To evaluate relationships between retinal vessel caliber and tests of visual function among people with AIDS.
Longitudinal, observational cohort study.
We evaluated data for participants without ocular opportunistic infections at initial examination (baseline) in the Longitudinal Studies of the Ocular Complications of AIDS (1998-2008). Visual function was evaluated with best-corrected visual acuity, Goldmann perimetry, automated perimetry (Humphrey Field Analyzer), and contrast sensitivity (CS) testing. Semi-automated grading of fundus photographs (1 eye/participant) determined central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR) at baseline. Multiple linear regression models, using forward selection, sought independent relationships between indices and visual function variables.
Included were 1250 participants. Smaller AVR was associated with reduced visual field by Goldmann perimetry ( P = .003) and worse mean deviation ( P = .02) on automated perimetry and possibly with worse pattern standard deviation (PSD) on automated perimetry ( P = .06). There was a weak association between smaller AVR and worse CS ( P = .07). Relationships were independent of antiretroviral therapy and level of immunodeficiency (CD4+ T lymphocyte count, human immunodeficiency virus [HIV] RNA blood level). On longitudinal analysis, retinal vascular indices at baseline did not predict changes in visual function.
Variation in retinal vascular indices is associated with abnormal visual function in people with AIDS, manifested by visual field loss and possibly by reduced CS. Relationships are consistent with the hypothesis that HIV-related retinal vasculopathy is a contributing factor to vision dysfunction among HIV-infected individuals. Longitudinal studies are needed to determine whether changes in indices predict change in visual function.
We have shown that variations in retinal vessel caliber among people with Acquired Immunodeficiency Syndrome (AIDS) are related to level of immunodeficiency (as manifested by CD4+ T lymphocyte count) and use of highly active antiretroviral drug therapy (HAART). Variations in vessel caliber are associated with increased mortality risk, which we attributed to the likelihood that morphologic changes of retinal arterioles and venules reflect life-threatening changes in cerebral and coronary vessels.
Reduced contrast sensitivity (CS) is also related to mortality among people with AIDS. Retinal microvasculopathy, which has been a common AIDS-related finding at autopsy, is thought to be a contributor to vision abnormalities among people with AIDS, including changes in visual field (VF), reduced CS, and altered color vision. Such a relationship with retinal vascular disease is thought to be the basis for the association between CS and death, supported by the fact that abnormal CS is also related to systemic diseases characterized by microvascular disease. An association between variations in retinal vessel caliber and visual function has not been shown directly, however.
In this study, we investigated relationships between vessel caliber indices and various measures of visual function (best-corrected visual acuity [BCVA], VF, and CS) among participants in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA). Based on relationships seen in the setting of other diseases, we hypothesize that narrower arterioles and dilated venules will be markers of worse visual function.
LSOCA is an NIH-sponsored prospective epidemiologic study of people with AIDS, which began in September 1998. A description of its design and methods and a summary of data for participants at study enrollment (baseline) have been published previously. Data were collected from study participants every 6 months per protocol. The current study includes data collected through December 31, 2008 for participants without ocular opportunistic infections at baseline.
We collected baseline demographic, medical, and laboratory information as described in a companion article dealing with the same cohort. AIDS-related information at baseline included time since AIDS diagnosis, lymphopenia as AIDS-defining illness, CD4+ T lymphocyte count (baseline and nadir), CD8+ T lymphocyte count, human immunodeficiency virus (HIV) RNA blood level (baseline and peak), history of HAART (on HAART at baseline; ever on HAART), and Karnofsky score. We collected data on the following visual function measures at baseline: BCVA, as per LSOCA protocol; CS; and various visual field variables, as described below. CS was determined using the method of Pelli-Robson and analyzed using protocols described in a previous LSOCA publication. Goldmann perimetry used a modified Diabetic Retinopathy Study protocol, in which a score is computed by summing the degrees of visual field along 12 meridians spaced 30 degrees apart, as described previously. Using this technique, the mean score for people with AIDS is approximately 700 ± 100 degrees of visual field. Automated perimetry was performed using the Humphrey Field Analyzer Model 600 or 700 (Carl Zeiss Meditec, Dublin, California, USA) and the 24-2 full-threshold program, as described in a previous LSOCA publication. As recommended by the manufacturer, automated perimetry test results were excluded from analyses as being unreliable if fixation losses were ≥20% or false-positive errors were ≥33% or false-negative errors were ≥33%. We also identified those participants who had cataract on examination at baseline.
The following vessel caliber indices were determined in a semi-automated manner by certified graders at the University of Wisconsin Fundus Photograph Reading Center (IVAN software; Department of Ophthalmology and Visual Science, University of Wisconsin, Madison, Wisconsin, USA) using a standardized protocol: central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR). An explanation of these indices, and procedures for their determination, are described in the companion article dealing with this cohort.
For purposes of this study, HAART was defined as the concurrent use of 3 or more antiretroviral drugs. Abnormal CS was defined as logCS <1.5, which corresponds to the lower 2.5 percentile for a normal control population described by Myers and associates. With regard to automated VF testing, abnormal mean deviation (MD) was defined as <−2.63 dB. Abnormal VF pattern standard deviation (PSD) was defined as >2.57 dB. The rationale for use of these thresholds is discussed in previous LSOCA publications.
