Association Between Abnormal Contrast Sensitivity and Mortality Among People With Acquired Immunodeficiency Syndrome




Purpose


To investigate the relationship between contrast sensitivity (CS) and mortality among people with acquired immunodeficiency syndrome (AIDS); and to explore the hypothesis that abnormal CS is a marker of systemic, life-threatening microvascular disease.


Design


Longitudinal, observational cohort study.


Methods


We evaluated 3395 eyes of 1706 individuals enrolled in the Longitudinal Study of the Complications of AIDS (1998–2008). CS was evaluated as a risk factor for death, and was compared to the presence of systemic diseases characterized by microvasculopathy (diabetes, cardiovascular disease, stroke, renal disease) and to laboratory markers of those diseases. Abnormal CS was defined as logCS <1.5 (lower 2.5th percentile for a normal control population).


Results


CS was abnormal in 284 of 1691 (16.8%) study participants at enrollment. There was a positive relationship between the presence of abnormal CS at study entry and mortality (relative risk 2.0, 95% confidence interval 1.7-2.3, P < .0001). Abnormal CS was related to the presence of cardiovascular disease, stroke, and renal disease (all P values ≤ .01), but abnormal CS remained associated with death even after adjustment for these diseases and for other known predictors of death among people with AIDS. Diseases characterized by microvasculopathy were more often identified as causes of death among individuals with abnormal CS than among those with normal CS, although the strength of the association was moderate ( P = .06).


Conclusions


Abnormal CS among people with AIDS is associated with increased mortality, and is independent of other risk factors for death that are monitored routinely. The relationship may indicate life-threatening microvascular disease in other organs.


Abnormalities of vision are common among people infected with human immunodeficiency virus (HIV), even in the absence of cytomegalovirus (CMV) retinitis or other intraocular opportunistic infections. It has been shown that the prevalence of reduced contrast sensitivity (CS) and abnormal color vision among HIV-infected individuals without clinically apparent retinal disease is 2- to 3-fold greater than in the general population. It is believed that these vision abnormalities are related to retinal damage, characterized by loss of ganglion cell axons, which is common among HIV-infected individuals. This condition, which has been termed neuroretinal disorder (NRD), may be caused, in part, by the retinal microvasculopathy of HIV disease.


Studies of CS in the general population and among specific groups, such as diabetics, have shown that reduced CS can have functional consequences, and may be a marker for systemic disorders. Among diabetics, for example, reduced CS is associated with retinal vascular disease, which in turn is associated with increased mortality.


In this study, we sought to ascertain similar relationships among HIV-infected individuals enrolled in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), and explored whether those who demonstrated reduced CS at baseline examination had an increased risk for death. We also explored the hypothesis that the association between CS and mortality reflects the presence of potentially life-threatening systemic diseases that are characterized by microvasculopathies, such as cardiovascular disease, stroke, and renal disease.


Methods


LSOCA is an ongoing, prospective, observational cohort study designed to collect data on ophthalmic conditions associated with acquired immunodeficiency syndrome (AIDS) that have been seen since the introduction of highly active antiretroviral therapies (HAART). Enrollment began in September 1998. Study participants must have a diagnosis of AIDS, as defined by 1993 Centers for Disease Control and Prevention criteria. A description of LSOCA design, methods, and baseline data has been published elsewhere. The current study includes data collected through December 31, 2008. Excluded from this investigation were study participants who had ocular opportunistic infections, which are associated with mortality and may cause abnormal CS.


Data Collection


By design, LSOCA participants without ocular opportunistic infections were seen every 6 months. At baseline (study enrollment) and at each follow-up visit, participants were interviewed about medical and treatment histories, and each underwent an ophthalmic examination that included determination of best-corrected visual acuity, determination of CS, Goldmann visual field testing, slit-lamp biomicroscopy, and dilated indirect ophthalmoscopy. Laboratory tests obtained at each visit included complete blood cell count, including leukocyte differential; platelet count; lymphocyte subset analyses; serum creatinine; serum lipid determinations; plasma HIV RNA level; and urine protein level. The method by which proteinuria was determined was not requested from investigators at the time of data collection. Beginning in 2005, blood pressure was measured and smoking status was determined at each visit. A Framingham mortality risk score was calculated for each participant; this score takes into account the following factors: gender, age, systolic blood pressure, treatment for hypertension, total cholesterol, high-density lipoprotein, and smoking status. Continuous covariates were categorized using clinically meaningful cut points, where applicable.


