In addition, the characteristics of the
disease in this group were similar to those in the pre-HAART era. Diagnosis is
usually presumptive because biopsy is difficult given the inaccessibility of the retina.
Serology is indicative of previous CMV infection, but not an active disease. Cultures
(serum, urine, and saliva) may be useful for monitoring therapy, considering that
patients frequently have disseminated CMV disease. Patients with positive cultures
for CMV while receiving therapy may be at a higher risk for relapse.
diagnosis of CMV retinitis is based on observations made during a dilated retinal
examination and indirect ophthalmoscopy, as was done for P.Z. Lesions appear as
fluffy, white retinal patches with retinal hemorrhage.
Once CMV retinitis is diagnosed, the patient should be thoroughly examined for
extraocular CMV disease. P.Z. will require regular ophthalmologic examinations,
along with retinal photographs, for life. As with HIV therapy, CMV deoxyribonucleic
acid (DNA) quantification in plasma or blood cells by polymerase chain reaction
may have a role in evaluating treatment efficacy and predicting symptomatic
CASE 77-3, QUESTION 2: What are the treatment options for CMV retinitis, and which one would be
Several treatment options exist for CMV retinitis: oral valganciclovir, IV
ganciclovir, IV ganciclovir followed by oral valganciclovir, IV foscarnet, and IV
cidofovir. Alternatives include combined IV ganciclovir plus foscarnet or intraocular
injections of ganciclovir, foscarnet, or cidofovir.
parenteral ganciclovir and foscarnet is similar to that in monotherapy, but it is more
toxic. This latter therapy should be reserved for patients with refractory disease
Intraocular implants and intraocular injections of ganciclovir have similar efficacy
in the treatment of CMV retinitis, but their benefit is localized to the infected eye and
may lead to an increased risk of contralateral retinitis and extraocular CMV disease.
Regimens consisting of systemic anti-CMV therapy have been associated with a 50%
reduction in mortality compared with those using intraocular therapy alone.
Therefore, concomitant systemic anti-CMV therapy is recommended (e.g., oral
valganciclovir or IV ganciclovir). The use of ganciclovir intraocular implants with
oral valganciclovir has shown to be more effective at preventing relapse of retinitis
than IV ganciclovir and likely oral valganciclovir.
12 Many providers prefer this as
the first-line therapy in patients with immediate sight-threatening lesions, although
others chose oral valganciclovir as the first-line treatment. The choice of agents
typically depends on drug efficacy, toxicity, stage of disease, and quality-of-life
Ganciclovir is an acyclic nucleoside with CMV activity superior to acyclovir.
Similar to other nucleosides, ganciclovir must be taken into cells and phosphorylated
before it can compete with endogenous nucleotides for binding to viral DNA
polymerase. Ganciclovir is poorly absorbed PO (bioavailability, approximately 5%–
9%), and the oral form is no longer marketed. The disposition of ganciclovir is
biexponential after IV administration (terminal half-life, approximately 2.5 hours).
The total body clearance is highly dependent on glomerular filtration and tubular
The dose-limiting toxicity is bone marrow suppression, with neutropenia occurring
in approximately 50% of patients. Thrombocytopenia is also observed. Absolute
neutrophil counts (ANCs) and platelets should be monitored weekly during
ganciclovir therapy. If the ANC falls to less than 1,000 cells/μL or the platelet count
falls to less than 50,000/μL, the monitoring frequency should be increased to twice
74 Ganciclovir is also available as an intraocular implant (Table 77-3).
Dosage adjustments must be made in patients with renal dysfunction (Table 77-4).
Patients who develop ganciclovir-induced bone marrow suppression can be given
granulocyte colony-stimulating factor (G-CSF). Both G-CSF (filgrastim) and
granulocyte-macrophage colony-stimulating factor (GM-CSF [sargramostim])
have been used successfully in stimulating production of WBC. Although neither of
these agents is FDA-approved for this indication, the use of the CSFs may allow for
continuation of sight-saving or life-prolonging therapy. Because GM-CSF may
stimulate HIV replication in macrophage cell lines,
concomitant antiretroviral therapy.
Valganciclovir is an oral monovalyl ester prodrug that is rapidly hydrolyzed to
ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir is 60%,
and a dose of 900 mg results in ganciclovir blood concentrations similar to those
obtained with a dose of 5 mg/kg of IV ganciclovir. Oral valganciclovir and IV
ganciclovir are equally effective as induction therapy for newly diagnosed CMV
retinitis in patients with AIDS.
78 The frequency and severity of adverse events were
similar in the two groups. Based on these data, oral valganciclovir is as effective as
and no more toxic than IV ganciclovir, and the convenience of the oral route suggests
it be the drug of choice for the long-term management of CMV retinitis in patients
Treatment of Cytomegalovirus Retinitis
IV Ganciclovir Valganciclovir IV Foscarnet
(acyclovirresistant) activity;
recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the
Cidofovir is a nucleotide analog that is phosphorylated intracellularly to an active
diphosphate metabolite. It is the most potent of all the available anti-CMV
compounds and is active against herpes simplex virus (HSV) and VZV, including
acyclovir-resistant isolates. Cidofovir does not require viral activation. Because
nucleotide analogs do not require virally encoded kinases for their activity, they
remain a treatment option for patients who have failed to respond to ganciclovir.
