AIDS-related cytomegalovirus gastrointestinal disease

INTRODUCTION — Cytomegalovirus (CMV) gastrointestinal disease is an uncommon but serious complication of acquired immunodeficiency syndrome (AIDS). Prior to the availability of potent antiretroviral therapy (ART), CMV gastrointestinal disease occurred in up to 5 percent of patients with AIDS, primarily in those with advanced immunosuppression. However, the incidence of CMV gastrointestinal disease has decreased substantially since ART became available [1,2]. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

A discussion of the pathogenesis and clinical manifestations of other CMV-related diseases in patients with human immunodeficiency virus (HIV) is found elsewhere. (See "AIDS-related cytomegalovirus neurologic disease" and "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis".)

NATURAL HISTORY — In persons with prior CMV infection and a CD4 cell count <50 cells/microL, reactivation of latent virus causes a systemic disease that is characterized by intermittent or constant viremia which can lead to colonization or localized infections in one or multiple target organs, including the gastrointestinal tract [3]. CMV gastrointestinal disease was first reported as a manifestation of AIDS in 1983. In early case series, patients generally died within several months without CMV-specific treatment, and hemorrhage or perforation often complicated the course of disease. The prognosis of such patients remained poor despite the advent of antiviral drugs for the treatment of CMV. As an example, the median survival was reported to be four months after the diagnosis of CMV colitis and eight months after CMV esophagitis, even with ganciclovir therapy [4-6]. However, as with all HIV-related opportunistic infections, the prognosis has improved markedly with the utilization of antiretroviral therapy (ART). (See 'Impact of ART' below.)

Risk factors — Most cases of CMV disease occur in the setting of advanced immunosuppression, with CD4 cell counts < 50 cells/microL [7]. The presence of CMV in blood (as measured by culture, CMV deoxyribonucleic acid (DNA) amplification, or antigen detection) is also a risk factor for the development of invasive disease [8]. However, patients with viremia may not have invasive disease. (See 'Viral detection' below.)

Impact of ART — The prognosis of patients with AIDS and CMV gastrointestinal disease has improved dramatically since effective ART became available in the late 1990s [9,10]. Most cases of end organ disease now occur in patients who are not receiving ART, either due to late diagnosis of HIV disease or poor adherence to prescribed therapy.

A large multicenter prospective European cohort examined the incidence and prognosis of invasive CMV disease in patients with AIDS during the pre- and post-ART eras [9]. A total of 707 of 8,556 patients had CMV disease diagnosed at either recruitment or at a follow-up visit: 449 with retinitis, 164 with gastrointestinal disease and 58 with concurrent retinitis and extraocular disease. The number of new cases of CMV related gastrointestinal disease significantly declined after the introduction of ART; 61 cases were diagnosed from 1994 to 1995 and 9 cases were diagnosed from 1998-2001.

CLINICAL MANIFESTATIONS — The most common sites of CMV related gastrointestinal involvement are the esophagus and the colon. Symptom presentation depends on the anatomic location of the infection.

Esophagitis — CMV esophagitis presents with odynophagia and may be accompanied by fever, nausea, or substernal burning pain [11]. CMV most commonly causes multiple ulcers at the lower esophageal sphincter, but diffuse esophagitis is also described [7,11].

Gastritis — CMV gastritis presents with substernal and/or epigastric burning pain. Gastrointestinal hemorrhage is a rare manifestation of CMV disease at this site [12].

Enteritis — CMV infection of the small bowel accounts for approximately 4 percent of all CMV infections of the gastrointestinal tract [13]. CMV enteritis is manifested clinically by generalized abdominal pain and diarrhea. Rare reports of dyspepsia and ileal perforation secondary to CMV have been reported [14,15].

Colitis — CMV colitis is the second most common manifestation of end organ disease after CMV retinitis. CMV colitis is associated with low-grade fever, weight loss, anorexia, malaise, and abdominal pain [16]. Explosive watery diarrhea is common, but can be sporadic [7]. Symptoms that suggest distal large bowel involvement include frequent small volume diarrhea, tenesmus, and/or hematochezia [17]. Extensive mucosal hemorrhage and perforation can be life-threatening complications.

Other — CMV can rarely cause large, painful ulcers of the mouth, pharynx, or anus [18]. In the oropharynx, these ulcers may be mistaken for aphthous ulcers or herpes simplex erosions.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS — In a patient with suspected CMV gastrointestinal disease, the diagnosis is based upon the following triad: clinical symptoms of gastrointestinal disease, visualization of characteristic lesions on endoscopy, and intranuclear or cytoplasmic inclusions on pathology [19]. A definitive diagnosis should be made in most settings, since empiric anti-CMV therapy can be associated with significant toxicity. (See 'Treatment' below.)

