Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group.

BACKGROUND: The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. METHODS: Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to one of three treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. RESULTS: The incidence of new cytomegalovirus disease at six months was 44.3 percent in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3 percent in the group assigned to the ganciclovir implant plus oral ganciclovir (P=0.002) and 19.6 percent in the group assigned to intravenous ganciclovir alone (P<0.001). As compared with placebo, oral ganciclovir reduced the overall risk of new cytomegalovirus disease by 37.6 percent over the one-year period of the study (P=0.02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo (P=0.03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposi's sarcoma by 75 percent (P=0.008) and 93 percent (P<0.001), respectively, as compared with placebo. CONCLUSIONS: In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposi's sarcoma.

Visual and anatomic outcomes associated with posterior segment complications after ganciclovir implant procedures in patients with AIDS and cytomegalovirus retinitis.

PURPOSE: To determine anatomic and visual acuity outcomes of posterior segment complications after ganciclovir implant surgery. METHODS: We reviewed the medical records of 63 patients with acquired immunodeficiency syndrome who had active cytomegalovirus retinitis in 82 eyes and who underwent 110 consecutive ganciclovir implant procedures. Preoperative and postoperative visual acuity, type of postoperative complication, treatment, and lines of visual acuity change were determined. RESULTS: Thirty-eight eyes of 19 patients had bilateral ganciclovir implant procedures, and 25 eyes of 19 patients underwent two or more ganciclovir implant procedures. Thirteen (12%) of 110 ganciclovir implant procedures developed posterior segment complications: rhegmatogenous retinal detachment in six, vitreous hemorrhage in four, endophthalmitis in two, and cystoid macular edema with epiretinal membrane in one. Treatment included pars plana vitrectomy with silicone oil in two cases and without silicone oil in three cases, scleral buckling in one, intravitreal antibiotic injection in two, and laser photocoagulation in two. Overall, median visual acuity was 20/25 preoperatively. Median follow-up was 6 months for all eyes and 7 months for eyes with complications. Postoperative median visual acuity was 20/25 for eyes without complications vs 20/40 at 1 month, 20/60 at 3 and 6 months, and 20/100 at 12 months in eyes with complications (P < .001). More eyes with than without complications lost 2 or more lines of visual acuity (P < .001). CONCLUSION: Postoperative complications occurred in 12% of the ganciclovir implant procedures and were associated with decreased visual acuity despite treatment.

Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of the International AIDS Society-USA panel.

PURPOSE: To describe the risks, benefits, and recommended use of the ganciclovir implant for the treatment of human immunodeficiency virus-related cytomegalovirus (CMV) retinitis in the era of potent antiretroviral therapy. METHODS: A panel of physicians with expertise in the use of the ganciclovir implant and in the management of CMV retinitis was convened by the International AIDS Society-USA. The panel reviewed and discussed available data, and developed recommendations for the use of the ganciclovir implant, the surgical technique, and related management issues. Recommendations were rated according to the strength and quality of the supporting evidence. RESULTS: The effect of potent antiretroviral therapy on the immunologic status of patients with human immunodeficiency virus disease has changed the manifestation and course of CMV retinitis in many patients. The clinical management of CMV retinitis and the role of the ganciclovir implant are thus changing. Factors in the decision to choose the ganciclovir implant include the patient's potential for immunologic improvement, location and severity of CMV retinitis, and the risks and costs associated with implantation and concomitant oral ganciclovir therapy. CONCLUSIONS: The ganciclovir implant is safe and effective for the treatment of CMV retinitis. The indications for its use should be modified to account for increased patient survival and the potential for CMV retinitis to be controlled by effective antiretroviral therapy. Optimal use of the ganciclovir implant and discontinuation of therapy in selected patients with improvement in immunity may result in better long-term visual outcomes.

Glycoprotein B subtyping of cytomegalovirus (CMV) in the vitreous of patients with AIDS and CMV retinitis.