Cidofovir is poorly absorbed PO (bioavailability, <5%) and has an intracellular
half-life of 17 to 65 hours, resulting in once-weekly induction and every-other-week
Eighty percent of this poorly soluble agent is excreted unchanged in the urine via
filtration and tubular secretion. Cidofovir is nephrotoxic; however, the administration
of probenecid (2 g administered 3 hours before the start of infusion and two 1-g
doses administered at 2 and 8 hours after infusion) blocks tubular secretion and
reduces nephrotoxicity. Prehydration with 1 L of normal saline is required 1 hour
before each dose and, if tolerated, repeated concomitantly with or after the cidofovir
infusion. Because nephrotoxicity is the most significant dose-limiting toxicity, other
nephrotoxic agents should be discontinued (e.g., nonsteroidal anti-inflammatory
drugs, and aminoglycosides), and renal function should be carefully monitored
throughout therapy (BUN, SCr, and proteinuria; Table 77-4). Dosage adjustment must
accompany any deterioration in renal function (Table 77-5).
The CBC should be checked at baseline because neutropenia has been reported in
approximately 20% of patients in clinical trials. Hypotony (reduction in intraocular
pressure) and uveitis (inflammation of the uveal tract of the eye) have also been
reported. Thus, monthly ophthalmologic examinations of the retina are necessary.
The role of cidofovir is limited. Although it offers the advantage of weekly and
biweekly dosing, its toxicity greatly limits its utility. Cidofovir appears to be as
efficacious as foscarnet and ganciclovir in the treatment of CMV retinitis, but limited
comparative studies have been performed. Finally, the efficacy of cidofovir in the
treatment of extraocular CMV (e.g., GI disease, pneumonitis, and encephalitis)
Dosage Adjustment for Cytomegalovirus Medications
Induction Dose Maintenance Dose
Foscarnet Induction dose: CrCl
Low Dose High Dose Low Dose High Dose
<0.4 Not recommended Not recommended
Induction CrCl (mL/minute) Induction Maintenance
25–39 450 mg daily 450 mg every
other week; QW, weekly; SCr, serum creatinine; TID, three times a day; TIW, three times a week.
BL et al. Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of Pneumocystis
Tuberculosis Treatment Recommendations for Patients Coinfected with HIV
Induction Maintenance Comments
Rifampin-Based Therapy (no concurrent use of PIs, Nevirapine, Etravirine, Rilpivirine, or
SM) daily or 2–3 × per week × 2
INH/RIF (or RFB) daily or 2–3 ×
per week (duration dependent on
RIF-containing regimens may have
significant drug–drug interactions
PZA, pyrazinamide; RFB, rifabutin; RIF, rifampin; SM, streptomycin.
Foscarnet is a pyrophosphate analog that acts by selectively inhibiting viral DNA
polymerases and reverse transcriptase. At doses currently recommended for
induction therapy (60 mg/kg every 8 hours or 90 mg/kg IV every 12 hours), peak
plasma foscarnet concentrations are higher than those that inhibit CMV in vitro
79 The dose-limiting toxicity of foscarnet is nephrotoxicity, probably
because its poor solubility results in crystallization in nephrons.
compared with ganciclovir, patients treated with foscarnet survived approximately 4
months longer; however, foscarnet-treated patients with reduced creatinine clearance
(<1.2 mL/minute/kg) had a poorer survival rate.
Because P.Z. has a low ANC, the bone marrow–suppressive effects of ganciclovir
and valganciclovir are of concern. Adjunctive therapy with G-CSF is an option.
Because he has good renal function (SCr, 0.8 mg/dL), foscarnet or cidofovir would
CASE 77-3, QUESTION 3: P.Z. will receive foscarnet, 90 mg/kg IV for 2 hours every 12 hours. How can
the risk of nephrotoxicity be minimized?
During foscarnet therapy, adequate hydration is important to prevent
nephrotoxicity. To establish diuresis, 750 to 1,000 mL of normal saline or 5%
dextrose should be administered before the first infusion of foscarnet. With
subsequent infusions, 500 to 1,000 mL should be administered, depending on the
foscarnet dose. Careful dosage titration based on P.Z.’s estimated creatinine
clearance may also minimize nephrotoxicity (Table 77-5). The SCr clearance should
be measured at least twice weekly and the dosage should be recalculated if the
creatinine clearance changes. CMV infection itself may also cause an acute increase
in the SCr owing to acute interstitial nephritis. Drugs with nephrotoxic potential, such
as amphotericin B or aminoglycosides, should be avoided.
CASE 77-3, QUESTION 4: What toxicities other than nephrotoxicity have been associated with foscarnet
Hypocalcemia can occur because foscarnet, a pyrophosphate analog, can bind to
unbound calcium. Electrolyte complications can be minimized by avoiding high
foscarnet plasma concentrations with slow infusions over 1 to 2 hours.
serum calcium and phosphate levels should be monitored twice weekly during
induction therapy and weekly during maintenance therapy, ideally when foscarnet is
at its highest concentration. Fatal hypocalcemia has been reported in an AIDS patient
receiving both foscarnet and parenteral pentamidine; thus, coadministration of these
Penile ulceration from foscarnet has been problematic, especially in
uncircumcised men. Characterized as a fixed drug eruption, careful attention to
genital hygiene may minimize the potential for penile ulceration. Other adverse
events associated with foscarnet include seizures, hypomagnesemia, anemia, nausea,
fever, and rash. Twice-weekly albumin, magnesium, and potassium levels are
required during induction therapy and then weekly during maintenance therapy. In
general, patients tolerate foscarnet less well than ganciclovir.
CASE 77-3, QUESTION 5: After 12 days of foscarnet therapy, P.Z.’s SCr has increased from 0.8 to 1.2
the remainder of the foscarnet treatment?
Valganciclovir, ganciclovir, foscarnet, and cidofovir are highly dependent on renal
elimination, and dosages (or dosing intervals) should be adjusted for even a modest
reduction in renal function (Table 77-5). Therefore, careful monitoring of renal
function is important throughout CMV therapy. P.Z.’s estimated creatinine clearance
is 1.2 mL/minute/kg; therefore, his foscarnet induction dosage should be adjusted to
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