Diffuse retinal dysfunction following immune reconstitution uveitis in patients with prior cytomegalovirus retinitis: a novel observation.

PURPOSE: To report continuing diffuse retinal dysfunction following resolution of immune reconstitution uveitis (IRU) in patients with cytomegalovirus retinitis (CMVR). METHODS: Retrospective case series describing two patients with IRU following CMVR who underwent serial fundus photography and macular optical coherence tomography. One patient had serial electrophysiology. RESULTS: Both patients had CMVR successfully treated with antiviral medication. The affected eyes later developed IRU that resolved with steroids. However, following resolution, chronic retinal damage was evidenced by ellipsoid line loss in one case and gradual optic disc cupping in the other. Electrophysiology in both cases revealed generalized retinal dysfunction worse in the eye with more severe IRU and demonstrated objectively the efficacy of treatment intervention in the patient with serial recordings. CONCLUSIONS: Patients with IRU following CMV retinitis may have continuing diffuse retinal dysfunction despite apparent recovery and normal visual acuity. An aggressive approach to inflammation control may be warranted in such patients.

Management of Ganciclovir Resistant Cytomegalovirus Retinitis in a Solid Organ Transplant Recipient: A Review of Current Evidence and Treatment Approaches.

Purpose: Cytomegalovirus retinitis (CMVR) is a serious and potentially sight-threatening infection in immunocompromised individuals. Strategies for the management of drug-resistant CMVR are described. Methods: A case of severe bilateral CMVR in a single lung transplant patient, with UL97 mutation conferring ganciclovir-resistance, is presented. Treatment with standard antiviral agent and adjuvant leflunomide, immunosuppression modifications (calcineurin inhibitors and corticosteroid), intravitreal antiviral therapy and novel use of CMV-immunoglobulin is described. A literature review to support drug-resistant CMVR management is presented. Results: Severe and progressive CMV retinitis was refractory to intravitreal foscarnet and systemic leflunomide. Drug-toxicity restricted systemic antiviral therapy options. The use of combined leflunomide and CMV-immunoglobulins, in the absence of viremia, has not been previously reported. Loss of ganciclovir-resistance was eventually observed permitting successful treatment with systemic and intravitreal ganciclovir. Conclusions: Drug-resistant CMVR is a complex clinical challenge. Multiple systemic and local treatment strategies may be necessary but toxicity, resistance, and co-morbidities may severely restrict available options.

Continued decline of aqueous interleukin-8 after multiple intravitreal injections of ganciclovir for cytomegalovirus retinitis.

PURPOSE: To evaluate the relationship between aqueous inflammation cytokines and cytomegalovirus (CMV) particles in patients with cytomegalovirus retinitis (CMVR), and evaluate the changes in aqueous inflammation cytokines during multiple intravitreal injections of antiviral drugs for CMVR. METHODS: There were 10 patients (12 eyes; 16 courses of treatment per eye) who underwent continued intravitreal ganciclovir or foscarnet for treatment of CMVR. Before each intravitreal injection, 50-100 µL of aqueous humor was removed and sent to the laboratory to examine the concentration of the CMV DNA load by using polymerase chain reaction and to examine the concentration of interleukin (IL)-1ß, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, and IL-12p70 using a cytometric bead array. RESULTS: A Kendall correlation test showed that the concentration of the CMV DNA load in the aqueous humor was significantly associated with the aqueous level of IL-6 (P<0.001, r=0.327) and IL-8 (P<0.001, r=0.381), but not significantly associated with IL-1ß, IL-10, IL-12p70, and TNF-α. The boxplots showed that the concentration of the aqueous CMV DNA load, IL-8 and IL-10 continuously declined after multiple intravitreal injections of antiviral drugs, and the decline trend of IL-8 was most remarkable. IL-1ß, IL-10, TNF-α, and IL-12p70 were negative in some of the aqueous levels of CMVR patients throughout the course of treatment (25.0%-62.5%). CONCLUSIONS: Our study showed that IL-8 was significantly associated with the aqueous level of CMV copies and continuously declined during a course of treatment that involved multiple intravitreal injections of antiviral drugs. IL-8 may be considered a good quantitative laboratory indicator of the recovery of CMVR.