When to suspect CMV gastrointestinal disease — The diagnosis of CMV gastrointestinal disease should be suspected in patients with CD4 cell counts <50 cells/microL who present with symptoms of esophagitis, gastritis, enteritis, or colitis. This diagnosis is most likely to occur in patients not receiving antiretroviral therapy. (See 'Clinical manifestations' above.)

Often, such symptoms have an alternate explanation. An approach to the evaluation of patients with HIV with these symptoms is discussed elsewhere. (See "Evaluation of the patient with HIV, odynophagia, and dysphagia" and "Evaluation of the patient with HIV and diarrhea".)

We suggest endoscopy and biopsy to diagnose CMV disease in the following settings:

●When the evaluation for more common causes of gastrointestinal disease is unrevealing. As an example, patients with persistent diarrhea should undergo endoscopy when stool studies for enteric pathogens, Clostridioides difficile, and ova and parasites, including Giardia, are negative.

●When empiric therapy for a more common etiology is not effective. As an example, patients with esophagitis are often treated empirically for candidiasis with fluconazole before evaluating other etiologies.

●As part of the initial evaluation in severely symptomatic patients who require hospitalization.

Endoscopic evaluation — Endoscopy provides visual information that supports a diagnosis of CMV and also provides the opportunity to obtain tissue for pathology. The endoscopic presentation of CMV can vary depending upon the location of disease. CMV esophagitis and gastritis appear as large shallow ulcers or erosions; the appearance of CMV colitis can range from punctate and superficial erosions to deep ulcerations and necrotizing colitis [7,20]. Biopsies should be taken from erosions or ulcers to make a definitive diagnosis. CMV inclusions can be seen in normal gastrointestinal mucosa in patients with advanced AIDS, but this does not correlate with clinical symptoms [21].

Pathology — CMV gastrointestinal disease is characterized histologically by mucosal inflammation, tissue necrosis, as well as vascular endothelial cell damage and the presence of intranuclear and intracytoplasmic inclusions. The characteristic cytomegalic cells (large cells containing eosinophilic intranuclear and frequently basophilic intracytoplasmic inclusions) are present in mucosal biopsies stained with hematoxylin and eosin (picture 1) [22]. In patients with severe colitis, cytomegalic inclusions can be seen in areas of perforation [23].

Additional testing — The presence of CMV in blood or tissue and/or a positive CMV antibody does not confirm a diagnosis of CMV disease in patients with HIV and advanced immunosuppression. As an example, in a study of patients with advanced AIDS and CMV viremia detected by polymerase chain reaction (PCR), fewer than 50 percent developed CMV end organ disease at one year despite receiving no anti-CMV therapy [24].

Viral detection — Blood tests to detect CMV by antigen detection, culture, or polymerase chain reaction (PCR) are not recommended in patients with AIDS because they cannot confirm or exclude the presence of end-organ disease [19]. In addition, positive CMV cultures of mucosal brushings or biopsies are not diagnostic because a substantial number of patients with low CD4 cell counts may have positive cultures in the absence of clinical disease [19,25].

Serology — CMV antibody is typically not useful in confirming AIDS-related CMV disease. However, CMV gastrointestinal disease is rare in AIDS patients who are CMV seronegative because infection results from reactivation of latent virus; thus, a negative serology suggests an alternate etiology for their symptoms. (See "Approach to the diagnosis of cytomegalovirus infection".)

Ophthalmologic evaluation in all patients with CMV disease — Patients with extraocular CMV disease often have concurrent CMV retinitis. As a result, any patient diagnosed with CMV gastrointestinal disease should have formal ophthalmologic screening for retinitis. If the initial examination is negative, it should be repeated if any visual symptoms occur, or at six-month intervals until the patient's absolute CD4 cell count has been restored to >50 cells/microL by antiretroviral therapy. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis" and "Treatment of AIDS-related cytomegalovirus retinitis".)

Differential diagnosis — The differential diagnosis depends upon the anatomic location of disease.

●In patients with esophageal disease, alternative infectious etiologies include candida or herpes simplex. Patients may also have a non-infectious cause for their symptoms, such as acid-reflux disease or aphthous ulcers. (See "Evaluation of the patient with HIV, odynophagia, and dysphagia".)