A 550-bp region of the cytomegalovirus (CMV) glycoprotein B (gB) gene was amplified by polymerase chain reaction (PCR) from 141 vitreous specimens of 120 patients with AIDS and CMV retinitis from three different metropolitan centers. The distribution of gB subtypes I, II, III, and IV were 19%, 43%, 12%, and 21%, respectively, based on restriction enzyme digestion patterns of PCR-amplified DNA. Two patients had simultaneous infection with two different gB subtypes. The ratio of gB subtypes was similar among the three geographically distinct patient populations. Two of 14 patients with bilateral vitreous specimens had different viral subtypes in each eye. In addition, different gB subtypes were observed in 1 of 6 patients with serial specimens. The ratio of different gB subtypes in the vitreous of patients with CMV retinitis is similar to that previously reported in the peripheral blood of patients with advanced AIDS.

Mutations in the cytomegalovirus UL97 gene associated with ganciclovir-resistant retinitis.

Vitreous from patients with cytomegalovirus (CMV) retinitis was studied in order to identify mutations in the CMV UL97 gene associated with clinical resistance to ganciclovir. Point mutations known to confer resistance (V460, I460, V594, and S595) were found in 6 of 11 study eyes. Rapid genetic screening by restriction enzyme analysis of viral DNA amplified directly from the vitreous was as effective as conventional sequencing in detecting these mutations. Repeat biopsy of 3 eyes revealed no change in the UL97 genotype. The UL97 genotype differed between eyes in 2 of 3 patients with bilateral, clinically resistant CMV retinitis. In summary, resistance mutations of the CMV UL97 gene are found in the vitreous of some, but not all, eyes with CMV retinitis that have not responded to ganciclovir therapy. These mutations can differ between eyes in patients with bilateral disease and can be rapidly detected using restriction digest analysis of polymerase chain reaction-amplified viral DNA.

Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS.

To assess the effect of intravenous cidofovir on delaying progression of previously treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomized, controlled comparison of two maintenance dose levels of cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite treatment with ganciclovir, foscarnet, or both were randomized to receive induction cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either 5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration were administered with each cidofovir dose. Retinitis progression was assessed in the first 100 patients by bilateral, full-field retinal photographs read at a central reading center by an ophthalmologist masked to treatment assignment. Incidence of side effects, changes in visual acuity, and mortality were also assessed. Median time to retinitis progression as assessed by retinal photography was not reached (95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to cidofovir. Reversible probenecid reactions including constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir therapy is effective in delaying progression of CMV retinitis that had previously progressed using other anti-CMV therapies.

Pharmacoeconomic analysis of 3 treatment strategies for cytomegalovirus retinitis in patients with AIDS.

A decision-analytical simulation model was constructed to perform a pharmacoeconomic analysis of the following 3 treatment strategies for previously untreated cytomegalovirus (CMV) retinitis in patients with AIDS: (i) intravenous foscarnet (IVF) for induction and maintenance therapy; (ii) intravenous ganciclovir (IVG) for induction and maintenance therapy; and (iii) intravenous ganciclovir for induction therapy, followed by oral ganciclovir for maintenance therapy (IVG-ORG). Patients who experienced significant adverse effects during, or who failed, initial therapy were switched once to one of the other 2 treatments. The model was used to estimate the direct medical cost (from the perspective of a public payer), survival, and survival adjusted for disutility because of lost vision, for each strategy in the first year following treatment initiation. The expected first-year costs of treatment initiated with IVF, IVG and IVG-ORG were $US47,918, $US38,817 and $US32,036 (1994 values), respectively, while expected first-year survival was 41 weeks, 35 weeks and 35 weeks, respectively. The incremental cost per incremental year of survival using IVF was $US78,000 versus IVG and $US138,000 versus IVG-ORG before adjustment for lost vision, and $US93,000 versus IVG and $US166,000 versus IVG-ORG after adjustment for lost vision. About 23% of the cost of the IVG treatment strategy was attributable to treatment-related adverse events, compared with 14% of the cost of IVF and 16% of the cost of IVG-ORG. Because of the high failure rate with IVG-ORG, initial treatment with IVG-ORG frequently led to switching to another treatment. Only 27% of the costs associated with the IVG-ORG treatment strategy were in fact attributable to the cost of induction and maintenance therapy prior to a switch to alternative treatment. In this analysis, initial treatment with IVG-ORG was the least costly approach for treating CMV retinitis in patients with AIDS. Initial treatment with IVF resulted in slightly longer survival adjusted for vision-related quality of life. New treatments for AIDS may reduce the survival benefit of initial treatment with IVF.