CS was determined using the method of Pelli-Robson. Briefly, participants sat or stood 1 m from the Pelli-Robson contrast sensitivity chart, using a +0.75-diopter lens in addition to their refractive corrections. Participants read the chart until at least 2 letters in a triple were missed. The logCS score was calculated as the total number of letters read correctly minus 3, then multiplied by 0.05. Because CS is linear on a log 10 scale, analyses used log 10 CS. The protocol used in LSOCA does not permit confusion between “C” and “O,” which is consistent with the technique described by Myers and associates but is unlike the protocol used in some other reported studies; this convention will potentially lower the distribution of CS values in LSOCA when compared to established norms in those other studies. This issue has been addressed previously by the SOCA Research Group.


We categorized study participants who died during follow-up on the basis of immediate and contributing causes of death, using information from available death certificates; specifically, we identified whether death was associated with diseases characterized by microvasculopathy (diabetes, cardiovascular disease, renal disease, stroke), liver disease (a major cause of morbidity and mortality among people with AIDS), AIDS-related opportunistic infections and malignancies, other AIDS-related disorders, or trauma.


Definitions


Abnormal CS was defined as logCS <1.5, which corresponds to the lower 2.5th percentile of a normal control population described by Myers and associates. The rationale for use of this threshold in studies of the LSOCA population has been discussed elsewhere. For purposes of this study, HAART was defined as the concurrent use of 3 or more antiretroviral drugs.


A participant was considered to have diabetes mellitus if the condition was self-reported at baseline or during follow-up, or if he or she was on any therapy for diabetes mellitus.


A participant was considered to have hypertension if the condition was self-reported at baseline; if he or she received treatment with antihypertensive medications; or if he or she had a systolic blood pressure >140 mm Hg or a diastolic blood pressure >85 mm Hg on at least 1 LSOCA visit.


A participant was considered to have cardiovascular disease if either coronary heart disease or peripheral vascular disease was self-reported or mentioned in medical records at baseline or if he or she was reported to have a cardiovascular event during follow-up.


A participant was considered to have a history of stroke if the condition was self-reported at baseline or if he or she was reported to have had a cerebrovascular event during follow-up.


A participant was considered to have renal disease if the condition was self-reported at baseline; if he or she had proteinurea of 2+ or more; or if his or her calculated glomerular filtration rate (GFR) was <60 mL/min, using the Modification of Diet in Renal Disease (MDRD) Study equation: 186 × (serum creatinine [mg/dL]) −1.154 × (age [y]) −0.203 × (0.742, if female) × (1.212, if black).


Data Analysis


Unless otherwise noted, the unit of analysis was the eye. Demographic, medical, and laboratory data were compared between study participants with abnormal CS in at least 1 eye versus those with normal CS in both eyes. CS at baseline was compared to the occurrence of death, both as a categorical variable (abnormal CS vs normal CS) and as a continuous variable; relationships were investigated for all participants and for subgroups based on best-corrected visual acuity (20/20 or better vs worse than 20/20), with and without adjustment for the following factors: CD4+ T-lymphocyte count, plasma HIV RNA level, HAART status (current use vs no current use), and date of CS measurement. We adjusted for date of examination in all multivariate analyses because we observed a secular trend in which there was a small, but significant, increase in mean logCS that may have been related to replacement of old contrast sensitivity charts in some clinics during the latter years of the study.


In a secondary, person-specific (as opposed to eye-specific) analysis, we compared abnormal CS to death after categorizing study participants into the following groups: abnormal CS in both eyes at baseline; abnormal CS in 1 eye at baseline; and abnormal CS in neither eye at baseline.


