groups for optimal
calculation of all other adjusted risk ratios.
To address the question of whether retinal detachment risk was increased
in ganciclovir implant groups during early follow-up (corresponding to the
early postoperative period for the implant groups), the "from implant" analysis
was repeated, censoring follow-up time at 60 days. The "from implant" analysis
was also repeated, pooling implant groups, to give a comparison of overall
ganciclovir implant treatment with respect to systemic therapy only.
SENSITIVITY ANALYSES
To assess whether inclusion of eyes managed prior to the availability
of ganciclovir implants and HAART altered results, risk was compared in eyes
that received systemic anti-CMV therapy diagnosed with retinitis before vs
after the availability of the ganciclovir implant, and in patients who did
not receive HAART diagnosed before vs after the availability of HAART. Additional
sensitivity analyses were conducted to determine whether classifying ganciclovir
implant status and follow-up time differently would alter results: (1) the
primary implant group was compared with the other groups combined (censoring
follow-up of the secondary implant group at the time of initial implant surgery);
and (2) all implant eyes were compared with all nonimplant eyes, with follow-up
time beginning at CMV retinitis diagnosis. To confirm that analysis by eye
(adjusting for increased correlation between eyes of the same patient) rather
than by patient did not alter results, the 2 sensitivity analyses as well
as the "from diagnosis" and the "from implant" analyses were repeated using
patients rather than eyes as the unit of observation.
RESULTS
COHORT
A total of 591 consecutive patients with AIDS who had CMV retinitis
affecting 911 eyes were evaluated at our center as of September 1, 1998. Of
these, 48 patients (69 eyes) never returned for follow-up. Nine other patients
had follow-up visits after diagnosis of CMV retinitis in their first eye,
but no follow-up after subsequent diagnosis in the second eye (9 eyes). Twenty-four
patients (33 eyes) did not receive specific anti-CMV therapy, either because
no such therapy existed at the time of their illness or by choice. For 5 patients,
the date of subsequent CMV retinitis diagnosis in the second eye was missing
(5 eyes). Eight patients had retinal detachment already present at the time
of CMV retinitis diagnosis in their only affected eye (8 eyes), while 14 patients
already had retinal detachment in 1 of 2 affected eyes by the time of CMV
retinitis diagnosis (14 eyes) but remained at risk for detachment in the second
eye. A final cohort of 773 eyes of 511 patients for analyses of time to retinal
detachment with the eye as the unit of observation (90.3% of treated eyes
at risk of retinal detachment) remained. For analyses of time to retinal detachment
with the patient as the unit of observation, 497 patients were at risk of
a first retinal detachment (not including the 14 with unilateral detachment
already present at the time of diagnosis, who were no longer at risk).
Comparing the demographic and clinical characteristics listed in Table 1 of the final cohort vs the groups
of patients with no follow-up, with no treatment, and with preexisting retinal
detachment, the only significant difference was seen in patients without follow-up
who were more likely to have an initial CD4+ T-lymphocyte count
less than 12 cells/µL (OR, 4.5; P = .01). Comparing
the eye-specific clinical characteristics listed in Table 1, the only significant difference between any of these groups
and the final cohort was that eyes with preexisting retinal detachment were
more likely to have lesions involving 25% or more of the retina (OR, 6.0; P<.001).
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Table 1. Association of Demographic and Clinical Characteristics With
Mode of Anti-CMV Therapy*
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DEMOGRAPHIC AND CLINICAL CHARACTERISTICS
Patient-specific demographic and clinical characteristics did not significantly
differ between the systemic therapy, primary implant, and secondary implant
groups, except that eyes of patients who received HAART were much more likely
to receive primary (OR, 30.3; P<.001) and secondary
(OR, 30.3; P<.001) implants than systemic anti-CMV
therapy (Table 1). Comparing eye-specific
clinical characteristics, the lesion size at the time of retinitis diagnosis
was similar in all anti-CMV treatment groups (data not shown). However, by
the time of initial implant surgery, secondary implant eyes had become significantly
more likely to have larger lesions than the other groups (P = .008). The lesion location distribution did not differ between
anti-CMV treatment groups (P = .35). Except for higher
usage of implants in eyes of patients who received HAART (see above), neither
patient- nor eye-specific characteristics differed significantly between HAART
groups (data not shown).
