University of Southern California Dissertations and Theses

Immune recovery vitritis in AIDS: Incidence, clinical predictors, sequellae, and treatment outcomes

(USC Thesis Other)

Immune recovery vitritis in AIDS: Incidence, clinical predictors, sequellae, and treatment outcomes

PDF

Download

Open document

Flip pages

Download a page range

Download transcript

Copy asset link

Request this asset

Transcript (if available)

Content INFORMATION TO USERS
This manuscript has been reproduced from the microfilm master. UM I
films the text directly from the original or copy submitted. Thus, some
thesis and dissertation copies are in typewriter face, while others may be
from any type of computer printer.
The quality of this reproduction is dependent upon the quality of the
copy submitted. Broken or indistinct print, colored or poor quality
illustrations and photographs, print bleedthrough, substandard margins,
and improper alignment can adversely affect reproduction.
In the unlikely event that the author did not send UMI a complete
manuscript and there are missing pages, these will be noted. Also, if
unauthorized copyright material had to be removed, a note will indicate
the deletion.
Oversize materials (e.g., maps, drawings, charts) are reproduced by
sectioning the original, beginning at the upper left-hand comer and
continuing from left to right in equal sections with small overlaps. Each
original is also photographed in one exposure and is included in reduced
form at the back of the book.
Photographs included in the original manuscript have been reproduced
xerographically in this copy. Higher quality 6” x 9” black and white
photographic prints are available for any photographs or illustrations
appearing in this copy for an additional charge. Contact UMI directly to
order.
UMI
A Bell & Howell Information Company
300 North Zeeb Road, Ann Arbor MI 48106-1346 USA
313/761-4700 800/521-0600
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
IMMUNE RECOVERY VITRITIS IN AIDS:
INCIDENCE, CLINICAL PREDICTORS, SEQUELLAE, AND
TREATMENT OUTCOMES
BY
Chrisandra Lee Shufelt
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(Applied Biometry and Epidemiology)
May 1999
Copyright 1999 Chrisandra Lee Shufelt
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
UMI Number: 1395136
UMI Microform 1395136
Copyright 1999, by UMI Company. All rights reserved.
This microform edition is protected against unauthorized
copying under Title 17, United States Code.
UMI
300 North Zeeb Road
Ann Arbor, MI 48103
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
U N IV ERSITY O F S O U T H E R N C A L IF O R N IA
T H E G R A D U A T E S C H O O L
U N IV E R S IT Y PA R K
LOS A N G E L E S . C A L IF O R N IA 00007
This thesis, written by
Chrisandra Lee Shufelt
under the direction of h& x. Thesis Committee,
and approved by all its members, has been pre
sented to and accepted by the Dean of The
Graduate School, in partial fulfillment of the
requirements for the degree of
Master of Science, Applied Biometry
D a te ..A $ x .i.l„ . 1 3 .* .- l$ 3 3 ._ _
COMM! t h :
Cnatn
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Dedicated to my parents for their love and support.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
ACKNOWLEDGEMENTS
I would like to express my deepest gratitude to my thesis committee:
Dr. Stanley Azen, committee chair, Dr. Wendy Mack and Dr. William Freeman for their
guidance, support, and expert advice.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
CONTENTS
Dedication ii
Acknowledgements iii
List of Tables and Figures v
Abstract vi
1 Introduction 1
2 Background 3
3 Incidence of IRV 5
3.1 Methods ....................................................................................... 5
3.2 Results........................................................................................... 7
4 Clinical Predictors, Sequellae, and Treatment Outcomes 10
4.1 M ethods....................................................................................... 10
4.2 Results........................................................................................... 13
5 Conclusions 22
Reference List 25
iv
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
LIST OF FIGURES AND TAJBLES
Figure 3.1
Figure 3.2
Table 4.1
Table 4.2
Figure 4.1
Table 4.3
The Kaplan-Meier curve for the time to ERV for all patients
The Kaplan-Meier curve for more severe ERV for all cohort
patients
Comparison of Clinical Factors Between Patients and Eyes With
and Without IRV
Distribution of CD4 Counts in Patients at Time of IRV Diagnosis
Stratified by Severity of Vitritis and by Occurrence o f Macular
Changes
The Kaplan-Meier curve for the time to macular changes for all
ERV patients
Visual Acuity Scores (logMar) for Eyes with ERV with Visual
Acuity loss Stratified by Treatment Status with Repository
Corticosteroids
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
ABSTRACT
Immune recovery vitritis (IRV) is a new syndrome of intraocular inflammation which
causes vision loss in patients with AIDS and cytomegalovirus (CMV) retinitis who
respond to highly active antiretroviral therapy (HAART). In this thesis, we present the
incidence, clinical predictors, clinical sequellae, and the effect of treatment on ERV in a
cohort of patients who responded to HAART and had CD4 levels of at least 60
cells/mm3. After 13.5 months of follow-up, 19 (59%) of 30 HAART responders
developed ERV (26 eyes). The annual incidence rate of ERV was 83 per 100 person-years.
Eyes with CMV surface area > 30% of the retina were at the highest risk (RR = 4.5) of
developing ERV (p = 0.03). ERV eyes responded favorably to anti-inflammatory therapy
without reactivation of retinitis. We concluded that symptomatic ERV develops in a
significant number of patients with CMV retinitis following successful HAART.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
1: INTRODUCTION
Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic
infection associated with AIDS, and the leading cause o f blindness among this patient
population. It is a progressive necrotizing retinitis that develops in severely
immunocompromised patients with CD4 T-lymphocyte counts usually less than 50
1,2
cells/mm. ’ Following the introduction o f combination antiretroviral treatment
including protease inhibitors in the treatment of AIDS, many patients with HTV disease
have shown laboratory and clinical evidence o f improvement of immune function. 1 ’3,4
Laboratory studies have shown evidence o f polyclonal expansion of T-lymphocytes and
improvement in CD4 T-lymphocyte function after t r e a t m e n t . ^
