Cytomegalovirus Retinitis in Patients with AIDS before and after Introduction of HAART in China

Abstract

Purpose:

To determine the prevalence of cytomegalovirus retinitis (CMVR) and other fundus lesions in subjects with acquired immunodeficiency syndrome (AIDS) before and after the introduction of highly active antiretroviral therapy (HAART) in China.

Methods:

The retrospective study included subjects with AIDS who consecutively attended a third referral center in Beijing before and after HAART was introduced. Comprehensive systemic and ophthalmic examinations, including CD4+ T-cell count, ophthalmoscopy, and fundus photography, were carried out.

Results:

A total of 173 HIV-infected, HAART-naive individuals and 267 people undergoing HAART were included in the study. The HAART-naive group as compared with the HAART group was significantly older (39.5 ± 11.5 years versus 36.7 ± 11.2 years; p = 0.02) and included significantly more men (p = 0.045). Prevalence of CMVR, microvascular retinopathy, and optic neuropathy in the HAART group (9.0 ± 1.8%, 7.9 ± 1.7%, and 4.9 ± 1.3%, respectively) were significantly (all p≤0.001) lower than in the HAART-naive group (20.2 ± 3.1%, 31.2 ± 3.5%, and 13.9 ± 2.6%, respectively). Microvascular retinopathy was significantly associated with HAART-naive status (p<0.001; odds ratio [OR] 0.20; 95% confidence interval [CI] 0.12, 0.36) and higher age (p = 0.002; OR 1.04; 95% CI 1.10, 1.06). Cytomegalovirus retinitis was significantly associated with CD4+ cell count <50 cells/μL (p = 0.001; OR 5.50; 95% CI 1.95, 15.5), HAART-naive status (p = 0.02; OR 0.23; 95% CI 0.07, 0.79), and lower best-corrected visual acuity (p<0.001; OR 5.44; 95% CI 2.11, 14.0).

Conclusions:

As in Western countries, prevalence of CMVR and microvascular retinopathy in Chinese subjects with AIDS were significantly associated with a low CD4+ cell count and a HAART-naive status as the 2 major risk factors.

Keywords

AIDS Cytomegalovirus retinitis HIV Microvascular retinopathy

Introduction

The number of people infected by the human immunodeficiency virus (HIV) worldwide has been estimated to be about 34 million, with the vast majority of these subjects living in low to medium income countries (1). The estimated number of HIV-infected subjects in China is approximately 780,000 persons, with 154,000 of them having acquired immunodeficiency syndrome (AIDS) at the end of 2011. The HIV/AIDS epidemic has been spreading from high-risk population groups to the general population (2). Despite the increasing public awareness and concern of HIV/AIDS in China, there is a paucity of data on HIV/AIDS-related retinal diseases available for China (3-6). Numerous reports from other countries described HIV-associated eye abnormalities, which affected about 70%-80% of all subjects early or late during the course of their disease (7-9). In the pre—highly active antiretroviral therapy (HAART) era, the most common AIDS-associated manifestation of cytomegalovirus (CMV) infection was retinitis, accounting for up to 85% of CMV-associated end-organ disease (10-12). The prevalence of CMV retinitis in AIDS varied between studies from different regions. In the United States, prevalence of CMV retinitis ranged from 20% to 40% in individuals with AIDS in the pre-HAART era. In the HAART era, a drop in newly diagnosed US cases of CMV retinitis by 55% to more than 90% was observed over a period of 2 to 3 years (13-16). In Tanzania, the prevalence of CMV retinitis in subjects with AIDS with a CD4+ T-cell count of less than 100 cells/μL was 1.3% (17). Studies from Asian countries including India, Thailand, and Japan reported prevalence figures ranging from 8.7% to 46% (18-20). In view of the wide range of data on the prevalence of CMV retinitis in subjects with AIDS and as few data were available for China, we conducted this study to assess the prevalence of CMV retinitis and other retinal lesions in subjects with AIDS in China, where HIV has been strongly stigmatized for a long time. We differentiated between subjects who were diagnosed before the introduction of HAART into clinical practice (HAART-naive group) and subjects who underwent HAART.

