Nicholas Butler, MD, is assistant professor of ophthalmology at the Wilmer Eye Institute’s Division of Ocular Immunology. Jennifer E. Thorne, MD, PhD, is professor of ophthalmology and epidemiology and the director of the Division of Ocular Immunology at Wilmer. Neither author reports any financial interests in any of the products mentioned in this article. Dr. Thorne can be reached at firstname.lastname@example.org.
In the United States, exposure to cytomegalovirus (CMV) is ubiquitous; seroprevalence rises from nearly 60% in patients 6 years or older to greater than 90% in individuals 80 years or older.1
In people with intact immune systems, initial infection with CMV causes minimal, if any, symptoms, although it can induce a mononucleosis-like syndrome in some patients. Cell-mediated immunity controls the virus and prevents specific organ disease in all but a rare few.
However, in the setting of advanced immunosuppression, such as AIDS, organ transplantation with iatrogenic immunosuppression, autoimmune disease, or malignancy, susceptible individuals can develop specific end-organ CMV disease (eg, encephalitis, esophagitis, colitis, and retinitis), carrying a significant risk of morbidity and mortality.
Of these diseases, retinitis (Figures 1-4) occurs at a greatly increased rate compared to other CMV diseases, at least in AIDS patients,2 and it confers an increased risk of mortality.3
The development of highly active antiretroviral therapy (HAART) in 1996 changed the landscape considerably. The four-year cumulative incidence of CMV retinitis in AIDS patients with immune suppression (CD4+ T cell count <100 cells/μL) has decreased by 72% in the post-HAART era, as determined in the Longitudinal Ocular Complications of AIDS (LSOCA) study.4
This cohort study, which has followed AIDS-defined patients for 15 years, likely included patients at relatively higher risk for developing ocular opportunistic infections than the general HIV population. In fact, the incidence of CMV retinitis has likely declined by 90% in many academic centers.
Nonetheless, patients still develop this sight-threatening disease, likely in the setting of diagnostic delay, noncompliance, or nonresponse to HAART, and the single most important risk factor for the development of CMV retinitis in AIDS patients remains a CD4+ T cell count <50 cells/μL.4
Because patients with AIDS live longer with HAART-induced immune recovery, a smaller percentage of those living with HIV remain at increased risk for developing CMV retinitis. As such, the proportion of non–AIDS-related CMV retinitis cases, those immunosuppressed by other means, and even cases in some otherwise healthy individuals might be increasing.
This article reviews the current CMV retinitis literature, with attention directed toward recent advances in the diagnosis and treatment of this disease.
Clinicians generally make the diagnosis of CMV based on clinical grounds alone, in the setting of a supportive history of an immune-compromised state (HIV/AIDS, iatrogenic, malignancy, or other).
Retinal lesions commonly appear peripherally in a peri-vascular distribution as a creamy white infiltrate, with a more granular border comprised of smaller satellite lesions. Less obviously involved spaces of “clear” retina separate the granular foci.
However, with time, these areas progress to active retinitis and scarring, suggesting involvement with the virus from the beginning. The active border generally advances posteriorly, at a rate of 250-350 μm/week, leaving a swath of scarred and necrotic retina with mottled pigmentation of the RPE in its wake. Lesions presenting more posteriorly can involve the retinal vessels and cause retinal hemorrhages, giving rise to the term “pizza pie” retinitis.
The clinical appearance of newly diagnosed CMV retinitis among highly immunosuppressed patients with AIDS has not changed appreciably from the pre-HAART era to the HAART era.5 However, the rates of developing retinitis and its attendant complications, such as retinal detachment6 and loss of visual acuity7 and visual field,8 have dramatically improved with HAART.
Because patients with HIV/AIDS live longer with HAART-induced immune recovery, the proportion of non–HIV/AIDS-related CMV retinitis might be rising, and the clinical features can be somewhat different in this population.
