Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 6: Disease-Specific Treatment

Cytomegalovirus Disease

July 2006

Background

Chronic infection with cytomegalovirus (CMV), a member of the human herpesvirus family, is common among sexually active adults. CMV is spread by sexual or other types of close personal contact, blood-to-blood contact (via transfusion or needle sharing), organ transplantation, and perinatal transmission. The estimated prevalence of CMV infection among adults ranges from 40% to 60% in resource-rich countries and from 80% to 100% in resource-poor countries. As with other herpesviruses, CMV is not cleared from the body, but is kept in a state of latency by an intact immune system. Chronic CMV infection rarely causes disease among immunocompetent persons, but it is a major cause of morbidity and mortality in HIV-infected patients with CD4 counts of <50 cells/µL. CMV can cause several clinical illnesses in immunocompromised patients, including chorioretinitis, pneumonia, esophagitis, colitis, encephalitis, polyradiculopathy, adrenalitis, and hepatitis. Symptomatic disease represents either primary infection or reactivation of latent infection that has escaped immunologic control. Effective antiretroviral therapy (ART) greatly reduces the risk of CMV reactivation and disease.

S: Subjective

The patient may report symptoms including the following:

• Floaters, scotomata (blind spots), "flashing lights," loss of peripheral or field vision (chorioretinitis)
• Headache, difficulty concentrating, sleepiness, personality changes (encephalitis, dementia)
• Mouth ulcerations
• Dysphagia or odynophagia (esophagitis)
• Abdominal pain and bloody diarrhea, weight loss, rectal ulcers, fever (colitis)
• Persistent fever, fatigue, weight loss (adrenalitis)
• Shortness of breath, dyspnea on exertion, dry cough (pneumonia; rare in patients with advanced HIV infection)
• Bilateral lower extremity weakness, urinary retention, incontinence, spasticity (polyradiculopathy)
• Low back pain, especially radiating to the perianal area (polyradiculopathy, myelitis)

Family members or caregivers may report confusion, apathy, lethargy, somnolence, withdrawal, or personality changes in the patient (CMV encephalitis, dementia).

The history should include questions about the presence and characteristics of the symptoms listed above, as well as the following:

• Duration of symptoms
• Associated symptoms
• Recent CD4 count; nadir CD4 count (risk is highest at <50 cells/µL)
• Whether the patient is taking ART; if so, date initiated, specific medications, and CD4 and HIV RNA responses

O: Objective

Perform a thorough physical examination, with particular attention to the following:

• Vital signs: Document fever.
• Weight: Compare with previous values; document weight loss.
• Eyes: Funduscopic examination in patients with CMV retinitis may show pathognomonic "cottage cheese in ketchup" yellow-white lesions, representing vascular hemorrhages and exudates.
• Nervous system: Evaluate mental status and perform a complete neurologic examination, including cranial nerves, sensation (sensory deficits may occur with preserved vibratory sense and proprioception), motor, deep tendon reflexes, coordination, and gait.

A: Assessment

For HIV-infected patients with advanced immunosuppression, the differential diagnosis includes the following:

• For suspected CMV retinitis, consider cotton-wool spots and progressive outer or acute retinal necrosis.
• For suspected CMV enteritis, consider gastrointestinal pathogens such as Mycobacterium avium complex, Cryptosporidium, other parasites, and lymphoma.
• For suspected CMV pneumonitis, consider Pneumocystis jiroveci pneumonia (PCP).
• For suspected CMV encephalitis, consider causes of neurologic deterioration such as progressive multifocal leukoencephalopathy, toxoplasmosis, central nervous system lymphoma, and other mass lesions.

P: Plan

Diagnostic Evaluation

CMV can be detected by serology, culture, antigen testing, nucleic acid amplification, or examination of tissue samples. However, serologic tests are not reliable for diagnosing CMV disease because most adults are seropositive and because patients with advanced AIDS may serorevert while remaining infected. Furthermore, for HIV-infected patients, demonstration of CMV in the blood, urine, semen, cervical secretions, or bronchoalveolar lavage (BAL) fluid does not necessarily indicate active disease, although patients with end-organ disease are usually viremic.

Diagnosis of end-organ disease generally requires demonstration of tissue invasion. The recommended evaluation is as follows.

CMV retinitis

Dilated retinal examination should be performed emergently by an ophthalmologist experienced in the diagnosis of CMV retinitis. The diagnosis is usually based on the identification of typical lesions.

Gastrointestinal CMV disease (esophagitis or colitis)

Perform endoscopy with visualization of ulcers, and conduct tissue biopsy showing viral inclusions to demonstrate viral invasion.