Methods

The study was conducted on individuals with AIDS, who were consecutively treated in the period from 2008 to 2010 in a tertiary hospital specializing in infectious diseases (Beijing Di Tan Hospital). The total group was divided into subjects who were HAART-naive and those who had undergone HAART therapy when they attended the hospital. The ethics committee of the Beijing Di Tan Hospital approved the study and the participants gave informed consent. Highly active antiretroviral therapy was defined as any combination of 3 or more antiretroviral drugs, or a combination containing one protease inhibitor and one non-nucleoside reverse transcriptase inhibitor. After obtaining a detailed medical history, all subjects underwent a medical examination including blood cell analysis and biochemical blood examination. A comprehensive ocular examination was carried out, which consisted of refractometry and measurement of best-corrected visual acuity, slit-lamp examination of the anterior segment, indirect binocular ophthalmoscopy, and fundus photography after pupillary dilatation. After pupillary dilation, the entire retina was examined to detect retinal changes in the periphery of the fundus.

The diagnosis of AIDS was based on the 1993 Centers for Disease Control and Prevention case surveillance definition of AIDS (21). Anemia was defined as a blood hemoglobin concentration less than 12 g/dL, and it was classified into severe, moderate, and mild anemia with hemoglobin levels of less than 7 g/dL, 7 g/dL to less than 10 g/dL, and 10 g/dL to less than 12 g/dL, respectively. Diagnosis of CMV retinitis was made clinically by a senior retinal specialist if the characteristic ophthalmoscopic appearance of a necrotizing retinitis with an edematous or granular white border with or without hemorrhage was detected at, or close to, the posterior pole of the eye. The diagnosis was confirmed by a panel of ophthalmologists by evaluation of fundus photographs. Human immunodeficiency virus—associated retinal microvasculopathy was defined by cotton-wool spots or retinal hemorrhages. Optic neuropathy was characterized by hemorrhages, edema, or pallor of the optic nerve head. According to the World Health Organization definition, low vision and blindness were defined as best-corrected visual acuity (BCVA) <20/60 and ≥20/400 and as BCVA <20/400 in the better-seeing eye, respectively. The causes for low vision and blindness were determined by the senior retinal specialist who examined the subjects directly.

Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 20.0, SPSS Inc., Chicago, IL). The frequency of CMV retinitis, microvascular retinopathy, optic neuropathy, low vision, and blindness were given as mean ± standard error; the values of all other parameters were presented as mean ± standard deviation. The chi-square test was used to compare categorical variables and the Student t test was used for continuous variables. Multiple logistic regression analysis was used to analyze those factors related to the prevalence of posterior segment lesions. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All p values were 2-sided and were considered statistically significant when the values were less than 0.05.

Results

The study included 173 subjects with AIDS who were HAART-naive and 267 consecutive subjects with AIDS undergoing HAART. The HAART-naive group as compared with the HAART group was significantly older (39.5 ± 11.5 years versus 36.7 ± 11.2 years; p = 0.02), and had significantly more men (men/women: 144/29 versus 200/67; p = 0.045). The subjects of the HAART group were under therapy for a mean period of 23.2 months (median 21 months; 95% confidence interval 1, 84).

In the HAART group, the infection had presumably occurred by heterosexual contacts in 30 (32%) subjects, by homosexual contacts in 25 (27%) subjects, by blood transfusions in 24 (26%) subjects, in association with drug abuse in 2 (2%) subjects, and from mother to baby in 13 (14%) subjects out of 94 subjects for whom information on the infection route could be obtained. White blood cell count of less than 4,000 cells/μL, 4,000-10,000 cells/μL, and >10,000 cells/μL was found in 35%, 60%, and 5% of the subjects, respectively. Anemia was detected in 39% of the subjects, including the mild, moderate, and severe form of anemia in 21%, 14%, and 4% of the subjects, respectively. A nadir CD4+ T-cell count of less than 50 cells/μL, 50-99 cells/μL, 100-199 cells/μL, and 200+ cells/μL was found in 26%, 15%, 15%, and 44% of the tested participants, respectively. Cytomegalovirus retinitis was found in 30 eyes of 24 (9.0%) subjects with bilateral involvement in 6 (2.2%) subjects. A microvascular retinopathy was present in 27 (5.1%) eyes of 21 (7.9%) subjects (cotton-wool spots: 21 [3.9%] eyes, 16 [6.0%] patients; retinal hemorrhages: 11 [2.1%] eyes, 9 [3.4%] patients). An optic neuropathy was detected in 22 (4.1%) eyes of 13 (4.9%) subjects, with optic disc pallor being the main type (50%). Visual impairment was present in 10 (3.7%) subjects, and 7 (2.6%) subjects were blind. The major causes for blindness were cataract in 4 subjects, corneal opacity in 1 subject, CMV retinitis at the posterior pole in 1 patient, and optic neuropathy in 1 subject. The major causes for visual impairment was CMV retinitis in 4 subjects, optic neuropathy in 2 subjects, uveitis in 1 subject, and unknown for 3 subjects. Mean best-corrected visual acuity was 0.10 ± 0.35 logMAR (median 0.0; range –0.18 to 2.0) in the right eye and 0.16 ± 0.44 logMAR (median 0.0; range –0.18 to 2.0) in the left eye. The best-corrected visual acuity in the better eye was significantly lower in the subjects with CMV retinitis than in those without retinitis (0.31 ± 0.51 logMAR versus 0.04 ± 0.20 logMAR; p<0.001). Optic neuropathy was detected in 13 (4.9%) subjects, including 4 (1.5%) subjects with unilateral optic neuropathy and 9 (3.4%) subjects with bilateral optic neuropathy. Eleven (50%) eyes showed marked optic disc pallor combined with marked reduction in the visibility of the retinal nerve fiber layer, and 11 (50%) eyes showed optic disc edema and hemorrhages.

