The effect of cytomegalovirus retinitis on the quality of life of patients with AIDS in the era of highly active antiretroviral therapy

The Effect of Cytomegalovirus Retinitis on the Quality of Life of Patients with AIDS in the Era of Highly Active Antiretroviral Therapy John H. Kempen, MD, PhD,1,2 Barbara K. Martin, PhD,2 Albert W. Wu, MD, MPH,2,3,4 Bruce Barron, MD,5 Jennifer E. Thorne, MD,1,2 Douglas A. Jabs, MD, MBA1,2,3 for the Studies of Ocular Complications of AIDS Research Group Purpose: To evaluate the effect of cytomegalovirus (CMV) retinitis on quality of life (QOL) in patients with the acquired immune deficiency syndrome (AIDS). Design: Enrollment data from a multicenter, prospective cohort study. Participants: Patients ⱖ13 years of age with AIDS in three groups: no CMV retinitis, 709 patients; longstanding CMV retinitis (diagnosed a median of 34.5 months previously), 212 patients; and newly diagnosed CMV retinitis (diagnosed ⱕ45 days previously), 50 patients. Methods: Patients were enrolled at 19 centers throughout the United States. CMV retinitis status was determined by ophthalmoscopy. Vision-related QOL was assessed with a questionnaire designed for patients with CMV retinitis. General health-related QOL was evaluated with a modified version of the Medical Outcomes Survey–HIV instrument. Health utility was measured with the EuroQol instrument. Main Outcome Measures: Patient-reported vision-related QOL, general health-related QOL, and health utility. Results: All domains of vision-related QOL were substantially lower in both the long-standing and newly diagnosed CMV retinitis groups than in the group with no CMV retinitis. The long-standing CMV retinitis group was similar to the no CMV retinitis group in most general health-related QOL domains and in health utility measures. The newly diagnosed CMV retinitis group scored substantially worse than the other groups in many of the general health-related QOL domains and in visual analog scale–measured health utility. Adjustment of selected scale scores for demographic characteristics and for CD4⫹ T-cell count, human immunodeficiency virus viral load, and use of highly active antiretroviral therapy (HAART) attenuated most of the differences in general health-related QOL, except that physical function scores remained significantly lower in the newly diagnosed CMV retinitis group. Adjustment did not alter the pattern of vision-related QOL results. Conclusions: These results suggest that in the HAART era, CMV retinitis is associated with reduced vision-related QOL in patients both with newly diagnosed and with long-standing disease, even though patients with long-standing CMV retinitis seem to have general health-related QOL and health utility similar to that of patients with AIDS who do not have CMV retinitis. Newly diagnosed CMV retinitis also is associated with lower general health-related QOL in most domains and with lower health utility. Ophthalmology 2003;110:987–995 © 2003 by the American Academy of Ophthalmology.

Originally received: March 7, 2002. Accepted: July 22, 2002. Manuscript no. 220185. 1 Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 2 Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. 3 Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 4 Department of Health Policy and Management, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. 5 Department of Ophthalmology, Louisiana State University, New Orleans, Louisiana. Supported by cooperative agreements from the National Eye Institute to The Johns Hopkins University School of Medicine (U10 EY08052), The Johns Hopkins University Bloomberg School of Public Health (U10 EY08057), and the University of Wisconsin, Madison (U10 EY08067). © 2003 by the American Academy of Ophthalmology Published by Elsevier Science Inc.

Additional support was provided by the National Center for Research Resources through the General Clinical Research Center grants 5MO1 RR00188 (Baylor College of Medicine), MO1 RR00052 (Johns Hopkins University School of Medicine), 5MO1 RR05096 (Louisiana State University), 5MO1 RR00865 (University of California, Los Angeles), 5MO1 RR05280 (University of Miami), 5M01 RR00046 (University of North Carolina), 5MO1 RR00043 (University of Southern California), and 5MO1 RR00047 (Weill Medical College of Cornell University). Additional support was obtained from National Eye Institute grants K23 EY00386 (JHK) and K24 E4004505 (DAJ). Dr. Jabs is the recipient of a Research to Prevent Blindness Senior Scientific Investigator Award. The authors have no proprietary or financial interests in the subject matter or materials discussed in this article. Reprint requests to John H. Kempen, MD, PhD, 550 North Broadway, Suite 700, Baltimore, MD 21205. E-mail: [email protected] The members of the Studies of Ocular Complications of AIDS Research Group are listed in the appendix. ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6420(03)00089-7

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Ophthalmology Volume 110, Number 5, May 2003 Cytomegalovirus (CMV) disease, most commonly manifested as retinitis,1,2 was reported to occur during the lifetime of approximately 30% of patients with the acquired immune deficiency syndrome (AIDS) in the era before the availability of highly active antiretroviral therapy (HAART).3 With the widespread use of HAART, the incidence of CMV retinitis has decreased by approximately 75%, although new cases continue to occur.4 –7 For patients already diagnosed with CMV retinitis, HAART substantially improves survival,7–11 reduces the risk of loss of visual acuity12 and of retinal detachment,13 and sometimes causes sustained immune recovery sufficient to control CMV infection without anti-CMV therapy.14 –20 In some cases, patients with CMV retinitis who develop immune recovery in response to HAART develop a uveitis in affected eyes, and this can cause vision loss.21–27 Measures of general health-related quality of life (QOL), based on patient responses to questions regarding functional status and subjective well-being, have been accepted widely as important outcomes for clinical and health services research in AIDS.28 Likewise, measures of vision-related QOL—the aspects of QOL most likely to be compromised by poor vision and by treatment for eye disorders— have become accepted in ophthalmology.29 Knowledge about the effect of CMV retinitis on QOL provides information to clinicians and patients about the expected outcomes of therapies and may help policy makers design payment programs and care services that meet the needs of patients. Information on the expected benefit of treatments in terms of health utility, reflecting the patient’s valuation of his or her health state, can be used to evaluate the cost-effectiveness of different strategies.30,31 The Studies of Ocular Complications of AIDS (SOCA) Research Group previously has characterized vision-related QOL and general health-related QOL of patients with AIDS and active CMV retinitis32–35 with a brief, self-reported instrument for patients with AIDS and CMV retinitis, which has been demonstrated to be reliable, valid, and responsive.35 Health utility in patients with AIDS and active CMV retinitis also has been measured with the EuroQol instrument36,37 as an adjunct to the SOCA QOL battery.34 However, neither direct comparison of these measures of QOL between patients with newly diagnosed CMV retinitis and patients with AIDS who do not have retinitis, nor the effect of long-standing CMV retinitis in long-term survivors (a common clinical scenario in the era of HAART) on QOL has been reported. In this article, we report a direct comparison of patients with AIDS without retinitis, with long-standing CMV retinitis, and with newly diagnosed CMV retinitis.