In elderly immunocompetent patients (other than the natural waning of immunity and increased prevalence of typical comorbidities that come with age), CMV retinitis appears to have an increased association with retinal arteriolar occlusions, even in the setting of minimal retinitis.9,10
Other investigators have echoed these findings. In patients with limited immune dysfunction (due to old age, diabetes, or noncytotoxic immunosuppression), CMV retinitis can present with typical peripheral, granular, and slowly progressive retinitis and an atypical panretinal occlusive vasculitis, mimicking acute retinal necrosis in its retinal vascular appearance only.11
Eighty percent of patients in this small series went on to develop neovascularization, due to the extent of induced retinal ischemia. In a series of 18 mostly younger Thai patients (mean age 49 years) without HIV, the majority of whom were immunosuppressed by other causes, retinal vasculitis appeared in 73%. Among this group, 81% primarily had arteritis, in contrast to CMV retinitis patients with HIV, in whom periphlebitis was more typical.12
Determining progression of retinitis, which involves documentation of nearly imperceptible border movement or the development of a new focus of retinitis, is optimally aided with serial fundus photographs. This becomes particularly important in deciding upon response to treatment.
Recently, investigators have demonstrated that hyperautofluorescence in areas of CMV retinitis bordering activity on fundus autofluorescence imaging may be a useful adjunct in differentiating between active and inactive retinitis when the clinical exam and photos are equivocal.13
Additionally, optical coherence tomography has revealed subhyaloid, presumed inflammatory, precipitates in a small series of patients with active CMV retinitis.14 Whether or not these examination and imaging findings add to our understanding of the clinical features of this disease in a meaningful way (ie, diagnostic relevance or response to treatment) remains to be determined.
In cases of diagnostic dilemma, especially in the absence of an identifiable source of host immunosuppression, polymerase chain reaction (PCR) of aqueous or vitreous samples can amplify CMV DNA and secure a diagnosis.15
In most clinical centers that treat cases of CMV retinitis frequently, PCR of ocular fluid is often performed at the initial consultation, because rapid differentiation among retinal infections associated with herpes simplex virus, varicella zoster virus, and CMV has important treatment implications.
More recently, a loop-mediated isothermal amplification (LAMP) assay demonstrated 100% concordance with PCR in detecting CMV DNA in vitreous samples of patients with CMV retinitis at a fraction of the cost, potentially increasing the diagnostic capabilities of clinicians in resource-limited settings.16
Most uveitis and retina specialists who regularly follow patients with HIV screen individuals with CD4+ T cell counts <50 cells/μL, using dilated fundus exams every three months.
As the cost of medicine increases, and in resource-limited settings in which the burden of CMV retinitis exceeds the supply of qualified physicians, the use of telemedicine screening for CMV retinitis with fundus photography has increased, demonstrating validity.17,18
In patients undergoing allogenic hematopoietic stem cell transplantation (HSCT) after conditioning with an alemtuzumab (Campath, Genzyme, Cambridge, MA)-based regimen, the frequency of CMV retinitis can approach 24%.19 Regular screening for retinitis in this population is also warranted.
Similarly, post-HSCT patients with a significant CMV viral load (peak CMV DNA level >7.64 x 104 copies/mL) are at increased risk of developing CMV retinitis (hazard ratio, 25.0; 95% confidence interval, 3.0-210.8), so physicians should monitor patients in this subgroup closely.20
Diagnostic delay can increase the risk of vision loss, both directly, through more fulminant retinitis and a greater likelihood of foveal or optic nerve involvement,21 and indirectly, because the burden of immune recovery uveitis (IRU) and its sequelae increases with the severity of CMV retinitis.22
Further, in elderly, otherwise healthy patients with CMV retinitis, delayed diagnosis has contributed to associated retinal arteriolar occlusions, with sometimes disastrous visual outcomes.9
Because no currently available agent is virucidal, the goal of therapy generally is to arrest viral replication/assembly until the host’s immune system has recovered sufficiently to assume this function.
