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Cytomegalovirus Disease
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Epidemiology

Cytomegalovirus (CMV) is a double-stranded DNA virus in the Herpesvirus family that can cause disseminated or localized end-organ disease among patients with advanced immunosuppression. Most clinical disease occurs in previously infected (seropositive) persons and so represents either reactivation of latent infection or reinfection with a novel strain.

End-organ disease caused by CMV occurs among persons with advanced immunosuppression, typically those with CD4+ counts <50 cells/µL, who are either not receiving or have failed to respond to ART (658Jabs DA, Van Natta ML, Kempen JH, et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2000;133:48-61., 658/, 660Arribas JR, Storch GA, Clifford DB, Tselis AC. Cytomegalovirus encephalitis. Ann Intern Med 1996;125:577-87.). Other risk factors include previous OIs and high plasma HIV RNA levels (>100,000 copies/mL).

Before potent ART, an estimated 30% of patients with AIDS experienced CMV retinitis some time between the diagnosis of AIDS and death (658Jabs DA, Van Natta ML, Kempen JH, et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2000;133:48-61., 658Jabs DA, Van Natta ML, Kempen JH, et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2000;133:48-61., 660Arribas JR, Storch GA, Clifford DB, Tselis AC. Cytomegalovirus encephalitis. Ann Intern Med 1996;125:577-87.). The incidence of new cases of CMV end-organ disease has declined by 75%-80% with the advent of ART and now is estimated to be <6 cases per 100 person-years (661Jabs DA, Van Natta ML, Holbrook JT, et al. Longitudinal study of the ocular complications of AIDS: 1. Ocular diagnoses at enrollment. Ophthalmology 2007;114:780-6.). For those with established CMV retinitis, recurrence of active lesions occurs at a rate of 0.58/person-year for those with CD4+ cells <50 cells/µL, a rate substantially lower than that seen in the pre-ART era. However, even for those with immune recovery sufficient to discontinue anti-CMV therapy (i.e., >100 cells/µL), relapse of the retinitis occurs at a rate of 0.03/person-year and can occur at CD4+ counts as high as 1,250 cells/µL (662Jabs DA, Van Natta M, Thorne JE, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: retinitis progression. Ophthalmology 2004;111:12.). Therefore, whether anti-CMV therapy is continued, regular ophthalmologic follow-up is needed.

Clinical Manifestations

Retinitis is the most common clinical manifestation of CMV end-organ disease. CMV retinitis occurs as unilateral disease in two thirds of patients at presentation, but in the absence of therapy or immune recovery, viremic dissemination results in bilateral disease in the majority of patients (663Jabs DA, Van Natta ML, Thorne JE, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: 2. Second eye involvement and retinal detachment. Ophthalmology 2004;111:2232-9.). For patients with unilateral CMV retinitis and CD4+ count <50 cells/µL, rates of contralateral disease approach those of the pre-ART era (663Jabs DA, Van Natta ML, Thorne JE, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: 2. Second eye involvement and retinal detachment. Ophthalmology 2004;111:2232-9.).

Peripheral retinitis might be asymptomatic or present with floaters, scotomata, or peripheral visual field defects. Central retinal lesions or lesions impinging on the macula or optic nerve are associated with decreased visual acuity or central field defects. CMV retinitis is a full-thickness necrotizing retinitis, and the characteristic ophthalmologic appearance is that of fluffy yellow-white retinal lesions, with or without intraretinal hemorrhage, and with little inflammation of the vitreous unless immune recovery with potent ART intervenes (658Jabs DA, Van Natta ML, Kempen JH, et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2000;133:48-61.). Blood vessels near the lesions might appear to be sheathed. Occasionally, CMV retinitis lesions, particularly peripheral lesions, might have a more granular appearance.

In the absence of ART or specific anti-CMV therapy, retinitis invariably progresses, usually within 10-21 days after presentation. Progression of retinitis occurs in "fits and starts" and causes a characteristic brushfire pattern, with a granular, white leading edge advancing before an atrophic gliotic scar (672Holland GN. AIDS and ophthalmology: the first quarter century. Am J Ophthalmol 2008;145(3):397-408.).

Colitis occurs in 5%-10% of persons with AIDS and CMV end-organ disease (659Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature. J Acquir Immune Defic Syndr 1991;4:29-35.). The most frequent clinical manifestations are fever, weight loss, anorexia, abdominal pain, debilitating diarrhea, and malaise. Extensive mucosal hemorrhage and perforation can be life-threatening complications.

Esophagitis caused by CMV, which occurs in <5%-10% of persons with AIDS who experience CMV end-organ disease, causes fever, odynophagia, nausea, and occasionally mid-epigastric or retrosternal discomfort. CMV pneumonitis is uncommon. CMV neurologic disease causes dementia, ventriculoencephalitis, or ascending polyradiculomyelopathy (664Arribas JR, Clifford DB, Fichtenbaum CJ, et al. Level of cytomegalovirus (CMV) DNA in cerebrospinal fluid of subjects with AIDS and CMV infection of the central nervous system. J Infect Dis 1995;172:527-31.). Patients with dementia typically have lethargy, confusion, and fever, mimicking that of HIV dementia. CSF typically demonstrates lymphocytic pleocytosis (although a mixture of neutrophils and lymphocytes might be evident), low-to-normal glucose levels, and normal-to-elevated protein levels. Patients with ventriculoencephalitis have a more acute course, with focal neurologic signs, often including cranial nerve palsies or nystagmus, and rapid progression to death. Periventricular enhancement of CT or MRI images is indicative of CMV ventriculoencephalitis rather than HIV-related neurologic disease. CMV polyradiculomyelopathy causes a Guillian-Barre-like syndrome characterized by urinary retention and progressive bilateral leg weakness. The clinical symptoms usually progress during several weeks to include loss of bowel and bladder control and to flaccid paraplegia. A spastic myelopathy has been reported and sacral paresthesia might occur. The CSF usually demonstrates a neutrophilic pleocytosis (usually 100-200 neutrophils/µL and some erythrocytes) accompanied by hypoglycorrhachia and elevated protein levels.