Material and Methods The Longitudinal Study of Ocular Complications of AIDS (LSOCA) is an ongoing multicenter epidemiologic study that evaluates ocular complications of AIDS. Patients with AIDS, according to the 1993 Centers for Disease Control and Prevention Revised Surveillance Case Definition,38 aged 13 years and older, are enrolled and followed up at 19 AIDS ophthalmology clinics throughout the United States (see Appendix). Institutional Review Board approval has been obtained at each site.

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At the time of enrollment, demographic characteristics are recorded. Patients also provide a medical and social history and undergo visual function testing, ophthalmologic examination, phlebotomy, and evaluation of QOL. Medical history includes a detailed history of antiretroviral therapy and whether the use of HAART has resulted in an immunologic response. For purposes of this article, “HAART response” is defined immunologically as an increase in the absolute CD4⫹ T-cell count by at least 50 cells per microliter above the nadir to a level ⬎100 cells per microliter13,24 as of, or before, study enrollment. Patients are classified as having CMV retinitis or not on the basis of ophthalmoscopy through a dilated pupil by a SOCAcertified ophthalmologist. CMV retinitis is diagnosed on the basis of its characteristic clinical appearance of a necrotizing, fullthickness retinitis39 or the characteristic clinical appearance of a healed CMV retinitis scar. For purposes of this article, the date of initial CMV retinitis diagnosis was used to characterize CMV retinitis as “newly diagnosed” (diagnosed ⱕ45 days before LSOCA enrollment) or “long-standing” (diagnosed ⱖ46 days before enrollment), because long-term survivors with CMV retinitis have different clinical characteristics than newly diagnosed patients.40 Best-corrected visual acuity is measured as the number of letters read from a logarithmic visual acuity chart41,42 under standardized illumination.43 With this method, more letters read represents better visual acuity (85 letters read corresponds to a visual acuity of 20/20), and a decrement of 15 letters denotes a doubling of the visual angle. Goldmann perimetry is performed according to a modified Diabetic Retinopathy Study technique in which the degrees of field along 12 clock-hour meridians, with the IV-4-e test stimulus, are summed.42,44 The sum, when divided by 6, gives the average diameter of the visual field. Laboratory studies include lymphocyte subset analysis, measured by flow cytometry. Human immunodeficiency virus (HIV) viral load is determined locally at each clinical center by using plasma specimens. Plasma CMV viral load is measured at a central laboratory by the Roche Amplicor System, with a threshold sensitivity of 400 copies per milliliter.45 Because CMV retinitis in patients with AIDS is associated with both visual and systemic morbidity, QOL is measured in both vision-related and general health-related QOL domains. Measurement is conducted before completion of the ophthalmologic examination to limit the effect that the eye examination findings may have on self-reported QOL. Vision-related QOL is measured with an instrument specifically developed to be responsive to the effects of CMV retinitis and its treatment,46 and it has been found to be a valid, reliable, and responsive measure of vision-related QOL in this setting.35 General health-related QOL is measured by using questions from the Medical Outcome Study–HIV Health Survey that address the domains of physical function, pain, role function, energy, social function, mental health, and cognitive function.47 The “general health perceptions” domain is based on the self-rated QOL question of the Medical Outcome Study–HIV Health Survey, supplemented by four general health items designed for use in a trial for treatment of Pneumocystis carinii pneumonia.48,49 The vision-related QOL and general health-related QOL scales used both provide a score from 0 to 100, with 100 representing the most favorable and 0 representing the least favorable possible QOL state for the domain measured. Health utility was measured with the EuroQol instrument— both the visual analog scale (VAS) and five-dimension (equation 5D) components.36,37 The VAS requires a patient to mark where his or her current health state lies on a “thermometer” scale, from 0 (death) to 100 (perfect health), yielding a utility score. The Multiattribute EuroQol (EQ-5D) generates a utility score based on patients’ answers to five questions about anxiety/depression, mobility, usual activities, pain/discomfort, and self-care. It is scored on a scale of ⫺0.594 (worst imaginable

Kempen et al 䡠 The Effect of CMV Retinitis on Quality of Life health) to 1 (perfect health) on the basis of the preferences of a standard population for each possible combination of answers. Thus, the EQ-5D score can range from ⫺0.594 to 1.00. Data from the enrollment visit of the first 1003 LSOCA subjects (enrolled between September 1998 and March 2001) are evaluated in this article. Statistical analysis was performed with SAS software (SAS for Windows, Version 8.1; SAS Institute Inc., Cary, NC). The distributions of demographic and clinical characteristics and of QOL scores in the CMV retinitis groups were compared by using the chi-square statistic for categorical data or linear regression for continuous data. Selected scale scores were subjected to multiple regression with general linear models to adjust for potentially confounding demographic and clinical characteristics.

Results As of July 2, 2001, 971 (96.8%) of the 1003 eligible patients had enrollment QOL measurements available in the LSOCA database. Of these, 709 (73%) did not have CMV retinitis; 212 (22%) had long-standing CMV retinitis (diagnosed a median of 34.5 months before enrollment); and 50 (5.1%) had newly diagnosed CMV retinitis. The long-standing CMV retinitis group had demographic and clinical characteristics similar to the group with no CMV retinitis, except that in the former group, the percentages of disabled or unemployed subjects (76.4% vs. 64.1%; P ⫽ 0.004) and with detectable CMV DNA in their plasma (8.0% vs. 1.9%; P ⬍ 0.0001) were higher (Table 1). More long-standing CMV retinitis patients than patients without CMV retinitis were men who had sex with men, and fewer were black. The median CD4⫹ T-cell count nadir also was substantially lower in the long-standing CMV retinitis group than in the no CMV retinitis group (11.5 vs. 41 cells per microliter; P ⬍ 0.0001), but the median current CD4⫹ T-cell counts were similar (166 vs. 163.5 cells per microliter; P ⫽ 0.83). In contrast, the group with newly diagnosed CMV retinitis had demographic and clinical characteristics that were substantially different from those of the other groups. Patients with newly diagnosed CMV retinitis were significantly more likely to be female, to be younger in age, to be black, to have detectable CMV DNA in their plasma, and to have been diagnosed with AIDS more recently, and they were less likely to be taking HAART currently and to have had immune recovery. The median HIV viral load was higher, and the median CD4⫹ T-cell count lower in the newly diagnosed CMV retinitis group than in the other two groups. However, the median CD4⫹ T-cell count nadir (9 vs. 11.5 cells per microliter; P ⫽ 0.36) and the proportion disabled or unemployed (77.6% vs. 76.4%; P ⫽ 0.28) in the newly diagnosed and longstanding CMV retinitis groups were similar. Visual acuity and visual field results were significantly better in the group without CMV retinitis than in the CMV retinitis groups (Table 1). In CMV retinitis patients’ worse eyes, visual acuity and visual field results were better in the newly diagnosed group than the long-standing group, but these values were similar for the better eyes of patients in these groups. QOL and health utility scores by CMV retinitis status are given in Table 2. The long-standing and newly diagnosed CMV retinitis groups scored substantially worse in vision-related QOL than the no CMV retinitis group on all three scales (P ⬍ 0.001). However, vision-related QOL scores were similar in the long-standing and newly diagnosed CMV retinitis groups. In contrast, general health-related QOL scores for the longstanding CMV retinitis group tended to be similar to, or better than, those for the no CMV retinitis group. The newly diagnosed CMV retinitis group scored substantially lower than the other groups for most scales. Exceptions included the cognitive function