Highly active anti-retroviral treatment (HAART) has affected the incidence,
severity and clinical course of CMV retinitis. The incidence of AIDS-related CMV
retinitis has decreased since the introduction of HAART.^ Others have suggested that
CMV retinitis is more easily controlled with anti-CMV therapy in patients who respond
to protease inhibitors.8
The HAART-mediated improvement of immune function in AIDS patients may
also alter the way the eye responds to CMV, resulting in a change in the clinical
manifestations of ocular CMV. Prior to the use of protease inhibitors, CMV retinitis was
typically characterized by minimal intraocular inflammation,9 possibly because of the
severe immunodeficiency involved. Since the advent of protease inhibitors,
inflammatory complications have been described in the setting of CMV retinitis. A new
ocular inflammatory syndrome has been described that develops in patients with inactive
1
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
CMV retinitis who have experienced an increase in CD4 T-lymphocyte levels in response
to HAART. 10 This immune recovery vitritis (IRV) manifests symptomatically with a
painless decrease in visual acuity and floaters and is characterized by posterior segment
inflammation, including vitritis, papillitis, and macular changes.
This report analyses data from a long-term study on IRV. In Chapter 2, we
present a background review of findings associated with IRV. In Chapter 3, we present
the methods and the statistical results of an incidence study which determines the
likelihood of developing IRV and evaluates the effect of time on the development of
IRV. In Chapter 4, we present the methods and results evaluating clinical predictors of
ERV, clinical sequaellae, the likelihood of macular changes in IRV eyes, and the effect of
repository corticosteroid treatment on visual acuity. Conclusions follow in Chapter 5.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
2: BACKGROUND
Clinical reports show a decrease in the incidence of CMV retinitis since the
introduction of HAART.^ Some patients who respond to combined antiretroviral
treatment with an increase in CD4 T-lymphocyte levels regain the ability to suppress
cytomegalovirus without specific anti-CMV therapy, thereby providing clinical evidence
of partial immune recovery in these patients. 1 M 2 Not all patients who undergo HAART
maintain high CD4 T-lymphocyte levels and low levels of HTV mRNA, but many
manifest improved immune function.9
In an initial report^ 4.2% of patients with CMV retinitis developed ERV,
suggesting that immune recovery vitritis is a relatively rare occurrence. The initial
reports however were limited by small groups of affected patients, and relatively short
follow-up.
The pathogenesis of IRV is unclear. Evaluation of comparable groups of patients
in the pre-HAART era failed to disclose a similar inflammation. Similarly, ERV did not
occur in patients who had not responded to HAART with elevation of CD4 T-lymphocyte
levels, or in HAART responders without CMV retinitis. These data suggest that an
immune response to CMV antigens in the eye is made possible by HAART-mediated
recovery of immune function.
Subsequent to initial reports, Zegans et a l^ described similar inflammatory
manifestations associated with CMV retinitis and elevated CD4 T-lymphocyte levels as a
result of combined antiretroviral treatment including protease inhibitors. The authors of
this series supported the hypothesis that the inflammatory manifestations reflect an
3
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
improvement in immune status in the affected patients. In contrast to other reports, this
group did not observe macular changes, such as cystoid macular edema, or epiretinal
membranes, but fluorescein angiography was not utilized, and the patient follow-up
period was relatively short.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
3: INCIDENCE OF ERV
3.1 METHODS
3.1.1 Study Cohort. We reviewed the database records o f all patients with CMV retinitis
from December 1996 through April 1998 at the AIDS Ocular Research Unit (AORU) of
the University of California, San Diego, in order to identify "HAART responders".
HAART responders were defined to be patients who demonstrated CD4 counts of at least
60 cells/mm^ as a result of HAART and maintained these CD4 counts for at least two
months. Diagnosis of CMV retinitis prior to HAART and assessment o f activity was
based on the typical ophthalmoscopic appearance^. The rationale for this choice of the
study cohort comes from previously published reports 10,13 ^ we^ as from our
experience with ERV, from which it has become evident that ERV develops in eyes of
patients with a history of CMV retinitis and HAART-mediated increase in CD4 T-
lymphocyte levels.
3.1.2 Determination of IRV. Full ophthalmoscopic examination was performed on all
patients in the study cohort. Visual acuity was assessed with the ETDRS visual acuity
chart. Vitritis was evaluated according to the grading system proposed by N u s s e n b l a t t . 14
Fluorescein angiography was performed on all patients with clinically apparent macular
changes, as well as in patients with vitritis and vision decrease, where macular changes
were not evident on examination. Additionally the levels o f CD4 T-lymphocytes and
HEV mRNA were monitored every two to three months, as indicated. All patients'
medications were reviewed in order to exclude from the IRV cohort those patients who
had received rifabutin or cidofovir within two months of the onset of inflammation.
5
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Patients were diagnosed with IRV if they developed clinically significant
intraocular inflammation in one or both eyes. IRV was defined as vitritis of 1+ or greater
severity which caused visually significant floaters and/or decrease in vision of one or
more lines with or without associated papillitis and macular changes. Patients were
diagnosed with more severe IRV if they had macular fluorescein leakage on fluorescein
angiography, and/or a two line or greater decrease in visual acuity.
3.1.3 Statistical Methods. For each eye that developed IRV, we calculated the time to
development of IRV from the time of response to HAART (i.e. the date of increase of
CD4 count over 60 cells/mm^). For eyes that did not develop IRV, we calculated the
time from response to HAART to the final examination date. For each eye that
developed more severe IRV, we calculated the time to development of more severe IRV
from the date of response to HAART. For eyes that did not develop more severe IRV