A phase II, double-masked, randomized, placebo-controlled evaluation of a human monoclonal anti-Cytomegalovirus antibody (MSL-109) in combination with standard therapy versus standard therapy alone in the treatment of AIDS patients with Cytomegalovirus retinitis.

ACTG 266 was designed as a randomized study to evaluate two doses of the human monoclonal antibody directed against CMV gH (MSL-109) versus placebo, each in combination with standard antiviral therapy for the treatment of newly diagnosed Cytomegalovirus (CMV) retinitis in AIDS patients. A total of 82 subjects were enrolled and received either placebo (n = 28), or MSL-109 at 15 mg (n = 26) or 60 mg (n = 28) every 2 weeks until disease progression was diagnosed. The primary endpoint, disease progression, was determined by masked reading of retinal photographs taken every 4 weeks read by a single investigator. The median time to progression was 8.0, 8.3, and 12.1 weeks in the placebo, MSL-109 15mg and MSL-109 60 mg cohorts, respectively (P = 0.087, placebo versus 60 mg cohort). There were 22 deaths during the study period (9, 9, and 4 in the placebo, MSL-109 15 mg and MSL-109 60 mg cohorts, respectively (P = 0.0058, placebo versus 60 mg cohort)). MSL-109 was well tolerated with no significant adverse events attributable to study medication. The unexplained survival advantage in the higher dose cohort was discordant with the findings of the parallel Studies of Ocular Complications of AIDS Research Group (SOCA)-Monoclonal Anti-CMV Retinitis Trial (MACRT), which was prematurely halted because of increased mortality in subjects treated with high-dose MSL-109, recognizing that A266 enrolled subjects with newly diagnosed, whereas the MACRT enrolled subjects with relapsed, CMV retinitis.

Complications of ganciclovir implant surgery in patients with cytomegalovirus retinitis: the Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial.

PURPOSE: To describe the complications of ganciclovir implant surgery in patients with cytomegalovirus retinitis. METHODS: Prospective data collection within the context of a randomized, controlled clinical trial, comparing a regimen of the ganciclovir implant plus oral ganciclovir to one of intravenous cidofovir for the treatment of cytomegalovirus retinitis in patients with AIDS. Adverse events were compared for patients undergoing implant surgery in the following groups: primary versus replacement implant surgery, inpatient versus outpatient surgery, and general versus local anesthesia. RESULTS: Fifty-six eyes of 42 patients underwent a total of 74 ganciclovir implant surgeries. Vitreous hemorrhage was the most common adverse event, occurring in 10% of eyes undergoing surgery with local anesthesia but in no eyes undergoing surgery with general anesthesia. All vitreous hemorrhages resolved within 60 days. Patients in the general anesthesia and inpatient surgery groups tended to have a lower risk of complications in the first 30 days than did patients in the local anesthesia and outpatient surgery groups, but no differences in the complication rate were found after 60 days. Visual acuity was similar among these different groups. There were no cases of endophthalmitis. CONCLUSION: Ganciclovir implant surgery in patients with AIDS and cytomegalovirus retinitis was associated with a low risk of serious complications in the first 60 days after surgery. Vitreous hemorrhage was the most commonly observed complication and resolved in all cases.

High-dose intravitreal ganciclovir and foscarnet for cytomegalovirus retinitis.