scale, on which the no CMV retinitis group scored less well than the long-standing and newly diagnosed CMV retinitis groups, and the role function scale, in which the no CMV retinitis group scored higher than each of the CMV retinitis groups. Health utility results differed according to which measure of health utility was used. For the VAS measure of health utility, the no CMV retinitis group and the long-standing CMV retinitis group scored similarly, whereas the newly diagnosed CMV retinitis group scored worse (overall P ⫽ 0.033). However, multiattribute EuroQol (EQ-5D) scores were similar among the three groups (overall P ⫽ 0.40). Multiple regression results for selected summary QOL scales are given in Table 3. Adjustment for the potentially confounding effects of demographic factors and clinical characteristics did not alter the pattern of lower visual function scores in the longstanding (P ⬍ 0.0001) and newly diagnosed (P ⫽ 0.017) CMV retinitis groups with respect to the no CMV retinitis group. Likewise, physical function scores in the newly diagnosed CMV retinitis group remained significantly lower than in the no CMV retinitis group (P ⫽ 0.036). However, adjustment for potential confounding attenuated the differences between the newly diagnosed CMV retinitis group and the other groups in general health perceptions (P ⫽ 0.12 and P ⫽ 0.093 with respect to the no CMV retinitis and long-standing CMV retinitis groups, respectively) and VAS health utility (P ⫽ 0.065 and P ⫽ 0.28, respectively). After adjustment, mental health scores were no longer significantly better in the long-standing CMV retinitis group than in the other groups (P ⫽ 0.061 and P ⫽ 0.16 with respect to the no CMV retinitis and newly diagnosed CMV retinitis groups, respectively). Even though most of the subjects studied were not elderly (mean age, 42 years), higher age was significantly associated with lower visual function (P ⬍ 0.0001). Detectable CMV DNA in the blood was associated with substantially lower VAS health utility (P ⫽ 0.0056). Current CD4⫹ T-cell count was more strongly associated with lower general health-related QOL and lower health utility than current use of HAART or current HIV viral load.

Discussion These results suggest that vision-related QOL is reduced substantially by CMV retinitis, whether newly diagnosed or long-standing. For patients with newly diagnosed CMV retinitis, this observation is consistent with a report that loss of visual acuity commonly occurs by the time CMV retinitis is diagnosed.12 For patients with long-standing CMV retinitis, the reduction in vision-related QOL is also consistent with knowledge about the clinical course of CMV retinitis in the era of HAART. Unlike many organ systems affected by common opportunistic complications of AIDS, the retina is a nonrenewing tissue with a low degree of plasticity. The precise localization of the highest degree of function in small structures, the macula and the optic nerve, makes it possible for small retinal lesions to cause major, irreversible visual damage. Although use of HAART is associated with decreased progression of retinal necrosis7 and with lower risk of retinal detachment,13 it cannot restore the retina when such damage already has occurred. In addition, HAART occasionally may cause vision loss via the mechanism of immune recovery uveitis, which occurred in 14% of our patients with long-standing CMV retinitis.40 Thus, patients with long-standing CMV retinitis would be expected to have vision-related QOL similar to, or worse than,

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Ophthalmology Volume 110, Number 5, May 2003 Table 1. Characteristics of the Patient Population by Cytomegalovirus (CMV) Retinitis Status

Variable n Time since retinitis diagnosis, mos, median (SD) Demographics Gender (% male) Age, yrs (mean) Race (%) White Black Hispanic Other Education (%) ⱕHigh school ⱖSome college Employment (%) Disabled/unemployed Employed Homemaker/student/retired HIV risk factors (%) MSM IDU, no MSM Other AIDS Time since AIDS diagnosis, mos (median) HAART ever (%) HAART current (%) HAART response (%) Nadir CD4⫹ T-cell count, cells/ ␮l (median) CD4⫹ T-cell count at enrollment, cells/␮l (median) CD4⫹ T-cell count at enrollment, category (%) ⱕ50 cells/␮l 51–100 cells/␮l 101–200 cells/␮l 201–500 cells/␮l ⬎500 cells/␮l HIV load at study enrollment Current HIV load (%) ⱕ400 copies/ml 401–2500 copies/ml 2501–75000 copies/ml ⬎75,000 copies/ml CMV load in blood ⱖ400 copies/ml (%) Vision Visual acuity (median, standard letters) Better eye Worse eye Visual field, average diameter (median, degrees) Better eye Worse eye

No CMV Retinitis

Long-standing CMV Retinitis

Newly Diagnosed CMV Retinitis

709 —

212 34.5 (19.3)

50 0.23 (0.37)