In the setting of HIV/AIDS, initiation of HAART is the most critical step in planning for long-term suppression of CMV retinitis. However, some infectious disease specialists favor a delay in HAART, with the hope of reducing the development of immune-recovery syndromes.23
Research has demonstrated the potential benefits of this strategy in the eye, including a lowered incidence of IRU.24 In the event that immune system recovery is unexpected (ie, transplant recipients requiring lifelong immunosuppression), the physician should provide indefinite virostatic treatment.
Cytomegalovirus DNA can be recovered from dormant CMV retinitis lesions. However, histopathology has revealed dysfunction in the assembly of intact virions in patients on chronic therapy.25
Although CMV retinitis can present as an isolated infection, often initially localized in only one eye, the disease itself is part of a systemic infection with implications for the fellow eye and other organs. As such, patients generally always receive systemic therapy, with or without concurrent local treatment.
The FDA has approved three intravenous drugs for the treatment of CMV retinitis: oral or intravenous ganciclovir (Cytovene, Roche, Nutley, NJ); intravenous foscarnet (Foscavir, AstraZeneca, Wilmington, DE); and intravenous cidofovir (Vistide, Gilead, Foster City, CA). Systemic therapies generally commence at higher induction dosages for two to three weeks, followed by lower maintenance doses to prevent relapse of the retinitis.
All three currently available intravenous drugs employ analogous mechanisms of action, specifically selective inhibition of viral DNA polymerase.26 Ganciclovir appeared first in 1989, followed by foscarnet in 1991.
A large randomized trial revealed no difference between intravenous ganciclovir and intravenous foscarnet with regard to the rate of retinitis progression. However, the Policy and Data Monitoring Board terminated the study due to a 79% increase in mortality in the ganciclovir arm.
The authors speculated that the survival difference stemmed from the intrinsic anti-HIV effects of foscarnet or the increased rates of concomitant zidovudine use in the foscarnet group (due to synergistic myelosuppressive effects of zidovudine with ganciclovir). However, more extensive analyses failed to demonstrate this latter hypothesis conclusively.
At any rate, this study occurred prior to the HAART era, and the authors presciently advised caution in applying their data widely, because an explosion of antiretroviral drugs occurred shortly after this study’s 1992 publication date.27
Because comparative trials have demonstrated similar efficacy for all systemic medications regarding time to progression of retinitis, the use of oral valganciclovir (Valcyte, Roche), an L-valyl ester prodrug of ganciclovir, has largely surpassed the use of intravenous formulations.28
Oral valganciclovir obviates much of the inconvenience and risk associated with intravenous therapy, although cost and myelosuppression remain issues. The drug achieves a bioavailability of 60%, comparable to intravenous ganciclovir and far greater than that of oral ganciclovir (5%).29
Several newer antiviral agents are in various stages of development, from preclinical experiments to phase 2 clinical trials. Cidofovir esters were 1,000 times more potent against human and murine CMV in in vitro studies, with improved oral bioavailability (88-97%) and less renal toxicity.
Other agents, such as maribavir (GlaxoSmithKline, Philadelphia, PA), BAY 38-4766 (Bayer, Pittsburgh, PA), and AIC246 (AiCuris, Wuppertal, Germany), inhibit viral activity through pathways other than the inhibition of viral DNA polymerase. As a result, they decrease the chances of cross-resistance with the currently FDA-approved medications.29
Patients commonly receive intravitreal injections of either ganciclovir or foscarnet, with or without systemic medication, to control sight-threatening retinitis (zone 1 disease) or to help bridge to an alternative systemic therapy when a suspicion of resistance arises.
