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Management Recommendations > CMV

Ward 86 Management Recommendations

Diagnosis and Treatment of AIDS-Related Cytomegalovirus End Organ Disease

updated April 2016

Contributors: Mark Jacobson, MD
Diane Havlir, MD

  1. CMV serologic assays are of very limited utility in diagnosis of CMV end organ disease (EOD). Virtually all AIDS-related CMV EOD occurs in AIDS patients with an absolute CD4 T-cell count of <50 cells/µL and results from reactivation of latent CMV infection, which can be identified by the presence of a positive serum CMV IgG titer result. However, >99% of AIDS patients who are men who have sex with men are CMV IgG positive, as are 75% of heterosexual AIDS patients, making serologic testing useful only for lowering the diagnostic possibility of CMV EOD in heterosexual AIDS patients. Also, a negative CMV IgG result does not completely eliminate CMV disease from consideration. Rare cases of CMV EOD have been reported in patients with negative CMV titer results.

  2. Serum and plasma CMV DNA or pp65 antigen assays have little utility in the diagnosis of CMV EOD. Whereas a positive result with either assay is associated with increased risk of developing CMV EOD, neither has adequate sensitivity or specificity to be useful in confirming or ruling out a diagnosis of CMV EOD.

  3. CMV retinitis is a clinical diagnosis that should be confirmed by an experienced ophthalmologist. CMV retinitis most commonly presents with symptomatic floaters caused by retinal debris in the vitreous. If the optic nerve or areas near the macula are involved, it can present with reduced visual acuity or a blind spot. Direct ophthalmoscopy can only reveal approximately 15% of the retinal area. Ruling out CMV retinitis requires an indirect, dilated funduscopic examination performed by an experienced ophthalmologist. CMV lesions appear as yellow-white, fluffy, or granular exudates, often located near retinal vessels and associated with hemorrhage. Small lesions may be difficult to differentiate from benign cotton wool spots; as a result, serial funduscopic examinations are sometimes required to make or rule out the diagnosis (cotton wool spots do not progress over time).

  4. CMV gastrointestinal (GI) disease requires mucosal biopsy for diagnosis. Viral culture and nucleic acid assays have no utility. CMV GI disease may occur anywhere from the pharynx to the anus, though most cases involve the esophagus or colon. Symptoms are site-specific (eg, odynophagia with CMV esophagitis or diarrhea and abdominal pain with CMV colitis). Diagnosis requires direct visual or endoscopic evidence of erosions or ulcers with the presence of CMV intranuclear or intracytoplasmic inclusions in a biopsy of the involved tissue. Many AIDS patients without CMV GI disease have positive CMV cultures or nucleic acid test results from GI mucosal brushings or biopsy of normal appearing tissue; thus, such tests are not diagnostically helpful.

  5. CMV neurologic disease is a clinical diagnosis, and the presence of CMV DNA in cerebrospinal fluid (CSF) can be confirmatory. CMV neurologic disease is the rarest form of AIDS-related CMV EOD. Several syndromes have been recognized.

    1. CMV encephalitis typically presents with altered sensorium. Sometimes fever is present. Periventricular enhancement is often seen on CT or MRI brain imaging.

    2. CMV polyradiculopathy usually presents with lower extremity weakness and areflexia. CSF often has a neutrophil-predominant pleocytosis.

    3. CMV myelitis typically presents with lower-extremity weakness and hyperreflexia. MRI of the spine will reveal cord enhancement.

    4. CMV mononeuritis multiplex can present as a motor weakness in the distribution of one or more peripheral nerves.

    5. Patients may have one or more of these syndromes simultaneously.

    6. In all forms of CMV neurologic disease, the presence of CMV DNA in CSF strongly supports the diagnosis.

How to Manage CMV EOD

  1. CMV Retinitis
    1. The location of retinal lesions is the key consideration in determining treatment. Patients who have immediately sight-threatening lesions (ie, within a disc diameter of the optic nerve head or two disc diameters of the macula) should receive an intravitreal injection of ganciclovir or foscarnet and initiate oral valganciclovir. Lesions outside these critical areas can be treated with oral valganciclovir alone. Valganciclovir should be administered every 12 hours for 2-3 weeks, then once daily.