Fifty eyes (of 35 patients) in the primary implant group underwent 76
implant surgerical procedures. Of these, 31 received 1 implant, 13 received
2, 5 received 3, and 1 eye received 4 during follow-up. Forty-nine secondary
implant eyes (of 39 patients) underwent 71 implant procedures, with 32, 12,
and 5 eyes having 1, 2, and 3 implants, respectively. The median time from
CMV retinitis diagnosis to initial implant surgery was 10 days for the primary
implant group (range, 1-27 days) and 218 days (range, 33-1244 days) for the
secondary implant group. Median follow-up time was similar for the systemic
therapy (0.42 year) and primary implant (0.52 year) groups. For the secondary
implant group, distribution of follow-up time was also similar when started
from the time of initial implant surgery (median, 0.49 year), but substantially
longer when started from the date of CMV retinitis diagnosis (median, 1.26
year).
Seventy-seven patients with a total of 116 eyes affected by CMV retinitis
were treated with HAART. Thirty-one of these patients (45 eyes) were observed
to have an immunologic response to HAART (as defined previously). The median
follow-up time was longer for patients receiving HAART (0.81 year) than patients
who did not receive it (0.41 year), primarily because of increased survival
in the HAART responder subgroup.
RETINAL DETACHMENT
Among the 773 eyes followed for the incidence of retinal detachment,
177 retinal detachments were observed (23%). The estimated median time to
retinal detachment for all eyes was 1.96 years. The retinal detachment rates
associated with patient- and eye-specific demographic and clinical characteristics
are presented in Table 2 and Table 3, respectively. The final Cox multiple
regression models for time to retinal detachment by eye are given in Table 4.
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Table 2. Incidence of Retinal Detachment (RD) by Patient-Specific Demographic
and Clinical Characteristics*
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Table 3. Association of Eye-Specific Clinical Characteristics With
Retinal Detachment (RD)*
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Table 4. Adjusted Relative Hazard for Retinal Detachment*
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Among eyes in the primary implant group, the retinal detachment rate
was two thirds that observed with systemic therapy (relative hazard [RH],
0.64; P = .25; Figure
1), but adjustment for other variables brought the risk ratio close
to unity (RH, 1.12; P = .79). In the secondary implant
group, with time-at-risk starting from date of first implant placement, the
retinal detachment rate was three quarters of that observed in the systemic
therapy group (RH, 0.76; P = .46), with the risk
ratio also close to unity after adjusting for other variables (RH, 1.06; P = .88). The apparent difference between simple and adjusted
risk ratios was primarily due to higher utilization of HAART in patients whose
eyes received implants. The adjusted overall comparison for either kind of
ganciclovir implant treatment vs systemic therapy showed no significant difference
in risk (RH, 1.09; P = .77). However, CMV lesions
involving zone 3 (RH, 1.80; P = .03 [adjusted RH,
1.77; P = .047]), and lesions involving greater than
25% of the retina (RH, 1.37; P = .048 [adjusted RH,
1.46; P = .03]) were associated with increased risk
of retinal detachment.
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Figure 1. Mode of anticytomegalovirus therapy
and retinal detachment. Kaplan-Meier curves are given depicting the proportion
of eyes without retinal detachment over time by anticytomegalovirus treatment
group. There is no significant difference among the 3 groups.
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Patients treated with HAART were substantially less likely to develop
retinal detachment than patients who did not receive HAART (RH, 0.40; P = .003; Figure 2).
Subset analysis demonstrated that patients observed to have an immunologic
response to HAART had less than one third the retinal detachment rate of patients
who did not receive HAART (RH, 0.30; P = .006; Figure 3). This effect remained statistically
significant after adjustment for other variables (adjusted RH, 0.36; P = .02). The subset receiving HAART but not observed to
have an immunologic response had a retinal detachment rate half that of the
group that did not receive HAART (RH, 0.52; P = .048);
however, this difference became less marked and statistically nonsignificant
after adjusting for other variables (adjusted RH, 0.65; P = .29). Patients with bilateral disease were also more likely to
have 1 or more retinal detachments than patients with unilateral disease (RH,
1.78; P<.003 [adjusted RH, 1.62; P = .01]). However, the individual eyes of these patients were not
observed to have significantly higher risk of retinal detachment than affected
eyes of patients with unilateral retinitis (adjusted RH, 1.28; P = .20).