Diagnosis

CMV viremia can be detected by PCR or antigen assays and is usually observed in end-organ disease, but viremia also might be present in the absence of end-organ disease (664Arribas JR, Clifford DB, Fichtenbaum CJ, et al. Level of cytomegalovirus (CMV) DNA in cerebrospinal fluid of subjects with AIDS and CMV infection of the central nervous system. J Infect Dis 1995;172:527-31., 665Dodt KK, Jacobsen PH, Hofmann B, et al. Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS 1997;11:21-8., 666Zurlo JJ, O'Neill D, Polis MA, et al. Lack of clinical utility of cytomegalovirus blood and urine cultures in patients with HIV infection. Ann Intern Med 1993;118:12-7., 667Rodriguez-Barradas MC, Stool E, Musher DM, et al. Diagnosing and treating cytomegalovirus pneumonia in patients with AIDS. Clin Infect Dis 1996;23:76-81., 668Wolf DG, Spector SA. Diagnosis of human cytomegalovirus central nervous system disease in AIDS patients by DNA amplification from cerebrospinal fluid. J Infect Dis 1992;166:1412-5., 669Deayton JR, Prof Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004;363:2116-21.). The presence of serum antibodies to CMV is not diagnostically useful, although a negative IgG antibody level indicates that CMV is unlikely to be the cause of the disease process.

The diagnosis of CMV retinitis is usually made based on recognition of characteristic retinal changes observed through a dilated pupil during an ophthalmoscopic examination performed by an experienced ophthalmologist. Diagnosis by such clinical examination has a 95% positive predictive value. In rare cases, diagnosis might be difficult and PCR of vitreous for CMV and other pathogens might be valuable in the differential diagnosis.

Demonstration of mucosal ulcerations on endoscopic examination combined with colonoscopic or rectal biopsy with histopathologic demonstration of characteristic intranuclear and intracytoplasmic inclusions is required for the diagnosis of CMV colitis (659Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature. J Acquir Immune Defic Syndr 1991;4:29-35.). The diagnosis of CMV esophagitis is established by the presence of extensive large, shallow ulcers of the distal esophagus and biopsy evidence of intranuclear inclusion bodies in the endothelial cells with an inflammatory reaction at the edge of the ulcer (659Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature. J Acquir Immune Defic Syndr 1991;4:29-35.).

Culturing CMV from a biopsy or cells brushed from the colon or the esophagus is not sufficient to establish the diagnosis of CMV colitis or esophagitis in the absence of histopathologic changes because certain persons with low CD4+ counts might be viremic and have positive cultures for CMV in the absence of clinical disease (669Deayton JR, Prof Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004;363:2116-21.).

Diagnosis of CMV pneumonitis should take into account pulmonary interstitial infiltrates, identification of multiple CMV inclusion bodies in lung tissue, and the absence of other pathogens that are more commonly associated with pneumonitis evident in this population (667Rodriguez-Barradas MC, Stool E, Musher DM, et al. Diagnosing and treating cytomegalovirus pneumonia in patients with AIDS. Clin Infect Dis 1996;23:76-81.). CMV neurologic disease is diagnosed on the basis of a compatible clinical syndrome and the presence of CMV in CSF or brain tissue (660Arribas JR, Storch GA, Clifford DB, Tselis AC. Cytomegalovirus encephalitis. Ann Intern Med 1996;125:577-87., 668Wolf DG, Spector SA. Diagnosis of human cytomegalovirus central nervous system disease in AIDS patients by DNA amplification from cerebrospinal fluid. J Infect Dis 1992;166:1412-5.). Detection of CMV is enhanced by PCR (665Dodt KK, Jacobsen PH, Hofmann B, et al. Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS 1997;11:21-8., 668Wolf DG, Spector SA. Diagnosis of human cytomegalovirus central nervous system disease in AIDS patients by DNA amplification from cerebrospinal fluid. J Infect Dis 1992;166:1412-5.).

Preventing Exposure

HIV-infected persons who belong to groups at risk with relatively low seroprevalence rates for CMV and who, therefore, cannot be presumed to be seropositive should be tested for antibody to CMV (BIII). These groups include patients who have not had contact with MSM or used injection drugs. HIV-infected adolescents and adults should be advised that CMV is shed in semen, cervical secretions, and saliva and that latex condoms must always be used during sexual contact to reduce the risk for exposure to CMV and to other sexually transmitted pathogens (AII).

HIV-infected adults and adolescents who provide child care or parents of children in day care facilities should be informed that they are at increased risk for acquiring CMV infection (BI). Similarly, parents and other caretakers of HIV-infected children should be advised of the increased risk to children at these centers (BIII). Risk for acquiring CMV infection can be diminished by optimal hygienic practices (e.g., hand-washing and use of latex gloves) (AII).

HIV-exposed infants and infected children, adolescents, and adults who are seronegative for CMV and who require blood transfusion should be administered only CMV antibody-negative or leukocyte-reduced cellular blood products in nonemergency situations (BIII).