Data Analysis and Statistical Techniques
Unless otherwise noted, the unit of analysis was the eye, and 1 eye per study participant was evaluated. Wong and associates have demonstrated a strong correlation between the eyes of an individual, for both CRAE and CRVE, and concluded that measurements from 1 eye accurately reflect a person’s systemic vascular status. If vessel caliber indices could be determined for both eyes, the eye with better photographic quality was selected as the study eye. Values for each vessel caliber index were grouped by quartiles and modeled ordinally. With regard to CRAE and CRVE, the first quartile contained narrower arterioles and venules, respectively, while the fourth quartile contained wider arterioles and venules. With regard to AVR, the first quartile included relatively narrower arterioles vs venules, while the fourth quartile included relatively wider arterioles vs venules.
Demographic, medical, and laboratory factors that were statistically related to vessel caliber indices in the companion study of this cohort were chosen as covariates in the adjusted models for each index in the cross-sectional portion of the study. The following baseline covariates were used in all adjusted models for the longitudinal portion of the study: current use of HAART, CD4+ T lymphocyte count, HIV RNA blood level, age, black race, mean corpuscular volume, hematocrit, and time since diagnosis of AIDS. Vessel caliber indices were used as predictors in: 1) cross-sectional analyses using linear regression of visual function variables at baseline; and 2) longitudinal analyses using Cox regression of incident events in visual function variables during follow-up.
Because diabetes mellitus can cause vascular disease similar to that seen in people with AIDS, we performed subgroup analyses, looking for significant ( P < .01) interactions between diabetes mellitus and relationships that involve vessel caliber. Similar subgroup analyses were performed to look for significant ( P < .01) interactions with hypertension. Because vessel caliber indices have been related to glaucomatous optic disc changes, subgroup analyses were also performed to look for significant ( P < .01) interactions with diagnoses of glaucoma or elevated intraocular pressure (>21 mm Hg) at baseline for those comparisons that involved visual field variables. Similar subgroup analyses were performed to look for significant ( P < .01) interactions between cataract and relationships that involve vessel caliber.
P values were 2-sided and were not adjusted for multiple comparisons. Statistical analyses were performed using SAS (SAS/STAT User’s Guide, Version 9.2, 2010; SAS Institute, Cary, North Carolina, USA) and Stata (Stata Statistical Software: Release 11, 2009; StataCorp LP, College Station, Texas, USA) statistical packages.
As of December 31, 2008, 2221 individuals had enrolled in LSOCA, 1712 of whom had no ocular opportunistic infections. The demographic, medical, laboratory, and ophthalmic examination data for this subpopulation are described in a previous publication. Among these 1712 eligible participants, 1250 eyes had vessel caliber measurements at baseline. There was a normal distribution of the vessel caliber indices.
Table 1 shows the relationships between vessel caliber indices and measures of vision function at baseline. There were significant relationships between smaller AVR and the following visual field measures: fewer total degrees of visual field on Goldmann perimetry ( P = .003) as well as worse MD ( P = .02) and worse PSD ( P = .06) on automated perimetry.
|Visual Function (Median)||Quartile||Comparisons|
|1||2||3||4||β b||P||β b||P|
|Visual acuity (standardized letters)|
|Contrast sensitivity (logCS units)|
|Goldmann visual field (degrees)|
|Humphrey visual field c|
|Mean deviation (dB)|
|Pattern standard deviation (dB)|
a Analyses involving CRAE were adjusted for age, race, hematocrit, time since diagnosis of AIDS, HAART (ever used), and CD4+ T lymphocyte count; analyses involving CRVE were adjusted for age, race, mean corpuscular volume, history of smoking, time since diagnosis of AIDS, and HAART (ever used and current use); analyses involving AVR were adjusted for age, race, mean corpuscular volume, hematocrit, time since diagnosis of AIDS, and current use of HAART.
c Excluded were 382 of 1250 eyes (31%) because of unreliable automated perimetry results. The number of eyes with reliable results for both mean deviation and pattern standard deviation by increasing quartile of CRAE were 222, 223, 204, and 219, respectively; by increasing quartile of CRVE were 211, 213, 222, and 222, respectively; and by increasing quartile of AVR were 217, 203, 214, and 234, respectively.
There was also a weak association between smaller AVR and worse CS ( P = .07). There was a weak association between smaller AVR and worse BCVA ( P = .06) on crude comparison, but the relationship was not significant on adjusted comparison.
Table 2 shows the relationships between vessel caliber indices at baseline and changes in vision function during follow-up. None of the vessel caliber indices at baseline were predictors of change in BCVA, CS, or visual field variables.
|Visual Event||Crude||Adjusted a|
|RR b /Quartile||95% CI||P||RR b /Quartile||95% CI||P|
|Visual acuity worse than 20/40 c|
|Visual acuity 20/200 or worse d|
|Contrast sensitivity <1.5 log units e|
|Mean deviation <−2.63 dB f|
|Pattern standard deviation >2.57 dB g|