INTRODUCTION — Acquired immunodeficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis is one of the most serious ocular complications in individuals with AIDS. It can progress to blindness, and in some cases, be accompanied by potentially fatal systemic disease. It is typically caused by reactivation of latent disease. CMV retinitis can be prevented by initiating antiretroviral therapy (ART) early in the course of human immunodeficiency virus (HIV) infection. However, CMV retinitis is still seen in patients who do not have access to these medications and/or are unable to adhere to their ART regimen.
The treatment of CMV retinitis will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of CMV retinitis are discussed elsewhere. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis".)
APPROACH TO TREATMENT — For patients who develop AIDS-related CMV retinitis, treatment consists of CMV antiviral therapy and antiretroviral therapy (ART) for HIV. In high-income settings, we suggest starting ART approximately two weeks after starting therapy to treat CMV . However, if there are concerns about follow-up (eg, patients who are unlikely to follow up with medical care, patients in resource-limited settings), ART should be initiated immediately. (See 'When to initiate antiretroviral therapy' below and 'Treatment in resource-limited settings' below.)
●For patients with newly diagnosed infection, we first assess the location of the lesions (central versus peripheral) and if the patient has immediate sight-threatening disease (lesions <1500 microns from the fovea or adjacent to the optic nerve head).
•For patients with immediate sight-threatening lesions, we recommend initial therapy with local intravitreal injections in conjunction with systemic therapy. Treatment should be started as soon as possible . (See 'Disease that is immediately sight threatening' below.)
•For patients without immediately sight-threatening disease, we recommend systemic therapy alone. (See 'Disease that is NOT immediately sight threatening' below.)
●The choice of which antiviral agents to use depends in part upon the individual’s ability to take oral medications, the presence of comorbid conditions, their concomitant medications, and their ability to adhere to treatment. Other factors that impact the choice of treatment include the diagnostic capacity to determine the severity of disease, the availability of oral antiviral agents, and/or skilled providers to perform intravitreal injections. (See 'Systemic therapy' below and 'Treatment in resource-limited settings' below.)
●For those with relapsed infection, we typically suggest dual therapy with IV ganciclovir (or oral valganciclovir) plus IV foscarnet, unless ART has only recently been initiated, in which case further immune reconstitution may be expected and reinduction with monotherapy valganciclovir or foscarnet may well suffice. (See 'Salvage therapy' below.)
Initial induction therapy is typically administered until retinitis has become inactive (usually two to three weeks). It is then followed by lower-dose maintenance therapy. (See 'Duration of induction therapy' below and 'Maintenance therapy for initial infection' below and 'Discontinuing maintenance therapy' below.)
Patients should be monitored closely on treatment to evaluate response to therapy and drug-induced complications (table 1). Patients should then continue to be monitored, even after they have been successfully treated for CMV retinitis, to evaluate for the onset of significant intraocular inflammation secondary to an immune reconstitution inflammatory syndrome. (See 'Patient monitoring' below and 'CMV immune reconstitution inflammatory syndromes' below.)
INDUCTION THERAPY FOR INITIAL INFECTION
Disease that is immediately sight threatening — We recommend a combination of intravitreal therapy plus systemic therapy for patients with immediate sight-threatening disease (lesions located <1500 microns from the fovea or adjacent to the optic nerve head) (table 1). Treatment should be administered as soon as possible. We use intravitreal therapy for such patients since it may take several days to achieve steady state intraocular drug levels with systemic therapy. There are no well-designed clinical trials evaluating the use of intravitreal therapy plus systemic therapy for patients with immediate sight-threatening disease. Although infection may be controlled with systemic therapy alone, we administer both modalities to minimize the risk of disease progression given the high risk of clinically significant vision loss.
Intravitreal therapy — Intravitreal therapy should be used in conjunction with systemic therapy for patients with immediate sight-threatening disease (see 'Systemic therapy' below). Either ganciclovir or foscarnet can be injected directly into the eye to achieve high drug levels. Several different regimens can be used [1-3]. We administer intravitreal injections of ganciclovir (2.5 mg in 0.05 ml volume) weekly for two to three injections. We prefer this formulation of intraocular ganciclovir, rather than one that requires a larger volume, to minimize the risk of increased ocular pressure. Foscarnet (2.4 mg/injection) can also be administered as intraocular therapy and should be given twice weekly for 1 to 4 doses over a period of 7 to 14 days. Potential adverse events related to intraocular injections include endophthalmitis, vitreous hemorrhage, and retinal detachment .
If systemic therapy is initiated within 24 hours of the initial intravitreal injection, subsequent injections are probably unnecessary. In addition, injections can be stopped as soon as the retinal opacity resolves, regardless of how many injections have been given.