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Figure 2. Highly active antiretroviral therapy
(HAART) and retinal detachment. Kaplan-Meier curves are given showing the
proportion of eyes without retinal detachment by treatment with HAART. Eyes
of patients who received HAART were significantly less likely to develop retinal
detachment (log-rank, P<.001).
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Figure 3. Response to highly active antiretroviral
therapy (HAART) and retinal detachment. Kaplan-Meier curves are given showing
the proportion of eyes without retinal detachment by treatment with and response
to HAART, demonstrating that the greatest benefit from HAART was observed
in eyes of patients who developed an immunologic response.
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Final Cox multiple regression models (Table 4) are reported both "from implant" (for comparing the secondary
implant vs systemic therapy groups) and "from diagnosis" (for all other comparisons)
(see definitions in the "Statistical Analysis" section). Although older age7 and CD4+ T-lymphocyte count7
previously have been reported as significantly associated with retinal detachment
risk in CMV retinitis, significant associations were not observed in our population.
A trend toward lower retinal detachment rates in nonwhite vs white subjects
was observed in our population, but was not statistically significant. Inclusion
or noninclusion of these 3 variables in the final models did not substantially
alter other associations, so they were omitted.
Results of the sensitivity analyses performed showed no important differences
from the results reported above. In particular, among eyes treated with systemic
therapy only, there was no significant difference in risk between those diagnosed
with retinitis before vs after ganciclovir implants became available (adjusted
RH, 0.77; P = .53). Neither was there a significant
difference among patients who did not receive HAART diagnosed before vs after
HAART became available (adjusted RH, 1.36; P = .54).
Inclusion in the multiple regression model of an indicator variable for whether
CMV retinitis diagnosis was made prior to or after ganciclovir implants or
HAART became available did not alter other associations. Comparison of retinal
detachment risk in the pooled implant groups to the systemic therapy group,
censoring follow-up after 60 days, showed no significant increase in retinal
detachment risk during the early postoperative period (RH, 1.29; P = .39).
COMMENT
Nonrandomized studies of treatment outcomes, while having the advantage
of being able to study a more "real world" population than will typically
enroll in a randomized clinical trial, lack design features to control selection
bias. Our primary results were robust to sensitivity analysis exploring this
and other issues. We also adjusted for the potentially confounding effects
of known risk factors for retinal detachment present at the time of CMV retinitis
diagnosis to account for differences between groups in pretreatment retinal
detachment risk. Nevertheless, interpretation of our results must bear in
mind concern about potential selection bias. Although studies at tertiary
care facilities such as ours can be subject to referral biases, we estimate
that our center provides ophthalmological care for more than 80% of all patients
with AIDS and CMV retinitis in our metropolitan area. The demographic makeup
of our cohort includes relatively large numbers of African American and female
patients, and of patients who had used intravenous drugs, reflecting the distribution
of risk factors among patients with advanced AIDS in Baltimore. We were able
to follow up a high percentage of treated patients with CMV retinitis at risk
for retinal detachment. Follow-up over time was relatively successful, with
the date of death known or a follow-up visit having occurred within 30 days
of the closing date for 87% of patients in the cohort.
We found no substantial difference in retinal detachment risk for the
eyes with CMV retinitis treated using ganciclovir implants (whether as initial
or secondary treatment) compared with systemic therapy only. This result agrees
with the retinal detachment results of previous large-scale clinical trials.10-11 Indeed, the unpublished Kaplan-Meier
curves for observed time to retinal detachment in the Roche Ganciclovir Study
Group31 and the Ganciclovir Implant Study Group32 trials bear a striking similarity to that from our
study (Figure 1), including the
slight dip observed in the early postoperative period for implant-treated
eyes. This transient early increase did not approach statistical significance.