CS (abnormal vs normal) at each visit was compared to the following factors at the same visit: history of stroke; the presence or absence of diabetes, hypertension, cardiovascular disease, or renal disease; laboratory markers of renal disease (proteinuria, GFR); and Framingham 10-year mortality risk score.


Abnormal CS at baseline and abnormal CS as a time-dependent variable were assessed as risk factors for death in crude comparisons, and time-dependent abnormal CS was assessed as a risk factor for death in several models that adjusted for various combinations of the following potential confounders: HAART status; current and nadir CD4+ T-lymphocyte counts; plasma HIV RNA level; visual acuity; history of stroke; the presence or absence of diabetes, hypertension, cardiovascular disease, or renal disease; Framingham 10-year mortality risk score; and date of CS measurement.


For study participants who died and for whom death certificates were available, causes of, or factors contributing to, death were compared between those with and those without abnormal CS.


Statistical Techniques


Differences were assessed using the Wilcoxon rank sum test for continuous data and the χ 2 test for categorical data. Assessment of time-independent and time-varying risk factors for death used Cox regression with staggered entry; time since diagnosis of AIDS was the time metric, and analysis accounted for the correlation between eyes of a given participant. P values were 2-sided and were not adjusted for multiple outcomes or multiple looks. Analyses were performed with both SAS (SAS/STAT User’s Guide, Version 9.2, 2008; SAS Institute, Cary, North Carolina, USA) and Stata (Stata Statistical Software: Release 10, 2007; StataCorp LP, College Station, Texas, USA) statistical packages.




Results


A total of 2221 individuals had enrolled in LSOCA as of December 31, 2008. There were no ocular opportunistic infections in 1712 individuals. CS measurements were available for 3363 eyes of 1691 study participants without ocular opportunistic infections at baseline; CS data were available for at least 1 visit (baseline or follow-up) for 3395 eyes (1706 participants without ocular opportunistic infections). Data were available from 14 250 patient visits, consisting of 28 319 eye visits. The percentage of eye visits for which data were missing was 83% for Framingham risk score; 60% for presence or absence of renal disease; 21% for cardiovascular disease; 22% for stroke; 7% for plasma HIV RNA level; 2% for CD4+ T-lymphocyte count; and ≤1% each for nadir CD4+ T-lymphocyte count, diabetes mellitus, hypertension, and use of HAART.


At the baseline visit, CS values ranged from logCS 0.00 to logCS 2.00 (median and mode logCS = 1.65). The distribution of CS values is shown in Figure 1 . CS was considered to be abnormal in 284 individuals. Demographic and medical data at baseline are described in Table 1 ; there were numerous relationships between abnormal CS and factors that reflect worse health status.




FIGURE 1


Histogram showing the distribution of contrast sensitivity (CS) values for 3363 eyes of 1691 participants without ocular opportunistic infections at study enrollment (baseline examination) in the Longitudinal Study of the Ocular Manifestations of AIDS. Abnormal CS (shaded area) was defined as logCS <1.5 (the lower 2.5th percentile for a normal control population described by Myers and associates. The mode (interrupted bar) was logCS 1.65 (n = 1778 eyes).


TABLE 1

Demographic, Medical, and Laboratory Factors at Baseline for 1691 Study Participants Without Ocular Opportunistic Infections in the Longitudinal Study of the Ocular Complications of AIDS






















































































































































































































































































