Preventing Disease

CMV end-organ disease is best prevented using ART to maintain the CD4+ count >100 cells/µL. Although oral valganciclovir would likely prevent the occurrence of CMV retinititis in patients with CD4+ counts <50 cells/µL, such therapy is not usually recommended because of cost, the potential to induce CMV resistance, the utility of treating disease when it occurs, and the lack of demonstrated survival advantage (DI). The primary method for preventing severe CMV disease is recognizing the early manifestations of the disease. Patients should be made aware of the importance of increased floaters in the eye and should be advised to assess their visual acuity regularly by using simple techniques (e.g., reading newsprint) (BIII). Regular funduscopic examinations performed by an ophthalmologist are recommended by certain specialists for patients with low (e.g., <50 cells/µL) CD4+ counts (CIII).

Natural history studies in the era of ART indicate that CMV viremia can be detected by PCR on at least one occasion in approximately 30% of those whose CD4+ counts remain <100 cells/µL (669Deayton JR, Prof Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004;363:2116-21.). Such detection of CMV infection by PCR correlates with the development of future CMV disease and death (669Deayton JR, Prof Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004;363:2116-21.). Furthermore, evidence from a cohort study indicates that patients with CMV retinitis administered systemic therapy had substantially reduced mortality (671Kempen JH, Jabs DA, Wilson LA, et al. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis 2003;37:1365-73.). These observations suggest that pre-emptive anti-CMV treatment administered to patients who have evidence of active infection but who have not yet exhibited end-organ disease could be a therapeutic strategy for preventing CMV end-organ disease. Unless future studies document that clinical benefit can be obtained from pre-emptive therapy, the treatment of patients with CMV viremia in the absence of organ system involvement is not recommended (DII).

Treatment of Disease

Oral valganciclovir, IV ganciclovir, IV ganciclovir followed by oral valganciclovir, IV foscarnet, IV cidofovir, and the ganciclovir intraocular implant coupled with valganciclovir are all effective treatments for CMV retinitis (AI) (672Holland GN. AIDS and ophthalmology: the first quarter century. Am J Ophthalmol 2008;145(3):397-408., 673Studies of Ocular Complications of AIDS Research, Group in collaboration with the AIDS Clinical Trials Group: Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. 4. Visual outcomes. Ophthalmology 1994;101:1250-61., 674Musch DC, Martin DF, Gordon JF, Davis MD, Kuppermann BD. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. N Engl J Med 1997;337:83-90., 675Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002;346:1119-26., 676Kempen JH, Jabs DA, Wilson LA, et al. Risk of vision loss in patients with cytomegalovirus retinitis and the acquired immunodeficiency syndrome. Arch Ophthalmol 2003; 121:466-76., 677Studies of Ocular Complications of AIDS Research Group. The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: The Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial. Am J Ophthalmol 2001;131:457-67.). Systemic therapy has been documented to reduce morbidity in the contralateral eye (710Martin DF, Kuppermann BD, Wolitz RA, Palestine AG, Li H, Robinson CA. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 1999;340:1063-70.). This therapy should be considered when choosing among oral, IV, and local options. The choice of initial therapy for CMV retinitis should be individualized based on the location and severity of the lesion(s), the level of underlying immune suppression, and other factors such as concomitant medications and ability to adhere to treatment (AIII). No one regimen has been proven in a clinical trial to have superior efficacy related to protecting vision, and thus clinical judgment must be used when choosing a regimen (673Studies of Ocular Complications of AIDS Research, Group in collaboration with the AIDS Clinical Trials Group: Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. 4. Visual outcomes. Ophthalmology 1994;101:1250-61., 674Musch DC, Martin DF, Gordon JF, Davis MD, Kuppermann BD. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. N Engl J Med 1997;337:83-90., 675Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002;346:1119-26., 676Kempen JH, Jabs DA, Wilson LA, et al. Risk of vision loss in patients with cytomegalovirus retinitis and the acquired immunodeficiency syndrome. Arch Ophthalmol 2003; 121:466-76., 677Studies of Ocular Complications of AIDS Research Group. The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: The Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial. Am J Ophthalmol 2001;131:457-67.). Forms of ganciclovir most often are the first choice for CMV infection or disease. Certain clinical trials were conducted with oral ganciclovir, a preparation that was poorly bioavailable and is no longer marketed. Instead, the prodrug valganciclovir, which is the valine ester of ganciclovir, is administered orally to deliver ganciclovir. In these guidelines, references to oral ganciclovir have been deleted and the equivalent dose of valganciclovir has been substituted.

The ganciclovir intraocular implant plus oral valganciclovir is superior to once-daily IV ganciclovir (and presumably to once-daily oral valganciclovir) for preventing relapse of retinitis (AI) (673Studies of Ocular Complications of AIDS Research, Group in collaboration with the AIDS Clinical Trials Group: Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. 4. Visual outcomes. Ophthalmology 1994;101:1250-61., 674Musch DC, Martin DF, Gordon JF, Davis MD, Kuppermann BD. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. N Engl J Med 1997;337:83-90., 675Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002;346:1119-26., 676Kempen JH, Jabs DA, Wilson LA, et al. Risk of vision loss in patients with cytomegalovirus retinitis and the acquired immunodeficiency syndrome. Arch Ophthalmol 2003; 121:466-76., 677Studies of Ocular Complications of AIDS Research Group. The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: The Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial. Am J Ophthalmol 2001;131:457-67.). For this reason, certain HIV specialists recommend the intraocular implant plus valganciclovir as the preferred initial therapy for patients with immediate sight- threatening lesions (adjacent to the optic nerve or fovea); for patients with small peripheral lesions oral valganciclovir alone may be adequate (BII). Certain ophthalmologists recommend an initial intravitreous injection of ganciclovir at the time CMV retinitis is diagnosed to deliver a high local concentration of ganciclovir to the eye immediately, until the ganciclovir implant can be placed (CIII).