These results suggest that placement of a ganciclovir implant into the posterior
segment using standard surgical techniques does not substantially increase
retinal detachment risk in eyes with CMV retinitis. Whether this conclusion
can be generalized to eyes with other disease processes amenable to treatment
using implantable reservoirs of medication remains to be seen.
We also found that use of HAART was associated with a 60% reduction
of retinal detachment risk in eyes of patients with CMV retinitis. Use of
HAART had the greatest effect on risk of retinal detachment of all variables
evaluated, larger than that associated with well-established risk factors
such as large lesion size6, 8, 25
and anterior lesion location.8, 27
Because not all patients treated with HAART received HAART throughout follow-up,
the extent of benefit may be underestimated. The greatest reduction in risk
was found in patients with observed immune recovery, suggesting that the benefit
may be conferred by improved immunity.
Several mechanisms may explain the reduced risk of retinal detachment
in eyes of patients with AIDS and CMV retinitis treated with HAART. HAART
has been reported to affect the clinical course of CMV retinitis, in that
patients who develop immune recovery usually regain the ability to suppress
retinitis progression without specific anti-CMV therapy.13-15
Therefore, it seems reasonable that the reduced risk of retinal detachment
in eyes of our patients who received HAART was the result of improved immune
control over CMV replication, which more successfully suppressed retinitis
activity, preventing progression to larger lesion sizes. Both current activity
of retinitis6 and larger lesion size6, 8, 25 are known risk factors
for retinal detachment in patients with AIDS and CMV retinitis. Another protective
factor may have been increased inflammatory activity within the retina of
patients treated with HAART. It has been suggested that such inflammation
may cause a strong adhesion between the retinal pigment epithelium and the
neurosensory retina,33-34 which
may be protective vs retinal detachment. Finally, it has also been suggested
that the attached posterior hyaloid may apply traction on susceptible necrotic
retina in this setting.33-34 Indeed,
Martin et al,35 observed that every retinal
detachment in their implant trial occured concurrently with a posterior vitreous
separation. Perhaps the different pattern of inflammation related to HAART-mediated
immune improvement alters the course of vitreous detachment, changing retinal
detachment risk. Our study is unable to discriminate which of these factors
may have been the primary protective mechanism(s) in our patients with CMV
retinitis who were treated with HAART.
As in prior studies, larger lesion size6, 8, 25
and involvement of the anterior retina near the vitreous base8, 36
were associated with increased risk of retinal detachment. Importantly, neither
of these factors nor use of HAART significantly modified retinal detachment
risk in eyes treated with implants vs systemic therapy only. Therefore, neither
large lesion size nor anterior lesion location seem to be a contraindication
to implant therapy. Higher risk of retinal detachment was observed in patients
with bilateral retinitis, but not in individual eyes of these patients, presumably
because patients with bilateral disease have 2 eyes at high risk rather than
1.
Our study found no statistical or substantial increase in retinal detachment
risk when CMV retinitis was treated with ganciclovir implants compared with
systemic therapy only. However, the use of HAART in patients with AIDS and
CMV retinitis was associated with a substantially lower rate of retinal detachment,
presumably due to improvement of immune competence against CMV.
AUTHOR INFORMATION
Accepted for publication June 16, 2000.
This study was supported in part by grants EY00386 and EY07127 (Dr Kempen)
and EY10268 (Dr Jabs) from the National Eye Institute, National Institutes
of Health, Bethesda, Md.
We thank Alfred Sommer, MD, MHS, for his helpful advice regarding this
manuscript, and Judith Southall for valuable secretarial assistance in its
preparation.
Corresponding author and reprints: John H. Kempen, MD, MPH, MHS,
550 N Broadway, Suite 700, Baltimore, MD 21205 (e-mail: jkempen{at}jhmi.edu).
From the Departments of Ophthalmology (Drs Kempen, Jabs, Dunn, and
West) and Medicine (Dr Jabs), The Johns Hopkins University School of Medicine,
and Departments of Epidemiology (Drs Kempen, West, and Tonascia) and Biostatistics
(Drs Kempen and Tonascia), The Johns Hopkins University School of Hygiene
and Public Health, Baltimore, Md. The authors have no proprietary or financial
interests in the subject matter or materials discussed in this article.
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