Cytomegalovirus (CMV) retinitis is a disease characterized by progressive, necrotizing retinitis that can lead to blindness in patients with immunocompromised states.1,2 Similar to other herpes viruses, CMV remains latent suppressed by cell-mediated immunity, unless the patient suffers from a significant local (regional corticosteroid therapy) or systemic immunodeficiency.2-8 It is the most common intraocular infection in patients with acquired immunodeficiency syndrome (AIDS) and, as such, many of the treatment approaches emanate from studies on cohorts of adult patients with AIDS-associated CMV retinitis.3,9,10 Non–AIDS-related CMV retinitis cases with pharmacologic immunosuppression and cases in some healthy individuals or those immunosuppressed by other means have also been reported.11,12-14 CMV retinitis affects AIDS patients as a relatively late-stage manifestation when CD4+ cell counts are profoundly suppressed (eg <50 cells/µL).1,2
Prior to the introduction of HAART, patients often experienced a catastrophic loss of vision due to CMV retinopathy and other intraocular infections.1,2,15,16 The development of HAART in 1996 dramatically changed the incidence rates of CMV retinitis and its attendant complications.17-19 The four-year cumulative incidence of CMV retinitis in AIDS patients with lowered CD4 counts was 7%, a 72% reduction in the post-HAART era as determined in 2012 by the Longitudinal Study of Ocular Complications of AIDS (LSOCA) study research groups.19 Consequently, the focus of anti-CMV treatment has shifted from short-term disease control to long-term maintenance of vision and quality of life considerations10 for patients on HAART.
To date, management of CMV retinitis has been influenced by the fact that all available treatments are virostatic.3 A histopathologic study on autopsy eyes demonstrated the presence of viral protein at the border of treated CMV lesions. With cessation of therapy, viral assembly apparently resumes and the retinal lesions start to enlarge.20, 21 Therefore, unless immune recovery occurs, chronic lifelong therapy may be required. Clinicians must determine when it is safe to discontinue anti-CMV drug treatment in patients who achieve immune recovery and how to best schedule follow-up visits or treat a CMV relapse.
Since 1989, prospective randomized trials have compared different treatment strategies for different disease presentations, while others compared drugs for efficacy, long-term effects on visual functions, morbidity, and mortality rates.
AIDS, SOCA, AND OCULAR COMPLICATIONS
SOCA were collaborative, randomized, prospective clinical NEI-funded trials designed to evaluate treatment options and long-term trends of ocular complications of AIDS. The study arms were designed to test emerging treatments for effectiveness in CMV retinitis with the propensity for preserving vision without decreasing survival or quality of life.
The first SOCA study, completed in 1991, compared foscarnet and ganciclovir in controlling CMV retinitis.22 Between 1989 and 1998, five clinical trials were completed, with the conclusion of the Ganciclovir Cidofovir CMV Retinitis trial (GCCRT) using the ganciclovir implant for the newly diagnosed or relapsed CMV retinitis patient.23-26 Since 1998, LSOCA, a prospective observational sub study, has been ongoing to monitor changes in trends in those with ocular complications with AIDS and the effects of long-term treatment on visual function, survival, and quality of life.19,27
ANTIVIRAL THERAPIES IN AIDS-ASSOCIATED CMV RETINITIS
Although CMV retinitis appears as an isolated infection, the disease is part of a systemic infection with implications for the fellow eye and other organs.28, 29 So, patients usually receive systemic, with or without concurrent local, therapy.
As of September 1996, the FDA had approved three drugs for the treatment of CMV retinitis: ganciclovir, foscarnet, and cidofovir; all are selective viral DNA polymerase inhibitors, generally commenced at higher induction doses for two to three weeks, followed by lower maintenance doses to prevent relapse of the retinitis.