80.4 42.4

84.4 41.7

67.3 37.2

54.1 28.5 14.1 3.3

57.1 19.3 18.9 4.7

44.9 42.9 6.1 6.1

33.7 66.3

26.4 73.6

33.3 66.7

64.1 28.6 7.3

76.4 18.9 4.7

77.6 22.4 0.0

62.9 7.8 29.3

71.9 2.9 25.2

56.2 4.2 39.6

87.5

89.9

87.7 61.9 57.9 41

76.7 67.9 59.8 11.5

163.5

166

P Value Overall

0.023 ⬍0.001 0.007

No vs. Long-standing CMV Retinitis

0.19 0.19 0.032

Long-standing vs. Newly Diagnosed CMV Retinitis

0.006 ⬍0.001 0.002

0.14

—

—

0.004

0.004

0.28

0.020

0.013

0.11

78.3

0.54

—

—

80.0 50.0 18.8 9

⬍0.001 0.047 ⬍0.001 ⬍0.001

⬍0.001 0.11 0.63 ⬍0.001

⬍0.001 0.017 ⬍0.001 0.36

24

⬍0.001

0.83

⬍0.001

⬍0.001

0.79

⬍0.001

⬍0.001 ⬍0.001

0.051 0.46

⬍0.001 ⬍0.001

23.5 12.4 19.9 35.0 9.2 2172

26.3 11.0 19.6 32.1 11.0 1150

71.4 8.2 10.2 10.2 0.0 31,283

39.2 11.1 27.0 22.7 1.9

44.5 11.5 22.0 22.0 8.0

6.7 13.3 26.7 53.3 29.8

⬍0.001

⬍0.001

⬍0.001

91 88

88 76

88 81

⬍0.001 ⬍0.001

⬍0.001 ⬍0.001

0.30 0.009

126 121

114 87

118 100

⬍0.001 ⬍0.001

⬍0.001 ⬍0.001

0.16 0.048

AIDS ⫽ the acquired immune deficiency syndrome; HAART ⫽ highly active antiretroviral therapy; HIV ⫽ human immunodeficiency virus; IDU ⫽ injection drug use; MSM ⫽ men who have sex with men; SD ⫽ standard deviation.

that in newly diagnosed patients, as observed in our study participants. The lower vision-related QOL in the CMV retinitis groups mirrored the reductions in visual acuity and

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visual field performance in these patients, providing confirmation of the validity of our vision-related QOL results. Measures of health-related QOL are reduced substan-

Kempen et al 䡠 The Effect of CMV Retinitis on Quality of Life Table 2. Distribution of Mean Quality of Life Scores by Cytomegalovirus (CMV) Retinitis Status

Variable Vision-related quality of life Visual function Visual symptoms Vision rating General health-related quality of life General health perceptions Physical function Pain Role function Energy Social function Mental health Cognitive function Quality of life rating Health utility Visual analog scale EQ-5D

P Value

No CMV Retinitis

Long-standing CMV Retinitis

Newly Diagnosed CMV Retinitis

Overall

No vs. Long-standing CMV Retinitis

Long-standing vs. Newly Diagnosed CMV Retinitis

82.4 87.2 64.5

71.4 69.7 49.1

75.6 62.6 46.9

⬍0.001 ⬍0.001 ⬍0.001

⬍0.001 ⬍0.001 ⬍0.001

0.36 0.10 0.67

60.5

61.8

50.1

0.004

0.37

0.001

70.1 65.0 45.2 53.9 73.4 67.4 74.6 65.7

70.1 69.7 37.4 55.6 71.2 71.2 81.3 67.8

57.7 61.6 31.6 46.6 58.0 64.7 80.3 57.5

0.004 0.050 0.014 0.070 0.004 0.012 0.001 0.023

0.76 0.029 0.026 — 0.41 0.007 0.001 0.15

0.003 0.064 0.32 — 0.010 0.033 0.96 0.009

72.5 0.71

72.3 0.73

63.9 0.75

0.033 0.40

0.91 —

0.015 —

EQ-5D ⫽ EuroQol multiattribute health utility measurement.

tially in patients with AIDS who have severe immune deficiency as indicated by low CD4⫹ T-cell counts49 –52 and high viral loads,48 effects that also were observed in our study participants. Compared with the no CMV retinitis group and the long-standing CMV retinitis group, patients with newly diagnosed CMV retinitis, on average, had lower general health-related QOL and health utility in most domains. Although the newly diagnosed CMV retinitis group tended to have lower CD4⫹ T-cell counts and higher HIV viral load than the other groups, adjustment for these and other factors only partially explained their lower QOL scores. Potential explanations of the residual reduction in QOL include the following: (1) incidence of CMV retinitis may be a marker indicating functional immunologic failure over and above that captured by CD4⫹/HIV viral load category, or (2) CMV viremia may cause systemic symptoms directly52 and/or via transactivation of HIV53 to a degree that is incompletely captured by a single measurement of CMV DNA in plasma. It is unlikely that being informed of the diagnosis of CMV retinitis led patients to report lower general health-related QOL, because questions addressing recent changes in health status showed no differences among groups (data not shown). In contrast, the group with long-standing CMV retinitis had general health-related QOL scores similar to or better than those in the group without CMV retinitis. At one time, patients with long-standing CMV retinitis had experienced immune compromise to a degree similar to that in the newly diagnosed CMV retinitis group, as indicated by similar median CD4⫹ T-cell count nadirs in these groups. However, enough had experienced immune recovery, as a result of HAART, that the current distribution of CD4⫹ T-cell counts was similar to that in the group without retinitis at the time

of enrollment. Immune recovery, which was observed in most of the long-standing CMV retinitis patients, and survivorship effects (discussed below) are likely explanations of the relatively high general health-related QOL and health utility scores in the long-standing CMV retinitis group. Thus, it seems that the main intermediate-term QOL consequence of CMV retinitis among intermediate-term survivors is reduced vision-related QOL. The benefits of avoiding loss of vision-related QOL in this group of people, who will bear visual disability for many years, are likely to be missed by standard cost-effectiveness analysis, in which the only measure of treatment effectiveness is health utility,30 which was not responsive to the deficits experienced by this group in our study. The best way to avoid loss of vision-related QOL would be through primary prevention of CMV retinitis. Unfortunately, no cost-effective specific anti-CMV prophylactic strategy exists to date.54 However, the reduced incidence of CMV retinitis in the HAART era4 –7 suggests that combination antiretroviral therapy already is preventing or delaying CMV retinitis for many patients. Our cross-sectional data are insufficient to evaluate whether CMV retinitis is associated with lower general health-related QOL or health utility outcomes in patients with AIDS over the long run. Long-term follow-up is needed to evaluate this issue. As with all observational studies, our study has inherent weaknesses that must be considered in interpreting results. However, a randomized study to evaluate the effect of CMV retinitis itself on QOL is not ethically possible. One issue arises from the recruitment of participants from subspecialty eye clinics. Because participants were able to attend the clinic and perform the study procedures, such patients may be healthier than otherwise comparable patients with AIDS,