(including those eyes diagnosed with less severe IRV), we calculated the time to the final
examination date from the date of response to HAART.
The incidence of ERV (and more severe IRV) was calculated as the ratio of the
number of patients with IRV in at least one eye divided by the patient-years of study.
The probability of developing IRV in at least one eye over time was estimated using
Kaplan-Meier methods. In situations where IRV occurred in only one eye, the time to
diagnosis of ERV was used in the analysis. To accommodate patients with ERV in both
eyes, we used the time to the first diagnosis of ERV. In the situation where both eyes did
not have ERV, the time to last examination was used for the analysis. Similar methods
were used for estimating the probability of developing more severe ERV. In situations
6
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
where more severe ERV developed in one eye but not the other, the eye with more severe
ERV was used in the analysis. Finally, to investigate a possible pro-inflammatory effect
of prior cidofovir therapy, analyses were repeated, excluding those eyes with a history of
local or systemic cidofovir treatment. Statistical comparisons were made using the
Iogrank test for comparing survival curves.
3.2 RESULTS
At the AOREJ, 54 patients with AEDS-related CMV retinitis were examined from
December 1996 through April 1998. Of these, 52 patients with inactive CMV retinitis
received HAART, and 30 patients were characterized as HAART responders. HAART
responders were followed for a median of 13.5 months (range: 3 - 24) following increase
in CD4 count. During the follow-up period, of the 30 patients (44 eyes) who had
responded to EEAART, 19 patients (63%) developed symptomatic ERV in 26 eyes (59%).
Fifteen (50%) IRV patients had more severe ERV in 16 (36 %) eyes. Thirteen (33%) of
the 30 patients, and 18 of the 44 eyes (41%), had a history o f cidofovir therapy.
3.2.1 Likelihood and Time to IRV. The annual incidence rate of ERV for HAART
responders was 83 per 100 person-years (=19/22.9 person-years). The annual incidence
rate for more severe ERV for EEAART responders was 60 per 100 person-years (=15/25.0
person-years).
Figure 3.1 presents the Kaplan-Meier curve for the time to ERV for all patients in
the cohort. The median time to ERV was 43 weeks (95% confidence interval =35-47
weeks). Also shown in the figure is the time to ERV for the 17 patients who had never
received cidofovir. The median event time was also 43 weeks (95% confidence interval
7
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
=26-87 weeks). For the 13 patients with prior cidofovir, the median event time was 44
weeks (not shown). There were no significant differences between the event patterns for
patients with and without cidofovir treatment (p=0.79 by logrank procedure).
Figure 3.1
All
No cidofovir 0.8
>
£ 0.6
e. 0.4
I
0.2
0 20 10 30 40 70 50 60 80
Time (weeks)
Figure 3.2 presents the Kaplan-Meier curve for more severe IRV for all cohort
patients. The median time to more severe IRV was 45 weeks (95% confidence interval =
40-107 weeks). Included in the figure is the time to more severe IRV for patients who
had never received cidofovir. The median event time was also 45 weeks (95%
confidence interval = 26-107 weeks). For patients who had received cidofovir, the
median event time was 57 weeks (not shown). There were no significant differences
between the event patterns for patients with and without cidofovir treatment (p = 0.74 by
the logrank test).
8
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Figure 3.2
— All
No cidofovir
U
o
s
M
0.8
| 0.6
c.
i 0.4
>
0 6
~ 0.2
i m
>
10 20 30 40 50 60 70 80 90 100 0
Time (weeks)
3.2.2 Characteristics of IRV. Symptoms of IRV included decrease in vision and
floaters. All of the 26 affected eyes had vitritis of 1-4+ severity. Nine eyes of 9 patients
developed clinically apparent macular edema, while 8 eyes of 7 patients developed
epiretinal membrane changes.
All IRV patients had inactive CMV retinitis in the affected eye(s) at the time of
diagnosis of vitritis, and were undergoing combination antiretroviral therapy with one or
two reverse transctriptase inhibitors (lamivudine, stavudine, zidovudine) and one or two
protease inhibitors (indinavir, ritonavir, nelfinavir, saquinavir). Consequently, all
patients had experienced an increase in CD4 count (range of increase: 41 to 707, median
increase: 111.5 cells /mm^). The increase in CD4 count preceded the onset of vitritis by
two to 84 weeks (median: 20 weeks)
9
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
4: CLINICAL PREDICTORS, SEQUELLAE,
AND TREATMENT OUTCOMES
4.1 METHODS
4.1.1 Study Cohort (UCSD). We prospectively followed all patients with CMV retinitis
from December 1996 through April 1998 at the AORU of the University of California,
San Diego, in order to identify "HAART responders". HAART responders were defined
to be patients who demonstrated CD4 counts of at least 60 cells/mm^ as a result of
HAART and maintained these CD4 counts for at least two months. This definition was
based on previously published report in which patients who fulfilled these criteria
successfully maintained inactivity of CMV retinitis without specific anti-CMV therapy,
thereby showing clinical evidence of immune recovery.^ Participation was entirely
voluntary, and we received informed consent from all patients.
4.1.2 Clinical Methods and Diagnosis of IRV. Full ophthalmoscopic examination,
including slit lamp biomicroscopy and bilateral indirect ophthalmoscopy was performed
on all patients at each visit. Assessment of visual acuity was based on the ETDRS vision
chart. Diagnosis of CMV retinitis and assessment of activity was based on the typical
ophthalmoscopic appearance 6,15,16 evidence of progression of retinitis borders in
subsequent examinations. This was recorded with retinal drawings and confirmed with
wide-angle (50-60 degree) fundus photographs. Vitreous activity was evaluated
according to the grading system (1+ to 4+) proposed by Nussenblatt. ^ Fluorescein
angiography was performed on all patients with clinically apparent macular edema or
epiretinal membrane, as well as in patients with vitritis and unexplained vision decrease,
10
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
where macular changes were not evident on clinical examination. Additionally, the
levels of CD4-T lymphocytes and HTV mRNA were monitored every two to three
months, as indicated.
Patients were diagnosed with IRV if they developed, clinically significant