In 1989, ganciclovir was the only drug approved for treatment of CMV retinitis in immunocompromised patients.3 It was administered twice daily at 5mg/kg IV infusions. A few years later, as foscarnet became available for investigational use, a large randomized trial, the Foscarnet-Ganciclovir CMV Retinitis Trial, designed to compare both drugs in terms of relative efficacy and safety in patients with AIDS,22 revealed no difference in terms of the rate of retinitis progression. However, it was stopped early as foscarnet showed a survival advantage for patients in the pre-HAART era.30, 31
With completion of the HPMPC trial in 1996, the efficacy of cidofovir, a nucleotide analogue with broad antiviral activity, was demonstrated in 64 newly diagnosed CMV retinitis patients randomized to treatment and deferral arms.24 In 51 patients on HAART, the Spanish Cidofovir Study Group further highlighted the efficacy of compassionate use of cidofovir in patients with previously treated retinitis who had relapsed or were unresponsive to induction with other anti-CMV agents.32 Although the numbers in those non-comparative trials were relatively small, cumulative data suggest its efficiency in delaying progression of CMV retinitis with a less intrusive administration regimen because of its prolonged intracellular half-life.24, 32-34 Induction dosing consists of once weekly infusions for two weeks, followed by infusions every other week during maintenance; no need for daily dosage administration and indwelling catheters.
Another useful addition came in 2000 with the introduction of valganciclovir, the L-valyl ester prodrug of ganciclovir, with high oral bioavailability (60%) and convenient once-daily dosing (900 mg once daily for 2 to 3 weeks result in serum ganciclovir levels comparable with those achieved with daily intravenous induction).10, 35 Oral valganciclovir has shown to be equally efficacious in comparative studies with intravenous ganciclovir for induction and maintenance for CMV retinitis in patients with AIDS.
A satisfactory response to induction therapy was achieved in 77% of patients assigned to intravenous ganciclovir and 72% assigned to oral valganciclovir in one study randomizing 80 patients to each treatment group.35 The median time to progression of retinitis was 125 and 160 days, respectively. Compared with intravenous therapy, oral valganciclovir also equally prevents and treats non-ocular CMV disease 36, and has hence become a preferred treatment option for most experts who had previously had a rather limited arsenal of drugs approved for CMV. A retrospective analysis of anti-CMV retinitis treatment in managed-care plans in the United States from 1997 to 2002 has shown that the use of oral valganciclovir has largely surpassed the use of intravenous formulations.37
DO COMBINATIONS WORK BETTER?
In vitro data suggest that combining anti-viral therapies is synergistic in inhibiting viral replication.38, 39 In the SOCA-CMV Retinitis Retreatment Trial, the combination of intravenous ganciclovir and foscarnet was more effective but more toxic than either drug alone for the treatment of persistently active or relapsed retinitis.23 Continuation of previous maintenance therapy plus induction with the other for 2 weeks followed by maintenance with both drugs was most effective in controlling CMV retinitis, but quality of life suffers greatly with the time required for the infusions.