The use of intravitreal therapy is supported by small non-randomized studies that found intravitreal injections with either ganciclovir or foscarnet were effective treatment for CMV retinitis . In addition, well-designed randomized trials demonstrated ganciclovir implants were better than intravenous (IV) ganciclovir as initial therapy [6,7]. As an example, in a randomized trial of 188 patients with AIDS and newly diagnosed cytomegalovirus retinitis, the median time to progression of retinitis ranged from 191 to 221 days in those who received implants (depending upon the dose) versus 71 days in those who received IV ganciclovir . However, ganciclovir implants are no longer being manufactured, and as such, are no longer a treatment option.
Systemic therapy — We prefer oral valganciclovir for systemic therapy, rather than IV therapy, given its good oral bioavailability, ease of administration, and the reduced risk of complications or toxicity from an indwelling venous catheter. However, several other systemic therapy options (ie, IV ganciclovir, IV foscarnet, IV cidofovir) are available. The choice depends in part on the patient’s ability to tolerate the individual agents. The antiviral agents used to treat CMV may require dose modifications for renal impairment; detailed dosing recommendations are available in the individual drug information monographs included within UpToDate and the individual topic reviews. (See "Ganciclovir and valganciclovir: An overview" and "Foscarnet: An overview" and "Cidofovir: An overview".)
●Oral valganciclovir — Valganciclovir is an orally administered prodrug of ganciclovir. Valganciclovir is given at doses of 900 mg twice daily with food for the first 14 to 21 days of induction therapy. Oral bioavailability is approximately 60 percent and is 10-fold higher than that with oral ganciclovir . Its oral formulation offers cost savings and the advantage of avoiding catheter-related complications associated with chronic intravenous therapies . The toxicity profile of valganciclovir is identical to that of IV ganciclovir and is mainly related to its effect on bone marrow suppression . (See 'Adverse reactions' below.)
Valganciclovir was found to be as effective as IV ganciclovir for induction therapy of CMV retinitis in a multicenter randomized trial of 160 patients with AIDS and newly diagnosed CMV retinitis . Although this study excluded patients with lesions located <1500 microns from the fovea or adjacent to the optic nerve head, we believe that the results can be extrapolated to those with immediate sight-threatening disease.
●IV ganciclovir or IV foscarnet — IV ganciclovir or foscarnet can be used for the treatment of CMV retinitis in individuals who are unable to tolerate oral therapy [12,13]. These agents were widely used prior to the introduction of oral valganciclovir. The only trial comparing IV ganciclovir and IV foscarnet for the treatment of CMV retinitis was a randomized, unblinded trial conducted in 234 patients with AIDS, and the two agents demonstrated equivalent efficacy .
The induction doses are as follows:
•Ganciclovir 5 mg/kg/dose every 12 hours
•Foscarnet 60 mg/kg/dose every eight hours, or 90 mg/kg/dose every 12 hours
We generally prefer ganciclovir rather than foscarnet for initial therapy as it is easier to administer and is generally better tolerated. We administer foscarnet to individuals who have adverse reactions to oral valganciclovir or IV ganciclovir, as well as those who are at risk for complications from ganciclovir (eg, patients with an absolute neutrophil count <500 cells/microL or a platelet count <20,000 cells/microL). The main adverse events of ganciclovir are hematologic; those of foscarnet are mainly related to renal toxicity and electrolyte disturbances. (See 'Adverse reactions' below and "Ganciclovir and valganciclovir: An overview" and "Foscarnet: An overview".)
●Cidofovir — We administer cidofovir to patients who are unable to tolerate any of the other treatment options (valganciclovir, ganciclovir, or foscarnet). The dose of cidofovir for CMV retinitis is 5/mg/kg/week for two weeks, then 5 mg/kg every other week. Saline hydration and high-dose probenecid therapy is given concomitantly with cidofovir to reduce the risk of serious renal injury [15,16] (table 1).
Cidofovir is contraindicated in patients with a creatinine >1.5 mg/dL, an estimated glomerular filtration rate ≤55 mL/min/1.73m2, or a urine protein ≥100 mg/dL. Serum creatinine, blood urea nitrogen, and urinalysis should be performed before infusions to detect renal dysfunction or proteinuria . In addition, cidofovir should be avoided in patients with a sulfa allergy because of cross hypersensitivity with probenecid (table 1). It should also be avoided in settings where the patient is at high risk for developing an immune reconstitution inflammatory syndrome (eg, patients initiating antiretroviral therapy [ART]) , since cidofovir has been associated with immune recovery uveitis . (See 'CMV immune reconstitution inflammatory syndromes' below.)
Cidofovir is a nucleoside monophosphate analogue with potent in vitro activity against CMV that is 10- to 100-fold greater than that of other anti-CMV drugs. In the pre-ART era, two randomized trials demonstrated the efficacy of cidofovir for the treatment of patients without immediately sight-threatening retinitis [15,16]. Cidofovir was also demonstrated to have utility in the treatment of patients who had failed therapy with ganciclovir or foscarnet . (See 'Relapsed infection' below.)
