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.

Reactive lymphocytes in lacrimal gland and vasculitic renal lesions of autoimmune MRL/lpr mice express L3T4.

The lacrimal gland inflammatory lesions and renal vasculitic lesions of autoimmune MRL/lpr mice were analyzed for the lymphocyte subsets present. The majority of cells were Thy-1.2+ T cells (mean, 85%) of the L3T4+ helper T phenotype (mean, 64 and 58%, respectively). Lesser numbers of Lyt-2+ suppressor/cytotoxic T cells, B cells, and macrophages were present. The finding that the majority of lymphocytes in both the lacrimal gland inflammatory lesions and renal vasculitis of MRL/lpr mice expressed L3T4 suggests that these cells may be capable of responding to antigen presentation and that an active immunologic response occurs at these sites.

Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA.

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. 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 the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.

Catheter complications in AIDS patients treated for cytomegalovirus retinitis.

PURPOSE: To describe the complications of central venous catheter use for intravenous therapy of cytomegalovirus (CMV) retinitis in patients with AIDS. METHODS: Retrospective review of 388 patients with AIDS and CMV retinitis treated with intravenous medications through an indwelling catheter. RESULTS: The catheter complication rate was 1.2 complications per person-year (0.33 complications per 100 catheter-days). Current injecting drug use increased the risk of infectious complications [hazard ratio (HR), 1.73; P=0.04] whereas former use did not (HR, 0.96; P=0.88). Subdermal port catheters increased the risk of bacteremia (HR, 1.78; P=0.05). Mortality for the first complication was 5.8%. Forty percent of patients required catheter removal, and 86.8% of these patients required reinsertion of another catheter. CONCLUSIONS: Catheter complications are a substantial problem in patients with CMV retinitis treated with daily intravenous therapy.

Familial granulomatous synovitis, uveitis, and cranial neuropathies.

A family is presented that had what is believed to be a previously undescribed syndrome of granulomatous synovitis, bilateral recurrent uveitis, and cranial neuropathies. Affected members included the proband, his brother, father, and probably the decreased paternal grandmother. Disease onset was in childhood. Each had symmetric, boggy polysynovitis of the hands and wrists, resulting in nearly identical boutonniere deformities. Hand radiography in the proband and his brother revealed no erosions or joint destruction despite more than 20 years of disease. Synovectomy specimens in the proband and his brother showed granulomatous inflammation with giant cells. Recurrent, nongranulomatous, acute iridocyclitis with visual impairment afflicted the proband, brother, and father. Apparently corticosteroid-responsive bilateral neurosensory hearing loss occurred in the proband, and a transient sixth cranial nerve palsy in his brother. All members of the family were antinuclear antibody-, rheumatoid factor-, and HLA-B27-negative. Serum angiotensin-converting enzyme levels were within normal limits in all family members. The inheritance pattern of this syndrome is most consistent with an autosomal dominant mode.

Ocular inflammation in MRL/Mp-lpr/lpr mice.

A systemic autoimmune disease spontaneously developed in MRL/Mp-lpr/lpr (MRL/lpr) mice. The disease was characterized by vasculitis, lymphadenopathy, glomerulonephritis, and autoantibody formation. Among the many autoimmune lesions are focal ocular inflammatory infiltrates involving the choroid and sclera. Of 104 mice examined histologically, the sclera was most often involved, with 30% of mice 5 months of age or older having scleral lesions that were often centered around small arteries. The choroid was the second most frequently involved tissue, with focal inflammation developing in 16% of these mice. Immunohistologic analysis of the ocular infiltrates showed that most of the mononuclear cells seen were L3T4 + T cells (CD4+ helper T cells), suggesting that the process was largely T cell-mediated. Smaller numbers of B cells and Lyt 2+ T suppressor/cytotoxic cells were seen. No such lesions were seen in congenic MRL/Mp- +/+, (NZBxNZW) F1 hybrid mice, and control BALB/c mice; vasculitis did not develop in all of the mice. These results suggest that the ocular lesions in MRL/lpr mice may be a model for ocular involvement in patients who have systemic necrotizing vasculitis.

Murine models of Sjögren's syndrome. Immunohistologic analysis of different strains.