Pulmonary CMV disease

Perform chest radiography showing interstitial pneumonia, and conduct lung tissue biopsy showing inclusion bodies.

Neurologic CMV disease

• Encephalitis: Magnetic resonance imaging (MRI) of the brain should be done to rule out mass lesions. Periventricular or meningeal enhancement may be detected with CMV disease. Lumbar puncture should be performed; cerebrospinal fluid (CSF) should be analyzed for CMV (by polymerase chain reaction, which is sensitive and specific), cell count (may show lymphocytic or mixed lymphocytic or polymorphonuclear pleocytosis), glucose (may be low), and protein (may be high). A brain biopsy may be performed if the diagnosis is uncertain after imaging and CSF evaluation.
• Polyradiculopathy: Spinal MRI should be done to rule out mass lesions. In CMV disease, nerve root thickening may be present. Lumbar puncture with CSF analysis should be performed, as described above.
• Myelitis: Spinal MRI should be done to rule out mass lesions. Cord enhancement may be present. Lumbar puncture with CSF analysis should be performed, as described above.

Other sites

Detection of CMV at other sites requires BAL, visualization with endoscopy, or tissue biopsy. Viral inclusions ("owl's eye cells") in biopsied tissue demonstrate invasive disease (as opposed to colonization). Because retinitis is the most common manifestation of CMV disease, patients with gastrointestinal, central nervous system, or pulmonary disease should undergo ophthalmologic evaluation to detect subclinical retinal disease.

Treatment

Ganciclovir, valganciclovir, foscarnet, and cidofovir may be effective for treating CMV end-organ disease. The choice of therapy depends on the site and severity of the infection, the level of underlying immunosuppression, the patient's ability to tolerate the medications and adhere to the treatment regimen, and the potential medication interactions.

Immune reconstitution through ART is also a key component of CMV treatment and relapse prevention. The optimal timing of ART initiation in relation to the treatment of CMV is not clear. CMV flares may occur if patients develop immune reconstitution inflammatory syndrome (see chapter Immune Reconstitution Syndrome), but in most cases of nonneurologic disease, ART probably should not be delayed.

CMV retinitis

Treatment consists of 2 phases: initial therapy and chronic maintenance therapy.

Initial therapy

Before the advent of valganciclovir, the preferred strategy for treating CMV retinitis involved ganciclovir intraocular implants and systemic therapy. Because implants deliver a higher dose of drug to the retina than any other modality (1.4 mcg/hour for up to 8 months), many experts still prefer them for patients with sight-threatening (zone 1) disease. About half of patients treated with implants develop disease in the contralateral eye, and a third experience systemic disease, within 3 months of implantation. Therefore, patients with implants should be treated systemically with valganciclovir (900 mg once daily; some experts increase this to 900 mg twice daily for patients with vision-threatening disease).

For patients with peripheral retinitis (beyond zone 1), oral valganciclovir (see below) is the preferred treatment because it is easy to administer and is not associated with the surgery- or catheter-related complications seen with intraocular treatments and intravenous therapies. This formulation quickly converts to ganciclovir in the body and has good bioavailability. Valganciclovir should be used only if the patient is thought to be capable of strict adherence. Other possible intravenous treatments include ganciclovir, ganciclovir followed by oral valganciclovir, foscarnet, and cidofovir. See below for dosing recommendations.

For sight-threatening disease, treat with ganciclovir intraocular implants plus valganciclovir 900 mg orally once daily or twice daily.

For peripheral disease, treat with valganciclovir 900 mg orally twice daily for 14-21 days.

Alternatives for initial therapy:

• Intravenous ganciclovir 5 mg/kg every 12 hours for 14-21 days
• Intravenous foscarnet 60 mg/kg every 8 hours or 90 mg/kg every 12 hours for 14-21 days
• Intravenous cidofovir 5 mg/kg weekly for 2 weeks, then every other week (must be given with probenecid [2 g orally 3 hours before, 1 g orally 2 hours after, and 1 g orally 8 hours after the cidofovir infusion] and intravenous saline to decrease the risk of renal toxicity)

Note: Valganciclovir, ganciclovir, and foscarnet require dosage adjustment in patients with renal insufficiency. Cidofovir is contraindicated in patients with renal insufficiency or proteinuria.

Monitor patients closely to gauge the response to therapy. Repeat the dilated retinal examination after the completion of induction therapy, 1 month after initiation of therapy, and monthly during anti-CMV therapy. Consult with a specialist if the response to therapy is suboptimal.