In the HAART-naive group, the infection routes were heterosexual sexual contacts (52 [29.9%] subjects), homosexual contacts (31 [17.8%] subjects), bisexual contacts (1 subject), transfusion of infected blood products (34 [19.5%] subjects), injection of narcotic drugs (3 [1.7%] subjects), mother to baby transmission (1 subject), and unknown (51 [29.3%] subjects) (22). A CMV retinitis was detected in 45 eyes of 35 (20.2%) patients, and a microvascular retinopathy was present in 88 eyes of 57 (32.9%) patients (cotton-wool spots: 23.7%; retinal hemorrhages: 11.6%). Among them, 31 patients (54.4%) showed bilateral involvement. In terms of lesion type, the cotton-wool spots were detected in 69 eyes of 41 patients, and retinal hemorrhage developed in 26 eyes of 20 patients. In 7 eyes of 4 patients, cotton-wool spots and retinal hemorrhages were simultaneously present. Visual impairment present in 10 (5.8%) subjects was due to CMV retinitis (n = 3 subjects), optic neuropathy (n = 3), uveitis (n = 1), cataract (n = 1), and unknown reasons (n = 2). Blindness present in 3 (1.8%) subjects was caused by CMV retinitis at the posterior pole (n = 2) and optic neuropathy (n = 1). In those eyes in which visual impairment or blindness were caused by CMV retinitis, the retinitis had affected the macular region.

Comparing the HAART group with the HAART-naive group revealed a significantly lower prevalence of CMV retinitis (9.0 ± 1.8% versus 20.2 ± 3.1%; p = 0.001), microvascular retinopathy (7.9 ± 1.7% versus 31.2 ± 3.5%; p<0.001), and optic neuropathy (4.9 ± 1.3% versus 13.9 ± 2.6%; p = 0.001) (Tab. I). If all retinal and optic nerve lesions were summarized, the difference in their prevalence was statistically significant between the groups (17.6 ± 2.3% versus 50.3 ± 3.8%; p<0.001). Interestingly, the prevalence of visual impairment (3.7% versus 5.8%, p = 0.22) and blindness (2.6% versus 1.8%, p = 0.55) did not differ significantly between the groups; the causes leading to visual impairment and blindness, however, differed between the groups. In the HAART-naive group, CMV retinitis was the major cause, while in the HAART group, the major cause was cataract.

Table I

DEMOGRAPHIC DATA AND EXAMINATION RESULTS OF PATIENTS WITH AIDS, STRATIFIED INTO PATIENTS WHO WERE HAART-NAIVE AND PATIENTS WHO UNDERWENT HAART THERAPY

	HAART-naive group	HAART group	p Value
Number	173	267
Age, y	39.5 ± 11.5	36.7 ± 11.2	0.02
Sex, M/F	144/29	200/67	0.045
Infection route, heterosexual/homosexual/blood transfusion/drug abuse/mother to baby/bisexual	52/31/34/3/1/1	30/25/24/2/13/0
Blood test
White blood cells count <4,000/mL	55.5%	35.0%	0.002
Anemia	110/173	39/100	<0.001
CD4+ T-cell count	56 ± 79	204 ± 163	<0.001
CD8 T-cell count	476 ± 386	628 ± 461	0.004
Ocular parameters
Cytomegalovirus retinitis	35 / 173 (20.2 ± 3.1%; 14.2, 26.3)	24 / 267 (9.0 ± 1.8%; 5.5, 12.4)	0.001 (0.39; 0.22, 0.68)
Retinal cotton-wool spots	53/173 (30.6 ± 3.5%; 23.7, 37.6)	16/267 (6.0 ± 1.5%; 3.1, 8.9)	<0.001 (0.14; 0.08, 0.26)
Retinal hemorrhage	1/173 (0.6 ± 0.6%; 0.00, 1.7)	9 / 267 (3.4 ± 1.1%; 1.2, 5.6)	0.10
Microvascular retinopathy	54 (31.2 ± 3.5%; 24.2, 38.2)	21 (7.9 ± 1.7%; 4.6, 11.1)	<0.001 (0.19; 0.11, 0.33)
Optic neuropathy	24/173 (13.9 ± 2.6%; 8.7, 19.1)	13/267 (4.9 ± 1.3%; 2.3, 7.5)	0.001 (0.32; 0.16, 0.64)
Any retinopathy	87/173 (50.3 ± 3.8%; 42.8, 57.8)	47/267 (17.6 ± 2.3%; 13.0, 22.2)	<0.001 (0.21; 95 0.14, 0.33)