With the advent of new oral formulations or implants the armamentarium only grows wider but we should note, however, that evidence in support of particular combinations and their dosing over others has been lacking. Albeit a convenient treatment option, not necessitating an indwelling venous catheter or an ocular surgical procedure, results of a phase I trial on the combination of intermittent intravenous cidofovir and daily oral ganciclovir for relapsed CMV retinitis in patients with AIDS have shown dose-limiting side effects and poor tolerance, which had heralded further consideration for less frequent dosing.40
Over the past decades, intravitreal drug injections of the available anti-CMV drugs were given to patients intolerant to systemic therapy.41-43 Now, patients commonly receive intravitreal injections to control sight-threatening retinitis (zone 1 disease) or to help bridge to an alternative regimen.9,10 Retinitis stabilizes to induction with two to three injections a week, while once weekly injections usually suffice for maintenance. Like ganciclovir, several non-controlled series of patients experienced successful induction therapy with injections of foscarnet solution.44-46 Cidofovir, because of concerns regarding ocular toxicities via intravitreal administration, is no longer recommended.47 A double-masked, randomized trial of three intravitreal doses was prematurely terminated due to high incidences of post-injection uveitis and hypotony (87% and 16%), sometimes with irreversible severe visual loss.48
The development of the sustained-release implant (approved in 1996) that releases intraocular ganciclovir at 1 μg/hour for up to eight months obviated the need for weekly injections during the maintenance phase. In a randomized study, the implant extended the mean time to retinitis progression to 221 days vs 76 days with intravenous ganciclovir therapy.49 Although coupling the ganciclovir implant with oral ganciclovir therapy has shown great efficacy against progression of retinitis (Data from the Ganciclovir Cidofovir CMV Retinitis Trial (GCCRT), SOCA completed in 2000),26 it is no longer commercially available, due to the declining incidence of CMV retinitis and perhaps the favorable ease of use of oral valganciclovir. In developing countries, intravitreal injections alone are still employed to evade the cost of sustained-release implants and systemic therapy9 (Figures 1, 2 and 3). We should indicate, however, that local therapy alone is associated with a higher risk of retinitis to the fellow eye, extraocular CMV-related disease, and increased mortality.49,50
THE ADVENT OF NEWER FORMULATIONS
While currently approved medications have shown efficacy against CMV, systemic treatment has inherent side effects (usually dose-limiting neutropenia and nephrotoxicity).9,23 Drug-resistant mutants have also evolved against AIDS, complicated further with cross-resistance as viral DNA polymerase is the target of all currently used systemic drugs.10
Despite the need for safer more convenient therapy, relatively fewer research programs have focused on anti-CMV drug development post-HAART, with additional progress expected from studies on pre-emptive treatment for other susceptible groups like organ recipients.9 Most of these compounds are in various stages of clinical development.
Of these, cidofovir esters have shown improved oral bioavailability and better safety profiles with enhanced efficacy against CMV infections.51,52 Others — maribavir, BAY 38-4766, and AIC246 — mostly inhibit viral activity through interference with pathways other than viral DNA polymerase decreasing chances of cross-resistance with available agents.53-55 There are also reports regarding oral leflunomide's success with ganciclovir- and foscarnet resistant- CMV retinitis in a series of organ transplant recipient patients.56, 57
In view of the role of immune recovery for control of AIDS-associated CMV retinitis, treatment entails combining HAART-induced immune system reconstitution with effective anti-CMV therapy. Treatment should be individualized considering the size and location of the retinitis, potential for immune recovery, and treatment-related side effects.10
In general, anti-CMV therapy should be maintained for at least six months until the retinitis is inactive, with CD4+ T cell counts greater than 100 cells/µL.58, 59 Long-term monitoring for CMV reactivation is needed, although clear data on optimum follow-up schedules are lacking. The US DHHS recommends that patients with immune recovery to >100 cells/µL for at least three to six months have anti-CMV therapy discontinued, but many authors await more robust evidence before treatment cessation.59, 60
Small peripheral lesions in HAART-naïve patients are often treated with systemic therapy alone, while combining both systemic with local therapy is perhaps the preferred treatment option for sight-threatening zone 1 disease, as intravitreal injections can quickly establish high intraocular antiviral concentrations and prevent progression. A brief period of observation for retinitis progression before initiation of anti-CMV treatment would probably not cause long-term adverse outcomes in patients with small far peripheral lesions which occupy less than 25% of the retinal area.24, 61
To suppress viral replication rapidly and minimize systemic complications, physicians induce therapy at high frequent doses for two to three weeks until the retinitis stabilizes (induction phase with one of these four systemic drugs: ganciclovir, foscavir, cidofovir, or oral valganciclovir) followed by a continuous lower-dose therapy (maintenance phase) to suppress viral replication. Comparative studies have shown varied side effect profiles but no significant differences between drug choices in terms of efficacy. 24, 26, 30, 35
While these drugs suppress CMV replication, they do not eliminate the virus from the eye. So, unless the patient has adequate reconstitution of the immune system functions, retinitis treatment may need to be continued indefinitely.
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