However, the use of cidofovir is quite limited due to its toxicity. Cidofovir can cause serious, irreversible nephrotoxicity via dose-dependent proximal tubular cell injury. Nephrotoxicity or probenecid intolerance (eg, fever, nausea, vomiting, rash) is treatment-limiting in approximately one-third to one-half of patients. The initial manifestations of renal toxicity are proteinuria and increased serum creatinine concentrations; with continued treatment, some patients have had a life-threatening Fanconi-like syndrome and renal failure. Neutropenia, peripheral neuropathy, abnormally low intraocular pressure, anterior uveitis, and alopecia have also been reported with cidofovir . (See 'Adverse reactions' below.)
Disease that is NOT immediately sight threatening — For patients with disease that is not immediately sight threatening, we recommend systemic therapy alone. Systemic therapy with oral valganciclovir, IV ganciclovir, or IV foscarnet has been found to be effective in treating CMV retinitis. We prefer oral valganciclovir rather than IV therapy. A detailed discussion on systemic therapy is found above. (See 'Systemic therapy' above.)
Although intravitreal therapy has been successfully used for initial treatment of CMV retinitis in patients without sight-threatening disease (see 'Intravitreal therapy' above), we prefer systemic therapy given the limitations of using intraocular injections . These include:
●The subsequent development of extraocular CMV disease or contralateral retinitis in patients treated for unilateral disease. Both occur in approximately one-third of patients who are treated with intravitreal therapy alone [7,21,22].
●No effect on CMV-related mortality .
●Need for patient acceptance and cooperation.
●Potential onset of serious adverse events related to intraocular injections (eg, endophthalmitis, vitreous hemorrhage, retinal detachment) .
●Weekly clinic visits, which could be difficult for certain patients.
DURATION OF INDUCTION THERAPY — The majority of patients being treated for CMV retinitis will receive systemic therapy. Induction therapy is typically administered for 14 to 21 days. However, the ultimate duration is determined by the patient’s response to therapy (see 'Ophthalmologic evaluation' below). On occasion, patients may not have access to systemic therapy and are treated with intravitreal therapy alone. The duration of induction therapy for such patients is described below. (See 'Treatment in resource-limited settings' below.)
After successful induction therapy, patients should transition to maintenance therapy with reduced doses of anti-CMV therapy. (See 'Maintenance therapy for initial infection' below.)
MAINTENANCE THERAPY FOR INITIAL INFECTION — Patients should receive maintenance therapy to reduce the risk of relapse (table 1). There are no randomized trials to support this approach. However, in a case series of patients with CMV retinitis, relapse occurred in five of seven patients who interrupted ganciclovir maintenance therapy 
Choice of agent — We suggest valganciclovir (900 mg daily) for maintenance therapy. There are no clinical trials comparing the efficacy of valganciclovir with other agents for chronic maintenance therapy of CMV retinitis. However, the ganciclovir area under the curve achieved with 900 mg of oral valganciclovir tablets is equivalent to that achieved with 5 mg/kg of intravenous ganciclovir .
If oral valganciclovir is not available or not tolerated, the maintenance dose of IV ganciclovir is 5 mg/kg/day as a single-daily dose for seven days a week or 6 mg/kg/day for five days per week. The maintenance dose of foscarnet is 90 to 120 mg/kg/day as a single infusion. Individuals receiving cidofovir should continue on every other week dosing. (See 'Systemic therapy' above.)
A discussion of maintenance therapy in patients without access to systemic therapy is described below. (See 'Treatment in resource-limited settings' below.)
Discontinuing maintenance therapy — We suggest that anti-CMV maintenance therapy be discontinued in patients receiving antiretroviral therapy (ART) for HIV if they meet all of the following criteria:
●They have quiescent retinitis.
●The lesions have been treated for at least three months with anti-CMV therapy.
●The CD4 count is ≥100 cells/microL for at least three months.
The patient's HIV viral load, adherence to ART, and likelihood of immune deterioration in the near future should also be considered in deciding whether to discontinue maintenance therapy. As an example, the authors would not discontinue maintenance therapy if a patient has virologic failure (HIV viral load >200 copies/mL on two consecutive measurements), as that could indicate poor adherence and imminent immune deterioration.
If maintenance therapy was discontinued, patients whose CD4 counts drop to <100 cells/microL should reinitiate maintenance therapy [1,26,27]. A discussion on discontinuing maintenance therapy in resource-limited settings is found below. (See 'Duration of therapy' below.)