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Ophthalmology Volume 110, Number 5, May 2003 Table 3. Multiple Regression Models: Adjusted Difference in Quality of Life Score Characteristic Female vs. male Higher age (per year) Race Black vs. white Hispanic vs. white Other vs. white Education ⱕHigh school vs. some college HIV risk factors IDU vs. MSM Other vs. MSM Current HAART No vs. yes Current CD4⫹ T-cell count (cells/␮l) ⱕ50 vs. ⱖ501 51–100 vs. ⱖ501 101–200 vs. ⱖ501 201–500 vs. ⱖ501 Current HIV viral load quartile (with respect to ⱕ400 copies/ml) 401–2500 copies/ml 2501–75,000 copies/ml 75,000 copies/ml CMV retinitis Long-standing vs. none Newly diagnosed vs. none CMV DNA load in blood ⬎400 copies/ml vs. ⱕ400 copies/ml

Visual Function

General Health

Physical Function

Mental Health

Health Utility (VAS)

⫺2.6 ⫺0.37* Overall P ⫽ 0.72 ⫺1.7 ⫺1.2 ⫺2.7

⫺2.7 ⫹0.17 Overall P ⫽ 0.38 ⫹5.7 ⫹3.2 ⫹2.6

⫺0.59 ⫺0.17 Overall P ⫽ 0.37 ⫹2.7 ⫹4.4 ⫹2.4

⫺2.7 ⫹0.23† Overall P ⫽ 0.72 ⫹1.7 ⫹1.9 ⫹2.1

⫺3.2 ⫹0.12 Overall P ⫽ 0.50 ⫹4.4 ⫹3.7 ⫹0.64

⫺3.1 Overall P ⫽ 0.33 ⫺4.5 ⫺2.0

⫺2.5 Overall P ⫽ 0.53 ⫺3.5 ⫺0.25

⫺7.0 Overall P ⫽ 0.20 ⫺6.4 ⫺3.9

⫺6.5 Overall P ⫽ 0.41 ⫹4.4 ⫹0.74

⫺1.5 Overall P ⫽ 0.27 ⫺2.7 ⫹1.8

⫺0.76 Overall P ⫽ 0.34 ⫺2.4 ⫺5.7 ⫺1.5 ⫺2.9 Overall P ⫽ 0.33

⫺1.8 Overall P ⫽ 0.001 ⫺9.3‡ ⫺9.0† ⫺6.7§ ⫺0.70 Overall P ⫽ 0.53

⫺2.3 Overall P ⫽ 0.21 ⫺7.4 ⫺7.1 ⫺6.2 ⫺4.1 Overall P ⫽ 0.20

⫺2.1 Overall P ⫽ 0.11 ⫺3.4 ⫺6.9§ ⫺1.2 ⫺0.79 Overall P ⫽ 0.41

⫺0.58 Overall P ⫽ 0.002 ⫺7.2‡ ⫺4.3 ⫺2.5 ⫹0.40 Overall P ⫽ 0.27

⫺1.8 ⫺1.8 ⫺0.10

⫺0.07 ⫺0.13 ⫺4.0

⫹0.86 ⫺3.3 ⫺4.0

⫺0.70 ⫹0.64 ⫹0.77

⫹0.50 ⫹0.85 ⫺0.23

⫺11.5* ⫺8.0§

⫹1.2 ⫺5.1

⫺1.5 ⫺8.9§

⫹3.3 ⫺1.7

⫺0.25 ⫺3.8

⫺1.9

⫺5.4

⫺7.1

⫹2.9

⫺8.9†

*P ⬍ 0.001. † P ⬍ 0.01. ‡ P ⬍ 0.005. § P ⬍ 0.05. CMV ⫽ cytomegalovirus; HAART ⫽ highly active antiretroviral therapy; HIV ⫽ human immunodeficiency virus; IDU ⫽ injection drug use; MSM ⫽ men who had sex with men; VAS ⫽ visual analog scale.

yet they may tend to have more visual complaints, motivating them to seek ophthalmic consultation. Thus, general health-related QOL and health utility may tend to be higher, and vision-related QOL may tend to be lower, in our subjects than in more “average” groups of patients with AIDS. However, because patients in the three groups were recruited from the same sites, it is unlikely that this effect caused the large differences we observed in comparisons between groups. Another issue is that of potential prevalence–incidence bias for the comparisons involving the longstanding CMV retinitis group. Subjects who survived long enough after CMV retinitis diagnosis to be enrolled in LSOCA would be expected to have higher health-related QOL scores than otherwise similar nonsurvivors would have had, which is the pattern we observed in most general health-related QOL and health utility scales. This mechanism is a potential explanation of differences we observed in which the long-standing CMV retinitis group scored better than another group, but it would be expected to attenuate rather than exaggerate differences in which the long-standing CMV retinitis group scored more poorly than another group, such as for vision-related QOL. Because long-term survivors with CMV retinitis and AIDS are precisely the group we wish to make inferences about, this issue is less important for our study than in other situations.

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In summary, we found that patients with AIDS and CMV retinitis, whether newly diagnosed or long-standing, had reduced vision-related QOL, even though patients with long-standing CMV retinitis had general health-related QOL and health utility similar to that for patients without CMV retinitis. In addition to poor vision-related QOL, patients with newly diagnosed CMV retinitis also tended to score more poorly in general health-related QOL and health utility, differences that were explained only partially on the basis of confounding demographic and clinical characteristics. Because vision-related QOL remains compromised by CMV retinitis even when general health-related QOL and health utility improve in response to HAART, strategies to prevent CMV retinitis in patients at high risk seem to be warranted.