Because ART can control CMV retinitis without anti-CMV therapy in patients who experience immune recovery, some clinicians might consider not treating small peripheral CMV lesions with anti-CMV therapy in ART-naïve patients. However, complications of CMV retinitis, including immune recovery retinitis and retinal detachment, are more common in patients with larger CMV lesions, and ART might take 3-6 months to fully control HIV replication and stimulate sufficient immune recovery to control the retinitis. Furthermore, consistent with natural history studies that associated CMV viremia with increased mortality in the pre- and current ART era (669Deayton JR, Prof Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004;363:2116-21., 678Bowen EF, Wilson P, Cope A, et al. Cytomegalovirus retinitis in AIDS patients: influence of cytomegaloviral load on response to ganciclovir, time to recurrence and survival. AIDS 1996;10:1515-20., 679Spector SA, Wong R, Hsia K, Pilcher M, Stempien MJ. Plasma cytomegalovirus (CMV) DNA load predicts CMV disease and survival in AIDS patients. J Clin Invest 1998;101:497-502.), evidence indicates that anti-CMV therapy decreases mortality among patients with CMV retinitis and immune compromise (671Kempen JH, Jabs DA, Wilson LA, et al. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis 2003;37:1365-73.). Therefore, even in ART-naïve patients with small peripheral lesions, treatment with systemic anti-CMV therapy, such as valganciclovir for the initial 3-6 months until ART has induced immune recovery, will likely be beneficial (BII).

For patients who have colitis or esophagitis, a majority of HIV specialists would recommend IV ganciclovir or foscarnet (or with oral valganciclovir if symptoms are not severe enough to interfere with oral absorption) for 21-28 days or until signs and symptoms have resolved (BII). Certain HIV specialists also would withhold therapy unless moderate-to-severe symptoms justify the use of systemic treatment if ART is to be initiated soon or can be optimized (BIII).

Criteria for establishing that CMV is the cause of pneumonitis and pulmonary dysfunction have been difficult to establish. If CMV is considered the cause of pulmonary dysfunction based on histology or cytology, treatment with IV ganciclovir, foscarnet, or cidofovir is logical, although few data establish that such therapy affects outcome (CIII).

For neurological disease, initiating therapy promptly is critical for an optimal clinical response. Although combination treatment with ganciclovir and foscarnet might be preferred as initial therapy to stabilize disease and maximize response (BII), this approach is associated with substantial rates of adverse effects, and optimal treatment for neurologic disease if ART can be optimized has not been established.

No data are available to demonstrate that starting ART among treatment-naïve patients with CMV retinitis would have an adverse effect on retinitis, gastrointestinal disease, or pneumonitis. Therefore, initiation of appropriate ART should be administered to those with acute CMV retinitis, gastrointestinal disease, or pneumonitis (BIII). Although no data indicate that IRIS worsens CMV neurologic disease syndromes, because of the localized morbidity that might occur with such an inflammatory reaction, a delay in initiating ART in this setting until clinical improvement occurs might be prudent (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Management of CMV retinitis requires close monitoring by an experienced ophthalmologist and the primary clinician. Consideration should be given to both treating the infected eye and preventing infection in the contralateral eye using systemic treatment (663Jabs DA, Van Natta ML, Thorne JE, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: 2. Second eye involvement and retinal detachment. Ophthalmology 2004;111:2232-9., 680Jabs DA. AIDS and ophthalmology in 2004. Arch Ophthalmol 2004;122:1040-2.).

Indirect ophthalmoscopy through a dilated pupil should be performed at the time of diagnosis of CMV retinitis, after completion of induction therapy, 1 month after the initiation of therapy, and monthly thereafter while the patient is on anti-CMV treatment (AIII). Monthly fundus photographs, using a standardized photographic technique that documents the appearance of the retina, provide the optimum method for following patients and detecting early relapse (AIII). For patients who have experienced immune recovery, the frequency of ophthalmologic follow-up can be decreased to every 3 months (AIII). Because relapse of retinitis might still occur among some patients with immune recovery, ophthalmologic follow-up might be indicated; however, the optimal timing and interval of such follow-up has not been established.

Adverse effects of ganciclovir include neutropenia, thrombocytopenia, nausea, diarrhea, and renal dysfunction. Adverse effects of foscarnet include anemia, nephrotoxicity, and electrolyte abnormalities. For patients receiving ganciclovir or foscarnet, monitoring of complete blood counts and serum electrolytes and renal function should be performed twice weekly during induction therapy and once weekly thereafter (AIII). Cidofovir is associated with dose-related nephrotoxicity and hypotony. For patients receiving IV cidofovir, blood urea nitrogen, creatinine, and urinalysis should be performed before each infusion; administration of the drug is contraindicated if renal dysfunction or proteinuria is detected. Even in the absence of retinitis with other CMV end-organ disease, periodic ophthalmologic examinations are needed to monitor for cidofovir-associated uveitis when this agent is used.

Immune recovery uveitis (IRU) is an ocular form of IRIS caused by an immunologic reaction to CMV, characterized by inflammation in the anterior chamber or vitreous in the setting of immune recovery after initiation of ART and is usually observed among those patients with a substantial rise in CD4+ counts in the first 4-12 weeks after initiation of ART (681Nguyen QD, Kempen JH, Bolton SG, Dunn JP, Jabs DA. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000;129:634-9., 682Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 1999;179:697-700., 683Robinson MR, Reed G, Csaky KG, Polis MA, Whitcup SM. Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy. Am J Ophthalmol 2000;130:49-56., 684Karavellas MP, Song M, Macdonald JC, Freeman WR. Long-term posterior and anterior segment complications of immune recovery uveitis associated with cytomegalovirus retinitis. Am J Ophthalmol 2000;130:57-64., 685Kempen JH, Min YI, Freeman WR, Holland GN. Friedberg DN, Dieterich DT . Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology 2006;113:684-94.). Ocular complications of uveitis include macular edema and the development of epiretinal membranes, which can cause loss of vision. Treatment usually requires periocular corticosteroids or short courses of systemic corticosteroids. Estimated response rates are 50%. One uncontrolled case series suggested that IRU (or CMV retinitis-associated IRIS) might respond to oral valganciclovir (686Kosobucki BR, Goldberg DE, Bessho K, et al. Valganciclovir therapy for immune recovery uveitis complicated by macular edema. Am J Ophthalmol 2004;137:636-8.).