PURPOSE: To describe the chronic use of high doses of intravitreal ganciclovir, in combination with foscarnet, for the treatment of cytomegalovirus retinitis. METHODS: A 31-year-old man with human immunodeficiency virus (HIV) infection and unilateral active cytomegalovirus retinitis was treated with escalating intravitreal injections of ganciclovir (up to 3.0 mg twice a week) in combination with foscarnet (up to 2.4 mg twice a week) over the course of approximately 1 year. RESULTS: Complete regression of the retinitis was obtained with high doses of intravitreal ganciclovir and foscarnet. Visual acuity in the affected eye remained 20/20 throughout the course of therapy. No ganciclovir retinal toxicity was identified. CONCLUSION: High doses of intravitreal ganciclovir in combination with foscarnet can be well tolerated and may be required to successfully control cytomegalovirus retinitis in some patients.

Therapeutic developments in cytomegalovirus retinitis.

The incidence of cytomegalovirus (CMV) retinitis in AIDS has declined significantly due to the use of highly active antiretroviral therapy (HAART). However, patients with HIV, especially those failing HAART, may still suffer with CMV retinitis, which can lead to significant loss of vision and blindness. Ganciclovir has traditionally been considered the recommended treatment for CMV retinitis; however, due to side effects and the possibility of developing viral resistance, other agents may be preferred in certain situations. Foscarnet, which has similar efficacy to ganciclovir but a different side effect profile, is more difficult to administer and is less well-tolerated. Intravenous cidofovir, which may be more effective than either iv. ganciclovir or foscarnet, can also be used as a first line agent; however, it is associated with toxicity (renal and ocular) and thus needs careful use. Local therapy for CMV retinitis has been a significant advance. The intraocular ganciclovir implant has the highest efficacy of the approved agents and is well-tolerated. Fomivirsen, an oligonucleotide injected intravitreally, is a newly approved agent which offers alternative treatment. Intravitreal ganciclovir or foscarnet, although not approved, have been used successfully in some patients especially those with recurrent or refractory disease. The development of new anti-CMV agents has been stalled by the decreased incidence of the disease. Valganciclovir, a prodrug of ganciclovir, offers excellent oral bioavailability and is the closest to approval of all the new anti-CMV drugs. High ganciclovir blood levels are achieved without the complications associated with the requirement for long-term iv. access. The monoclonal antibody (mAb) MSL-109, did not offer a significant advantage when added to traditional anti-CMV therapy. Development plans of other agents such as cyclic HPMPC and lobucavir have been put on hold by their respective manufacturers. Adefovir is a nucleotide analogue that possesses anti-CMV activity, but is currently only being pursued for the treatment of hepatitis B virus. Other compounds possessing significant anti-CMV activity, including BAY 38-4766 and GW1263W94 are still in the early stages of development.

In vitro antiviral susceptibilities of isolates from cytomegalovirus retinitis patients receiving first- or second-line cidofovir therapy: relationship to clinical outcome.

Blood culture isolates from patients receiving first- (peripheral retinitis) or second-line (relapsing retinitis) therapy with intravenous cidofovir were obtained from three clinical trials for in vitro antiviral susceptibility analyses. Isolates from 6 patients obtained after 14.3 weeks (mean) of first-line cidofovir therapy showed complete susceptibility to cidofovir, ganciclovir, and foscarnet. Isolates from 20 patients were obtained after 17.3 weeks (mean) of second-line cidofovir therapy. Ten showed complete susceptibility to all inhibitors, 3 showed low-level ganciclovir resistance (<6-fold) but were sensitive to cidofovir and foscarnet, and 7 showed moderately reduced susceptibility (<8-fold) to cidofovir and high-level resistance (8- to 23-fold) to ganciclovir in vitro. Four of these 7 isolates showed reduced susceptibility (4-fold) to foscarnet. Notably, there was no difference in time to retinitis progression in patients that were on cidofovir therapy when sensitive isolates were compared with those showing reduced susceptibility to cidofovir in vitro.

Update on cidofovir for CMV retinitis.