Small observational studies suggest that patients who have sustained CD4 counts ≥100 cells/microL for six months or longer on ART can safely discontinue CMV maintenance therapy without recurrence of CMV retinitis [28-31]. The patients described in these reports generally had CD4 counts that were <50 cells/microL at the time when CMV retinitis was diagnosed, which then increased to >150 cells/microL after initiating potent combination ART regimens. Most of the patients who relapsed had CD4 counts that dropped to <50 cells/microL at the time of relapse.
It is important to review the symptoms of CMV retinitis when maintenance therapy is discontinued. On occasion, patients with improved CD4 cell counts and viral suppression can still have a relapse of CMV retinitis [32,33]. Although patients may have an increase in the absolute CD4 cell count on ART, they may not have sufficient immune reconstitution of T cell subsets to prevent a recurrence of retinitis. In one study using immunophenotypic markers, patients on ART with a history of prior CMV retinitis had significantly lower numbers of CD4-naïve and memory T cells compared with AIDS patients with a prior history of pneumocystis pneumonia but not CMV retinitis .
RELAPSED INFECTION — Most patients with CMV retinitis who are not treated with (or do not respond to) antiretroviral therapy (ART) for their HIV eventually relapse on maintenance therapy with breakthrough viral reactivation that results in further retinal necrosis. Breakthrough can occur despite continued anti-CMV therapy. Renewed activity is manifested as new retinal lesions, new opacifications, or advancement of the border of old lesions.
Reasons for failure — Clinical relapses that occur less than three months after anti-CMV therapy is initiated may be due to any of the following factors:
●Absence of ART-mediated immune reconstitution
●Healing of the initial retinal lesions might strengthen the blood-retina barrier and block drug from crossing into the retina and vitreous
●Poor adherence to anti-CMV medications
If an individual relapses after prolonged use of anti-CMV therapy, the relapse may be due to drug-resistant CMV . The presence of drug-resistant virus is associated with an increased risk of progression of CMV retinitis and development of disease in the contralateral eye [35,36]. Risk factors for drug resistance include inadequate drug concentrations and frequent discontinuation of therapy.
However, the incidence of CMV resistance in patients with HIV has declined since the introduction of potent ART. As an example, in one prospective observational study of 257 patients with CMV retinitis, the incidence of drug resistance decreased from 28 percent prior to 1996, to 9 percent after 1996 . In this study, all cases of resistance occurred among patients with CD4 counts <50 cells/microL; in addition, CMV-positive blood cultures at baseline were associated with a fourfold risk of developing resistance.
Evaluation for drug resistance — Patients with a detectable CMV viral load in the blood can be assessed for the presence of drug-resistant virus. Vitreal aspirates can also be assessed for drug-resistant virus in patients with active CMV retinitis. Drug resistance generally results from alterations in two different viral genes, namely the phosphotransferase gene (pUL97) and the viral deoxyribonucleic acid (DNA) polymerase gene (pUL54). Low-level ganciclovir resistance is due to mutations in the UL97 gene; high-level resistance is due to mutations in both UL97 and UL54 genes .
Genotypic testing is the best way to assess for the presence of resistance since these assays can be completed within a few days if testing is performed directly on blood rather than culture isolates . Genotypic resistance is defined by the presence of a mutation known to confer resistance . An alternative approach is a phenotypic assay, where resistance is measured by the ability of CMV to grow in the presence of an anti-CMV drug. However, phenotypic assays are not well standardized and take four weeks to perform; thus, they are not practical for clinical use
Genotyping of CMV can be accomplished by directly amplifying the UL97 gene from blood specimens via polymerase chain reaction (PCR) in less than 48 hours. A prospective study of 845 paired specimens was conducted to compare direct PCR amplification of blood specimens to culture isolates for accuracy in susceptibility testing and their association with progression of CMV retinitis . The study demonstrated the following results:
●There was >90 percent agreement in the genotypic results of direct amplification of blood specimens compared with culture isolates.
●Agreement between phenotypic resistance and the detection of UL97 mutations was >92 percent for PCR-amplified blood specimens and >97 percent for culture isolates.
●Progression of retinitis correlated with the detection of UL97 mutations in PCR-amplified blood specimens (odds ratio 7.0 for leukocytes, 9.0 for plasma) and for culture isolates (odds ratio 18.0).
Although blood culture results were the strongest predictor of progression of CMV retinitis, the much faster results obtained with direct PCR amplification of CMV DNA in blood supports the clinical utility of this approach.
Salvage therapy — For most patients who relapse on maintenance therapy, we suggest IV ganciclovir (or oral valganciclovir) plus IV foscarnet (table 1). However, if a patient does not have immediately sight-threatening disease, and only recently initiated ART, we would re-administer induction therapy using the same agent they previously received.