intraocular inflammation in the setting of inactive CMV retinitis. We defined this as
vitritis of 1+ or greater severity^ which caused visually significant floaters and/or
decrease in vision of one or more lines, with or without associated papillitis and macular
changes. The primary criterion for IRV diagnosis was the presence of objective clinical
signs of vitreous inflammation (cells, haze). However to exclude possible cases of
residual vitreous debris due to CMV retinitis, we included in the IRV cohort only those
patients with symptomatic onset of vitreous inflammation. Cases of asymptomatic vitritis
were followed, but were not included in the cohort of IRV patients unless they became
symptomatic. All patients' medications were reviewed, to exclude patients who had
received rifabutin or cidofovir 1 ? within two months of the onset of inflammation.
All patients were evaluated regularly at 2 to 4 week intervals and all patient data were
immediately entered into an electronic database. Changes in severity of inflammation,
and visual acuity were recorded. Patients with IRV who developed macular edema on
clinical examination and fluorescein angiography with associated vision decrease were
treated with one or more repository steroid injections. Local or systemic corticosteroids
and non-steroidal anti-inflammatory agents were not utilized. The decision to treat was
made in the interest of the patients, in conjunction with the internist. Treatment results
were monitored with clinical examination and fluorescein angiography as needed, and
11
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
changes in visual acuity and severity o f inflammation were recorded.
4.1.3 Statistical Methods. Cox regression analysis was used to identify clinical
predictors of ERV. Demographic and medical history factors included gender, age, and
length o f time between clinical events (HTV, AIDS and CMV diagnoses, HAART
response). Clinical factors included the retinal area of CMV retinitis (calculated as a
18
percentage of zones 1 and 2 of the retina utilizing retinal drawings and wide-angle
fundus photographs^), concomitant systemic corticosteroid treatment of AIDS-related
disorders unassociated with IRV, and the presence of silicone oil in the vitreous cavity
following trans pars plana vitrectomy for retinal detachment. All o f the above analyses
were conducted on a per-patient basis, except for silicone oil, which was analyzed on a
per-eye basis. Eyes with ERV were grouped according to severity of vitritis (mild = 1+ vs.
moderate = 2-3+). To evaluate the effect of CD4 count on the severity of vitritis, we
compared median CD4 T-lymphocyte levels at the time of ERV diagnosis using Wilcoxon
rank sum tests. For patients with bilateral ERV, the eye with the more severe vitritis was
used in the analysis.
For each eye with ERV, we calculated the time to development of clinically
evident macular changes (CME or ERM) from the time of diagnosis of ERV. The
probability of developing macular changes over time was estimated using Kaplan-Meier
methods. Similar analyses were conducted using CME or ERM as the clinical endpoints.
These analyses were conducted on a per-eye basis. To accommodate patients with
macular changes in both eyes, we used the time to the first diagnosis of a macular change.
For eyes with IRV that did not develop macular changes, we calculated the time from
12
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
IRV diagnosis to the final examination date. To evaluate the effect of CD4 count on the
development of macular changes in patients with ERV, we compared CD4 T-lymphocyte
levels at the time of ERV diagnosis using Student t tests. Similar analyses were
conducted for clinical factors found to be predictive of ERV.
For patients who developed IRV and developed a 2+ line loss in visual acuity
during follow-up, we compared visual acuity outcomes between eyes that were treated
with repository corticosteroid therapy to eyes that were not treated. Eyes with subjective
floaters as the only symptom of IRV were not included in the analysis. We constrated
visual acuity scores (expressed as logMar units) prior to the diagnosis of ERV, at the time
of the visual acuity loss after diagnosis of ERV, and at the final examination. Analyses
utilized analysis of covariance procedures with visual acuity (pre ERV, or at the time of
ERV) as the covariate. For treated patients, we also evaluated the effect of treatment
delay on changes in visual acuity. Analyses utilized independent and paired t-tests.
These analyses were conducted on a per-eye basis.
4.2 RESULTS
4.2.1 Occurrence and Clinical Description of IRV. At the AIDS Ocular Research Unit
of the University of California, San Diego, between December 1996 and April 1998, 54
patients with AIDS- related CMV retinitis were examined, 52 of whom received
HAART. Forty-six of these 52 patients were followed to the end of the study period,
April 1998. Thirty patients responded to HAART with an increase in CD4 T-lymphocyte
levels to 60 cells/mm^ or greater. HAART responders were followed for a median of
21.5 months (range: 6-46) from the first examination date, and for a median of 13.5
13
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
months (range = 3 to 24 months) following increase in CD4 count. Of these 30 patients
(44 eyes), 19 (63%) developed ERV in 26 eyes (59%). Fifteen patients were males and 4
were females; the average age was 40.4 (range = 30 to 63). Three eyes of two patients
had asymptomatic mild vitritis (1+) and were not included in the IRV cohort. Using
Kaplan-Meier methods, the annual incidence rate of ERV for HAART responders was 83
per 100 persons.
Following initiation of HAART, all patients who developed ERV had an increase
in CD4 T-lymphocyte levels (range of increase: 51 to 707 cells/mm^, median increase:
113). HEV rnRNA levels varied from undetectable to 595,316 copies/ml at the onset of
IRV. The onset of IRV occurred two to 84 weeks (median: 20 weeks) following increase
in CD4 T-lymphocyte count. Fourteen patients had discontinued anti-CMV therapy
prior to the diagnosis of ERV, and the remaining five patients, who were receiving oral
ganciclovir, discontinued this therapy within six months following the onset of ERV.^
Retinitis remained inactive in all cases for the duration of the study period. None of these
patients experienced reactivation of CMV retinitis. None of the patients had received
intravitreal or systemic cidofovir within 2 months of the onset of inflammation; none had
received rifabutin prior to IRV onset. Intraocular inflammation manifested as visually