Risk for retinitis in patients with AIDS can be assessed by quantitation of threshold levels of cytomegalovirus DNA burden in blood.

Cytomegalovirus (CMV) retinitis in patients infected with human immunodeficiency virus (HIV) is a significant clinical problem. Seventy-five patients with CD4 T cell counts <100/mm3 were monitored prospectively every 2 months for CMV DNA burden. The target for DNA amplification was a 162-bp fragment from the CMV immediate early gene. CMV DNA burden, at levels of > or =320 in white blood cells or > or =32 in plasma (P = .001), particularly when sustained (P = .005 and .008, respectively), distinguished patients who developed retinitis from those who remained free of disease. Progression to retinitis was not consistently accompanied by increases in CMV burden, indicating that quantitation of CMV burden beyond threshold levels is not necessary to predict risk for development of retinitis. Virus isolation from WBC, but not urine, was also significantly associated with risk for retinitis (P = .001).

Cytomegalovirus gB genotype distribution differs in human immunodeficiency virus-infected patients and immunocompromised allograft recipients.

Cytomegalovirus isolates can be grouped into 4 gB and 2 gH genotypes. gB genotypes were studied in patients infected with human immunodeficiency virus (HIV) and in allograft transplantation recipients. In allograft recipients, the distribution of gB 1, -2, -3, and -4 in leukocytes and urine, respectively, was 36%, 21%, 43%, and 0% and 39%, 30%, 17%, and 13%. However, in leukocytes of HIV-infected patients with <100/microL CD4 cells, gB1 was found significantly less often than in allograft recipients (11% vs. 36%) but gB2 was more frequent (56% vs. 21%; P < .05). The decreased incidence of gBl and increased incidence of gB2 compared with allograft recipients was also seen in urine of HIV-infected patients and reflected the distribution seen in leukocytes. gB4 was found significantly more often (P < .05) in semen than in leukocytes of HIV-infected patients with < 100/microL CD4 cells. gB1-4 genotypes were similar in patients with < 100/microL CD4 cells with or without retinitis.

An economic evaluation of oral compared with intravenous ganciclovir for maintenance treatment of newly diagnosed cytomegalovirus retinitis in AIDS patients.

This prospective, clinical economic study was done to determine the cost impact of oral compared with intravenous (i.v.) ganciclovir for the maintenance treatment of newly diagnosed cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). Efficacy and safety data were extracted from a trial of oral and i.v. ganciclovir. Medical care utilization and reimbursement data were obtained from the clinical trial, a survey of home care and nursing companies, an 11-member physician panel, and a Medicaid cost database. The primary outcome measures were time to first retinitis progression and associated direct medical care expenditures. Nonmedical costs and quality-of-life benefits were not considered. Based on masked evaluation of retinal photographs, the Kaplan-Meier mean time to first progression was 62 days for i.v. ganciclovir and 57 days for oral ganciclovir (a nonsignificant difference). he expected mean cost of treatment for i.v. ganciclovir was significantly different at $8587.00 compared with $4938.00 for oral treatment. Sensitivity analysis using funduscopically determined mean time to first progression showed similar cost savings. We concluded that oral ganciclovir is a cost-saving alternative to i.v. ganciclovir for the maintenance treatment of AIDS patients with newly diagnosed CMV retinitis. Cost differences are attributable to reduced home care expenditures and lower incidence and costs of treating major adverse events in the oral treatment group.

Human cytomegalovirus (CMV) DNA in plasma reflects quantity of CMV DNA present in leukocytes.

A quantitative DNA amplification assay for human cytomegalovirus (CMV) DNA has been used to evaluate the relationship between quantities of CMV DNA in plasma and those in infected leukocytes (WBC) from human immunodeficiency virus-infected patients. The target sequence for DNA amplification was a region of the immediate-early 1 gene of CMV. The quantitation assay uses an internal control that is coamplified with each patient sample DNA and contains a sequence for detection by colorimetric hybridization with the same bases, but in different order than in the CMV immediate-early 1 region used for hybridization of amplified patient sample DNA. Results showed that patients with CMV disease had more CMV DNA in both WBC and plasma than those without disease. However, in this study, copy numbers of CMV DNA in WBC were higher than those in plasma. The gB and gH variants were the same in plasma and WBC.