Combination therapy is the only salvage treatment strategy supported by clinical trial data. In a randomized, controlled trial of salvage therapy for patients with AIDS and relapsed CMV retinitis, patients were randomized to one of three regimens :
●High-dose ganciclovir (induction with 5 mg/kg IV every 12 hours for two weeks followed by maintenance at 10 mg/kg per day)
●High-dose foscarnet (induction with 90 mg/kg IV every 12 hours for two weeks followed by maintenance at 120 mg/kg per day)
●Continuation of previous therapy plus induction with the other drug (either ganciclovir or foscarnet) for two weeks followed by standard maintenance doses of both ganciclovir (5 mg/kg per day) and foscarnet (90 mg/kg per day)
The combined regimen was twice as effective as either drug alone, delaying time to further progression: 1.3 months with foscarnet; 2.0 months with ganciclovir; and 4.3 months with combination therapy. Several other visual outcome measures (rate of visual field loss and change in amount of retinal area involved by CMV) were also significantly better in patients given the combination regimen. However, cross-resistance to the different antiviral agents used to treat CMV may be present , and some patients may not respond to salvage therapy.
For patients who cannot tolerate dual therapy, we administer monotherapy with a different agent (eg, foscarnet for patients who started on ganciclovir). We do not use cidofovir unless the patient cannot tolerate and/or fails all of the other treatment options. Fomivirsen, an antisense oligonucleotide, was used in the past for salvage therapy, but is no longer manufactured [43-46].
In addition to systemic therapy, there is anecdotal experience that local therapy may be effective, with weekly intravitreal injection of ganciclovir in a dose of 2.5 mg (or 5 mg) in 0.05 mL volume, until active retinitis has resolved.
For patients who have either clinical or virologic resistance or intolerance to the agents approved for treatment of CMV retinitis, newer anti-CMV agents (letermovir and maribavir) can be considered. However, these agents have only been studied in transplant populations, and in these populations, there is only very limited experience treating CMV retinitis. (See "Prevention of viral infections in hematopoietic cell transplant recipients" and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients".)
Letermovir is a CMV viral terminase complex inhibitor that is used for prophylaxis of CMV disease in allogeneic hematopoietic stem cell transplantation (HSCT) recipients and may also have a role for treatment of CMV viremia in solid organ transplant recipients. In one report, letermovir was used for salvage treatment in four solid organ transplant recipients who had documented ganciclovir-resistant CMV retinitis . While all four patients improved clinically, only one had CMV viremia suppressed, and the clinical outcome may have been impacted by the concomitant use of intravitreal foscarnet injections  or changes in immunosuppressive therapy. If letermovir is being considered for patients with HIV, it can have problematic drug interactions with several non-nucleoside reverse transcriptase and protease inhibitor antiretroviral drugs used for HIV treatment, as well as all rifamycins used to treat tuberculosis.
Maribavir is a CMV UL97 gene product inhibitor that has been studied as a treatment for refractory or drug-resistant CMV infection in solid organ transplant and HSCT recipients. Clinical and virologic responses have been reported in these transplant populations, and in the United States, the Food and Drug Administration has granted expanded access status for this drug. There have been no reports describing the use of maribavir for treating CMV retinitis.
PATIENT MONITORING — Management of CMV retinitis requires close monitoring by an experienced ophthalmologist and the HIV provider.
Ophthalmologic evaluation — Dilated indirect ophthalmoscopy should be performed after two weeks of induction therapy, and monthly thereafter while the patient is on anti-CMV treatment . Monthly fundus photographs are optimal for detecting early relapse.
Certain patients should have additional monitoring.
●For patients with immediately sight-threatening retinitis, some clinicians perform weekly dilated retinal exams until there is evidence of healing.
Patients who have been successfully treated for CMV retinitis need ongoing ophthalmologic examinations to monitor for the onset of intraocular inflammation secondary to an immune reconstitution inflammatory syndrome. Monitoring at three-month intervals is appropriate with progressively longer intervals over time. Patients should be instructed to call immediately should visual symptoms recur. A discussion on the different immune recovery syndromes is found below. (See 'CMV immune reconstitution inflammatory syndromes' below.)
Adverse reactions — The laboratory monitoring and dose-limiting toxicities of the agents used to treat CMV retinitis are summarized in the table (table 1). For patients receiving anti-CMV therapy, several interventions may help reduce or prevent the adverse reactions seen with these agents. As examples:
●Ganciclovir and valganciclovir have been associated with bone marrow suppression. Granulocyte-colony stimulating factor (G-CSF) is well tolerated and can be used to facilitate dosing of ganciclovir and valganciclovir; it can also reduce the risk of bacterial infections [49-51]. Subcutaneous administration of G-CSF (10 mcg/kg/day) can be administered to patients with an absolute neutrophil count (ANC) <500 cells/microL with a target to keep the ANC in the 500 to 1000 cell range. Complete blood counts with differentials should be drawn just prior to the next dose of growth factor.