Abnormal CS (<1.5 logCS) a in Either Eye (n=284) Normal CS (≥1.5 logCS) in Both Eyes (n=1407)
Factor N c Value d N c Value d P Value b
Demographics
Age 283 43 years 1402 43 years .16
Female 283 26% 1402 18% .001
Black 283 46% 1402 35% .0005
HIV infection risk group 275 1385 <.0001
MSM only 38% 58%
IDU only 14% 9%
Both MSM and IDU 6% 4%
Heterosexual contact 36% 25%
Other 6% 4%
AIDS history
Interval since AIDS diagnosis (median) 273 4.5 years 1371 3.7 years .006
Lymphocytopenia as AIDS-defining illness 283 61% 1402 66% .11
Weight 261 72 kg 1283 75 kg .0007
Immunology/virology
CD4+ T-lymphocyte count 282 166 cells/μL 1393 194 cells/μL .02
Nadir CD4+ T-lymphocyte count 273 38 cells/μL 1387 44 cells/μL .28
CD8+ T-lymphocyte count 280 731 cells/μL 1385 776 cells/μL .15
HIV RNA blood level 258 3.0 log copies/mL 1348 2.8 log copies/mL .28
Peak HIV RNA blood level 264 5.3 log copies/mL 1348 5.3 log copies/mL .12
Hematology
Hemoglobin concentration 283 13.3 g/dL 1397 13.8 g/dL .0004
Median hematocrit 282 39.2% 1399 40.4% .0008
Mean corpuscular volume 282 97.2 fL 1400 98.0 fL .45
Platelet count 281 217 × 10 3 cells/μL 1390 212 × 10 3 cells/μL .44
Leukocyte count 283 4.5 × 10 3 cells/μL 1400 4.6 × 10 3 cells/μL .51
Absolute neutrophil count 282 2.4 × 10 3 cells/μL 1394 2.3 × 10 3 cells/μL .90
Comorbidities
Hypertension 282 26% 1402 20% .03
Diabetes mellitus 283 10% 1402 9% .71
Renal disease 283 5% 1402 7% .43
Cardiovascular disease e 199 9% 1103 7% .33
Peripheral vascular disease 198 7% 1097 4% .11
Stroke 198 8% 1093 4% .02
Antiretroviral treatment
Ever on HAART 225 88% 1172 90% .20
Currently on HAART 282 79% 1402 85% .006
Mean Karnofsky score 283 82 1401 85 .0002
Visual function (better eye)
Visual acuity (standardized letters) 283 83 1402 90 <.0001
Goldmann visual field (degrees) 279 730 1398 756 <.0001
Presence of cotton-wool spots 283 5% 1401 3% .02

AIDS = acquired immunodeficiency syndrome; CS = contrast sensitivity; HAART = highly active antiretroviral therapy; HIV = human immunodeficiency virus; IDU = intravenous drug user; MSM = men who have sex with men.

a Corresponds to the lower 2.5th percentile for a normal control population described by Myers and associates.


b Wilcoxon rank sum test for continuous variables; χ 2 test for categorical variables.


c The number of study participants for whom data were available.


d Values other than percentages represent medians unless otherwise stated.


e Includes coronary heart disease and peripheral vascular disease.



Abnormal CS and reduced CS (when considered as a continuous variable) at baseline were associated with increased risk of death ( Table 2 , Figure 2 ). Despite the known relationship between abnormal CS and low CD4+ T-lymphocyte count, the relationship between abnormal CS and mortality remained significant after adjustment for CD4+ T-lymphocyte count, indicating that CS is not simply a marker for the immunodeficiency reflected by a low CD4+ T-lymphocyte count.



TABLE 2

Abnormal Contrast Sensitivity at Baseline as a Risk Factor for Death Among 1691 Study Participants (3363 Eyes) Without Ocular Opportunistic Infections in the Longitudinal Study of the Ocular Complications of AIDS

































































































































































































Risk Factor Eye Deaths Eye Visits RR a 95% CI P Value b
CS threshold (logCS ≤1.5 vs logCS >1.5)
All eyes
Crude 801 3363 2.0 1.6–2.5 <.0001
Adjusted c 748 3178 1.9 1.5–2.4 <.0001
Eyes <20/20 at baseline
Crude 200 692 1.5 1.1–2.1 .01
Adjusted c 181 637 1.6 1.1–2.3 .006
Eyes ≥20/20 at baseline
Crude 601 2671 2.1 1.6–2.8 <.0001
Adjusted c 567 2541 1.8 1.3–2.6 .0002
Interaction of visual acuity threshold and CS
Crude .14
Adjusted c .72
CS as continuous variable (per 0.05 logCS)
All eyes
Crude 801 3363 0.96 0.94–0.97 <.0001
Adjusted c 748 3178 0.95 0.94–0.97 <.0001
Eyes <20/20 at baseline
Crude 200 692 0.98 0.96–1.00 .06
Adjusted c 181 637 0.97 0.95–1.00 .02
Eyes ≥20/20 at baseline
Crude 601 2671 0.92 0.88–0.95 <.0001
Adjusted c 567 2541 0.94 0.90–0.98 .002
Interaction of visual acuity threshold and CS
Crude .003
Adjusted c .17