AIDS: Cidofovir, a member of a new class of antiviral compounds, is showing it can slow the progression of cytomegalovirus (CMV) retinitis in untreated and previously treated HIV-infected patients. Results from phase I/II studies are highlighted, as are data on cidofovir's potency, safety, therapeutic value, and susceptibility and resistance characteristics. Concluding comments discuss future efforts on evaluating cidofovir's therapeutic role.^ieng

An economic exploration of oral and intravenous ganciclovir in the induction and maintenance treatment of AIDS-related cytomegalovirus retinitis.

The objective of the study was to compare the impact of oral and i.v. ganciclovir on resource use and direct health care costs, from the perspective of the UK National Health Service (NHS). The analytical framework used was cost analysis. The sources of data were an open, randomized clinical trial, and additional research which collected resource use and cost data. From the perspective of the UK NHS, the expected cost of i.v. ganciclovir for initial induction and 140 days maintenance and reinduction therapy was pounds 730 higher than that of oral (pounds 8145 vs pounds 7415). Conservative estimates which did not favour oral ganciclovir were used wherever possible. Overall, the resource use and costs of maintenance therapy with oral ganciclovir calculated in the model used for this study were lower than those of i.v. ganciclovir, principally reflecting lower costs for the administration of therapy. In this model the drug cost of ganciclovir maintenance therapy was excluded.

[Ganciclovir-resistant cytomegalovirus infection: 2 cases with different clinical impact]. / Ganciclovir-resistente Zytomegalievirus-Infektion: 2 Fälle mit unterschiedlicher klinischer Bedeutung.

Swiss cases of cytomegalovirus (CMV) resistance to antiviral drugs have not been reported to date. We describe both a documented and a presumed case of ganciclovir-resistant CMV infection. A bone marrow transplant recipient with an episode of CMV viremia and antigenemia underwent broncho-alveolar lavage from which a CMV strain was isolated. The sensitivity of this strain to ganciclovir and foscarnet was tested in a plaque reduction assay, which was performed in 6 different fibroblast lines. The inhibitory drug concentration which reduced viral plaque formation by 50% (IC50) was a median of 12.7 microM (range 6.1-29.6) for ganciclovir (resistance defined as IC50 > 6 microM), which documented the presence of CMV resistance to ganciclovir. The strain was sensitive to foscarnet. This ganciclovir-resistant CMV strain had no clinical impact, although the patient was treated with ganciclovir. A second patient had Aids and subsequently developed CMV retinitis which was treated with intravenous ganciclovir for 3 weeks, followed by longterm oral ganciclovir therapy. Approximately 4 1/2 months after initiation of antiviral therapy the patient developed fatal CMV multi-organ disease while on continued oral ganciclovir treatment, which suggested the occurrence of CMV resistance to this agent. CMV organ disease was documented at autopsy by histology and immunochemistry, but virus was not cultured. The different outcomes in these two patients suggest that the type of underlying immunodeficiency may be a decisive factor for the clinical relevance of drug-resistant CMV infection.

Ocular iontophoretic supplementation of intravenous foscarnet therapy.

PURPOSE: Reactivation of cytomegalovirus retinopathy during intravenous antiviral therapy is usually treated with higher doses of drug. We sought to determine whether ocular iontophoresis increases the intravitreal foscarnet concentration attained by intravenous injection. METHODS: We injected foscarnet (120 mg/kg or 180 mg/kg) intravenously into 24 rabbits and determined the time of maximal concentrations in serum and vitreous humor. We injected the same doses into 24 additional rabbits and administered ocular foscarnet iontophoresis one hour later. Vitreous humor concentrations were assayed at one, four, eight, 24, 60, and 120 hours after iontophoresis and compared with those from injection alone. RESULTS: Maximum serum and vitreous humor concentrations were achieved one hour after each intravenous dose. Maximum vitreous humor concentrations were achieved four hours after 120 mg/kg intravenous doses plus iontophoresis and eight hours after 180-mg/kg intravenous doses plus iontophoresis. Vitreous humor levels were significantly higher in eyes receiving intravenous foscarnet (120 mg/kg, P < .0001; 180 mg/kg, P < .0001) plus ocular Foscarnet iontophoresis than in those receiving intravenous foscarnet alone. Vitreous humor foscarnet levels in eyes receiving 120 mg/kg intravenously did not differ significantly from those in the group receiving 180 mg/kg intravenously (P < .1). The intravenous dose did not significantly affect vitreous humor levels after iontophoresis (P < .1). Vitreous concentrations fell below therapeutic levels (25 microM) in all eyes 60 hours after intravenous foscarnet and ocular foscarnet iontophoresis. CONCLUSIONS: Ocular iontophoresis significantly increased intravitreous foscarnet concentrations above those attained by intravenous injection alone and may be an effective alternative to increasing the intravenous drug dose in patients with reactivated cytomegalovirus retinopathy.