    2. IV ganciclovir is an alternative for those who cannot swallow pills or absorb medication. Foscarnet is an alternative for those who have severe myelosuppression that cannot be adequately reversed by growth factor medication (see section on Management of Neutropenia in Patients with HIV Disease). Dosing of either IV medication should be every 12 hours for 2 weeks, then once daily.

    3. If a dilated funduscopic examination has revealed healing of all retinal lesions and the patient is on antiretroviral therapy (ART) and has sustained a rise in CD4 count to >50 cells/µL for 6 months, CMV treatment can be discontinued.

    4. Anti-CMV medication should be reinstituted if the patient's CD4 count subsequently drops below 50 cells/µL again.

    5. Dilated funduscopic examinations should be performed biweekly initially, then monthly until all retinal lesions have healed. Patients with large areas of retinal involvement, particularly in the peripheral retina, are at high risk of developing retinal detachment, and early surgical intervention for retinal detachment may result in a better vision outcome.

    6. For patients who have recurrence of active retinitis on treatment or progression of retinitis to previously uninvolved areas of the retina, combining ganciclovir (or valganciclovir) with intravenous foscarnet therapy has been shown in a randomized trial to result in better vision outcomes than giving a higher than standard dosage of ganciclovir or foscarnet alone.(1)

    7. See Table 1 below for information on dosing and possible adverse effects.

  2. CMV GI Disease
    1. Oral valganciclovir (or IV ganciclovir for patients who cannot swallow pills or absorb oral medication) is first-line therapy for CMV GI disease. Foscarnet is an alternative for those who have severe myelosuppression that cannot be adequately reversed by growth factor medication (see section on Management of Neutropenia in Patients with HIV Disease).

    2. Treatment should be administered every 12 hours until symptoms resolve (usually 3-6 weeks). Anti-CMV medication can be discontinued once symptoms have resolved. Studies conducted in the era before patients could be immune reconstituted with ART showed no benefit from continuing therapy once symptoms resolve.

    3. All patients with CMV GI disease should have a dilated funduscopic examination. CMV retinitis is commonly present in patients with CMV GI disease, and the presence of retinitis requires longer-term treatment as described above.

    4. See Table 1 below for information on dosing and possible adverse effects.

  3. CMV Neurologic Disease
    1. Because efficacy of monotherapy for CMV neurologic disease has been poor in uncontrolled studies (there have been no randomized trials), we favor treating patients who have severe neurologic impairment with combined ganciclovir (oral valganciclovir or IV ganciclovir) and foscarnet.

    2. Both agents should be administered every 12 hours until symptoms resolve or stabilize, then patients can be switched to a daily regimen until 6 months after ART has achieved a rise in CD4 count to >50 cells/µL. We use valganciclovir alone during this second phase of treatment when the patient has resolution of neurologic abnormalities. Anti-CMV medication should be reinstituted if the patient's CD4 count subsequently drops below 50 cells/µL.

    3. Because CMV retinitis is commonly present in patients with CMV neurologic disease, all patients should have a dilated funduscopic examination.

  4. Timing of Initiating ART in Patients with Newly Diagnosed CMV EOD

    See section on Initiating Antiretroviral Therapy in Hospitalized HIV-Infected Patients.

