Secular trends in opportunistic infections, cancers and mortality in patients with AIDS during the era of modern combination antiretroviral therapy.

OBJECTIVES: The aim of the study was to estimate the incidence of, determine risk factors for, and investigate the consequences of opportunistic infections (OIs) and malignancies among patients with the acquired immune deficiency syndrome (AIDS) in the era of modern combination antiretroviral therapy (cART). METHODS: Three enrolment periods (1998-2002, 2003-2005 and 2006-2012), corresponding to changes in predominant cART regimens, were compared among 1889 participants enrolled in a prospective cohort study, the Longitudinal Study of Ocular Complications of AIDS (LSOCA). Incidences of AIDS-related OIs and cancers were estimated. Multivariate logistic and Cox regression models were used to determine the effect of demographic and clinical characteristics on OIs and mortality. RESULTS: Between participants enrolled in the 1998-2002 and 2006-2012 enrolment periods, the incidence of OIs decreased from 27 per 1000 person-years (PY) to 11 per 1000 PY (P < 0.001), and mortality decreased from 41 per 1000 PY to 18 per 1000 PY (P < 0.0001), corresponding to improvements in cART regimens. CONCLUSIONS: Improvements in cART regimens led to a progressive decline in the incidence of OIs and mortality between 1999 and 2013 among patients with AIDS in the era of modern cART.

Insurance status and mortality among patients with AIDS.

OBJECTIVES: The aim of the study was to evaluate risk factors for mortality, including health care insurance status, among patients with AIDS in the era of modern combination antiretroviral therapy (cART). METHODS: This study was part of the prospective, multicentre, observational Longitudinal Study of the Ocular Complications of AIDS (LSOCA). Patients were classified as having private health care insurance, Medicare, Medicaid, or no insurance. Hazard ratios (HRs) for death were calculated using proportional hazards regression models and staggered entries, anchored to the AIDS diagnosis date. RESULTS: Among 2363 participants with AIDS, 97% were treated with cART. At enrolment, 31% of participants had private insurance, 29% had Medicare, 24% had Medicaid, and 16% were uninsured. Noninfectious, age-related diseases, such as hypertension, diabetes, and renal disease, were more frequent among persons with Medicare than among those with private insurance. Compared with those who were privately insured, mortality was greater among participants with Medicare [adjusted HR (HRadj ) 1.35; 95% confidence interval (CI) 1.08-1.67; P = 0.008]. Among participants with a suppressed HIV viral load, compared with those who were privately insured, HRadj values for mortality were 1.93 (95% CI 1.08-3.44; P = 0.02) for those with Medicare and 2.09 (95% CI 1.02-4.27; P = 0.04) for those with Medicaid. Mortality among initially uninsured participants was not significantly different from that for privately insured participants, but these participants typically obtained ART and insurance during follow-up. Compared with privately insured participants, time-updated HRadj values for mortality were 1.34 (95% CI 1.05-1.70; P = 0.02) for those with Medicare, 1.34 (95% CI 1.01-1.80; P = 0.05) for those with Medicaid, and 1.35 (95% CI 0.97-1.88; P = 0.05) for those who were uninsured. CONCLUSIONS: In persons with AIDS, compared with those with private insurance, those with public insurance had increased mortality, possibly as a result of a greater burden of noninfectious, age-related diseases.

Factors affecting attrition in a longitudinal study of patients with AIDS.

Anecdotal data have suggested that retention of HIV-infected patients with immune recovery in longitudinal studies may be difficult as they resume normal activities. This study evaluated risk factors for attrition among patients with AIDS in a cohort study in the era of highly active antiretroviral therapy. Patients with AIDS enrolled in the Longitudinal Study of Ocular Complications of AIDS were evaluated every three months with demographic, clinical and laboratory data collected. Lost to follow-up was defined as any patient who missed all study visits and could not be contacted for 12 consecutive months, who had not died and who did not re-enter the study at a later date. Of the 1,052 patients studied, 77 (7.3%) were lost to follow-up (rate = 0.03/person year). In the multivariate analysis, factors associated with attrition were CD4+ T-cell count category (hazard ratio (HR) = 2.03; 95%CI: 1.01, 4.24; P = 0.05 for CD4+ count < or = 50 cells/microL and HR = 1.96; 95%CI: 1.12, 3.40; P = 0.02 for CD4+ count 51-200 cells/microL) and detectable HIV viral load (HR = 1.29; 95%CI: 1.07, 1.53; P < 0.001 for HIV viral load >400 copies/mL). These data suggest that patients with compromised immunologic status are at an increased risk for being lost to follow-up.