Appendix: Members of the Studies of Ocular Complications of AIDS Research Group Baylor College of Medicine, Cullen Eye Institute, Houston, Texas: Richard Alan Lewis, MD, MS (Director); Richard C. Allen, MD; Pamela Frady; Ronald Gross, MD;

Kempen et al 䡠 The Effect of CMV Retinitis on Quality of Life Silvia Orengo-Nania, MD; Laura Shawver, COT; James W. Shigley, CRA; Benita Slight, COT; Steven Spencer, BA, COMT; and Stephen P. Travers, CRA. Emory University Eye Center, Atlanta, Georgia: Daniel F. Martin, MD (Director); Denise Armenger; John Closek, COT; Alex DeLeon; David Furukuwa, PA; Deborah Gibbs, COMT; James Gilman, CRA; Bob Myles, CRA; James P. Steinberg, MD; and Sandra Strittman (former members: Antonio Capone, Jr, MD; and Baker Hubbard, MD). Indiana University, Indianapolis: L. Joseph Wheat, MD (Director); Janice Brown; Thomas Ciulla, MD; Ronald Danis, MD; Jean Craft, RN, CS; Janet Hernandez, RN; Linda Pratt, RN; Tim Steffens, CRA; and Beth Zwickl, RN, CS, MSN (former member: Janet Stuart). Johns Hopkins University School of Medicine, Baltimore, Maryland: J. P. Dunn, MD (Director); Stephen G. Bolton, CRNP; Diane M. Brown, RN; Lisa M. Brune, RN, BSN; Dennis Cain; David Emmert; Douglas A. Jabs, MD, MBA; John H. Kempen, MD, PhD; Laura G. Neisser, COT; George B. Peters, III, MD; Richard D. Semba, MD, MPH; and Jennifer E. Thorne, MD (former members: Patricia Barditch, MD; Rebecca Becker, PA-C; Terry George; Paul A. Latkany, MD; Quan D. Nguyen, MD; Susan LaSalvia, RN; and Aruna Subramanian, MD). Louisiana State University Medical Center, New Orleans: Bruce Barron, MD (Director); Robin Bye, RN; Rebecca Clark, MD; Larry Dillon, COT; and Christine Jarrott, RN (former members: John Bennett, COT; Mandi Conway, MD; and Gholam Peyman, MD). New Jersey Medical School, Newark: Ronald Rescigno, MD (Director); Rosa Paez-Boham, COST; and Marta Paez-Quinde (former member: Eileen Buroff). New York Hospital—Cornell Medical Center, New York, New York: Murk-Hein Heinemann, MD (Director); Kenneth Boyd; Charles Cole, MD; Roberta Janis, RN, BSN; Jean Mamakos, RN, MSN; Joseph Murphy, MD; Diane (Iglesias) Rivera, COA; and Kent Sepkowitz, MD (former member: Firas M. Rahhal, MD). New York University Medical Center, New York, New York: Dorothy N. Friedberg, PhD (Director); Adrienne Addessi, MA, RN; Douglas Dieterich, MD; Jason Hill; Richard Hutt, RN; Monica Lorenzo-Latkany, MD; and Maria Pei, COA (former member: Alex McMeeking, MD). Northwestern University, Chicago, Illinois: David V. Weinberg, MD (Director); Alexander Habib; Jill Koecher; Alice T. Lyon, MD; Annmarie Mun˜ ana, RN; Robert L. Murphy, MD; and Jonathan Shankle (former members: Daniel Andrews, MD; Steve Grohmann, MD; Robert Hirshstick, MD; Pamela Hulvey; Frank Palella, MD; Peter Pertel, MD; Michelle Till, MD; Jamie VonRoen, MD; and James Yuhr). Rush University, Chicago, Illinois: Mathew W. MacCumber, MD, PhD (Director); Bruce Gaynes, OD, PharmD; Harold Kessler, MD; Pauline Merrill, MD; and Frank Morini (former member: Andrea Kopp). University of California, Irvine, Irvine, California: Baruch D. Kuppermann, MD, PhD (Director); Marcia Alcouloumre, MD; Donald N. Forthal, MD; Jeff Grijalva, COT; Santosh Patel, MD; Mark Thomas, CRA; Bret Trump; and Melody Vega, COA (former members: Karen Lopez; Nader Moinfar, MD; and Randy Williams). University of California, Los Angeles, Los Angeles, California: Gary N. Holland, MD (Director); Robert D. Almanzor; Margrit E. Carlson, MD; Suzette A.

Chafey, RN, NP; Ann K. Johiro, RNC, FNP; Ardis A. Moe, MD; Susan S. Ransome, MD; Robert Stalling, COA; and Dennis Thayer, CRA. University of California, San Diego, San Diego, California: William R. Freeman, MD (Director); Tom Clark; Francesca Torriani, MD; and Tekeena Young (former members: Sunan Chaidhawanqual, MD; Lingyun Cheng, MD; Mark Cleveland; Randall L. Gannon; Claudio Garcia, MD; Marietta Karavellas, MD; Mi-Kyoung Song, MD; and Dorothy Wong). University of California, San Francisco, San Francisco, California: Jacque Duncan, MD (Director); Fermin Ballesteros; Robert Bhisitkul, MD, PhD; David Clay; Michael Deiner; Jacqueline Hoffman; Alexander Irvine, MD; Mark Jacobson, MD; Todd Margolis, MD, PhD; and Michael Narahara (former members: Judith Aberg, MD; James Larson; Jody Lawrence, MD; and James O’Donnell, MD). University of North Carolina, Chapel Hill, Chapel Hill, North Carolina: Travis A. Meredith, MD (Director); Debra Cantrell; Kelly DeBoer; Angela Jeffries; Roje Kaemaz; Maurice B. Lander, MD; Kean T. Oh, MD; Cecilia A. Sotelo, RN; and David Wohl, MD (former members: Stephanie Betran; David Eifrig, MD; John Foley, MD; Jan Kylstra, MD; Barbara Longmire; Sharon Myers; Jeremy Pantell; Susan Pedersen, RN; Cadmus Rich, MD; Charles van der Horst, MD; and Samir Wadhvania). University of Pennsylvania Medical Center, Philadelphia, Pennsylvania: Charles W. Nichols, MD (Director); Mark Bardsley, BSN; Cheryl C. Devine, MD; Rob Roy MacGregor, MD; Albert M. Maguire, MD; Keith Mickelberg, RN; and William Nyberg (former members: Christopher Helker, RN, MSPH; and Karen McGibney, RN). University of Southern California, Los Angeles, California: Jennifer I. Lim, MD (Director); Tom S. Chang, MD; Francoise Kramer, MD; Lori Levin, MPH; Tracy Nichols, COA, CRA; Christopher Pelzek, MD; and A. Frances Walonker, CO, MPH (former members: John Canzano, MD; and Christina Flaxel, MD). University of South Florida, Tampa, Florida: Peter Reed Pavan, MD (Director); Sandra Gompf, MD; Bonnie Hernandez, COT; JoAnn Leto, COT; Sharon Millard, RN, COT; Scott Paulter, MD; Nancy Rovira, COA; and Wyatt Saxon (former members: James Habib, MD; and Jeffrey Nadler, MD). University of Texas Medical Branch, Galveston, Galveston, Texas: Helen K. Li, MD (Director); Robert I. Blem, MD; John Horna, BS; Vivian Keys; Zbigniew Krason; Beverly B. Mizell, RN; Lan-Chi Nguyen; and Michelle Onorato, MD (former members: Richard Irwin; Richard B. Pollard, MD; Kim Schuenke, PhD; and Sami H. Uwaydat, MD). Chairman’s Office, The Johns Hopkins University School of Medicine, Baltimore, Maryland: Douglas A. Jabs, MD, MBA (Study Chairman); Nancy H. Davidson; Judy C. Southall; and Maria Stevens (former members: Wanda M. Chaney, BS; and Joan L. Klemstine). Coordinating Center, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland: Curtis L. Meinert, PhD (Director); Debra A. Amend-Libercci; Cathleen S. Bosley; Karen L. Collins; Betty J. Collison; Joan Dodge; John Dodge; Michele Donithan, MHS; Kevin Frick, PhD; Adele M. Kaplan Gilpin, JD, PhD; Judith Harle; Janet T. Holbrook, MS, MPH, PhD; Milana R. Isaacson, BS; Rosetta M. Jackson; John H. Kempen, MD, PhD; Hope Livingston; Barbara K. Martin, PhD; Jennifer Meyers;