Management of Treatment Failure

For patients without immune recovery after initiation of ART and who are receiving chronic maintenance therapy with systemic anti-CMV drugs, relapse of retinitis is likely to occur. Although drug resistance might be responsible for some episodes of relapse, early relapse is most often caused by the limited intraocular penetration of systemically administered drugs (687Jabs DA, Wingard JR, de Bustros S, et al. Cytomegalovirus retinitis: intraocular drug penetration. Arch Ophthalmol 1986;104:1436-7., 688Kuppermann BD, Quiceno JI, Flores-Aguilar M, et al. Intravitreal ganciclovir concentration after intravenous administration in AIDS patients with cytomegalovirus retinitis: implications for therapy. J Infect Dis 1993;168:1506-9., 689Arevalo JF, Gonzales C, Capparelli EV, et al. Intravitreous and plasma concentrations of ganciclovir and foscarnet after intravenous therapy in patients with AIDS and cytomegalovirus retinitis. J Infect Dis 1995;172:951-6.). Because it results in greater drug levels in the eye, the placement of a ganciclovir implant in a patient who has relapsed while receiving systemic treatment (IV ganciclovir or oral valganciclovir) is usually recommended and often will control the retinitis for 6-8 months until the implant requires replacement (BIII) (690Marx JL, Kapusta MA, Patel SS, et al. Use of the ganciclovir implant in the treatment of recurrent cytomegalovirus retinitis. Arch Ophthalmol 1996;114:815-20., 691Hatton MP, Duker JS, Reichel E, Morley MG, Puliafito CA. Treatment of relapsed cytomegalovirus retinitis with the sustained-release ganciclovir implant. Retina 1998;18:50-5.).

When patients relapse while receiving maintenance therapy, reinduction with the same drug followed by reinstitution of maintenance therapy can control retinitis, although for progressively shorter periods (692Ocular Complications of AIDS Research Group. Combination foscarnet and ganciclovir therapy vs. monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. Arch Ophthalmol 1996;114:23-33.), and the majority of specialists recommend this approach for initial treatment of patients who experience relapsed disease (AII). Changing to an alternative drug at the time of first relapse typically does not result in superior control of the retinitis but should be considered if drug resistance is suspected or if side effects or toxicities interfere with optimal courses of the initial agent (AIII) (692Ocular Complications of AIDS Research Group. Combination foscarnet and ganciclovir therapy vs. monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. Arch Ophthalmol 1996;114:23-33.). The combination of ganciclovir and foscarnet is usually superior to systemic therapy with either agent alone and might be considered for patients with relapsed retinitis (692Ocular Complications of AIDS Research Group. Combination foscarnet and ganciclovir therapy vs. monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. Arch Ophthalmol 1996;114:23-33.); however, this combination of drugs is accompanied by greater toxicity (BI).

Drug resistance occurs among patients receiving long-term therapy (693Jabs DA, Enger C, Dunn JP, Forman M. Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. J Infect Dis 1998;177:770-3., 694Jabs DA, Enger C, Forman M, Dunn JP. Incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. Antimicrob Agents Chemother 1998;42:2240-4., 695Jabs DA, Martin BK, Forman MS, et al. Longitudinal observations on mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis 2001;132:700-10., 696Emery VC, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Natl Acad Sci U.S.A 2000; 97:8039-44.). Reported rates in the pre-ART era were approximately 25% per person-year (693Jabs DA, Enger C, Dunn JP, Forman M. Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. J Infect Dis 1998;177:770-3., 697Jabs DA, Enger C, Dunn JP, Forman M, Hubbard L. Cytomegalovirus retinitis and viral resistance: 3. Culture results. Am J Ophthalmol 1998;126:543-9., 698Weinberg A, Jabs DA, Chou S, et al. Mutations conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis 2003;187:777-84.) and reported rates are similar for ganciclovir, foscarnet, and cidofovir (693Jabs DA, Enger C, Dunn JP, Forman M. Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. J Infect Dis 1998;177:770-3., 694Jabs DA, Enger C, Forman M, Dunn JP. Incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. Antimicrob Agents Chemother 1998;42:2240-4.). In the ART era, the rate of resistance appears to be less, approximately 10% per person-year. Low-level resistance to ganciclovir occurs through mutations in the CMV UL97 (phosphotransferase) gene, and high-level resistance to ganciclovir typically occurs because of mutations in both the CMV UL97 and UL54 (DNA polymerase) genes (699Chou S, Erice A, Jordan MC, et al. Analysis of the UL97 phosphotransferase coding sequence in clinical cytomegalovirus isolates and identification of mutations conferring ganciclovir resistance. J Infect Dis 1995;171:576-83., 700Chou S, Guentzel S, Michels KR, Miner RC, Drew WL. Frequency of UL97 phosphotransferase mutations related to ganciclovir resistance in clinical cytomegalovirus isolates. J Infect Dis 1995;172:239-42., 701Smith IL, Cherrington JM, Jiles RE, Fuller MD, Freeman WR, Spector SA. High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. J Infect Dis 1997;176:69-77., 702Jabs DA, Martin BK, Forman MS, Dunn JP. Mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis 2001;183:333-7., 703Chou S, Lurain NS, Thompson KD, Miner RC, Drew WL. Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. J Infect Dis 2003;188:32-9., 704Chou S, Van Wechel LC, Lichy HM, Marousek GI. Phenotyping of cytomegalovirus drug resistance mutations by using recombinant viruses incorporating a reporter gene. Antimicrob Agents Chemother 2005;49:2710-5.). Resistance to foscarnet or cidofovir each occurs because of mutations in the CMV UL54 gene. High-level resistance to ganciclovir is frequently associated with cross resistance to cidofovir (701Smith IL, Cherrington JM, Jiles RE, Fuller MD, Freeman WR, Spector SA. High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. J Infect Dis 1997;176:69-77.) and occasionally to foscarnet (703Chou S, Lurain NS, Thompson KD, Miner RC, Drew WL. Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. J Infect Dis 2003;188:32-9.).