Lacrimal gland inflammation develops in several strains of autoimmune mice, including MRL/Mp-lpr/lpr (MRL/lpr), MRL/Mp-+/+ (MRL/+), and NZBxNZW F1 hybrids (NZB/W). These mice all develop an autoimmune disease characterized by glomerulonephritis and autoantibody formation, but each strain has unique clinical features and immunologic abnormalities. Previous studies have suggested that the intrinsic immunologic defect in MRL/lpr mice may be at the level of T cells, while in NZB/W mice it appears to be B cell-mediated. Immunohistologic analysis of the lacrimal gland lesions was performed on all three strains. Although T cells predominated (MRL/lpr 85%, MLR/+ 78%, and NZB/W 57%), differences in the immunohistologic profiles did exist. NZB/W mice had a significantly higher percentage of B cells (33% vs. 10% for MRL/lpr and 13% for MRL/+) and a correspondingly lower percentage of T cells. MRL/lpr mice differed from MRL/+ mice in that they exhibited a significantly higher percentage of helper T cells (63% vs. 49%) and a lower percentage of suppressor/cytotoxic T cells (14% vs. 30%). Class II antigen expression could be detected on the mononuclear cells at inflammatory sites within the lacrimal glands of all three strains, suggesting T cell activation and an active autoimmune immunologic event occurring in the lacrimal gland.

Autoimmune ocular disease in MRL/Mp-lpr/lpr mice is suppressed by anti-CD4 antibody.

MRL/Mp-lpr/lpr(MRL/lpr) mice spontaneously have a systemic autoimmune disease, characterized by vasculitis, lymphadenopathy, glomerulonephritis, and autoantibody formation. Among the many autoimmune lesions present are focal ocular inflammatory infiltrates, involving the choroid and sclera. These lesions appear to be related to the vasculitis seen in MRL/lpr mice and are mediated by L3T4-positive helper T-cells (CD4-positive T-cells). Systemic treatment of MRL/lpr mice with a monoclonal anti-L3T4 antibody (anti-CD4) resulted in a dramatic reduction of both the frequency and severity of the ocular disease, supporting the hypothesis that the CD4-positive T-cells play an essential role in the pathogenesis of the choroiditis and scleritis in this strain.

Murine models of Sjögren's syndrome. Evolution of the lacrimal gland inflammatory lesions.

Lacrimal gland inflammation develops in a number of autoimmune mice, including the MRL/Mp-lpr/lpr (MRL/lpr), MRL/Mp(-)+/+ (MRL/+), and NZB x NZW F1 hybrid (NZB/W) strains. The authors studied the evolution of this process, MRL/lpr mice had inflammatory lesions at 4 weeks old. The lesions had enlarged by 2 months and were fully developed by 4 to 5 months of age. In MRL/+ mice, 4-week-old mice had no lesions, although some focal inflammation was detectable at 3 months old. Significant abnormalities were present at 6 months, and persisted and increased throughout life, with all mice having extensive lesions at 18 months or older. In NZB/W mice, the authors detected no lesions until 6 months of age, and these lesions were fully developed in 9 months. Immunocytochemical profiles, of the cell types infiltrating the lacrimal gland, showed differences not only between the strains, but also in each strain as inflammation progressed. All three types of mice had L3T4+ T cells as the major lymphocyte component, although MRL/+ had significantly more Lyt 2+ T cells than the other strains. NZB/W mice had significantly more B cells than the two MRL substrains. In both NZB/W and MRL/+ mice, there was a significant increase in the B cell population, and a decrease in the percentage of L3T4+ T cells. There was a significant decline in Lyt 2+ T suppressor/cytotoxic cells in both NZB/W and MRL/lpr mice. This last finding was consistent with the more rapid development of inflammation in these strains than in the MRL/+ mice, where Lyt 2+ T suppressor/cytotoxic cells persist. Together, these results indicate that the autoimmune response in murine models of Sjögren's syndrome is a dynamic, evolving process with strain-related changes in lymphocyte subsets.

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.

Paradoxic effect of anti-CD4 therapy on lacrimal gland disease in MRL/Mp-lpr/lpr mice.

PURPOSE: MRL/Mp-lpr/lpr mice (MRL/lpr) spontaneously develop lacrimal gland inflammatory lesions and are a model for the human disease Sjögren's syndrome. Therapy with monoclonal antibodies (mAb) to CD4 ameliorates the autoimmune renal, vasculitic, and intraocular inflammatory lesions in MRL/lpr mice. The effect of anti-CD4 mAb therapy on lacrimal gland immunopathology was evaluated. METHODS: From 1 to 5 months of age, MRL/lpr mice were treated with weekly intraperitoneal injections of 2 mg anti-CD4 mAb, after which they were killed and their lacrimal glands were removed for histologic evaluation and immunocytochemistry. Control mice were administered weekly intraperitoneal injections of either saline or normal rat immunoglobulin. RESULTS: Anti-CD4 mAb treatment produced no reduction in lacrimal gland inflammation but did change its morphology. In control mice, there were multiple sharply delineated foci of inflammatory cells in the lacrimal gland, whereas in anti-CD4 mAb-treated mice, there was a more diffuse inflammation surrounding ill-defined foci that spread throughout the gland. Immunocytochemistry revealed that in control mice, lesions were composed predominantly of CD4+ T cells, but in anti-CD4 mAb-treated mice, CD8+ T cells predominated. CONCLUSIONS: Although anti-CD4 mAb therapy of MRL/lpr mice eliminated autoimmune renal disease, autoantibody formation, and ocular inflammatory disease, it had a paradoxic effect on lacrimal gland lesions. Lacrimal gland lesions in the anti-CD4 mAb-treated mice were not decreased, but they had a different morphology and a different immunocytochemical profile.