Induction dosing with intravitreal medications requires injections two to three times weekly, while once weekly generally is sufficient for maintenance. In developing countries, where cost can be a major barrier to treatment, intravitreal strategies alone are being increasingly employed, demonstrating comparable efficacy in terms of control of retinitis at only 11.7% and 11.1% of the cost of sustained-release implants and systemic therapy, respectively.30
We should reiterate, however, that local therapy alone was associated with a higher risk of other end organ involvement (including the fellow eye) and death in the pre-HAART era.31–33 This association has continued into the current HAART era.28,34
Further, the latest data from LSOCA have indicated that patients treated with intravitreal therapy alone, compared to those treated with systemic regimens (with or without intravitreal therapy) or the ganciclovir implant, might have worse ocular outcomes, in terms of final VA, progression of retinitis, and loss of visual field, even after adjusting for known confounders.34
The authors have highlighted, however, the relatively small sample size of patients with local therapy alone and the potential for unrecognized, and hence unmeasured, bias.
Much of the data in support of intravitreal approaches for CMV retinitis have come from adult patients with AIDS. However, more recently, reports have emerged of the safety and efficacy of intravitreal ganciclovir for CMV retinitis in neonates with congenital infection35,36 and in patients post-HSCT.37
In some instances of temporary iatrogenic immunosuppression (ie, patients in remission post-treatment for autoimmune disease or cancer), ongoing immunosuppression can stem from systemic treatment of CMV retinitis, because ganciclovir and valganciclovir can be profoundly myelosuppressive.
Stopping systemic anti-CMV therapy and initiating intravitreal ganciclovir or foscarnet can induce sufficient immune recovery to provide long-term drug-free remission of CMV retinitis.38
However, if immune recovery does not or cannot occur, the rates of relapse of infection with ongoing intravitreal injections are comparable to those with systemically administered regimens, even with aggressive therapy.39,40
In 1996, the FDA approved a sustained-release, intra-ocular ganciclovir implant (Vitrasert, Bausch + Lomb, Rochester, NY). In the pre-HAART era, this implant demonstrated superiority over intravenous ganciclovir in terms of median time to the progression of retinitis (221 days for the 1 μg/hour implant vs 71 days for intravenous ganciclovir).31
As expected, patients treated with the implant alone developed CMV disease outside of the treated eye at higher rates, and oral or intravenous ganciclovir significantly reduced this risk.31,32
Complication rates associated with the ganciclovir implant, most commonly for cataract, vitreous hemorrhage, and retinal detachment, have remained relatively high (0.19/eye-year). However, severe vision loss is infrequent (0.005/eye-year for ≥6 lines of vision loss).41
Beyond the known benefit that immune recovery has on mitigating the complications of CMV retinitis, it seems that immune recovery may similarly decrease the rates of complications associated with the implant.41
Although the ganciclovir implant, coupled with oral ganciclovir, offers the greatest protection against progression of retinitis demonstrated to date,32 it is no longer on the market due to unfavorable economics with the declining incidence of CMV retinitis. The effectiveness and ease of use of oral valganciclovir likely hastened the departure of the implant as well.