●Foscarnet is associated with renal toxicity and electrolyte abnormalities, including infusion–related decreases in ionized calcium. To minimize these risks, patients should receive concomitant saline (generally 0.5 to 1 L) with each dose of foscarnet. In addition, electrolytes (calcium, magnesium, phosphate, potassium) should be monitored twice weekly during induction therapy and weekly during maintenance therapy, and replaced as necessary. (See "Foscarnet: An overview", section on 'Toxicity'.)
●For patients receiving cidofovir, probenecid and intravenous fluids should be administered to decrease the risk of nephrotoxicity. (See 'Systemic therapy' above and "Cidofovir: An overview", section on 'Toxicity'.)
WHEN TO INITIATE ANTIRETROVIRAL THERAPY — Patients may already be on antiretroviral therapy (ART) when they are diagnosed with CMV retinitis. For such patients, ART should not be interrupted. However, many patients with CMV retinitis are not on ART. The timing of when to initiate ART in the setting of CMV retinitis is not clear because the benefit of immune recovery must be weighed against the risk of developing an immune reconstitution inflammatory syndrome (IRIS). (See 'CMV immune reconstitution inflammatory syndromes' below.)
For patients in high-income settings, we suggest ART be initiated approximately two weeks after initiating therapy to treat CMV . However, in resource-limited settings, ART should be initiated immediately because the high early mortality risk (due in part to concurrent infections other than CMV and extraocular CMV disease) generally outweighs the risk of developing IRIS. A discussion on the management of patients with CMV retinitis in resource-limited settings is found below. (See 'Treatment in resource-limited settings' below.)
Studies evaluating ART initiation include a case-historical control study, where the risk of developing immune recovery uveitis was greater in patients starting ART at the same time as anti-CMV therapy compared with those who delayed initiation of ART . However, lack of immune recovery in patients with CMV retinitis can increase the risk of progressive CMV disease and retinal detachment with subsequent vision loss . (See 'Relapsed infection' above.)
CMV IMMUNE RECONSTITUTION INFLAMMATORY SYNDROMES — After initiation of antiretroviral therapy (ART) for HIV, patients with CMV retinitis may develop significant intraocular inflammation secondary to an immune reconstitution inflammatory syndrome (IRIS) [4,54]. ART should not be stopped in the setting of IRIS given the importance of immune recovery, but anti-inflammatory therapy may provide some benefit as described below. Thus, any patient with HIV with new visual symptoms after initiation of ART should be referred promptly for ophthalmic examination. The pathogenesis of IRIS is presented elsewhere. (See "Immune reconstitution inflammatory syndrome".)
The IRIS syndrome associated with CMV retinitis is referred to as immune recovery uveitis (IRU). It can become clinically apparent any time after initiation of ART, ranging from weeks to years, and can manifest even when CMV retinitis is completely inactive. The initial inflammatory response occurs when immunity is restored , then wanes as retinitis becomes inactive, although persistent low-grade inflammation and complications can persist for years. Patients can present clinically with vitritis or other manifestations of uveitis, such as anterior chamber inflammation with posterior synechiae, cystoid macular edema, epiretinal membrane formation, or cataract. This condition can lead to significant ocular morbidity [18,53,56-58].
The clinical manifestations of IRIS associated with CMV retinitis are due to inflammation and not drug failure. Thus, we do not modify the dose of the anti-CMV agent (typically valganciclovir) if patients are receiving maintenance therapy. In addition, we do not restart ganciclovir or valganciclovir in patients with CMV-IRU if they have completed anti-CMV therapy and are without evidence of CMV reactivation [59,60]. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis", section on 'Clinical manifestations'.)
The benefit of anti-inflammatory treatment for CMV-IRU has received limited systematic study. Uncontrolled treatment studies with anti-CMV therapy or glucocorticoids have not provided convincing evidence that either intervention is beneficial in patients with CMV-IRU [38,61-63]. However, given the severe consequences of CMV-IRU, we use the following approach to manage inflammation:
●We administer treatment to reduce inflammation in patients with vitritis and/or macular edema when the visual acuity is reduced and vision is symptomatically compromised with blurred vision.
•We first initiate topical glucocorticoids (eg, difluprednate one drop four times per day) for six weeks. The intraocular pressure should be measured at four to six weeks; if above the normal range, glaucoma drops can be added, or glucocorticoid therapy reduced or discontinued.
•If, at six weeks, there has been inadequate clinical improvement of vitritis or macular edema with topical glucocorticoids, and there has been no evidence of secondary glaucoma, we switch to posterior sub-tenons glucocorticoid injections (eg, 1 mL of triamcinolone [40 mg/mL] every four to six months). Intraocular pressure should continue to be monitored monthly during this period. Treatment is continued as long as symptoms of IRU persist and intraocular pressures remain adequately controlled.
●Surgical intervention for cataract removal is commonly needed in patients with IRU within several years. Less commonly, there may be need for vitrectomy for patients who develop epiretinal membranes or fail to clear vitreous inflammation.
