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Treatment of cytomegalovirus (CMV) retinitis depends on several factors, including the location of the lesion and the patient’s previous exposure to ART. In general, because CMV retinitis is associated with increased mortality and systemic anti-CMV therapy has been shown to decrease mortality, all patients should receive some form of systemic therapy.[Jabs 2005; Kempen 2003; Jabs 2013] In fact, systemic anti-CMV therapy showed a 50% reduction in mortality (95% CI: 0.3-0.7; P = .006), a 90% reduction in new visceral CMV disease (95% CI: 0.04-0.4; P = .004), and among those with unilateral CMV retinitis at presentation, an 80% reduction in second eye disease (95% CI: 0.10.5; P = .0005) when compared with those using only intraocular therapy (implants or injections).[Jabs 2013] An oral form of ganciclovir, valganciclovir, has similar bioavailability vs intravenous ganciclovir[Martin 2002] and typically is the preferred agent for systemic therapy. Induction dosing is valganciclovir 900 mg twice daily for 2 weeks followed by a maintenance regimen of valganciclovir 900 mg once daily for 1 week. As with ganciclovir, reversible bone marrow suppression is a potential complication, and blood counts must be monitored regularly. Zone 1, or central, CMV involvement is immediately vision threatening and should be treated with intravitreal anti-CMV therapy. A sustained-release ganciclovir ophthalmic implant provides a higher concentration of drug to the eye[Martin 1994] vs intravenous ganciclovir. The implant—which requires a surgical procedure for placement and can be replaced every 6-8 months—has been associated with better control of CMV retinitis and lower rates of retinitis progression[Musch 1997] vs systemic therapy. However, local treatment of CMV retinitis alone, using intravitreal injections or sustained-release implantable devices, is associated with a higher rate of contralateral eye involvement, other organ involvement such as the gastrointestinal tract, and increased mortality,[Jabs 1995; Jabs 2005; Kempen 2003; Martin 1999; Kempen 2005] because of the systemic nature of the disease. Adverse effects of the implant surgery include endophthalmitis (0.46%), vitreous hemorrhage (10%), and cataract (2%).[Shane 2003; Dunn 2004] In patients with low CD4+ cell counts despite ART, intravitreal therapy may also be considered for lesions involving Zone 2 or 3, because of the absence of immune recovery. Table 1 presents a suggested treatment approach based on current recommendations.[Jabs 2008] However, the sustained-release ganciclovir ophthalmic implant is currently unavailable in the United States; therefore, intravitreal injections of ganciclovir, as described below, may be used in its place. Intravitreal injections of ganciclovir, foscarnet, or cidofovir all provide higher intraocular drug concentration and can be used as a temporizing measure until an implant is surgically placed.[Jabs 2008] If needed, intravitreal ganciclovir 2000 µg/0.1 mL is given twice weekly for 3 weeks for induction, then weekly thereafter.[Banker 2008; van der Meer 1996] Intravitreal foscarnet 2400 µg/0.1 mL is also given twice weekly for 3 weeks for induction and once weekly thereafter.[van der Meer 1996] Cidofovir 20 µg/0.1 mL is rarely given intravitreally because of its association with uveitis and intravitreal administration is not recommended[Stewart 2010] ; however, it can be given as a one-time dose and repeated every 5-6 weeks as needed.[Rahhal 1996] Risks of intravitreal injections include intraocular infection, damage to the lens or retina, and glaucoma. A recent study showed that regimens containing intravitreal injections had greater rates of retinitis progression (adjusted HR: 3.4; P = .004) and greater visual field loss (for loss of one half of the normal field, adjusted HR: 5.5; P < .01) compared with systemic treatment only.[Jabs 2013] In addition to valganciclovir, 3 intravenous (IV) anti-CMV therapies are available: ganciclovir, foscarnet, and cidofovir. In patients with normal renal function, IV ganciclovir is given with an induction dose of 5 mg/kg twice daily for 2-3 weeks, followed by maintenance therapy at the same concentration once daily.[van der Meer 1996] The most frequent systemic adverse effect of ganciclovir is reversible bone marrow suppression; patients should have blood counts measured twice weekly during induction and weekly during maintenance therapy. Induction for IV foscarnet is 60 mg/kg 3 times once daily or 90 mg/kg twice daily for 2-3 weeks, with a maintenance dose of 90-120 mg/kg once daily.[van der Meer 1996; Stewart 2010] Systemic adverse effects of foscarnet included reversible renal toxicity, which can be reduced by adjusting dosages based on the patient’s renal function. Induction with IV cidofovir is 5 mg/kg/week for 2 weeks, followed by a maintenance dose of 3-5 mg/kg every 2 weeks.[Vrabec 2004; Stewart 2010] Renal toxicity is a common and potentially serious adverse effect of the medication, and the dose should be adjusted for renal clearance. To reduce renal uptake, probenecid 2 g is given concomitantly 3 hours before, with probenecid 1 g at 2 and 8 hours after each cidofovir infusion.[Vrabec 2004] Cidofovir is also associated with ocular adverse effects that limit its use, including hypotony,[Davis 1997] uveitis (rate of 0.35/person-year),[HPMPC 2000] and an increased risk of immune recovery uveitis (IRU).[Song 2003] Intravenous foscarnet and cidofovir usually are used in cases of drug resistance. Retinal detachments and IRU are associated with lesion size[Jabs 2004b; Kempen 2006] ; therefore, tailoring therapy to control the progression of retinitis is critical. One study suggested that delaying the initiation of ART may decrease the incidence of IRU.[Ortega-Larrocea 2005] Patients receiving CMV treatment should be followed monthly unless there is evidence of immune recovery. Serial fundus photographs are an objective measure to chart the progression of disease. As long as patients remain immunocompromised, they must be followed closely for evidence of recurrence or progression of disease. In patients with immune recovery, follow-up can be decreased to every 3 months. Regular screening for CMV retinitis has been recommended in the past for patients with CD4+ cell counts < 50 cells/mm3, usually at 3-month intervals, but that approach has never been validated.[Wohl 2000] Gene and Drug Resistance In the pre-HAART era, prolonged anti-cytomegalovirus (CMV) antiviral therapy resulted in approximately 25% of patients developing resistant CMV within 1 year.[Jabs 1998a] Since the introduction of ART, however, the incidence of drug resistance to anti-CMV drugs has decreased to 10.7% at 1 year and 17.2% at 2 years after diagnosis of retinitis. Risk factors associated with resistance are CD4+ cell counts < 50 cells/mm3 and a positive CMV culture or detectable CMV RNA at diagnosis of retinitis. The occurrence of resistant CMV is associated with an increased risk for mortality.[Jabs 2010b] Resistance to anti-CMV agents has been associated with mutations in the genes CMV UL97 and UL54.[Hu 2002] UL97 codes for a phosphotransferase and is associated with resistance to ganciclovir, because ganciclovir requires phosphorylation to be active against CMV-infected cells.[Chou 1995] Mutations in UL54, which codes for DNA polymerase, are found in strains resistant to ganciclovir, foscarnet, and cidofovir. Low-level ganciclovir resistance is typically associated with mutations in UL97; high-level ganciclovir resistance is associated with mutations in UL54 and UL97.[Chou 1995; Chou 1997; Smith 1997; Jabs 2001] High-level ganciclovir-resistant CMV also is resistant to cidofovir.[Chou 1997] Foscarnet resistance is associated with UL54 mutations that localize to a different region from those associated with ganciclovir resistance.[Weinberg 2003] Drug resistance is associated with adverse clinical outcomes, including increased retinitis progression, increased loss of retinal area, and increased rate of visual impairment.[Jabs 2003] CMV resistance testing may be beneficial in cases of CMV disease progression in the presence of treatment. Phenotypic resistance is defined by the ability of CMV to grow in the presence of an anti-CMV drug. Genotypic resistance is defined by the presence of a mutation that is associated with a resistant phenotype. Good correlation has been shown between genotype and phenotype of culture isolates,[Jabs 2001] as well as between isolates cultured from blood and vitreous[Hu 2002] suggesting that resistant mutations can be tested using blood samples. There has also been good correlation for genotype of the UL97 gene from PCR-amplified blood products and phenotypic resistance in blood culture isolates.[Jabs 2006] This result has important clinical implications due to the faster turnaround time of PCRamplified and sequenced blood samples vs studies using culture isolates. For additional information from inPractice on cytomegalovirus infection, click here.