Cytomegalovirus Disease

Background

Although chronic infection with cytomegalovirus (CMV) rarely causes disease among immunocompetent persons, it is a major cause of morbidity and mortality in HIV-infected patients with CD4 counts of <50 cells/µL. CMV infection causes disease in several organ systems, including the central nervous system (CNS) (chorioretinitis, encephalitis, polyradiculopathy, myelopathy) and the gastrointestinal (GI) tract (oral ulcers, esophagitis, hepatitis, colitis, intestinal perforation), as well as life-threatening adrenalitis and pneumonitis. The prevalence of chronic infection with CMV, a member of the human herpesvirus family, is high among sexually active adults (40-60% in resource-rich countries and 80-90% in resource-poor countries). 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. As with other herpesviruses, CMV is not cleared from the body, but is kept in a state of latency by an intact immune system. 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.

Immune reconstitution inflammatory syndrome

Although effective ART greatly reduces the risk of CMV reactivation and disease, patients on effective ART may experience CMV-related visual changes.

• Patients without a previous history of CMV disease will occasionally present with full-blown CMV retinitis after starting ART. This is thought to reflect delayed restoration of CMV-specific immunity. It is diagnosed and treated in an identical manner as for patients diagnosed with CMV disease who are not taking effective ART.
• Approximately 20% of patients with previously treated CMV retinitis may experience CMV-related immune reconstitution uveitis (IRU) after starting successful ART. Symptoms include floaters and moderate, occasionally severe, vision loss. The most common causes of vision loss are posterior disease, specifically cystoid macular edema (CME) and epiretinal membrane formation (ERM), although inflammation of the anterior region and cataract formation also can occur. It is not clear whether treatment with steroids or anti-CMV antivirals is effective. (See chapter Immune Reconstitution Inflammatory Syndrome.)

S: Subjective

The patient may present with symptoms involving various organ systems, including the following:

• CNS, including the eye:
  • Floaters, scotomata (blind spots), "flashing lights," loss of peripheral or field vision (chorioretinitis)
  • Headache, difficulty concentrating, sleepiness, personality changes (encephalitis, dementia)
  • 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)
• GI tract disease:
  • Mouth ulcerations
  • Dysphagia or odynophagia (esophagitis)
  • Abdominal pain and bloody diarrhea, weight loss, rectal ulcers, fever (colitis)
• Disease outside the CNS or GI tract:
  • Persistent fever, fatigue, weight loss (adrenalitis)
  • Shortness of breath, dyspnea on exertion, dry cough (pneumonia; rare in patients with advanced HIV infection)
  • Pancytopenia (bone marrow infection)

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 when count is <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, HIV retinopathy, and progressive outer or acute retinal necrosis.
• For suspected CMV encephalitis: consider other causes of neurologic deterioration such as progressive multifocal leukoencephalopathy, toxoplasmosis, CNS lymphoma, and other mass lesions.
• For suspected CMV enteritis: consider gastrointestinal pathogens such as Mycobacterium avium complex,Cryptosporidium, other parasites, and lymphoma.
• For suspected CMV pneumonitis: consider Pneumocystis jiroveci and other respiratory pathogens.

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 usually are 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 usually is based on the identification of typical lesions. Diagnosis and monitoring should include serial examinations with photography to assess and follow response to treatment and to detect failure to respond early enough to change therapy.

Other sites

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

Neurologic CMV disease

• Encephalitis: Magnetic resonance imaging (MRI) of the brain should be done to rule out mass lesions. CMV effects may appear as periventricular or meningeal enhancement. Lumbar puncture should be performed; cerebrospinal fluid (CSF) should be analyzed for CMV (by PCR, 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.

Gastrointestinal CMV disease (esophagitis or colitis)

• Perform endoscopy with visualization of ulcers and obtain tissue biopsy to look for inclusion bodies.

Pulmonary CMV disease

• Perform chest radiography showing interstitial pneumonia and obtain lung biopsy to look for inclusion bodies.

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 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 Inflammatory Syndrome), but in most cases of nonneurologic disease, ART probably should not be delayed.

CMV retinitis

Treatment consists of two 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 one third experience systemic disease, within 3 months of implantation. Therefore, patients with implants also should be treated systemically with valganciclovir (900 mg once daily; some experts increase this to 900 mg BID for patients with vision-threatening disease).

For patients with peripheral retinitis (beyond zone 1), oral valganciclovir alone (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 IV 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 IV 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 PO once daily or BID.
• For peripheral disease: treat with valganciclovir 900 mg PO BID for 14-21 days.

Alternatives for initial therapy:

• IV ganciclovir 5 mg/kg Q12H for 14-21 days
• IV foscarnet 60 mg/kg Q8H or 90 mg/kg Q12H for 14-21 days
• IV cidofovir 5 mg/kg weekly for 2 weeks, then every other week (must be given with probenecid [2 g PO 3 hours before, 1 g PO 2 hours after, and 1 g PO 8 hours after the cidofovir infusion] and IV saline to decrease the risk of renal toxicity)
• Intraocular injections with antiviral agents

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

Monitor patients closely to gauge the response to therapy. Repeat the dilated retinal examination after completion of induction therapy, 1 month after initiation of therapy, and monthly during anti-CMV therapy, with photography to document progression or resolution of disease. 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 be instructed to report any vision loss immediately.

Chronic maintenance therapy

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

• Valganciclovir 900 mg PO once daily
• IV foscarnet 90-120 mg/kg once daily

Discontinuation of maintenance therapy can be considered for patients with inactive CMV and sustained immune reconstitution on 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 with CMV 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.

Neurologic CMV disease

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

Gastrointestinal and pulmonary CMV disease

These infections are usually treated with IV ganciclovir or foscarnet for 21-28 days unless the patient is able to absorb oral medications, in which case valganciclovir PO 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.

Immune reconstitution inflammatory syndrome retinitis or uveitis

Urgent consultation with experts is recommended.

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 after starting 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.
• For patients who experience significant vision loss, offer referral to education, training, and support services to help them adjust.
• 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

• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.
• Drew WL, Lalezari JP. Cytomegalovirus and HIV. In: Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]. San Francisco: UCSF Center for HIV Information; May 2006. Accessed June 13, 2012.
• Goldberg DE, Smithen LM, Angelilli A, et al. HIV-associated retinopathy in the HAART era. Retina. 2005 Jul-Aug;25(5):633-49.
• Jacobsen MA. AIDS-Related Cytomegalovirus Gastrointestinal Disease. In: UpToDate v14.1. Accessed June 13, 2012. [Registration required.]
• Jacobsen MA. AIDS-Related Cytomegalovirus Neurologic Disease. In: UpToDate v14.1. Accessed June 13, 2012. [Registration required.]
• Jacobsen MA. Treatment of AIDS-Related Cytomegalovirus Retinitis. In: UpToDate v14.1. Accessed June 13, 2012. [Registration required.]
• Kempen JH, Min YI, Freeman WR, et al.; Studies of Ocular Complications of AIDS Research Group. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology. 2006 Apr;113(4):684-94.