Ocular inflammation in autoimmune MRL/Mp mice.

Congenic mice of the MRL/Mp strain spontaneously develop an autoimmune connective tissue disease that shares immunologic and histopathologic features with the human disorders systemic lupus erythematosus, rheumatoid arthritis, and systemic vasculitis. The autoimmune disorder in these mice is markedly accelerated by the recessive gene lpr. Older MRL/Mp-lpr/lpr mice develop significant inflammatory ocular disease, including choroiditis, scleritis, and orbital vasculitis. Animals of both the MRL/Mp-+/+ and MRL/Mp-lpr/lpr substrains develop lacrimal gland inflammatory infiltrates. The MRL/Mp mouse provides a potential model for ocular inflammatory disease and for Sjögren's syndrome.

Th1 versus Th2 immune responses in autoimmune lacrimal gland disease in MRL/Mp mice.

PURPOSE: In MRL/Mp-lpr/lpr (MRL/lpr) and MRL/Mp-+/+ (MRL/+) mice, a T-cell-driven lacrimal gland inflammation spontaneously develops that is a model for Sjögren's syndrome. The lacrimal gland lesions in these mice were evaluated by immunohistochemistry for the relative contributions of T-helper (Th)1 versus Th2 immune responses. METHODS: Frozen sections of lacrimal glands from MRL/lpr and MRL/+ mice ages 1 through 5 months were stained with monoclonal antibodies to the cytokines interferon (IFN)-gamma and interleukin (IL)4 and to the cell surface costimulatory molecules B7-1 and B7-2, which are associated with Th1 and Th2 responses, respectively. RESULTS: The median proportion of cells staining for IL-4 ranged from 30% to 67% over time for MRL/lpr mice and from 30% to 55% for MRL/+ mice. The median proportion of cells staining for IFN-gamma ranged from 1% to 5% for MRL/lpr mice and from 0% to 3% for MRL/+ mice. The proportion of cells staining positively for IL-4 was significantly greater than for IFN-gamma in both MRL/lpr (mean difference, 33%; P = 0.0001) and MRL/+ mice (mean difference, 42%; P = 0.0002). The median proportion of cells staining positively for B7-2 ranged from 20% to 38% for MRL/lpr mice and from 16% to 34% for MRL/+ mice. The median proportion of cells staining for B7-1 ranged from 2% to 10% for MRL/lpr mice and from 2% to 5% for MRL/+ mice. The proportion of cells staining positively for B7-2 was significantly greater than for B7-1 for both MRL/lpr mice (mean difference, 15%; P = 0.001) and for MRL/+ mice (mean difference, 19%; P = 0.006). CONCLUSIONS: On the basis of immunohistochemistry for cytokines and costimulatory molecules, inflammatory lacrimal gland lesions in MRL/lpr and MRL/+ mice appear to be a largely Th2 phenomenon.

Cyclosporine therapy suppresses ocular and lacrimal gland disease in MRL/Mp-lpr/lpr mice.