A recovered immune system can control CMV retinitis in the absence of ongoing prophylactic therapy. The Department of Health and Human Services currently recommends that HIV patients with CD4 counts of >100 cells/μL for at least three to six months discontinue anti-CMV therapy41; data from LSOCA support adherence to these recommendations.43
Physicians should still follow these patients with dilated exams every three months, because not all immune-recovered patients will suppress the retinitis without therapy, and the risk of relapse persists for five years at minimum.28
While HAART-induced immune recovery may indefinitely control the infection, it has also been associated with the development of IRU in nearly 20% of patients with CMV retinitis.22,28
Many of these patients are at increased risk for vision loss, mainly from CME, which may be responsive to local or systemic corticosteroids but often recrudesces. The fluocinolone acetonide implant (Retisert, Bausch + Lomb) appears to control IRU and CME in a few eyes, but long-term data to ascertain the risk of retinitis reactivation have been limited.44
If immune recovery does not occur (or is not possible), relapse of retinitis is the norm, even in patients with strict adherence to suppressive therapy. Early relapse often relates to insufficient intraocular concentration of drug, while late relapse typically stems from emergent resistance.28
Mutations in the CMV UL97 gene, a viral phosphotransferase necessary for ganciclovir activation, confer low-level resistance to ganciclovir, while mutations in both the CMV UL97 and CMV UL54 genes lead to high-level ganciclovir resistance. Researchers have theorized that low-level ganciclovir-resistant CMV should respond to cidofovir, but high-level resistance mandates foscarnet therapy.28
In practice, physicians rarely prescribe cidofovir due to high rates of associated renal toxicity and hypotonous uveitis. Beyond the implications for the eye with CMV retinitis, demonstration of resistant CMV in the blood confers a 65% increase in mortality in patients with AIDS and CMV retinitis.45
Coinfection by multiple strains of CMV may exist in any one patient. Due to variance in selective pressures among differing body sites, it is possible to demonstrate peripheral blood resistance to ganciclovir in the setting of ocular susceptibility46; so when assessing for resistance to ganciclovir in cases of CMV retinitis, ocular fluid analysis with PCR is informative.47
Until newer antivirals reach the level of commercial availability, treatment of CMV retinitis in the setting of drug resistance remains a particular challenge. Oral leflunomide (Arava, Sanofi-Aventis, Bridgewater, NJ), an immunosuppressive agent with anti-CMV activity, has demonstrated efficacy in transplant patients with systemic CMV infection48 and also in multi–drug-resistant CMV retinitis.49
An additional advantage of leflunomide includes a significant cost reduction, compared to intravenous ganciclovir or oral valganciclovir. However, due to variability in half-life of the active metabolite, serum level monitoring is mandatory (range from 25 ng/mL to 80 μg/mL).48
Given the cost advantage and well-demonstrated inferiority of intravitreal injections alone for CMV retinitis, it may be beneficial to add oral leflunomide to intravitreal therapy in resource-limited locales. We should note, however, that evidence in support of this combination has been lacking.
Monitoring for response to treatment with frequent clinical examinations, supplemented with fundus photography, is critical, as randomized CMV retinitis treatment trials previously advocated.50,51
Because the disease may progress very slowly, border movement may evade detection if the physician relies on fundus examinations and memory alone.
Despite the manifest benefits of HAART on incidence and severity, CMV retinitis remains the most common ocular opportunistic infection in patients with AIDS.7,52 Patients with a CD4+ T cell count <50 continue to be at increased risk of CMV retinitis, and frequent screening in this population is essential to detect the disease before it becomes sight-threatening.
Initiation of HAART has direct and indirect benefits, although the optimal timing of initiation, with regard to the risk of immune reconstitution syndromes, remains under investigation.
Further, among non-HIV infected individuals, we may witness an increasing number of CMV retinitis cases in otherwise immunosuppressed people, because more clinicians use immunosuppressive therapy for auto-immune diseases and malignancies.
As a group, our collective education during the AIDS epidemic regarding the clinical features of CMV retinitis may contribute to an increased ability to recognize and diagnose the disease in atypical settings, such as the immunocompetent host. However, the disease in patients without AIDS may be phenotypically distinct, with a greater likelihood of sight-threatening retinal arteriolar occlusions.
Newer anti-CMV therapeutics, with better safety profiles and increased efficacy, are in various stages of development. Their emergence on the market is critical in addressing the high rates of reactivation and antiviral resistance that occur with long-term virostatic therapy for CMV retinitis.
In the developing world, where resources may limit the use of oral valganciclovir or intravenous ganciclovir, intra-vitreal injections alone likely confer a worse prognosis, in terms of other end-organ damage and overall mortality. Adjuvant agents, such as oral leflunomide or oral ganciclovir, may be cost-effective options in mitigating the systemic consequences of this disease in such locales. RP
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