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Ophthalmology Volume 110, Number 5, May 2003 Nancy Min, MPH, PhD; Laurel Murrow, MS; Pamela Scott, MA; Michael Smith; Paul Smith; Erica Smothers; James A. Tonascia, PhD; Mark L. Van Natta, MHS; Emily West; Claudine Woo, MPH; Albert Wu, MD, MPH; and Alice Zong (former member: Maria J. Oziemkowska, MS, MPH). Fundus Photograph Reading Center, University of Wisconsin, Madison, Wisconsin: Matthew D. Davis, MD (Director); Jane Armstrong; Sheri Glaeser; Larry Hubbard; Dolores Hurlburt; Jeffrey Joyce; Linda Kastorff; Michael Neider; Nancy Robinson, AB; Therese Traut; Marilyn Vanderhoof-Young; and Hugh Wabers. National Eye Institute, Bethesda, Maryland: Natalie Kurinij, PhD. National Institute of Allergy and Infectious Diseases, Bethesda, Maryland: Beverly L. Alston, MD. Officers of the Study: Douglas A. Jabs, MD, MBA (Chair); Matthew D. Davis, MD; Janet T. Holbrook, PhD; Natalie Kurinij, PhD; and Curtis L. Meinert, PhD (former member: James A. Tonascia, PhD). Steering Committee: Douglas A. Jabs, MD, MBA (Chair); Beverly L. Alston, PhD; Rebecca Clark, MD; Tom Clark, CRA; Matthew D. Davis, MD; William R. Freeman, MD; Janet T. Holbrook, MS, MPH, PhD; Gary N. Holland, MD; Larry D. Hubbard, MAT; Mark Jacobson, MD; Natalie Kurinij, PhD; Curtis L. Meinert, PhD; Annmarie Mun˜ ana, RN; P. Reed Pavan, MD; Steven Spencer, BA, COMT; Dennis Thayer; and Francesca Toriani, MD (former members: Adrienne Addessi, MA, RN; Janet Davis, MD; Dorothy Friedberg, MD; James Gilman; Robert Murphy, MD; James A. Tonascia, PhD; Charles van der Horst, MD; and Fran Wallach). Policy and Data Monitoring Board: John P. Phair, MD (Chair); Beverly L. Alston, MD; Brian P. Conway, MD; Barry R. Davis, MD, PhD; Matthew D. Davis, MD; Douglas A. Jabs, MD, MBA; Argye Hillis, PhD; Janet T. Holbrook, MS, MPH, PhD; Natalie Kurinij, PhD; Curtis L. Meinert, PhD; Robert B. Nussenblatt, MD; Harmon Smith, PhD; and Richard J. Whitley, MD (former members: B. William Brown, Jr, PhD (Chair); James E. Grizzle, PhD; and James A. Tonascia, PhD). Visual Function Quality Assurance Committee: Steven Spencer, BA, COMT (Chair); Richard Alan Lewis, MD, MS (Advisor); Jeff Grijalva, COT; Deborah Gibbs, COMT; Milana Isaacson, BS; Laura G. Neisser, COT; and Rosa Paez-Boham, COST (former members: Ferman Ballesteros and Karen Lopez).

References 1. Hoover DR, Saah AJ, Bacellar H, et al. Clinical manifestations of AIDS in the era of Pneumocystis prophylaxis. N Engl J Med 1993;329:1922– 6. 2. Gallant JE, Moore RD, Richman DD, et al. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group. J Infect Dis 1992;166:1223–7. 3. Hoover DR, Peng Y, Saah A, et al. Occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression. Arch Ophthalmol 1996;114:821–7. 4. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338:853– 60. 5. Varani S, Spezzacatena P, Manfredi R, et al. The incidence of

994

6.

7. 8.

9.

10.

11. 12. 13. 14.

15.

16. 17.

18.

19.

20.

21. 22.