●In patients with gastritis, Helicobacter pylori should be considered as should non-infectious causes such as acid related disorders, medication related dyspepsia, or malignancy.

●Enteritis can result from a variety of pathogens that involve the small and/or large bowel. Potential infectious etiologies in patients with advanced immunosuppression include bacteria (Salmonella, Shigella, Campylobacter, Yersinia, C. difficile), fungi (Histoplasma capsulatum, Cryptococcus), mycobacteria (Mycobacterium tuberculosis, or Mycobacterium avium complex), parasites (Entamoeba histolytica, Giardia lamblia, Cryptosporidium, Cystoisospora, Microsporidia), and viruses (HIV, adenovirus). Symptoms can also be due to non-infectious causes, such as medication related side effects or malignancies including lymphoma and Kaposi's sarcoma. (See "Evaluation of the patient with HIV and diarrhea".)

TREATMENT

Overview — All patients with symptomatic CMV gastrointestinal disease should receive anti-CMV therapy. In addition, we initiate empiric treatment in patients suspected of having CMV gastrointestinal disease (ie, severe clinical symptoms, CD4 cell count< 50 cells/microL, and suggestive endoscopic findings) while awaiting pathologic confirmation.

Treatment of CMV gastrointestinal disease includes induction therapy, initiation of antiretroviral therapy (ART), and maintenance therapy in selected patients:

●Patients with CMV gastrointestinal disease should receive induction therapy with an antiviral agent (usually ganciclovir) for three to six weeks or until signs and symptoms have resolved. For patients with severe disease, intravenous therapy is recommended. Oral therapy (ie, valganciclovir) can be used once a patient can absorb and tolerate oral agents and/or in patients with mild disease. (See 'Induction therapy' below.)

●ART should be initiated if the patient is not already on it and is tolerating anti-CMV therapy. However, the timing of ART initiation depends upon the presence or absence of concurrent CMV retinitis. (See 'Ophthalmologic evaluation in all patients with CMV disease' above and 'When to initiate ART' below.)

●Maintenance therapy, usually with oral valganciclovir, is given to patients with concurrent CMV retinitis and those who relapse after induction therapy. (See 'Ophthalmologic evaluation in all patients with CMV disease' above and 'Maintenance therapy' below.)

Induction therapy — Ganciclovir is the preferred agent for treatment of AIDS-related CMV gastrointestinal disease [19]. Both ganciclovir and foscarnet are effective for initial management [26-28]. These agents produced similar clinical improvement in a small open-label randomized trial [29]. However, we prefer ganciclovir because of the cost, inconvenience, and renal side effects associated with foscarnet. Foscarnet may be used in patients with contraindications to ganciclovir, such as refractory leukopenia or thrombocytopenia, and/or when there is a concern for ganciclovir resistance. Ganciclovir and foscarnet have very different side effect profiles that are summarized in (table 1).

The induction doses of these agents for the treatment of CMV gastrointestinal disease are the same as for CMV retinitis:

●Intravenous ganciclovir is dosed as 5 mg/kg/dose every 12 hours

●Intravenous foscarnet is dosed as 60 mg/kg/dose every eight hours or 90 mg/kg/dose every 12 hours

The use of oral therapy — Oral valganciclovir (900 mg twice daily) may be used for induction therapy, in place of intravenous ganciclovir, in patients who can tolerate and absorb oral medications (eg, mild disease or after symptomatic improvement following initial intravenous therapy). Oral therapy allows for easier home administration and decreases the risk of catheter related line infections. Valganciclovir has not been studied in the treatment of CMV gastrointestinal disease. However, it has proven efficacy in patients with CMV retinitis [30].

Oral valganciclovir is a valine ester of ganciclovir, is rapidly absorbed and hydrolyzed to ganciclovir, and has high bioavailability. A 900 mg dose of valganciclovir is comparable to 5 mg/kg of intravenous ganciclovir. Valganciclovir and ganciclovir have similar toxicity profiles. (See "Ganciclovir and valganciclovir: An overview".)

Duration — The recommended duration of therapy for CMV gastrointestinal disease in patients with AIDS is three to six weeks [19]. This is based upon expert opinion and small studies in the pre-ART era [7,26,29,31]. We determine the duration of therapy according to the patient’s response to treatment. As an example, a patient who symptomatically improves within one week of treatment may only need three to four weeks of induction therapy, while a patient who is slower to respond should be treated for the full six weeks. Patients who have persistent symptoms after six weeks of treatment may have an alternative diagnosis and/or CMV drug resistance. Management of such patients is discussed below.