significant floaters (all patients) and painless decrease in visual acuity. A decrease in
vision of one to five lines on the ETDRS chart was noted in 21 ERV eyes, while 5 eyes
had visually significant floaters without a change in visual acuity.
All 26 eyes with ERV had mild to moderate vitritis (1-3+). Of these, 9 eyes in 9
patients had macular edema on clinical examination. Fluorescein angiography revealed
14
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
macular fluorescein leakage consistent with CME, with mild to moderate optic disk
leakage. Eight eyes of 7 patients developed macular changes consistent with ERM.
Fluorescein angiography revealed diffuse leakage of fluorescein in the posterior pole,
with mild optic disk leakage. (Figure 1). O f the 16 eyes which developed macular
changes, three eyes had inactive CMV retinitis involving zone 1 of the retina.
Juxtafoveal inactive CMV retinitis was present in only one of these three eyes.
4.2.2 Clinical Predictors and Factors Associated with IRV. Table 4.1 presents the
relative risk (RR) of developing IRV for demographic and clinical factors. Development
of IRV was not related to gender (p = 0.87), age (p = 0.38), and average time to the
following clinical events: a) HTV or AIDS diagnosis to CMV diagnosis, b) CMV
diagnosis to HAART response, and c) HAART response to the final examination (all p >
0.40). In contrast, eyes with the largest area o f CMV retinitis were at greater risk of
developing IRV. Compared to eyes in the first quartile of CM TV area (< 18% o f the
retina), eyes in the upper quartile (> 30% of the retina) of CMV area had a 4.5-fold
increase in the risk of developing IRV (p = 0.03). Of the two patients (2 eyes) who were
receiving concomitant systemic corticosteroid treatment, none developed IRV (p =
0.13— data not shown in table). Similarly, none of the four eyes (2 patients) with silicone
oil in the vitreous cavity developed clinically evident vitritis or macular changes (p =
0.01—data not shown in table).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Table 4.1: Comparison of Clinical Factors
Between Patients and Eyes With and Without IRV
Per-Patient Characteristic Risk Ratio P-value1
Gender
Male 1.0
Female 1.1 (0.4, 3.4) 0.87
Age (yr.)
<40 1.0
>40 0.65 (0.25, 1.70) 0.38
Average CMV Area (% of retina)
lSTquartile (0-18) 1.0
2n d quartile (18-23.5) 3.3 (0.65, 16.7) 0.15
3rd quartile (23.5-30) 3.1 (0.78, 12.7) 0.11
4th quartile (30-60) 4.5 (1.1, 18.3) 0.03
Clinical Event Times1
HIV to CMV (<30 mos.) 1.0
HTV to CMV (>30 mos.) 1.45 (0.57, 3.7) 0.44
ADDS to CMV (<19 mos.) 1.0
AIDS to CMV (>19 mos.) 0.70 (0.26, 1.9) 0.47
CMV to HAART (< 10 mos.) 1.0
CMV to HAART (> 10 mos.) 1.47 (0.57,3.74) 0.42
1 median time was used as the cutpoint.
Table 4.2 summarizes the CD4 counts for patients with IRV. The median (range)
CD4 count at the time of IRV diagnosis was 147 (range = 79 to 734). There was no
statistically significant difference in the average CD4 count at the time of IRV diagnosis
between the eight patients with mild vitritis (severity =1+) and the 11 patients with
moderate vitritis (severity = 2-3+), p = 0.92.
16
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Table 4.2: Distribution of CD4 Counts in Patients at Time of
IRV Diagnosis Stratified by Severity of Vitritis and by
Occurrence of Macular Changes
Characteristic Median (Min, Max) P-value1
At Time of ERV Diagnosis (n = 19) 147 (79, 734)
—
By Severity of Vitiritis
Mild (n = 8) 144(96, 271) 0.92
Moderate (n = 11) 169 (79, 734)
By Occurrence of Macular Changes
None (n = 5) 121 (84,373)
__
CME or ERM (n= 14) 158 (79, 734) 0.57
CME only (n = 8) 166 (104, 271) 0.55
ERM only (n = 6) 155 (79, 734) 0.79
1 Wilcoxon Rank-Sum test comparing mild to moderate ER V and the group with no
macular changes with CME+ERM, CME and ERM groups. CME = cystoid macular
edema; ERM = epiretinal membranes
4.2.3 Clinical Follow-up Post IRV diagnosis and Sequellae of IRV. Two out of 19
IRV patients (3 eyes) were diagnosed on the last examination date before the end of the
study period and therefore had no follow-up. Follow-up of the remaining 17 patients (23
eyes) ranged from two to 64 weeks (median: 20 weeks). Posterior segment inflammation
started in all cases with anterior vitritis of mild to moderate severity (1-2+) and
progressed to involve the posterior vitreous within one to four weeks. In 4 eyes, vitritis
fluctuated in severity between 1+ and 2+, with associated vision changes. Four eyes had
stable vitritis on consecutive examinations, while 1 eye developed progressively more
severe vitritis, without evidence of macular changes at the last examination.
Of the 16 IRV eyes that developed macular changes, 6 eyes had clinically
17
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
apparent macular edema and three had evidence o f ERM at the time of IRV diagnosis.
Over the follow-up period after IRV diagnosis, 3 additional eyes developed CME, while
5 additional eyes developed ERM, with associated vision decrease. (One eye developed
CME, followed by ERM formation). Macular changes did not resolve without or prior to
corticosteroid therapy in any of these eyes during follow-up, and 3 cases of CME grew
progressively more severe. Inflammatory manifestations did not resolve without
treatment in any of the eyes with IRV during the follow-up period.
Figure 4.1 presents the Kaplan-Meier curve for the time to macular changes for all
ERV patients. The median time to macular changes was 43 weeks (95% confidence
interval = 25-57 weeks). Also shown in the figure is the time to macular changes
stratified by the type of change (CME or ERM). The median time to both CME and
ERM was also 43 weeks. There was no difference in the median CD4 count at ERV
diagnosis for eyes with and without macular changes (p = 0.57, Table 4.2). Further, there
were no differences in the median CD4 counts for eyes with CME or ERM when these
were compared separately to eyes without macular changes (p > 0.50, Table 4.2). In
addition, the average CMV area was associated with the likelihood of macular changes in
eyes with ERV (17.4% ± 8.3% for eyes with macular change vs. 24.5% ± 2.7% for eyes
without macular change, p = 0.01).
18
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Figure 4.1
Both CME and
ERM
CME Only
0.8
C D
ERM Only 0.6
« u
0.4
0.2
0 10 20 30 40 S O 60 70 80 90 100
Time (weeks) from IRV diagnosis
4.2.4 Effect of Treatm ent for ERV on Visual Acuity. Twenty (out of 44) ERV eyes
developed a visual loss of 2+ lines during follow-up. O f these eyes, a total of 5 eyes were