Combination therapy improves CMV treatment.

AIDS: A new study reveals that the two-drug combination of foscarnet and ganciclovir has synergistic activity against CMV and can control the opportunistic infection twice as long as monotherapy. However, increased cost and decreased quality of life may affect decisions to abandon monotherapy. The two-drug combination is more inconvenient to administer and is so hard to tolerate that nearly half of the study subjects opted to go back to the monotherapy. Combination therapy is recommended for patients not responding to high-dose monotherapy or who have new lesions that threaten the optic nerve. Other treatment options are under consideration, including an eye implant for delivering ganciclovir.^ieng

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.

Local therapy for cytomegalovirus retinopathy.

PURPOSE: We sought to understand better the efficacy and risks of local therapies (direct placement of drug into the eye) for the treatment of cytomegalovirus retinopathy. This understanding can be used to design rational treatment regimens, to formulate indications for use of local therapy, and to establish criteria for assessment of future results in this area. METHODS: We collected information about local therapies through a review of published literature. RESULTS: Intraocular injection of ganciclovir and foscarnet and implantation of intraocular devices that slowly release ganciclovir are able to decrease the activity of cytomegalovirus retinopathy lesions and prevent their enlargement for variable periods of time. The time to disease progression (lesion enlargement) may be longer with intraocular devices than with current treatments using intravenously administered antiviral drugs. Local therapies have many advantages (for example, convenience, reduced cost, and lack of systemic toxicity), but there are potential disadvantages, including endophthalmitis, increased rates of retinal detachment, and development of nonocular cytomegalovirus disease and cytomegalovirus retinopathy in fellow, uninvolved eyes. CONCLUSIONS: Local therapies are effective for the treatment of cytomegalovirus retinopathy, but their relative risks and benefits, when compared with those of intravenous drug therapy, have yet to be fully evaluated. We anticipate that local therapy will be an important treatment modality for selected patients with cytomegalovirus retinopathy. Indications include the use of local therapy as an alternative therapy for patients who are unable to receive systemic therapy (intolerance to intravenous or oral medication, or lack of intravenous access) and as supplementation in patients whose retinal disease is incompletely controlled by maximum tolerated systemic medications. The use of local therapy as sole initial treatment in lieu of systemic therapy remains controversial. Its most useful role may be in conjunction with oral forms of antiviral drugs now in development.

Mutations in human cytomegalovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma.

Specific mutations in the UL97 region of human cytomegalovirus (HCMV) have been found to confer resistance to laboratory-adapted strains subjected to ganciclovir selection. In this study, mutations in the UL97 region of HCMV isolates obtained from patients receiving ganciclovir therapy were examined to determine whether they would confer ganciclovir resistance, and if these mutations could be detected directly in the plasma of AIDS patients with progressive HCMV disease despite ganciclovir treatment. A single nucleotide change within a conserved region of UL97 was found in five resistant isolates, resulting in an amino acid substitution in residue 595: from leucine to phenylalanine in one, and from leucine to serine in four resistant isolates. A sixth resistant isolate demonstrated a single nucleotide change, leading to a threonine to isoleucine substitution in residue 659. The role of the 595 amino acid substitution in conferring ganciclovir resistance was confirmed by marker transfer experiments. In further studies, direct sequencing of HCMV DNA present in plasma obtained from persons with resistant viruses revealed the identical amino acid substitutions in plasma as those present in the cultured viruses. These findings indicate that clinical resistance to ganciclovir can result from specific point mutations in the UL97 gene, and that the emergence of the resistant genotype can be detected directly in patient plasma.