Quantitation of human cytomegalovirus DNA from peripheral blood cells of human immunodeficiency virus-infected patients could predict cytomegalovirus retinitis.

Human cytomegalovirus (CMV) DNA copy number in white blood cells from both human immunodeficiency virus (HIV)-seronegative and HIV-seropositive patients was amplified from the immediate-early region of CMV DNA and quantified by colorimetric detection of the hybridization of the amplification product to a detector oligonucleotide probe in microtiter wells. By Mann-Whitney U test, significantly higher (P < .05, two-tailed) copy numbers of CMV DNA were detected in HIV-seropositive patients with retinitis than in either patients with < 100 CD4 cells/mm3 and no symptomatic CMV disease or HIV-seropositive patients with > 100 CD4 cells/mm3. By prospective monitoring for increases in CMV DNA copy number, it may be possible to identify HIV-seropositive patients who are at imminent risk for development of symptomatic CMV retinitis.

The progressive outer retinal necrosis syndrome. A variant of necrotizing herpetic retinopathy in patients with AIDS.

BACKGROUND: The progressive outer retinal necrosis syndrome is a recently recognized variant of necrotizing herpetic retinopathy. This report characterizes more fully its clinical features and course. METHODS: Using standardized clinical criteria, patients with progressive outer retinal necrosis syndrome from four institutions were identified. Patient records were reviewed retrospectively for the following data: medical and demographic characteristics, presenting symptoms, physical findings, course, responses to treatment, and outcomes. RESULTS: Thirty-eight patients (65 involved eyes) were studied. All had acquired immune deficiency syndrome. A known history of cutaneous zoster was documented in 22 (67%) of 33 patients. Median CD4 lymphocyte count was 21/mm3 (range, 0-130/mm3). Median follow-up was 12 weeks. The most common presenting symptom was unilateral decreased vision (35 of 65 eyes, 54%); median visual acuity at presentation was 20/30 (range, 20/20 to no light perception [NLP]). Anterior chamber and vitreous inflammatory reactions were absent or minimal in all patients. Typical retinal lesions were multifocal, deep opacities scattered throughout the periphery, although macular lesions also were present in 21 eyes (32%) at diagnosis. Lesions progressed rapidly to confluence. Initial intravenous antiviral therapy appeared to reduce disease activity in 17 (53%) of 32 eyes, but treatment did not alter final visual outcome. Visual acuity was NLP in 42 (67%) of 63 eyes within 4 weeks after diagnosis. Retinal detachment occurred in 43 (70%) of 61 eyes, including 13 (93%) of 14 eyes that received prophylactic laser retinopexy. CONCLUSION: The progressive outer retinal necrosis syndrome is characterized by features that distinguish it from cytomegalovirus retinopathy, acute retinal necrosis syndrome, and other necrotizing herpetic retinopathies. Visual prognosis is poor with current therapies.

Deficiency in antibody response to human cytomegalovirus glycoprotein gH in human immunodeficiency virus-infected patients at risk for cytomegalovirus retinitis.

Human immunodeficiency virus (HIV)-infected patients at risk for symptomatic human cytomegalovirus (CMV) infection were studied for serum antibody to CMV glycoproteins gH and gB. Antibody titers to gB in HIV-seropositive patients, irrespective of CD4 cell counts or presence of CMV retinitis, were significantly higher than titers in HIV-seronegative, CMV-seropositive patients but were comparable to titers detected in HIV-seronegative patients with CMV mononucleosis. In contrast, antibody to gH was rarely detected in HIV-seropositive patients with CD4 cell counts > 100/mm3 compared with patients with counts > 100/mm3. The inability to detect gH antibody at a time of high risk for symptomatic CMV retinitis suggests that immune intervention with either gH-specific vaccine or passive immunotherapy may benefit HIV-infected persons at risk for symptomatic CMV disease.