Note: Retinal detachment may occur in up to 50-60% of patients in the first year after diagnosis. Regular follow-up with an ophthalmologist is required for all patients. Patients should report any vision loss immediately.

Chronic maintenance therapy

After initial CMV treatment, lifelong maintenance therapy with valganciclovir or intravenous foscarnet should be given to prevent recurrence, and the patient needs regular reevaluation by an ophthalmologist. Recommended dosages for maintenance therapy are as follows:

• Valganciclovir 900 mg orally once daily
• Intravenous foscarnet 90-120 mg/kg once daily

Discontinuation of maintenance therapy can be considered for patients with inactive CMV and sustained immune reconstitution during ART (CD4 count of >100-150 cells/µL for at least 6 months). However, the decision should be guided by factors such as the extent and location of the CMV lesions and the status of the patient's vision. An ophthalmologist who is experienced in caring for HIV-infected patients should be involved in making any decision to discontinue therapy, and patients should receive regular ophthalmologic follow-up. Maintenance therapy should be resumed if the CD4 count drops below 100-150 cells/µL or the patient develops other signs of HIV progression.

Gastrointestinal and pulmonary CMV disease

These infections are usually treated with intravenous ganciclovir or foscarnet for 21-28 days unless the patient is able to absorb oral medications, in which case oral valganciclovir is an option (refer to the dosing suggestions above). Some specialists recommend a follow-up endoscopy to verify regression of lesions before discontinuing therapy. Many experts do not recommend maintenance therapy for gastrointestinal CMV infections unless the disease recurs.

Neurologic CMV disease

The optimal treatment of neurologic disease has not been determined. Prompt initiation of dual therapy with intravenous ganciclovir and foscarnet may be effective in some patients.

Monitoring CMV therapies

The medications used to treat CMV have several important potential adverse effects, and monitoring for these is required. Valganciclovir and ganciclovir have been associated with bone marrow suppression, neutropenia, anemia, thrombocytopenia, and renal dysfunction. Foscarnet has been associated with cytopenia, renal insufficiency, electrolyte abnormalities, and seizures. For patients taking these medications, perform complete blood count with differential and check electrolytes and creatinine twice weekly during initial therapy and once weekly during maintenance therapy. Cidofovir has been associated with renal insufficiency and ocular hypotony. For patients taking cidofovir, check creatinine and blood urea nitrogen and perform urinalysis (for proteinuria) before each dose. Intraocular pressure must be checked at least every 6 months.

Patient Education

• Educate patients about the importance of ART in treating CMV. Urge patients to start ART if they have not done so already.
• Patients with CMV retinitis may have to remain on suppressive therapy for life to prevent blindness. Patients with CMV esophagitis or enteritis usually see improvements within 2-4 weeks of therapy.
• Treatment of CMV retinitis halts progression of the infection but does not reverse the damage already done to the retina. Warn patients that vision will not return to pre-CMV status.
• Advise patients to report any visual deterioration immediately. Retinal detachment or progression of CMV must be treated immediately to avoid further vision loss.
• With gastrointestinal disease, recurrence of symptoms warrants repeat endoscopy. Advise patients to report any recurrence of symptoms.
• Adverse reactions to current therapies are common. Educate patients about these and advise them to promptly report any adverse reactions.
• Help patients cope with the possibility of therapeutic failure, and, in the case of CMV retinitis, permanent loss of vision.
• Teach patients how to maintain indwelling venous access lines, if used. Have patients demonstrate these techniques before discharge.

References

• Bartlett JG, Gallant JE. Medical Management of HIV Infection, 2005-2006 Edition. Baltimore: Johns Hopkins AIDS Service; 2005.
• Drew WL, Lalezari JP. Cytomegalovirus and HIV. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]. San Francisco: UCSF Center for HIV Information; May 2006. Accessed June 1, 2006.
• Jacobsen MA. AIDS Related Cytomegalovirus Gastrointestinal Disease. In: UpToDate v14.1. Accessed June 1, 2006. [Registration required.]
• Jacobsen MA. AIDS Related Cytomegalovirus Neurologic Disease. In: UpToDate v14.1. Accessed June 1, 2006. [Registration required.]
• Jacobsen MA. AIDS Related Cytomegalovirus Retinitis. In: UpToDate v14.1. Accessed June 1, 2006. [Registration required.]
• U.S. Public Health Service, Infectious Diseases Society of America. Guidelines for the Treatment of Opportunistic Infections in Adults and Adolescents Infected with Human Immunodeficiency Virus. MMWR Morb Mortal Wkly Rep 2004;53(RR-15):1. Accessed January 1, 2006.