cytomegalovirus (CMV) antigenemia and CMV disease is reduced by highly active antiretroviral therapy. Eur J Epidemiol 2000;16:433–7. Baril L, Jouan M, Agher R, et al. Impact of highly active antiretroviral therapy on onset of Mycobacterium avium complex infection and cytomegalovirus disease in patients with AIDS. AIDS 2000;14:2593– 6. Deayton JR, Wilson P, Sabin CA, et al. Changes in the natural history of cytomegalovirus retinitis following the introduction of highly active antiretroviral therapy. AIDS 2000;14:1163–70. Walsh JC, Jones CD, Barnes EA, et al. Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors. AIDS 1998;12:613– 8. Binquet C, Saillour F, Bernard N, et al. Prognostic factors of survival of HIV-infected patients with cytomegalovirus disease: Aquitaine Cohort, 1986 –1997. Groupe d’Epidemiologie Clinique du SIDA en Aquitaine (GECSA). Eur J Epidemiol 2000;16:425–32. Casado JL, Perez-Elias MJ, Marti-Belda P, et al. Improved outcome of cytomegalovirus retinitis in AIDS patients after introduction of protease inhibitors. J Acquir Immune Defic Syndr Hum Retrovirol 1998;19:130 – 4. Lee V, Subak-Sharpe I, Shah S, et al. Changing trends in cytomegalovirus retinitis with triple therapy. Eye 1999;13:59 – 64. Kempen JH, Jabs DA, Wilson LA, et al. Risk of vision loss in patients with cytomegalovirus retinitis and the acquired immune deficiency syndrome. Arch Ophthalmol (in press). Kempen JH, Jabs DA, Dunn JP, et al. Retinal detachment risk in cytomegalovirus retinitis related to the acquired immunodeficiency syndrome. Arch Ophthalmol 2001;119:33– 40. MacDonald JC, Torriani FJ, Morse LS, et al. Lack of reactivation of cytomegalovirus (CMV) 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;177:1182–7. Jabs DA, Bolton SG, Dunn JP, Palestine AG. Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol 1998;126:817–22. Whitcup SM, Fortin E, Lindblad AS, et al. Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis. JAMA 1999;282:1633–7. MacDonald JC, Karavellas MP, Torriani FJ, et al. Highly active antiretroviral therapy-related immune recovery in AIDS patients with cytomegalovirus retinitis. Ophthalmology 2000; 107:877– 81. Mezzaroma I, Carlesimo M, Pinter E, et al. Clinical and immunologic response without decrease in virus load in patients with AIDS after 24 months of highly active antiretroviral therapy. Clin Infect Dis 1999;29:1423–30. Jouan M, Saves M, Tubiana R, et al. Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIVinfected patients receiving highly active antiretroviral therapy. AIDS 2001;15:23–31. Curi AL, Muralha A, Muralha L, Pavesio C. Suspension of anticytomegalovirus maintenance therapy following immune recovery due to highly active antiretroviral therapy. Br J Ophthalmol 2001;85:471–3. Karavellas MP, Lowder CY, Macdonald JC, et al. Immune recovery vitritis associated with inactive cytomegalovirus retinitis: a new syndrome. Arch Ophthalmol 1998;116:169 –75. 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 Ophthalmol 1998;125:292–300.

Kempen et al 䡠 The Effect of CMV Retinitis on Quality of Life 23. Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 1999;179:697–700. 24. Nguyen QD, Kempen JH, Bolton SG, et al. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000;129:634 –9. 25. Karavellas MP, Song M, Macdonald JC, Freeman WR. Longterm posterior and anterior segment complications of immune recovery uveitis associated with cytomegalovirus retinitis. Am J Ophthalmol 2000;130:57– 64. 26. Robinson MR, Reed G, Csaky KG, et al. Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy. Am J Ophthalmol 2000;130:49 –56. 27. Karavellas MP, Azen SP, MacDonald JC, et al. Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes. Retina 2001;21:1–9. 28. Wu AW. Quality of life assessment comes of age in the era of highly active antiretroviral therapy [editorial]. AIDS 2000;14: 1449 –51. 29. Mangione CM, Lee PP, Gutierrez PR, et al. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol 2001;119:1050 – 8. 30. Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Costeffectiveness in Health and Medicine. New York: Oxford University Press, 1996. 31. Freedberg KA, Losina E, Weinstein MC, et al. The cost effectiveness of combination antiretroviral therapy for HIV disease. N Engl J Med 2001;344:824 –31. 32. The Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus Retreatment Trial. Arch Ophthalmol 1996;114:23–33. 33. The Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. MSL-109 adjuvant therapy for cytomegalovirus retinitis in patients with acquired immunodeficiency: the Monoclonal Antibody Cytomegalovirus Retinitis Trial [published erratum appears in Arch Ophthalmol 1998;116:296]. Ophthalmology 1997;115:1528 –36. 34. The Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: the Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial. Am J Ophthalmol 2001;131:457– 67. 35. Martin BK, Kaplan Gilpin AM, Jabs DA, et al. Reliability, validity, and responsiveness of general and disease-specific quality of life measures in a clinical trial for cytomegalovirus retinitis. J Clin Epidemiol 2001;54:376 – 86. 36. The EuroQol Group. EuroQol—a new facility for the measurement of health-related quality of life. Health Policy 1990; 16:199 –208. 37. Brooks R. EuroQol: the current state of play. Health Policy 1996;37:53–72. 38. Centers for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case defini-

39. 40. 41. 42.

43. 44.

45.

46.

47.

48.

49. 50.

51.

52. 53. 54.

tion for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992;41:1–19. Jabs DA. Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 1995;93:623– 83. Jabs DA, Van Natta ML, Kempen JH, et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2002;133:48 – 61. Ferris FL III, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol 1982;94: 91– 6. The Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group (ACTG). Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial: 1. Rationale, design, and methods. Control Clin Trials 1992;13:22–39. Ferris FL III, Sperduto RD. Standardized illumination for visual acuity testing in clinical research. Am J Ophthalmol 1982;94:97– 8. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology 1978;85:82–106. Jabs DA, Forman M, Enger C, Jackson JB. Comparison of cytomegalovirus loads in plasma and leukocytes of patients with cytomegalovirus retinitis. The Cytomegalovirus Retinitis and Viral Resistance Study Group. J Clin Microbiol 1999;37:1431–5. Wu AW, Coleson LC, Holbrook J, Jabs DA. Measuring visual function and quality of life in patients with cytomegalovirus retinitis. Development of a questionnaire. Studies of Ocular Complication of AIDS Research Group. Arch Ophthalmol 1996;114:841–7. Wu AW, Rubin HR, Mathews WC, et al. A health status questionnaire using 30 items from the Medical Outcomes Study. Preliminary validation in persons with early HIV infection. Med Care 1991;29:786 –98. Safrin S, Finkelstein DM, Feinberg J, et al. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group. Ann Intern Med 1996;124:792– 802. Weinfurt KP, Willke RJ, Glick HA, et al. Relationship between CD4 count, viral burden, and quality of life over time in HIV-1-infected patients. Med Care 2000;38:404 –10. Chan KS, Revicki DA. Changes in surrogate laboratory markers, clinical endpoints, and health-related quality of life in patients infected with the human immunodeficiency virus. Eval Health Prof 1998;21:265– 81. Wu AW, Revicki DA, Jacobson D, Malitz FE. Evidence for the reliability, validity and usefulness of the Medical Outcomes Study HIV Health Survey (MOS-HIV). Qual Life Res 1997;6:481–93. Klemola E, Kaariainen L. Cytomegalovirus as a possible cause of a disease resembling infectious mononucleosis. Br Med J 1965;5470:1099 –102. Nardiello S, Digilio L, Pizzella T, Galanti B. Cytomegalovirus as a co-factor of disease progression in human immunodeficiency virus type 1. J Clin Lab Res 1994;24:86 –9. Kempen JH, Frick KD, Jabs DA. Incremental cost effectiveness of prophylaxis for cytomegalovirus disease in patients with AIDS. Pharmacoeconomics 2001;19:1199 –208.

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