When to initiate ART — Most patients with CMV gastrointestinal disease are not on ART. However, ART should be continued in the minority of affected patients already on treatment.

For patients who are antiretroviral naïve, the timing of ART depends upon the presence or absence of concurrent CMV retinitis:

●If CMV retinitis has been excluded, ART should begin as soon as the patient can tolerate oral medication and within two weeks. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions".)

●For those with CMV retinitis, the timing of ART initiation is less clear, and is discussed in detail elsewhere. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'When to initiate antiretroviral therapy'.)

The initiation of ART results in immune recovery, and is an important adjunct in the treatment of opportunistic infections, including those with CMV retinitis [32,33]. However, ART can produce an immune reconstitution inflammatory syndrome (IRIS) in the eye of patients with CMV retinitis, resulting in visual loss. IRIS is extremely rare in patients with isolated gastrointestinal disease after initiating ART. One such case of recurrent CMV colitis as a manifestation of IRIS has been reported [34]. In addition, three cases of unmasking underlying CMV disease after ART initiation in patients not previously known to have CMV have been reported as a manifestation of IRIS [35-37]. (See "Immune reconstitution inflammatory syndrome" and "Treatment of AIDS-related cytomegalovirus retinitis", section on 'CMV immune reconstitution inflammatory syndromes'.)

Maintenance therapy — Chronic maintenance therapy is not recommended for CMV gastrointestinal disease unless there is concurrent retinitis or recurrent gastrointestinal disease after induction therapy has been discontinued [19]. Low quality data in patients without retinitis suggest that maintenance therapy does not prevent relapse or improve survival [29].

Patients with recurrent gastrointestinal disease should be reinduced prior to initiation of maintenance therapy (see 'Induction therapy' above). After successful induction, maintenance therapy consists of valganciclovir, 900 mg given once daily, a dose that is effective in patients with CMV retinitis. There are no guidelines regarding when to discontinue maintenance in patients with relapsed GI disease. We suggest discontinuing treatment in patients who have sustained CD4 cell counts >100 cells/microL for six months or longer on ART.

A detailed discussion of maintenance therapy for patients with CMV retinitis is found elsewhere. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'Discontinuing maintenance therapy'.)

Treatment failure — Some patients may fail induction therapy, or relapse despite chronic maintenance therapy. Clinical failure could result from one or more of the following:

●Resistance to anti-CMV therapy (see 'Approach to patients with suspected drug resistance' below)

●Concurrent GI infection that is not being adequately treated

●Noninfectious etiology of the GI symptoms

Approach to patients with suspected drug resistance — Drug-resistant AIDS-related CMV disease is rare. However, the likelihood is increased in patients who have had prior exposure to anti-CMV agents, and in those who have not achieved adequate serum drug levels (eg, due to poor adherence or absorption).

If drug resistance is suspected, we send serum for CMV PCR. If the serum CMV PCR is positive, we send genotype testing for drug resistance to help guide therapy. If the PCR is negative or genotypic testing shows no evidence of resistance, a repeat work-up, including biopsy, should be done. (See 'Differential diagnosis' above.)

Treatment of suspected or confirmed drug-resistant CMV consists of combination therapy with ganciclovir plus foscarnet. For patients who cannot tolerate combination therapy, an alternative option is maribavir.

●Ganciclovir plus foscarnet − For patients with suspected drug-resistance based upon a detectable CMV DNA, we suggest combination therapy with ganciclovir plus foscarnet (rather than monotherapy with the alternative induction agent) while awaiting the results of genotypic resistance testing. If resistance is confirmed, we continue combination therapy for six weeks. These suggestions are based upon data from the treatment of CMV retinitis; there are no studies of drug-resistant CMV gastrointestinal disease.

●Maribavir – Maribavir is an alternative option for patients with either clinical or virologic resistance or intolerance to combination ganciclovir and foscarnet. Although maribavir has only been studied in the transplant population and there is very limited experience treating CMV end-organ disease with this agent, it is orally bioavailable and relatively well tolerated. Maribavir is a CMV UL97 gene product inhibitor that was approved by the US Food and Drug Administration (FDA) in November 2021, for treatment of post-transplant CMV infection refractory to therapy with other approved antiviral agents. While there are limited data of maribavir treatment for AIDS-related CMV end-organ disease, beneficial clinical and virologic responses were reported in transplant populations [38], as were virologic responses in an earlier phase 1 study of patients with advanced HIV disease who had asymptomatic CMV shedding [39].