Although early relapse is typically not a result of resistance, later relapse often is. Because patients with resistant CMV nearly always have mutations in the CMV UL97 gene, and because a limited number of mutations are responsible for most drug resistance, susceptibility testing in peripheral blood using a CMV DNA PCR assay and sequencing for CMV UL97 mutations or using a point mutation assay (705Wolf DG, Smith IL, Lee DJ, et al. Mutations in human cytomegalovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma. J Clin Invest 1995;95:257-63., 706The Vitravene Study Group. A randomized controlled clinical trial of intravitreous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol 2002;133:467-74.) might be reasonable for patients who relapse on therapy (707Jabs DA, Martin BK, Ricks MO, Forman MS, Group. Detection of ganciclovir resistance in patients with AIDS and cytomegalovirus retinitis: correlation of genotypic methods with viral phenotype and clinical outcome. J Infect Dis 2006;193:1728-37.). Virus in the eye and in the blood are identical in >90% of cases (708Hu H, Jabs DA, Forman MS, et al. Comparison of cytomegalovirus (CMV) UL97 gene sequences in the blood and vitreous of patients with acquired immunodeficiency syndrome and CMV retinitis. J Infect Dis 2002;185:861-7.), so evaluating the blood for resistance is reasonable, and the detection of resistance in the blood or urine correlates with clinical behavior of the retinitis (709Jabs DA, Martin BK, Forman MS, et al. Cytomegalovirus resistance to ganciclovir and clinical outcomes of patients with cytomegalovirus retinitis. Am J Ophthalmol 2003;135:26-34.). Sequencing the UL97 gene from PCR-amplified specimens from blood can be accomplished in <48 hours, correlates well with conventional drug susceptibility testing and clinical outcomes (707Jabs DA, Martin BK, Ricks MO, Forman MS, Group. Detection of ganciclovir resistance in patients with AIDS and cytomegalovirus retinitis: correlation of genotypic methods with viral phenotype and clinical outcome. J Infect Dis 2006;193:1728-37.), and, therefore, has clinical utility (BII) when conventional methods of culture and susceptibility testing and viral sequencing are not available or are too time consuming or costly. Conversely, CMV viral load measurements are of limited utility clinically because of their poor positive predictive value, but do have reasonable negative predictive value and might have utility in excluding resistance when sequencing is not available (BII). UL97 mutants usually respond to foscarnet, as do most UL54 mutants (except those associated with resistance to foscarnet).

Patients with low-level ganciclovir-resistant isolates in the eye might respond to a ganciclovir implant because of the higher local levels of ganciclovir resulting from this form of therapy. However, patients with high-level ganciclovir-resistant isolates typically will not respond and will require a switch to alternative therapy.

Preventing Recurrence

After induction therapy, secondary prophylaxis (i.e., chronic maintenance therapy) is recommended for life (AI) (664Arribas JR, Clifford DB, Fichtenbaum CJ, et al. Level of cytomegalovirus (CMV) DNA in cerebrospinal fluid of subjects with AIDS and CMV infection of the central nervous system. J Infect Dis 1995;172:527-31., 668Wolf DG, Spector SA. Diagnosis of human cytomegalovirus central nervous system disease in AIDS patients by DNA amplification from cerebrospinal fluid. J Infect Dis 1992;166:1412-5., 673Studies of Ocular Complications of AIDS Research, Group in collaboration with the AIDS Clinical Trials Group: Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. 4. Visual outcomes. Ophthalmology 1994;101:1250-61., 674Musch DC, Martin DF, Gordon JF, Davis MD, Kuppermann BD. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. N Engl J Med 1997;337:83-90., 710Martin DF, Kuppermann BD, Wolitz RA, Palestine AG, Li H, Robinson CA. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 1999;340:1063-70.), unless immune reconstitution occurs as a result of ART. Regimens demonstrated to be effective for chronic suppression in randomized, controlled clinical trials include parenteral ganciclovir or valganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration through intraocular implant (AI). Repetitive intravitreous injections of fomivirsen also have been demonstrated to be effective in randomized clinical trials, but this drug is no longer available in the United States.

Repetitive intravitreous injections of ganciclovir, foscarnet, and cidofovir have been effective for secondary prophylaxis of CMV retinitis in uncontrolled case series. Because of the risk for hypotony and uveitis, the intravitreal administration of cidofovir should be reserved for extraordinary cases. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically should be combined with oral valganciclovir.

The choice of a chronic maintenance regimen for patients treated for CMV disease should be made in consultation with a specialist. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should consider the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to ART.

Patients with lesions that immediately threaten vision need prompt anti-CMV therapy because progression of the retinitis can occur during the time in which immune recovery is occurring (674Musch DC, Martin DF, Gordon JF, Davis MD, Kuppermann BD. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. N Engl J Med 1997;337:83-90., 675Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002;346:1119-26.). Patients with retinitis that immediately threatens sight still might benefit most from the use of the ganciclovir implant because of its ability to deliver high concentrations of drug locally and its superior ability to control retinitis progression (BI). However, replacement of the ganciclovir implant at 6-8 months might not be necessary for those with sustained immune recovery. If the ganciclovir implant is used, it should be combined with oral valganciclovir until immune recovery occurs (BIII).