AIDS = acquired immunodeficiency syndrome; CI = confidence interval; HAART = highly active antiretroviral therapy; OR = odds ratio.

Values are n, mean ± SD, n (mean ± SD; 95% confidence interval), or p value (odds ratio; 95% confidence interval).

In univariate analysis, the microvascular retinopathy was significantly associated with older age (p<0.001), lower mean nadir CD4+ cell count (p<0.001), presence of a nadir CD4+ cell count of <50 cells/μL (p = 0.002), and HAART-naive status (p<0.001). In multivariate analysis, presence of microvascular retinopathy remained to be significantly associated with HAART-naive status (p<0.001; OR 0.20; 95% CI 0.12, 0.36) and older age (p = 0.002; OR 1.04; 95% CI 1.10, 1.06), while the presence of a CD4+ cell count of <50 cells/μL (p = 0.18), mean CD4+ cell count (p = 0.07), and sex (p = 0.69) were not significantly associated. In univariate analysis, the presence of CMV retinitis was significantly associated with a CD4+ cell count of less than 50 cells/μL (p<0.001), lower mean CD4+ cell count (p = 0.006), lower best-corrected visual acuity (p<0.001), and HAART-naive status (p = 0.001). In multivariate analysis, CMV retinitis remained significantly associated with the presence of CD4+ cell count <50 cells/μL (p = 0.001; OR 5.50; 95% CI 1.95, 15.5), HAART-naive status (p = 0.02; OR 0.23; 95% CI 0.07, 0.79), and lower best-corrected visual acuity (p<0.001; OR 5.44; 95% CI 2.11, 14.0).

Discussion

Despite the increasing number of patients with HIV/AIDS in China, there is a paucity of HIV/AIDS-related ocular morbidity data in China. We retrospectively studied 440 patients with AIDS who were consecutively treated in a tertiary infectious disease center in Beijing, and who either were naive to HAART therapy since they attended the hospital before HAART was introduced into China or who had undergone HAART after the clinical introduction of HAART. The prevalence of CMV retinitis, microvascular retinopathy, and optic neuropathy were significantly (all p≤0.001) lower in the HAART group than in the HAART-naive group. Microvascular retinopathy was significantly associated with HAART-naive status (p<0.001) and higher age (p = 0.002). Cytomegalovirus retinitis was significantly associated with the presence of CD4+ cell count <50 cells/μL (p = 0.001), HAART-naive status (p = 0.02), and lower best-corrected visual acuity (p<0.001).

The prevalence of fundus lesions in our HAART-naive study population was lower than in populations included in previous investigations from Western countries before the HAART era. Prevalence of CMV retinitis in people with AIDS was reported to be as high as 40% in North America before HAART was available (23-26). Cytomegalovirus retinitis and cotton-wool spots were found in 20.8% and 32.8%, respectively, of subjects with AIDS in Taiwan (27), while CMV retinitis was uncommon in subjects with AIDS from Africa (28, 29). The much lower prevalence figures for CMV retinitis reported from the African continent, as opposed to those found in our study and from North America, probably reflect the fact that many HIV-infected individuals die from other AIDS-related conditions before their immune status decreases to levels at which CMV retinitis typically develops. Interestingly, however, even in those African subjects with low CD4+ levels, the prevalence of CMV retinitis was very low, reported as 1.3% (11). Additional potential reasons for the geographic variation in the prevalence of fundus lesions in subjects with AIDS include differences in socioeconomic conditions, variations in basic health care availability, and different patterns of endemic diseases such as tuberculosis, malaria, and malnutrition.