treated with 2 to 5 posterior sub-tenon injections of methyl prednisolone in polyethylene
glycol (Depo Medrol) administered at 4 to 8 week intervals. All 5 o f these eyes exhibited
macular edema. The duration of follow-up of patients with macular changes after
initiation of repository corticosteroid therapy ranged from 12 to 48 weeks (median: 24
weeks). Four eyes with clinically apparent macular edema did not undergo corticosteroid
therapy during the follow-up period, as the patients elected to postpone treatment.
Table 4.3 summarizes visual acuity expressed as logMar for the 20 (out o f 44)
ERV eyes with visual loss of 2+ lines. Average (+SD) logMar scores are given for treated
and untreated patients prior to ERV, at the time of ERV diagnosis and at the final
examination. Prior to ERV, there were no statistically significant differences in visual
acuity between treated and untreated eyes (p = 0.75). However, after adjusting for pre-
19
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
ERV visual acuity, eyes with the worst visual acuity were those that were treated with
repository corticosteroids (p < 0.0001). At the final examination, after adjusting for
differences in worst visual acuity, treated eyes were significantly better than non-treated
eyes (p < 0.0001). Table 4.3 also reports the number of eyes that had a two line
improvement in visual acuity at the final examination. Of the treated eyes, 4 out of 5
(80%) demonstrated a two line improvement as compared to 0 out of 15 untreated eyes
(0% ),p< 0.001.
Table 4.3: Visual Acuity Scores (logMar) for Eyes with ERV with Visual Acuity loss
Stratified by Treatment Status with Repository Corticosteroids
Visual Acuity
Measurement (ETDRS)
Treated
Eyes
(n = 5)
Untreated
Eyes
(n = 15)
p-value
Pre IRV1 0.14 ± 0.063 0.11 ±0.04 0.751
Worst VA score after 0.52 + 0.06 0.30 + 0.03 <0.00012
diagnosis of ERV2
Final VA score3 0.06 ±0.06 0.39 ±0.03 <0.00013
Two-line Improvement4
Yes 4 (80%) 0 (0%) <0.001 4
No 1 ( 20%) 15 (100%)
1 Student t-test comparing treated to untreated groups
2 ANACOVA adjusting for pre IRV visual acuity (VA)
3 ANACOVA adjusting for worst ER V visual acuity (VA)
4 Chi-square test
5 Mean (sem)
For the five eyes with macular changes that underwent corticosteroid treatment, the
median time from diagnosis of IRV to initiation of treatment was 12 weeks (range = 0 to
64 weeks). We compared the change in visual acuity from ERV diagnosis to the final
examination between patients who received early treatment (<12 weeks) and those that
received late treatment (>12 weeks). There were no differences in outcome between the
20
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
three patients who were treated early with the 2 patients who were treated later (-0.23 +
0.15 vs. -0.30 + 0.14, p = 0.66). Vitritis decreased in severity in all five treated eyes. On
clinical examination all treated eyes showed persistent cystoid macular changes on
ophthalmoscopy. Post-treatment fluorescein angiography revealed decreased macular
and optic disc fluorescein leakage as compared with pre-treatment images, and therefore
macular edema was considered to have improved.
21
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
5: CONCLUSIONS
IRV is a significant cause of visual morbidity in patients with CMV retinitis since
the introduction of HAART. The clinical spectrum of inflammation includes vitritis,
papillitis, macular edema and epiretinal membrane formation, and results in a decrease in
vision and visually significant floaters in the affected patients. 10
This inflammatory syndrome seems to be associated with CMV retinitis and an
increase in CD4 T-lymphocyte levels as a result o f HAART. The pathogenesis of this
inflammation is unknown. Similar inflammatory complications have not been reported in
the pre-HAART era. Additionally, IRV did not develop in our patients with CMV
retinitis who were receiving HAART but had not responded with an increase in CD4
count, or in the eyes of patients who had responded to HAART in the absence of CMV
retinitis, m This suggests that ERV may be caused by an immunologic reaction to CMV
and may reflect increased immune competence.
Following the initial reports of intraocular inflammation associated with HAART
in the setting of CMV retinitis, 10’ 13 we evaluated 19 out of 30 HAART responders
(63%) and 26 out of 44 eyes (59%) with symptomatic ERV. This cohort was followed
for a median o f 13.5 months, in order to more accurately describe this new inflammatory
syndrome. The present study is the largest, with the longest follow-up yet reported to
describe ERV. All of the patients had symptomatic intraocular inflammation with vision
decrease and/or visually significant floaters.
In Chapter 3 we reported that the annual incidence rate o f IRV for HAART
responders was 83 per 100 person-years and the median time to ERV was 43 weeks. To
22
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
estimate the prevalence of more severe inflammation, we set more stringent criteria and
included only those eyes with fluorescein angiographically-proven macular changes and
/or two or more lines of vision loss. We found that 15 of 30 patients (50%) developed
more severe IRV in 16 of 44 eyes (36%). The annual incidence rate for more severe IRV
for HAART responders was 60 per 100 person-years and the median time to IRV was 45
weeks.
Finally in Chapter 3, we performed the above analyses excluding all eyes of
patients who had previously received cidofovir, to investigate a possible effect of this
drug on the development of inflammation. There were no significant differences between
the event patterns for patients with and without cidofovir treatment, thereby suggesting
that prior cidofovir use was not a causative factor of inflammation in this cohort of
patients.
Chapter 4 investigated possible risk factors and revealed that the surface area of
CMV retinitis (inactive) was positively associated with the development of IRV (p =
0.01). Compared to eyes in the first quartile of CMV area (< 18% of the retina), eyes in
the upper quartile (> 30% of the retina) of CMV area had a 4.5-fold increase in the risk of
developing IRV (p = 0.03). Interestingly, CD4 T-lymphocyte levels in ERV patients were
not associated with the severity of inflammation. It is possible that with further
improvements in HAART and higher CD4 T-lymphocyte levels, inflammation in ERV
may be more severe. Concomitant use of systemic corticosteroids for non-ocular AEDS-
related indications may be a protective factor, but our numbers were too small to