Chronic maintenance therapy is not routinely recommended for gastrointestinal disease but should be considered if relapses occur (BII). A role for maintenance therapy for CMV pneumonitis has not been established (CIII).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Multiple case series have reported that maintenance therapy can be discontinued safely among adult and adolescent patients with CMV retinitis whose CD4+ counts have indicated a sustained (e.g., 3-6 months) increase to >100 cells/µL in response to ART (711Tural C, Romeu J, Sirera G, et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis 1998;177:1080-3., 712Vrabec TR, Baldassano VF, Whitcup SM. Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology 1998;105:1259-64., 713Macdonald JC, Torriani FJ, Morse LS, et al. Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy. J Infect Dis 1998;177: 1182-7., 714Whitcup SM, Fortin E, Lindblad AS, et al. Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis. JAMA 1999;282:1633-7., 715Jabs DA, Bolton SG, Dunn JP, Palestine AG. Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol 1998;126:817-22., 716Jouan M, Saves M, Tubiana R, et al. Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 2001;15:23-31.). Such patients have remained disease free for >30-95 weeks in clinical trials and case series, whereas during the pre-ART era, retinitis typically reactivated in <6-8 weeks after stopping CMV therapy. Plasma HIV RNA levels were varied among these patients, demonstrating that the CD4+ count is the primary determinant of immune recovery to CMV. Discontinuing secondary prophylaxis (chronic maintenance therapy) is reasonable for patients with a sustained (3-6 months) increase in CD4+ counts >100 cells/µL in response to ART (BII) (711Tural C, Romeu J, Sirera G, et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis 1998;177:1080-3., 712Vrabec TR, Baldassano VF, Whitcup SM. Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology 1998;105:1259-64., 713Macdonald JC, Torriani FJ, Morse LS, et al. Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy. J Infect Dis 1998;177: 1182-7., 714Whitcup SM, Fortin E, Lindblad AS, et al. Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis. JAMA 1999;282:1633-7., 715Jabs DA, Bolton SG, Dunn JP, Palestine AG. Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol 1998;126:817-22., 717Torriani FJ, Freeman WR, Macdonald JC, et al. CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy. AIDS 2000;14:173-80., 718Walmsley SL, Raboud J, Angel JB, et al. Long-term follow-up of a cohort of HIV-infected patients who discontinued maintenance therapy for cytomegalovirus retinitis. HIV Clin Trials 2006;7:1-9.). Such decisions should be made in consultation with an ophthalmologist and should include magnitude and duration of CD4+ count increase, anatomic location of the retinal lesions, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring (BII). The relapse rate among patients whose anti-CMV therapy has been discontinued for immune recovery is 0.03 per person-year (i.e., 3% per year) and no level of CD4+ count is absolutely safe (relapses have been reported at CD4+ counts of 1,250 cells/µL). Therefore, all patients who have had anti-CMV maintenance therapy discontinued should continue to undergo regular ophthalmologic monitoring for early detection of CMV relapse and for IRU, optimally every 3 months (AII). Monitoring CMV viral load has poor positive predictive value for relapse of the retinitis and, therefore, is not recommended (DII).

Relapse of CMV retinitis occurs frequently among patients whose anti-CMV maintenance therapies have been discontinued and whose CD4+ counts have decreased to <50 cells/µL (717Torriani FJ, Freeman WR, Macdonald JC, et al. CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy. AIDS 2000;14:173-80.). Therefore, reinstitution of secondary prophylaxis should occur when the CD4+ count has decreased to <100 cells/µL (AIII).

Special Considerations During Pregnancy

The diagnostic considerations among pregnant women are the same as for nonpregnant women. Indications for treatment of CMV infection during pregnancy are the same as for nonpregnant HIV-infected adults (AIII). For retinal disease, use of intraocular implants or intravitreous injections for local therapy should be considered in the first trimester, if possible, to limit fetal exposure to systemically administered antiviral drugs (CIII). Systemic antiviral therapy as discussed should then be started after the first trimester.

Ganciclovir is embryotoxic among rabbits and mice and teratogenic (i.e., cleft palate, anophthalmia, aplastic kidney and pancreas, and hydrocephalus) in rabbits (719Faqi AS, Klug A, Merker HJ, Chahoud I. Ganciclovir induces reproductive hazards in male rats after short-term exposure. Hum Exp Toxicol 1997;16:505-11., 720Miller BW, Howard TK, Goss JA, et al. Renal transplantation one week after conception. Transplantation 1995;60:1353-4., 721Pescovitz MD. Absence of teratogenicity of oral ganciclovir used during early pregnancy in a liver transplant recipient. Transplantation 1999;67:758-9.). Safe use in human pregnancy after organ transplantation has been reported (719Faqi AS, Klug A, Merker HJ, Chahoud I. Ganciclovir induces reproductive hazards in male rats after short-term exposure. Hum Exp Toxicol 1997;16:505-11., 720Miller BW, Howard TK, Goss JA, et al. Renal transplantation one week after conception. Transplantation 1995;60:1353-4.), and use in late pregnancy to treat fetal CMV infection in HIV-uninfected women has also been reported (722Adler SP, Nigro G, Pereira L. Recent advances in the prevention and treatment of congenital cytomegalovirus infections. Semin Perinatol 2007;31:10-8.). Foscarnet is associated with an increase in skeletal anomalies or variants in rats and rabbits. No experience with use early in human pregnancy has been reported. A single case report of use in the third trimester described normal infant outcome (723Alvarez-McLeod A, Havlik J, Drew KE. Foscarnet treatment of genital infection due to acyclovir-resistant herpes simplex virus type 2 in a pregnant patient with AIDS: case report. Clin Infect Dis 1999;29:937-8.). Cidofovir is embryotoxic and teratogenic (i.e., meningomyelocele and skeletal abnormalities) among rats and rabbits. No experience with use of cidofovir in human pregnancy has been reported; use in pregnancy is not recommended (DIII).