Prevention of CMV EOD

  1. Ophthalmologic screening for early detection of CMV retinitis is not recommended unless visual symptoms are present. Any patient with AIDS and new visual symptoms should have a dilated funduscopic examination by an experienced ophthalmologist as soon as possible. Some ophthalmologists also recommend screening with dilated funduscopic exams for all AIDS patients with an absolute CD4 count of <50 cells/µL, independent of whether or not visual symptoms are present. This recommendation is not based on evidence of visual outcome benefit but simply on the fact that up to 40% of patients with a CD4 count of <50 cells/µL developed CMV retinitis in the era before modern ART became available. The incidence of CMV retinitis has dropped precipitously in the last 15 years, to the point that screening patients who do not have visual symptoms (or another form of CMV EOD) has little, if any, yield.
  2. Prophylaxis for patients at high risk of CMV EOD is not recommended. As noted above, serum or plasma CMV DNA or pp65 antigen positivity is associated with an increased risk of developing CMV EOD. However, in a trial in which patients with advanced AIDS but no CMV EOD had regular monitoring for such evidence of CMV viremia and those who became viremic were randomized to valganciclovir or placebo, active therapy did not significantly reduce CMV EOD incidence.(2) This result argues against any clinical utility of virologic screening or antiviral prophylaxis.

References

  1. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus Retreatment Trial. Arch Ophthalmol. 1996 Jan;114(1):23-33.
  2. Wohl DA, Kendall MA, Andersen J, et al; A5030 Study Team. Low rate of CMV end-organ disease in HIV-infected patients despite low CD4+ cell counts and CMV viremia: results of ACTG protocol A5030. HIV Clin Trials. 2009 May-Jun;10(3):143-52.

Table 1. Drug Dosing and Toxicity Monitoring for CMV End Organ Disease

DrugDose/Frequency/DurationCommon ToxicitiesSafety Monitoring
Valganciclovir
  • Retinitis: 900 mg PO BID for 2-3 weeks, then daily until CD4 >50 cells/µL for 6 months
  • GI disease: 900 mg BID until resolved
  • Neurologic disease: 900 mg BID until resolved, then daily until CD4 >50 cells/µL for 6 months
  • Neutropenia, thrombocytopenia
  • Most patients who develop dose-limiting neutropenia (ie, absolute neutrophil count <500 cells/µL) can continue treatment with adjuvant granulocyte-colony stimulating factor therapy (see section on Management of Neutropenia in Patients with HIV Disease).
  • We use a platelet threshold of ≤20,000/µL for holding therapy.
  • Check absolute neutrophil and platelet counts weekly during twice-daily therapy, then monthly during daily therapy. Monitor renal function and adjust dosage when reduced.
Intravenous ganciclovir
  • Retinitis: 5 mg/kg IV BID for 2-3 weeks, then daily until CD4 >50 cells/µL for 6 months
  • GI disease: 5 mg/kg BID until resolved
  • Neurologic disease: 5 mg/kg BID until resolved, then daily until CD4 >50 cells/µL for 6 months
Same as for valganciclovirSame as for valganciclovir
Intravenous foscarnet
  • Retinitis: 90 mg/kg IV BID* for 2-3 weeks, then daily until CD4 >50 cells/µL for 6 months
  • GI disease: 90 mg/kg BID* until resolved
  • Neurologic disease: 90 mg/kg BID* until resolved, then daily until CD4 >50 cells/µL for 6 months
  • Renal insufficiency, hypocalcemia, hypomagnesemia, hypokalemia, hypophosphatemia, seizure, arrhythmia, genital ulcer, fluid overload, anemia
  • Must administer by IV infusion pump to control rate. If rate is too fast, life-threatening ionized hypocalcemia or hypomagnesemia may occur.
  • Check serum creatinine, calcium, phosphorus, magnesium, potassium, hemoglobin twice weekly during twice-daily therapy, then weekly during daily therapy.
  • IV saline hydration with dosing can reduce risk of azotemia.
Intravitreal ganciclovir2 mgRarely, intraocular infection or hemorrhageNone
Intravitreal foscarnet2.4 mgRarely, intraocular infection or hemorrhageNone
* Small changes in renal function require dosage adjustment.
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