●Other agents − We do not recommend using alternative agents, such as cidofovir or letermovir, unless combination ganciclovir and foscarnet therapy and/or maribavir have failed or the patient is intolerant of these medications. Cidofovir has never been studied for CMV gastrointestinal disease, and is associated with serious toxicity. Letermovir is a CMV viral terminase complex inhibitor that is approved only for prophylaxis of CMV disease in allogeneic hematopoietic cell transplant recipients. Thus far, its use in a few cases of CMV end-organ disease has not clearly provided benefit to the patient. In addition, letermovir can have problematic drug interactions with several non-nucleoside reverse transcriptase and protease inhibitor antiretroviral drugs used for HIV treatment, as well as all rifamycins used to treat tuberculosis.

PATIENT MONITORING — Patients with AIDS-related CMV gastrointestinal disease should be monitored for resolution of their symptoms and drug toxicity. The medications used for the treatment of CMV disease have very different side effect profiles. The laboratory monitoring and dose-limiting toxicities of these agents are summarized in (table 1). A detailed discussion of the potential side effects from these agents is found elsewhere. (See "Ganciclovir and valganciclovir: An overview", section on 'Toxicity' and "Foscarnet: An overview", section on 'Toxicity'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV".)

SUMMARY AND RECOMMENDATIONS

●Natural history − AIDS-related cytomegalovirus (CMV) disease is almost always the result of reactivation of latent infection. End-organ disease probably results from the hematogenous spread of CMV. (See 'Natural history' above.)

●Risk factors − Risk factors for CMV disease include CMV viremia and advanced immunosuppression, particularly when CD4 cell counts are less than 50 cells/microL. (See 'Risk factors' above.)

●Clinical manifestations − CMV disease can involve any part of the gastrointestinal tract; however the most common locations include the esophagus and colon. (See 'Clinical manifestations' above.)

●Diagnosis − The diagnosis of CMV gastrointestinal disease is based upon the following triad: clinical symptoms of gastrointestinal disease, visualization of ulcers or erosions, and pathology showing tissue destruction and viral inclusion bodies. (See 'Diagnosis and differential diagnosis' above.)

●Additional testing − Laboratory testing for CMV viral load and serology are not clinically helpful in most situations. (See 'Additional testing' above.)

●Ophthalmologic evaluation − Patients with extraocular CMV disease often have concurrent CMV retinitis. As a result, any patient diagnosed with CMV gastrointestinal disease should have a formal ophthalmologic examination. (See 'Ophthalmologic evaluation in all patients with CMV disease' above.)

●Treatment

•Induction therapy

-In patients with CMV gastrointestinal disease, we suggest induction therapy with ganciclovir or valganciclovir rather than foscarnet (Grade 2B); foscarnet is more expensive, inconvenient, and associated with renal toxicity. Patients who do not tolerate treatment with one drug can be switched to the other. The doses and duration of therapy are discussed above. (See 'Induction therapy' above.)

-In patients who can tolerate and absorb oral medication, we suggest induction with oral valganciclovir instead of intravenous ganciclovir (Grade 2C). (See 'The use of oral therapy' above.)

•Maintenance therapy − In patients who complete induction treatment for CMV gastrointestinal disease (without retinitis), we suggest not giving maintenance therapy (Grade 2C). However, in patients with relapsed CMV gastrointestinal disease, we do suggest maintenance therapy with oral valganciclovir after repeated induction therapy (Grade 2C). In such patients on antiretroviral therapy (ART) who have sustained CD4 cell counts >100 cells/microL (for six months or longer), we suggest discontinuing valganciclovir (Grade 2C). (See 'Maintenance therapy' above.)

•Initiation of ART − In patients who are not receiving ART and who do not have CMV retinitis, we suggest initiation of ART for HIV disease once they can tolerate and absorb oral medications (Grade 2C). For those with concurrent CMV retinitis the timing of ART initiation is less clear, and is discussed elsewhere. (See 'When to initiate ART' above and "Treatment of AIDS-related cytomegalovirus retinitis", section on 'When to initiate antiretroviral therapy'.)

•Patient monitoring − Patients with AIDS-related CMV gastrointestinal disease should be monitored for resolution of their symptoms and drug toxicity. (See 'Patient monitoring' above.)

•Refractory symptoms − If drug resistance is suspected in patients who fail to respond to anti-CMV therapy, we use combined therapy with ganciclovir and foscarnet. (See 'Treatment failure' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.