High dose intravitreal foscarnet in the treatment of cytomegalovirus retinitis in AIDS.

The efficacy and tolerance of high dose intravitreal foscarnet for cytomegalovirus retinitis in patients with AIDS was studied. Foscarnet in a dose of 2400 micrograms was injected directly into the vitreous of 11 patients (15 eyes). Five patients had active retinitis (eight eyes, 53.3%), and received a 3 week induction therapy of six injections as the first step. Six patients had initial inactive retinitis (seven eyes, 46.7%), and received only maintenance therapy which consisted of a weekly injection. The main indications for intravitreal therapy were: myelosuppression, kidney toxicity, catheter related sepsis, or refusal of intravenous therapy. The patients were followed for a mean period of 16 weeks (range 8-28 weeks) and received a total of 304 injections. Vitreous foscarnet levels were measured by high performance liquid chromatography. After a 3 week course of induction therapy, complete resolution of the active retinitis was seen in 62.5% (5/8 cases), while 37.5% (3/8 cases) had partial resolution. No cases failed to respond or progress. The rate of relapse on maintenance therapy was 33% (five of 15 eyes) by 20 weeks, and two of these eyes did not respond to reinduction and progressed in involvement of the macula or optic nerve. Neither important local complications nor intraocular drug toxicity were observed. Vitreous foscarnet levels in two different patients were 896 mumol/l and 74.9 mumol/l at 22 3/4 hours and 42 1/2 hours after the injection. Intravitreal foscarnet appears to be a safe, effective, and useful alternative in patients with intolerance to intravenous and viral therapy.

Effect of foscarnet induction treatment on quantitation of human cytomegalovirus (HCMV) DNA in peripheral blood polymorphonuclear leukocytes and aqueous humor of AIDS patients with HCMV retinitis. The Italian Foscarnet Study Group.

The aim of this study was to investigate peripheral blood polymorphonuclear leukocytes and, whenever possible, aqueous humor from 65 AIDS patients with ophthalmoscopically diagnosed human cytomegalovirus (HCMV) retinitis to determine (i) whether patients consistently carry viral DNA and (ii) to what extent foscarnet induction treatment decreases viral DNA levels. HCMV DNA was quantified by PCR using densitometric analysis of hybridization products obtained from external standards and a standard curve from which the number of genome equivalents of test samples, normalized by using an internal amplification control, was interpolated. Results showed that 56 of 65 patients (86.1%) were positive for HCMV DNA prior to induction treatment. Of 41 of the 56 patients (73.2%) whose blood had become DNA negative after induction, only 5 had a high viral load (> 5,000 genome equivalents per 2 x 10(5) polymorphonuclear leukocytes) prior to induction, whereas as many as 13 of the 15 (26.8%) patients remaining DNA positive after induction had a high viral load prior to induction. Finally, of the nine patients (13.8%) with DNA-negative blood prior to induction treatment, three were shifted to foscarnet from ganciclovir, while six were erroneously enrolled in the study. Pre- and postinduction aqueous humor samples were obtained from 12 patients; all of these were DNA positive prior to induction, whereas after induction, 4 became negative, 6 showed a marked decrease in viral DNA, and 2 had nearly stable low DNA levels. In conclusion, PCR is a valuable tool for etiologic diagnosis and monitoring of HCMV retinitis treatment in AIDS patients. HCMV DNA is consistently present in the blood and aqueous humor of all patients with HCMV retinitis. Foscarnet induction treatment is highly effective in suppressing or reducing DNA levels in both blood leukocytes and aqueous humor.