Ocular manifestations of vasculitis.

Systemic necrotizing vasculitis is characterized by inflammation of blood vessels and often affects the eyes. Ocular manifestations of vasculitis may involve any part of the eye or orbit. The frequency of ocular involvement generally is dependent on the size and type of blood vessels affected by the vasculitis. This article reviews the major types of ocular inflammation and then addresses the ocular manifestations of specific systemic vasculitides.

Longitudinal observations on mutations conferring ganciclovir resistance in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis: The Cytomegalovirus and Viral Resistance Study Group Report Number 8.

PURPOSE: Cytomegalovirus retinitis is the most common intraocular infection in patients with acquired immunodeficiency syndrome (AIDS). With prolonged suppressive anticytomegalovirus maintenance therapy, resistance occurs in over 25% of patients. We evaluated longitudinal changes in the cytomegalovirus genotype in patients with cytomegalovirus retinitis who developed ganciclovir resistance that was demonstrated in either the blood or urine. METHODS: Patients with AIDS and previously untreated cytomegalovirus retinitis were followed prospectively for the occurrence of resistance while on treatment. Blood and urine specimens were obtained periodically for cytomegalovirus culture according to a predetermined schedule. Positive isolates were tested for phenotypic susceptibility and for mutations in the UL97 and UL54 genes. RESULTS: A mutation conferring resistance to ganciclovir in either the UL97 or UL54 gene was detected in 18 patients. In general, patients with a genotypically resistant virus developed increasing phenotypic resistance over time. There was a suggestion that unless therapy was changed, UL97 mutations tended to persist. In seven of eight patients, the mutations identified in isolates from the blood and urine were identical. In selected patients, there was a suggestion that a mixed population of cytomegalovirus might be present. Progression of the retinitis in an involved eye (15 of 18), contralateral eye retinitis (10 of 11), and extraocular cytomegalovirus disease (5 of 18) occurred commonly among patients with resistant virus. CONCLUSION: Resistance-conferring mutations in the cytomegalovirus genome emerge and may persist when the selective pressure for resistance is maintained. Some patients appear to harbor complex subpopulations of virus with different mutations and different levels of phenotypic resistance. Changes in therapy may result in a shift in virus population and changes in the cytomegalovirus genotype identified.

Cytokines in autoimmune lacrimal gland disease in MRL/MpJ mice.

PURPOSE: MRL/MpJ-+/+ (MRL/+) and MRL/MpJ-lpr/lpr (MRL/lpr) mice show spontaneous development of a T-cell-driven lacrimal gland inflammation that is a model for Sjögren syndrome. The lacrimal gland lesions in these mice were evaluated by quantitative RT-PCR for selected cytokine mRNA for the relative contributions of T-helper (Th)1 versus Th2 immune responses and by RT-PCR and immunohistochemistry for the contribution of the interleukin (IL)-2/IL-2 receptor (IL-2R) autocrine pathway. METHODS: RNA was isolated from lacrimal glands of MRL/+ mice ages 1 to 9 months and from MRL/lpr mice ages 1 through 5 months, and competitive RT-PCR was used to quantify mRNA for the cytokines IL-2, -4, -10, and -12 and interferon (IFN)-gamma. Frozen sections of lacrimal glands from MRL/+ and MRL/lpr mice ages 2 through 5 months were stained for the IL-2R. RESULTS: IL-2 and -12 mRNA transcripts were below the limit of detection (<10(-3) fg/pg hypoxanthine phosphoribosyl transferase gene; HPRT) in both MRL/+ and MRL/lpr mice of all ages. When detectable, IFN-gamma transcripts were present in low amounts and were below the limit of detection in most samples. IL-4 transcripts were present in 100- to 1000-fold greater amounts than IFN-gamma transcripts. IL-10 transcripts were detectable in both MRL/+ and MRL/lpr mice. IL-2R typically was detected on less than 10% of lymphocytes infiltrating lacrimal gland lesions in both substrains. CONCLUSIONS: On the basis of RT-PCR for cytokine mRNA, autoimmune lacrimal gland lesions in MRL/+ and MRL/lpr mice appear to be largely Th2-mediated. There does not appear to be a direct role for the IL-2/IL-2R autocrine pathway within the microenvironment of the lacrimal gland.

Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease.

OBJECTIVE: To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies. METHODS: Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation. RESULTS: Nine cases of uveitis and 7 cases of scleritis were treated. Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1). Three patients had uveitis without associated systemic disease. Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease. Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor. No patient discontinued treatment because of adverse drug effects. CONCLUSION: TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis.

Photographic measures of cytomegalovirus retinitis as surrogates for visual outcomes in treated patients.

OBJECTIVE: To evaluate photographic measures of cytomegalovirus (CMV) retinitis as surrogate outcomes for changes in vision in patients with CMV retinitis related to the acquired immunodeficiency syndrome. METHODS: Data from 3 clinical trials of CMV retinitis treatments were analyzed. Two photographic assessments of retinitis in eyes involved at baseline were evaluated: progression (lesion border movement > or = 750 microm or occurrence of a new lesion) and change in area of retina involved with retinitis. Vision measures were decline in best-corrected visual acuity and change in visual field. Photographic measures were evaluated as surrogate outcomes based on 4 criteria: (1) association with vision measure; (2) ability to account for treatment-related differences in vision measure; (3) data completeness; and (4) sample size requirements. RESULTS: Data from 1001 involved eyes (666 patients) were analyzed. Progression and change in area involved were predictive of declines in vision measures, accounted for 50% and 66% of the treatment effect on visual field, and were available from 93% and 64% of involved eyes, respectively. Sample size estimates for a clinical trial were smallest with progression as the design outcome. CONCLUSION: Progression and change in area involved met the first and second criteria for surrogate outcomes for visual field loss; a complete evaluation for visual acuity decline was not possible because treatment-related differences were not observed. Progression met the logistical and sample size criteria better than change in area of retina involved with retinitis.

Reliability, validity, and responsiveness of general and disease-specific quality of life measures in a clinical trial for cytomegalovirus retinitis.

The objective of this study was to evaluate a questionnaire for assessing general and disease-specific quality of life among people with cytomegalovirus (CMV) retinitis. Cross-sectional and longitudinal analyses of data from 279 people enrolled in the CMV Retinitis Retreatment Trial were used. At baseline, Cronbach's alpha and multitrait analysis were used to assess internal consistency and discriminant construct validity for scales of general health, vision, and treatment impact. Associations of scales with clinical measures of health and vision were assessed at baseline with Pearson correlations and t tests, and over time with generalized estimating equations regression. Internal consistency coefficients ranged from .68 to.88. Criteria for discriminant validity were fulfilled for most scales; however, the general health perceptions and energy scales were highly correlated. Scales were moderately correlated with clinical measures at baseline. Over time, scale scores were associated with Karnofsky scores and clinical measures of CMV retinitis and vision. General and CMV retinitis-specific quality of life measures appear reliable, valid, and responsive.

Retinal detachment risk in cytomegalovirus retinitis related to the acquired immunodeficiency syndrome.

OBJECTIVES: To compare the incidence of retinal detachment in patients treated with the ganciclovir implant compared with those treated using systemic therapy only, among 511 patients with the acquired immunodeficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis and to describe the influence of highly active antiretroviral therapy (HAART) on retinal detachment incidence. PATIENTS AND METHODS: All patients with AIDS and CMV retinitis at 1 center were followed up prospectively from CMV retinitis diagnosis for incidence of retinal detachment. Patient- and eye-specific data regarding demographic and clinical characteristics were collected at the time of CMV retinitis diagnosis. Use of anti-CMV and antiretroviral treatments and the development of an immunologic response to HAART during follow-up were recorded. RESULTS: No significant difference in the rate of retinal detachment was found between eyes treated with systemic therapy only and those treated with ganciclovir implants, whether used as primary therapy or subsequent to using systemic anti-CMV therapy. The use of HAART was associated with a 60% reduction in retinal detachment rate (P<.001), with the greatest benefit observed among patients who developed an immunologic response to HAART. CONCLUSIONS: Our results suggest that there is no substantial excess risk of retinal detachment when patients with AIDS and CMV retinitis are treated with ganciclovir implants as opposed to systemic anti-CMV therapy only. However, the use of HAART in these patients appears to reduce the risk of retinal detachment substantially.