PURPOSE: MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop an autoimmune disease characterized by lymphoproliferation, vasculitis, glomerulonephritis, autoantibody production, and ocular and lacrimal gland inflammation. Lacrimal gland lesions in MRL/lpr mice are a model for the human disorder Sjögren's syndrome. The target organ lesions in MRL/lpr mice, including those in the eye and lacrimal gland, are composed largely of CD4+ T cells, with lesser numbers of CD8+ T cells and B cells. Cyclosporine therapy was evaluated for its effect on the autoimmune disease, particularly in the eye and lacrimal gland. METHODS: MRL/lpr mice were administered cyclosporine intraperitoneally at a dosage of 2 mg daily from age 1 to 5 months. Animals were killed at 5 months and evaluated for the presence of autoimmune disease. Control groups consisted of animals given daily injections with either saline or the cyclosporine diluent. RESULTS: Cyclosporine therapy was effective in reducing the ocular and lacrimal gland disease. Intraocular inflammation was present in 73% of control animals but in only 15% of cyclosporine-treated animals (P < 0.003). Multifocal lacrimal gland inflammatory infiltrates were present in 100% of controls but in only 23% of cyclosporine-treated animals (P < 0.0001). Mean percent area involved by lacrimal gland inflammation was reduced from 19.7% to 4.7% by cyclosporine therapy (P = 0.0003). Systemic autoimmune disease manifestations, including lymphoproliferation, vasculitis, glomerulonephritis, and serologic abnormalities, also were improved. CONCLUSIONS: Chronic cyclosporine therapy, started at an early age, is effective in controlling the autoimmune disease in MRL/lpr mice, including the ocular and lacrimal gland lesions.

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.

Bullous pemphigoid autoantibodies are markers of corneal epithelial hemidesmosomes.

Sera from patients with bullous pemphigoid (BP) contain autoantibodies that bind to the BP antigen, which is a component of the epithelial-stromal junction of the cornea. Previous studies, employing direct immunoelectron microscopy (IEM) on perilesional skin of patients have localized the BP antigen to the lamina lucida. On this basis, studies of corneal epithelial-stromal adhesion and wound healing have employed BP antigen as a marker of the lamina lucida of the corneal basement membrane zone (BMZ). The authors used indirect IEM with BP autoantibodies on frozen sections of cornea and found that the majority of the BP antigen is intracellular and is closely associated with the corneal epithelial hemidesmosome. Only a small amount of BP antigen appears to be extracellular, limited to the portion of the lamina lucida directly beneath individual hemidesmosomes. When rabbit corneal epithelium is extracted and analyzed by Western immunoblotting, BP autoantibodies recognize two polypeptides of molecular weights of 240 and 180 kilodaltons, which comigrate with BP antigens extracted from epidermis. BP autoantibodies are a specific marker of corneal epithelial hemidesmosomes and can be used as a probe to identify and study the role of hemidesmosomes in epithelial-stromal adhesion.

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.

Design of clinical trials for drug combinations: cytomegalovirus retinitis--foscarnet and ganciclovir. The CMV retinitis retreatment trial.

The Cytomegalovirus Retinitis Retreatment Trial was a multicenter clinical trial designed to evaluate three treatments for the treatment of relapsed CMV retinitis; (1) foscarnet; (2) 'high-dose' ganciclovir, and (3) combination foscarnet and ganciclovir. Two hundred seventy-nine patients were enrolled and randomly assigned to one of these three regimens. Patients were followed monthly for 6 months and every 3 months thereafter. Outcomes of interest included: (1) mortality; (2) retinitis progression; (3) change in retinal area affected by CMV; (4) loss of visual field; (5) loss of visual acuity; (6) quality of life; and (7) treatment side effects.

Summary of the II International Symposium on Cytomegalovirus.

Human cytomegalovirus (HCMV) is a highly species-specific DNA virus belonging to the Betaherpesvirinae subfamily of the herpesviridae family. Like other herpesviruses, primary infection with HCMV is followed by persistence of the virus in a latent form. The sites of latency are still largely undefined, but they probably include bone marrow progenitor cells and peripheral blood monocytes. From these sites, the virus can reactivate, resulting in renewed shedding of the virus, or, in immunocompromized persons, development of disease. Humans are the only reservoir of HCMV and transmission occurs by person-to-person contact. Infection with HCMV is common. In most developed countries, HCMV seroprevalence steadily increases after infancy and 10-20% of children are infected before puberty. In adults, the prevalence of antibodies ranges from 40 to 100%. Although HCMV has a world-wide distribution, infection with HCMV is more common in the developing countries and in areas of low socioeconomic conditions, which is predominantly related to the closeness of contacts within these populations. Except for a mononucleosis-like illness in some persons, infection with HCMV rarely causes disease in immunocompetent individuals. However, HCMV can cause severe morbidity and mortality in congenitally infected newborns and immunocompromized patients, most notably transplant-recipients and HIV-infected persons. This article provides a review of the information presented at the Second International Symposium on Cytomegalovirus organized and convened by The Macrae Group (New York City, NY) in Acapulco, Mexico on 24-28 April 1998. During this symposium, the state-of-the-art knowledge on diagnosis, treatment and prophylaxis of HCMV infections were discussed, and, based on this information, attempts to highlight the future directions in basic and clinical research areas that need to be stimulated to facilitate advancement in prevention and treatment of CMV disease.