TREATMENT IN RESOURCE-LIMITED SETTINGS
Prevention of end-organ disease — CMV retinitis continues to be a cause of blindness among patients with AIDS in resource-limited settings [20,64-67]. In retrospective analyses of 94 patients from Myanmar  and 91 patients from South Africa  with CMV retinitis, 45 and 42 percent of patients, respectively, either died or were lost to follow-up within a year.
Since lack of diagnostic capacity continues to be a central problem in the management of this disease in resource-limited settings, prevention of CMV end-organ disease should be part of the management of patients with very advanced HIV disease in such countries. Virologic screening with CMV RNA in patients with low CD4 counts at the time of initiation of antiretroviral therapy [ART] may help detect viremic patients prior to the development of clinical CMV end-organ disease and allow for systemic pre-emptive treatment of CMV viremia. Systemic pre-emptive treatment of CMV viremia may soon be feasible with the availability of generic valganciclovir formulations.
A report suggests that clinical CMV end-organ disease can be identified in advance by virologic monitoring. In a large prospective case series from India, a serum CMV viral load >5.4 log10DNA/mL, as measured by polymerase chain reaction assay, was associated with the development of clinical CMV end-organ disease .
Antiviral regimens — Early diagnosis and anti-CMV therapy is the best way to prevent CMV-related complications (eg, retinal detachment and immune recovery uveitis [CMV-IRU]). In addition, in resource-limited settings, ART for HIV should be initiated immediately because the high early mortality risk generally outweighs the risk of developing a CMV-IRU. This is in contrast to high-income settings where ART is initiated approximately two weeks after anti-CMV induction therapy because such patients are typically monitored more closely and receive better supportive care for concurrent infections other than CMV. Additional discussions on initiating ART and immune reconstitution syndromes are found above. (See 'When to initiate antiretroviral therapy' above and 'CMV immune reconstitution inflammatory syndromes' above.)
Treatment for CMV retinitis should include systemic therapy with oral valganciclovir . However, several issues impact the approach to treatment in resource-limited settings: it may be difficult to determine the severity of CMV retinitis (eg, whether or not sight-threatening disease is present or absent); there are limited options for managing toxicity to initial therapy (eg, granulocyte stimulating factor to treat neutropenia); and alternative systemic antiviral agents such as foscarnet are typically not available. (See 'Adverse reactions' above and 'Systemic therapy' above.)
●If the severity of the disease can be adequately determined:
•Patients without sight-threatening disease should receive valganciclovir 900 mg twice daily for 14 to 21 days and then transition to 900 mg once daily. Unlike high-income settings, the transition to maintenance therapy is typically based upon protocol and not exam findings. As of April 2015, this medication is included in the 19th World Health Organization Model list of essential medications . (See 'Systemic therapy' above.)
•Patients with sight-threatening disease (lesions located <1500 microns from the fovea or adjacent to the optic nerve head) should receive systemic therapy with oral valganciclovir (as above) in conjunction with intravitreal injections. A detailed discussion of treatment for sight-threatening disease is found above. (See 'Disease that is immediately sight threatening' above.)
●In resource-limited settings, patients typically present with advanced retinitis. Thus, if there is limited diagnostic capacity to discriminate between immediate sight-threatening and other categories of disease, it may be reasonable to administer intravitreal ganciclovir injections for induction therapy (2.5 mg in 0.05 mL volume weekly for two to three injections), in combination with oral valganciclovir. In addition, certain health care systems may function more successfully with a consistent treatment protocol.
Prior to initiating therapy, we obtain baseline laboratories, including a complete blood count, platelets, and creatinine. For those with an estimated glomerular filtration rate (eGFR) between 10 and 59 mL/min/1.73m2, the dose of valganciclovir can be reduced as described in the Lexi drug monograph within UpToDate.
We avoid systemic therapy and use intravitreal injections alone for:
●Patients with neutrophils ≤500 cells/microL, a platelet count ≤20,000/microL, or a hemoglobin <8 g/dL
●Those with an eGFR of <10 mL/min/1.73m2
Intravitreal therapy alone may also be used in patients who need to discontinue systemic therapy with valganciclovir because of neutropenia (≤500 cells/microL), thrombocytopenia (≤20,000/microL), severe anemia (<8 g/dL), or an eGFR<10 mL/min/1.73m2. For patients receiving oral valganciclovir, a complete blood count, platelets, and creatinine should be obtained at a minimum of two weeks after starting therapy and then monthly over the course of treatment. Labs should be monitored more frequently if possible as described in the table (table 1).
Patients initiating therapy with intraocular injections alone require injections weekly until treatment can be discontinued (see 'Duration of therapy' below). Although lack of medical personnel trained in this technique may be a barrier to treatment, primary care clinicians can be trained to administer intravitreal injections . This is particularly important in areas where valganciclovir is not available (eg, because of cost). A discussion of the limitations of intraocular therapy is found above. (See 'Disease that is NOT immediately sight threatening' above.)
Duration of therapy — The duration of therapy for CMV retinitis in resource-limited settings is independent of the type of treatment (eg, systemic or intravitreal alone), and we extend treatment until all three of the following conditions are met :
•Patients have received anti-CMV therapy for a minimum of three months
•Active CMV retinitis has completely resolved
•The patient has received ART for at least three months and has achieved a CD4 count ≥100 cells/microL or a CD4 count that has increased by >50 cells/microL above baseline
Although these recommendations are similar to those in high-income settings, the criteria for immunologic recovery prior to discontinuing treatment is less stringent. (See 'Discontinuing maintenance therapy' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)
SUMMARY AND RECOMMENDATIONS
●AIDS-related cytomegalovirus (CMV) retinitis is one of the most serious ocular complications in individuals with AIDS, and it can progress to sight-threatening or systemic disease. Although CMV retinitis can be prevented by initiating antiretroviral therapy (ART) early in the course of HIV infection, this disease is still seen in patients who do not have access to these medications and/or are unable to adhere to their ART regimen. (See 'Introduction' above.)
●For patients with immediately sight-threatening lesions, we recommend initial therapy with an immediate intravitreal injection of ganciclovir or foscarnet plus systemic therapy for CMV rather than systemic therapy alone (Grade 1B). Criteria for sight-threatening lesions are lesions <1500 microns from the fovea or adjacent to the optic nerve head. If systemic therapy is initiated within 24 hours of the initial intravitreal injection, subsequent injections are probably not necessary. (See 'Disease that is immediately sight threatening' above.)
●For patients without immediately sight-threatening CMV retinitis, we recommend systemic therapy rather than local therapy (Grade 1B). Oral valganciclovir is as effective as intravenous therapy and is therefore typically the preferred systemic therapy. (See 'Disease that is NOT immediately sight threatening' above.)
●Induction therapy with systemic antiviral medications is typically administered for 14 to 21 days. However, the ultimate duration is determined by the patient’s response to therapy. After successful induction therapy, patients should transition to maintenance therapy with reduced doses of anti-CMV therapy. (See 'Duration of induction therapy' above and 'Maintenance therapy for initial infection' above.)
●Dilated indirect ophthalmoscopy should be performed two weeks after initiating therapy. For patients with immediately sight-threatening disease, some clinicians perform weekly dilated retinal exams until there is evidence of healing. Patients should be followed monthly thereafter while the patient is on anti-CMV treatment; fundus photographs obtained at these visits are optimal for detecting early relapse. (See 'Patient monitoring' above.)
●For patients in high-income settings who are not already on ART, we suggest that ART be started approximately two weeks after initiating CMV therapy rather than starting concurrently with CMV therapy or delaying therapy significantly longer than two weeks (Grade 2C). However, in resource-limited settings, ART should be initiated immediately. (See 'When to initiate antiretroviral therapy' above and 'Treatment in resource-limited settings' above.)
●CMV maintenance therapy can be discontinued in patients who are on ART if they meet all of the following criteria: received anti-CMV therapy for at least three months, have quiescent retinitis, and have a CD4 count ≥100 cells/microL for at least three months. However, the patient's HIV viral load and adherence to ART should also be considered when making this decision so CMV therapy is not stopped in patients who are at risk for immune deterioration in the near future. If maintenance therapy is discontinued, it should be restarted if the CD4 count subsequently drops below 100 cells/microL. (See 'Discontinuing maintenance therapy' above.)
●Any patient who develops vision loss, visual blurring, floaters, or ocular pain on CMV therapy should be evaluated by an ophthalmologist to determine if these symptoms are related to CMV progression, relapse, retinal detachment, or an immune reconstitution inflammatory syndrome (eg, CMV immune recovery uveitis). ART should not be stopped in the setting of IRIS given the importance of immune recovery, but anti-inflammatory therapy may provide some benefit. (See 'CMV immune reconstitution inflammatory syndromes' above.)
●For most patients who relapse on maintenance therapy, we suggest IV ganciclovir (or oral valganciclovir) plus foscarnet (Grade 2B). However, if a patient does not have immediately sight-threatening disease, and only recently initiated ART, we would re-administer induction therapy using the same agent they previously received. (See 'Relapsed infection' above.)
●In resource-limited settings, the treatment of CMV retinitis should include systemic therapy with oral valganciclovir. However, several issues may impact the approach to treatment: it may be difficult to determine the severity of CMV retinitis; there are limited options for monitoring and managing toxicity to initial therapy; and in some areas, valganciclovir may not be available. (See 'Treatment in resource-limited settings' above.)
ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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