critically evaluate this possibility. The presence of silicone oil in the vitreous cavity was
23
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
found to be a protective factor (p=0.01), as none o f the eyes with silicone oil exhibited
vitritis or inflammatory macular changes. It is possible that the presence of silicone oil
might prevent the development, or alternatively the detection of inflammatory cellular
material within the vitreous cavity.
Corticosteroid treatment in this study was reserved for more severe cases of ERV
with CME and vision decrease of at least two lines. This resulted in improvement of
vision in all of the 5 treated eyes, without reactivation of retinitis in any case.
Comparison of treated to untreated eyes with regard to visual acuity change, revealed that
4 out of 5 (80%) demonstrated a two line improvement as compared to 0 out of 21
untreated eyes (0%), p < 0.001. In our study, there were no differences in outcome
between patients who were treated early with those who were treated later (p = 0.66).
Corticosteroid therapy in the study was not standardized with regard to number and
frequency of injections, and treatment was restricted to cases of clinically evident
macular edema with vision decrease. We did not systematically study prophylactic
treatment regimens for early or subclinical macular edema and it remains to be seen
whether such therapy will prevent the vision-threatening complications described in this
study.
Further studies are needed to determine whether ERV remains a chronic disease
over many years, the long-term clinical and visual outcome, the role of other treatment
modalities, as well as immunologic studies to further elucidate the pathogenesis of this
syndrome.
24
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
REFERENCES
1. Cameron B, Heath-Chiozzi M, Kraveik S, et al. Prolongation of life and
prevention of AIDS in advanced HTV immunodefficiency with ritonavir.
(abstract) In 3rd Conference on Retroviruses and Opportunistic Infections:
program and abstracts.(Washington DC). Alexandria, VA: Infectious Diseases
Society of America, 1996:162.
2. Kupperman BD, Petty JG, Richmand DD, et al. Correlation between CD4+
counts and prevalence of cytomegalovirus retinitis and human immunodefficiency
virus -related noninfectious retinal vasculopathy in patients with acquired
immunodefficiency syndrome. Am JOphthal 1993;115:575-582.
3. Stein D, Drusano G, Steigbigel R, et al. Two year follow-up of patients treated
with indinavir 800 mg q8h (abstract). In: 4th Conference on Retroviruses and
Opportunistic Infections: program and abstracts (Washington DC). Alexandria,
VA: Infectious Diseases Society of America, 1997:100.
4. Hirsch M, Meibohm A, Rawlins S, Leawitt R, Group PIS. Indinavir (IDV) in
combination with zidovudine (ZDV) and lamivudine (3TC) in ZDV experienced
patients with CD4 cell counts <50 cells/mm^ (abstract LB7). In: 4th Conference
on Retroviruses and Opportunistic Infections :program and abstracts (Washington
DC). Alexandria, VA: Infectious diseases Society of America.
5. Lederman M, Conici E, Landay A, et al. Partial immune reconstitution after 12
weeks of HAART (AZT, 3TC, ritonavir). Preliminary results of ACTG 315
(abstract). In: 4th Conference on Retroviruses and Opportunistic Infections:
program and abstracts (Washington DC). Alexandria, VA: Infectious Diseases
Society of America, 1997:208.
6. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antitretroviral
therapy on CD4T- cell homeostasis and function in advanced HTV disease.
Science, 1997;277:112-6.
7. Baril L, Jouan M, Caumes E, Mengual X, Bricaire F, Katlama C. The impact of
highly active aniretroviral therapy on the incidence of CMV disease in AIDS
patients.(abstract). In the Program and Abstracts of the 37th Interscience
Conference on Antimicrobial Agents and Chemotherapy (Toronto). Washington,
DC: American Society for Microbiology, 1997:248
8. Whitcup SM, Fortin E, Nussenblat RB, Polis MA, Muccioli C, Belfort R Jr.
Therapeutic effect of combination antiretroviral therapy on cytomegalovirus
retinitis. JAMA 1997; 19: 1519-1520.
9. Palestine AG, Rodrigues MM, Macher AM, et al. Ophthalmic involvement in
acquired immunodefficiency syndrome. Ophthalmology 1984; 91: 1092-1099.
25
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
10. Karavellas MP, Lowder CY, Macdonald JC, Avila CP, Freeman WR. Immune
recovery vitritis associated with inactive CMV retinitis; A new syndrome. Arch
Ophthal 1998; 116:169-175.
11. Tural C, Romeu J, Sirera G, et al. Long lasting remission of cytomegalovirus
retinitis without maintenance therapy in human immunodefficiency virus-
infected patients. J infect Dis 1998; 177: ? 1080-3.
12. Macdonald JC, Torrianni FJ, Morse LS, et al. Lack of reactivation of
cytomegalovirus retinitis after stopping CMV maintenance therapy in AIDS
patients with sustained elevations in CD4 T cells in response to highly active
antiretroviral therapy. J Infect Dis 1998; 177:11827
13. 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 Ophthal 1998; 125: 292-300.
14. Nussenblatt RB, Palestine AG, Chan CC, et al. Standardization of vitreal
inflammatory activity in intermediate and posterior uveitis. Ophthalmol 1985; 92:
467-471.
15. Holland GN, Pepose JS, Petit TH et al. Acquired immune defficiency syndrome:
Ocular manifestations. Ophthalmology 1983; 90: 859-73.
16. Freeman WR, Lemer CW, Mines JA et al. A prospective study of the ophthalmic
findings in the acquired immune deficiency syndrome. Arch Ophthal 1984; 97:
133-142.
17. Chavez de la Paz E, Arevelo JF, Kirsch LS, et al. Anterior nongranulomatous
uveitis after intravitreal HPMPC (cidofovir) for the treatment o f cytomegalovirus
retinitis. Ophthalmology. 1997; 104: 539-544.
18. Holland GN, Buhles WC Jr., Mastre B, Kaplan HJ. A controlled retrospective
study of ganciclovir treatment for cytomegalovirus retinopathy. Use of a
standardized system for the assessment of disease outcome. UCLA CMV
Retinopathy. Study Group. Arch Ophthal. 1989 107(12):1759-66.
19. Freeman WR, Friedberg DN, Berry C, et al. Risk factors for development of
rhegmatogenous retinal detachment in patients with cytomegalovirus retinitis. Am
J. Ophthal. 1993; 116(6):713-20.
26
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
IMAGE EVALUATION
TEST TARGET (Q A -3 )
f/
/
✓
/ s
J'A
j S t ^
< • ' M /
« L > 4k.
CP,
, / r
1 .0
l.l
1 2. 8 S i ,
I£ 2.2
12.0
1 .8
1.25
1 .4
1 . 6
IIV U G E . I n c
1653 East Main Street
Rochester, NY 14609 USA
Phone: 716/482-0300
Fax: 716/288-5989
© 1993. Applied Image. Inc.. All Rights Reserved
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

