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.
Although effective ART greatly reduces the risk of CMV reactivation and disease, patients on effective ART may experience CMV-related visual changes.
The patient may present with symptoms involving various organ systems, including the following:
The history should include questions about the presence and characteristics of the symptoms listed above, as well as the following:
Perform a thorough physical examination with particular attention to the following:
For HIV-infected patients with advanced immunosuppression, the differential diagnosis includes the following:
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:
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.
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.
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.
Treatment consists of two phases: initial therapy and chronic maintenance 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.
Alternatives for initial therapy:
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.
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:
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.
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.
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.
Urgent consultation with experts is recommended.
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.