CI = confidence interval; CS = contrast sensitivity; RR = relative risk for death.

a Calculated from Cox regression using method of staggered entry for interval since AIDS diagnosis as time metric and accounting for correlation of eyes within a given study participant.


b Based on Cox proportional hazards model, accounting for correlation between eyes.


c Adjusted for baseline CD4+ T-lymphocyte count, HIV RNA blood level, highly active antiretroviral therapy (current use vs no current use), and date of CS measurement.




FIGURE 2


Deaths per person-year of follow-up versus contrast sensitivity (CS) at study enrollment (baseline examination) in the Longitudinal Study of the Ocular Manifestations of AIDS. Vertical bars represent 95% confidence intervals. The shaded area corresponds to abnormal CS (corresponds to the lower 2.5th percentile for a normal control population described by Myers and associates).


Because CS is associated with visual acuity, we analyzed the relationship between CS and death both for eyes with visual acuity of 20/20 or better and for eyes with visual acuity worse than 20/20; CS was strongly related to death for both subgroups. Lack of significant interaction between the visual acuity threshold and CS after adjustment for CD4+ T-lymphocyte count, plasma HIV RNA level, and HAART status provided further evidence that the relationship between CS and death was independent of visual acuity. All subsequent analyses considered all eyes, regardless of visual acuity.


In the secondary, person-specific analysis that compared abnormal CS to death after categorizing the 1691 study participants on the basis of abnormal CS in 2 versus 1 versus 0 eyes, 131 participants (8%) had abnormal CS in both eyes at baseline; 153 (9%) had abnormal CS in 1 eye at baseline; and 1407 (85%) had abnormal CS in neither eye at baseline. The relative risk of death comparing participants with abnormal CS in 2 versus 0 eyes was 2.3 (95% CI, 1.7-3.0; P < .0001), while the relative risk of death comparing participants with abnormal CS in 1 versus 0 eyes was 1.6 (95% CI, 1.1-2.1; P = .006), consistent with a dose effect. Despite the discrepant CS values between eyes in some participants, there was a strong relationship between CS values when right and left eyes of the same participant were compared (rank correlation coefficient, 0.69; P < .0001), consistent with the hypothesis that abnormal CS is related to a generalized disease process.


Table 3 shows relationships between abnormal CS and diseases that are associated with microvasculopathy, laboratory measures that are associated with renal disease, and Framingham 10-year risk scores. There were significant positive associations with cardiovascular disease, stroke, renal disease, laboratory abnormalities that reflect renal disease, and Framingham 10-year risk score.



TABLE 3

Relationship Between Abnormal Contrast Sensitivity and Disease Factors Associated With Microvasculopathy or Death Among 1706 Study Participants Without Ocular Opportunistic Infections in the Longitudinal Study of the Ocular Complications of AIDS






























































Abnormal CS a , b in Either Eye vs Normal CS in Both Eyes
Disease Factor a OR c 95% CI P Value Number of Person-Visits
Diabetes (yes vs no) 1.3 0.9–1.8 .18 14 215
Hypertension (yes vs no) 1.0 0.8–1.2 .83 14 214
Cardiovascular disease d (yes vs no) 1.6 1.1–2.4 .01 12 669
Stroke (yes vs no) 2.6 1.5–4.5 .001 12 590
Renal disease (yes vs no) 1.7 1.2–2.4 .006 6393
Proteinurea (≥2+ vs < 2+) 1.7 1.0–2.8 .04 6399
Glomerular filtration rate e (<60 vs ≥60 mL/min) 1.6 1.1–2.4 .01 6393
Framingham 10-year risk score (≥3% vs <3%) 0.6 0.4–1.0 .04 2882

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Jan 17, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Association Between Abnormal Contrast Sensitivity and Mortality Among People With Acquired Immunodeficiency Syndrome
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