The role of Fas-Fas ligand-mediated apoptosis in autoimmune lacrimal gland disease in MRL/MpJ mice.

PURPOSE: MRL/MpJ mice spontaneously develop lacrimal gland inflammation and are a model for the human disorder Sjögren's syndrome. MRL/MpJ-lpr/lpr (MRL/lpr) and MRL/Mp-+/+ (MRL/+) mice are congenic substrains, which differ only by a single autosomal recessive gene, the lpr mutation. This mutation results in defective Fas protein, defective lymphocytic apoptosis, and accelerated autoimmune lacrimal gland disease in MRL/lpr mice. We evaluated apoptosis in the lacrimal glands of MRL/lpr and MRL/+ mice. METHODS: Inflammatory cells in the lacrimal glands of MRL/lpr and MRL/+ mice were evaluated for apoptosis with TUNEL staining and Fas and Fas ligand expression with immunohistochemistry. RESULTS: MRL/lpr mice had a greater percentage of the lacrimal gland replaced by inflammatory infiltrate (30.3% +/- 7.0%) than did MRL/+ mice (13.0% +/- 3.0%, P = 0.02). However, similar amounts of lymphocytic apoptosis were present in the lacrimal glands of MRL/lpr and MRL/+ mice. The mean number of apoptotic cells per unit area of inflammation was 23.8 +/- 2.4 in MRL/lpr mice and 24.6 +/- 6.0 in MRL/+ mice (P = 0.91). Fas expression was absent on lymphocytes in MRL/lpr mice but was present on lymphocytes in MRL/+ mice. Fas ligand expression was present on epithelial structures in both substrains. CONCLUSIONS: The accelerated lacrimal gland disease inflammation in MRL/lpr mice does not appear to be due to decreased apoptosis in the microenvironment of the lacrimal gland of MRL/lpr mice. It appears that in MRL/lpr mice there is defective extrathymic lymphoid apoptosis, permitting a relatively greater expansion of autoreactive T cells, which subsequently invade the lacrimal gland.

Patient notification and follow-up after suspension of treatment protocols. experience from four clinical trials of treatments for AIDS-related CMV retinitis.

We reviewed procedures for and data about patient notification of the suspension of the treatment protocol for four clinical trials. We also examined how data collected after the suspensions were used. All four trials were designed to evaluate treatments for cytomegalovirus retinitis in patients with AIDS and were conducted by the Studies of Ocular Complications of AIDS Research Group. Documentation that patients were notified of the results varied from 62--100% with three of the four studies documenting the process for > or =92% of patients. The median time between the recommendation for protocol suspension and patient notification varied from 7--49 days with three of the four trials at 12 days or fewer. Most of the analyses of data collected after the suspension of the treatment protocol did not focus on comparisons among treatment groups. Although they provided useful information about the long-term outcomes and the nature of the disease, they did not alter the conclusions about safety and efficacy from the randomized portion of the trial. Control Clin Trials 2001;22:62-68

Incremental cost effectiveness of prophylaxis for cytomegalovirus disease in patients with AIDS.

Cytomegalovirus (CMV) disease, an opportunistic complication in patients with AIDS, causes substantial morbidity and has high treatment costs. Although prevention of this disease is highly desirable, incremental cost-effectiveness estimates for proposed prophylactic strategies in the era prior to the availability of highly active antiretroviral therapy (HAART) were unfavourable relative to other specific antimicrobial prophylactic strategies in patients with AIDS. With the availability of HAART, several inputs upon which previous estimates of the incremental cost-effectiveness ratio for anti-CMV prophylaxis were based probably changed substantially. To assess the incremental cost effectiveness of prophylaxis in the HAART era, data are needed on visual outcomes and utility for patients with CMV retinitis and AIDS, on better strategies for identifying subpopulations at high risk for CMV disease and on the prophylactic efficacy of valganciclovir. Cost-effectiveness analysis could potentially contribute by exploring thresholds of population risk, prophylactic effectiveness, and drug pricing in order to identify conditions under which prophylaxis for CMV disease in patients with AIDS could potentially become cost effective.

Mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis.

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with acquired immunodeficiency syndrome. In a prospective study of 210 patients with CMV retinitis, 26 were identified as having either a phenotypic or a genotypic ganciclovir-resistant isolate from either blood or urine cultures. For blood culture isolates with an IC(50) >6.0 microm for ganciclovir, the sensitivity and specificity for detecting a UL97 mutation were 95% and 98%, respectively, whereas for an IC(50) >8.0 microM they were 79% and 99%, respectively. Although there were trade-offs between the 2 thresholds for blood culture isolates, for urine culture isolates an IC(50) >8.0 microM appeared to be better at identifying genotypic resistance. UL97 mutations identified in both the blood and urine cultures of individual patients were identical in 87.5% of cases. High-level ganciclovir resistance (IC(50), >30 microM) typically, but not invariably, was associated with a mutation in both the UL97 and UL54 genes.

Episcleritis and scleritis: clinical features and treatment results.

PURPOSE: To evaluate the clinical experience with episcleritis and scleritis at a tertiary care eye center. METHODS: Retrospective chart review. RESULTS: One hundred thirty-four patients with scleral inflammation were seen over a 12-year period. Thirty-seven patients had episcleritis, and 97 patients had scleritis. Ocular complications occurred in only 13.5% of patients with episcleritis but in 58.8% of patients with scleritis (P <.0001). No patient with episcleritis had a decrease in visual acuity, whereas 15.9% of patients with scleritis did. Only 16.7% of patients with episcleritis required more than topical corticosteroids for treatment, and these patients required oral nonsteroidal anti-inflammatory drugs. Conversely, 30.4% of patients with scleritis required nonsteroidal anti-inflammatory drugs, 31.9% oral prednisone, and 26.1% systemic immunosuppressive drugs (P <.0001). Necrotizing scleritis and posterior scleritis more often were associated with ocular complications, occurring in 91.7% and 85.7%, respectively, than were diffuse anterior scleritis and nodular anterior scleritis (P =.020). Patients with necrotizing scleritis and posterior scleritis were more likely to be treated with oral corticosteroids or immunosuppressive drugs (90% and 100%, respectively) than were patients with diffuse anterior scleritis and nodular anterior scleritis (56.4% and 21.4%, respectively, P =.002). CONCLUSIONS: Scleritis is a severe ocular inflammation, often associated with ocular complications, and nearly always treated with systemic medications. Nearly 60% of these patients will need oral corticosteroids or immunosuppressive drugs to control the disease.

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE: To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS: A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE: Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS: The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Risk factors for advancement of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Studies of Ocular Complications of AIDS Research Group.

OBJECTIVE: To identify ocular and systemic factors that predict advancement of cytomegalovirus (CMV) retinitis during treatment. METHODS: Patients with acquired immunodeficiency syndrome were enrolled in a multicenter clinical trial designed to evaluate foscarnet sodium and ganciclovir sodium as therapy for newly diagnosed CMV retinitis. Ocular characteristics at baseline and measurements of retinitis were assessed from fundus photographs by graders at a fundus photograph reading center. The following measures of advancement were assessed: (1) lesion border movement of at least 750 microm or development of a new lesion in involved eyes; (2) rate of increase in retinal area with CMV in involved eyes; and (3) development of retinitis in uninvolved eyes of patients with unilateral disease at baseline. RESULTS: In eyes with retinitis, risk factors at baseline for advancement while receiving treatment included smaller area involved, active margins of retinitis, and posterior location. Risk factors for development of retinitis in uninvolved fellow eyes included blood and urine cultures positive for CMV and lower CD8(+) T-lymphocyte count. CONCLUSIONS: Lesion characteristics can be used to predict advancement of preexisting disease, whereas only systemic factors are associated with development of bilateral disease. These analyses describe retinitis activity before the introduction of potent antiretroviral therapies but provide an important reference point for patients in whom CMV retinitis develops after failure or intolerance of antiretroviral agents. Arch Ophthalmol. 2000;118:1196-1204