Linked assets

University of Southern California Dissertations and Theses

Conceptually similar

PDF

A comparative study of environmental factors associated with multiple sclerosis in disease-discordant twin pairs

PDF

An exploration of nonresponse with multiple imputation in the Television, School, and Family Project

PDF

Evaluation of the efficacy of two lipid-lowering treatments using serial quantitative coronary angiography: Two- and four-year treatment results

PDF

Influence of body weight and weight change on carotid IMT and IMT progression: A pooled analysis using subject-level data from four clinical trials

PDF

Rates of cognitive decline using logitudinal neuropsychological measures in Alzheimer's disease

PDF

Does young adult Hodgkin's disease cluster by school, residence and age?

PDF

Imputation methods for missing items in the Vitality scale of the MOS SF-36 Quality of Life (QOL) Questionnaire

PDF

Associations of physical fitness and other risk factors with cardiovascular and non-violent mortality

PDF

Imputation methods for missing data in growth curve models

PDF

Development and evaluation of standardized stroke outcome measures in a population of stroke patients in rural China

PDF

Interaction of dietary fiber and serum cholesterol on early atherosclerosis

PDF

Extent, prevalence and progression of coronary calcium in four ethnic groups

PDF

The Magnitude And Rate Of Decline In Alpha-Fetoprotein Levels In Children With Unresectable Or Metastatic Hepatoblastoma, Predict Outcome

PDF

Familiality and environmental risk factors of peptic ulcer: A twin study

PDF

Descriptive epidemiology of thyroid cancer in Los Angeles County, 1972-1995

PDF

Association between latchkey status and smoking behavior in middle school children

PDF

The Native American Periodontal Study: Characteristics Of The Study Population

PDF

Impact of heterogeneity on evidence for linkage to type 2 diabetes mellitus in the Finnish population

PDF

The Effect Of Non-Sampling Measurement Errors On Relative Risk Estimates Of Coronary Heart Disease In Framingham Women

PDF

A joint model for Poisson and normal data for analyzing tumor response in cancer studies

Asset Metadata

Creator Shufelt, Chrisandra Lee (author)

Core Title Immune recovery vitritis in AIDS: Incidence, clinical predictors, sequellae, and treatment outcomes

School Graduate School

Degree Master of Science

Degree Program Applied Biometry

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag biology, biostatistics,health Sciences, ophthalmology,OAI-PMH Harvest

Language English

Contributor Digitized by ProQuest (provenance)

Advisor Azen, Stanley (committee chair), Freeman, William (committee member), Mack, Wendy (committee member)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-30645

Unique identifier UC11341422

Identifier 1395136.pdf (filename),usctheses-c16-30645 (legacy record id)

Legacy Identifier 1395136.pdf

Dmrecord 30645

Document Type Thesis

Rights Shufelt, Chrisandra Lee

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA