Download Treatment of cytomegalovirus (CMV) retinitis depends on several

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.
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