The prevalence of any fundus lesions in our HAART study population (17.6 ± 2.3%) and of CMV retinitis (9.0 ± 1.8%) was comparable with findings from previous reports from mainland China (30-33). Wang and colleagues reported that in 718 subjects with HIV/AIDS from eastern China, CMV retinitis was the most common ocular complication, with a prevalence of 10.6% (33). Another study from Shanghai found a prevalence of CMV retinitis of 7.6% in 303 subjects with AIDS (31). In a 2008 investigation by Wang et al, CMV retinitis was not found in any of 105 HIV-infected subjects (32). The prevalence of fundus lesions in our study population after HAART was higher than in recent studies from the United States, where CMV retinitis and HIV-associated retinopathy have virtually disappeared. One of the reasons for the differences may be that in the United States, subjects are routinely started on HAART before the CD4+ count falls below 200 cells/μL, and consequently, CMV retinitis has become rare. Also, even in subjects with low CD4+ counts, HIV-associated fundus lesions can resolve rapidly on HAART, often within 1 to 2 months. Differences between countries in the application of HAART and in the therapy for CMV retinitis may also explain differences in the frequency of CMV retinitis in subjects with AIDS and the final visual outcome. In China, HAART is usually provided for free, but testing and treatment must be paid for by patients, and sometimes, patients may be able to afford only a short course of anti-CMV retinitis medication. Also, it may not be uncommon to find a delayed diagnosis and sometimes insufficient treatment of AIDS-related CMV retinitis leading to a relatively poor clinical outcome (31, 34).

Based on the optic disc morphology, the prevalence of optic neuropathy was 13.9% in the HAART-naive group and 4.9% in the HAART group. We might have underestimated the frequency of optic neuropathy, since we did not perform perimetry, nor did we measure the thickness of the retinal nerve fiber layer or perform any other imaging technique to quantify the optic nerve. Optic neuropathy with or without concomitant associated brain involvement may also be encountered in patients with syphilis, which is a common coinfection in people diagnosed with HIV/AIDS. It was previously reported that 60% of HIV-infected subjects with neurologic symptoms had neuro-ophthalmologic manifestations upon clinical examination, which means that neurologically symptomatic HIV-infected subjects commonly exhibit neuro-ophthalmologic manifestations (35). In the interpretation of our data on optic neuropathy, one has to take into account that the reasons for optic neuropathy were not fully explored since optic nerve damage could have been caused by retinal microangiopathy or owing to cerebral reasons such as a previous cryptococcal meningitis.

The easiest explanation for the difference in the frequency of CMV retinitis, microvascular retinopathy, and optic neuropathy between the HAART group and the HAART-naive group was that there were fewer subjects at risk with fewer subjects with low CD4+ counts. A possible explanation for the prevalence of 9% of CMV retinitis in the HAART group may be that HIV was diagnosed in these subjects at a late stage of the disease, such when the CD4+ cell count was already below 50 cells/μL. This would also fit with the stigma carried by the diagnosis of HIV in China.

Potential limitations of our study should be mentioned. First, this was a retrospective hospital-based study with a relatively small number of subjects and the inherent risk of subject selection bias. Secondly, the diagnosis of CMV retinitis was made based on the appearance of retina. We may have overestimated the frequency of CMV retinitis since we did not perform an antigen test in aqueous humor samples. It could thus be possible to have confounded a retinitis caused by herpes simplex virus with a CMV retinitis, in particular if lesions were located in the fundus periphery. One may also consider that the diagnosis of CMV retinitis is almost exclusively a clinical one, since antigen tests in aqueous or vitreous humor samples are not routinely performed. Although necrotizing herpetic retinopathies such as acute retinal necrosis syndrome may have been confounded with CMV retinitis, the acute retinal necrosis syndrome and similar entities would have been associated with intense aqueous and vitreous inflammatory reactions, which would have been detected clinically. Third, some patients in the HAART group, in particular those with visual impairment, had uveitis, which could have been an immune recovery uveitis. Due to the retrospective study design, however, we did not have enough clues to describe these situations as immune recovery uveitis.

In conclusion, prevalence of CMV retinitis and microvascular retinopathy in Chinese subjects after HAART introduction was similar to Western countries and significantly lower than before HAART introduction. As in Western countries, low CD4+ cell count and a HAART-naive status were major factors associated with CMV retinitis and microvascular retinopathy.

Footnotes

Financial Support: Supported by Research Fund of Capital Medical Development (2009-3155).

Conflict of Interest Statement: None of the authors has conflict of interest with this submission.

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