On the basis of limited data, toxicity reports and studies, and ease of use of the various drugs, valganciclovir is recognized as the treatment of choice during pregnancy (BIII). No experience has been reported with the use of valganciclovir in human pregnancy, but concerns are expected to be the same as with ganciclovir. The fetus should be monitored by fetal-movement counting in the third trimester and by periodic ultrasound monitoring after 20 weeks of gestation to look for evidence of hydrops fetalis indicating substantial anemia. Because toxicity of foscarnet is primarily renal, weekly monitoring of amniotic fluid volumes by ultrasound is recommended after 20 weeks of gestation to detect oligohydramnios if foscarnet is used.

Rarely, ultrasound findings in the fetus (e.g., cerebral calcifications, abdominal and liver calcifications, hydrops, microcephaly, ventriculomegaly, ascites, and echogenic fetal bowel) might indicate the possibility of in utero CMV infection among pregnant women with CMV end-organ disease (724Gerber S, Hohlfeld P: Screening for infectious diseases. Childs Nerv Syst 2003;19:429-32.). In this case, consideration of invasive testing (i.e., amniocentesis and fetal umbilical blood sampling) must be individualized on the basis of clinical history and serologic findings, gestational age, potential risk for HIV transmission, and maternal preference (725Lipitz S, Achiron R, Zalel Y, et al. Outcome of pregnancies with vertical transmission of primary cytomegalovirus infection. Obstet Gynecol 2002;100:428-33.). Referral to a maternal-fetal medicine specialist for evaluation, counseling, and potential further testing is recommended.

On the basis of data in HIV-uninfected women, transmission of CMV from mother to infant might occur in utero. However, symptomatic infection in the newborn is usually related to primary CMV infection in the mother during pregnancy, and because >90% of HIV-infected pregnant women are CMV antibody positive in the majority of studies, the risk for symptomatic infection in the fetus is low (726Stagno S, Pass RF, Cloud G, et al. Primary cytomegalovirus infection in pregnancy: incidence, transmission to fetus, and clinical outcome. JAMA 1986; 256:1904-8., 727Yow MD, Williamson DW, Leeds LJ, et al. Epidemiologic characteristics of cytomegalovirus infection in mothers and their infants. Am J Obstet Gynecol 1998;158:1189-95., 728Kovacs A, Schluchter M, Easley K, et al. Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1-infected women. N Engl J Med 1999;341:77-84., 729Quinn TC, Piot P, McCormick JB, et al. Serologic and immunologic studies in patients with AIDS in North America and Africa: the potential role of infectious agents as cofactors in human immunodeficiency virus infection. JAMA 1987;257:2617-21., 730Mussi-Pinhata MM, Yamamoto AY, Figueiredo LT, Cervi MC, Duarte G. Congenital and perinatal cytomegalovirus infection in infants born to mothers infected with human immunodeficiency virus. J Pediatr 1998;132:285-90.). Therefore, treatment of asymptomatic maternal CMV infection during pregnancy solely to prevent infant infection is not indicated (DIII).

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Cytomegalovirus (CMV) disease
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues

Preferred therapy for CMV retinitis

For immediate sight-threatening lesions
transparent gifgrey bulletGanciclovir intraocular implant + valganciclovir 900 mg PO (bid for 14-21 days, then once daily) (AI)
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transparent gifgrey bulletOne dose of intravitreal ganciclovir may be administered immediately after diagnosis until ganciclovir implant can be placed (CIII)
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For small peripheral lesions
transparent gifgrey bulletValganciclovir 900 mg PO bid for 14-21 days, then 900 mg PO daily (BII)
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Preferred chronic maintenance therapy (secondary prophylaxis) for CMV retinitis
transparent gifgrey bulletValganciclovir 900 mg PO daily (AI); or
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transparent gifgrey bulletGanciclovir implant (may be replaced every 6-8 months if CD4+ count remains <100 cells/µL) + valganciclovir 900 mg PO daily until immune recovery (BIII)
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Alternative therapy for CMV retinitis
transparent gifgrey bulletGanciclovir 5 mg/kg IV q12h for 14-21 days, then 5 mg/kg IV daily (AI); or
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transparent gifgrey bulletGanciclovir 5 mg/kg IV q12h for 14-21 days, then valganciclovir 900 mg PO daily (AI); or
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transparent gifgrey bulletFoscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for 14-21 days, then 90-120 mg/kg IV q24h (AI); or
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transparent gifgrey bulletCidofovir 5 mg/kg/week IV for 2 weeks, then 5 mg/kg every other week with saline hydration before and after therapy and probenecid 2 g PO 3 hours before the dose followed by 1 g PO 2 hours after the dose, and 1 g PO 8 hours after the dose (total of 4 g) (AI) Note: This regimen should be avoided in patients with sulfa allergy because of cross hypersensitivity with probenecid
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Alternative chronic maintenance (secondary prophylaxis) for CMV retinitis
transparent gifgrey bulletGanciclovir 5 mg/kg IV 5-7 times weekly (AI); or
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transparent gifgrey bulletFoscarnet 90-120 mg/kg body weight IV once daily (AI); or
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transparent gifgrey bulletCidofovir 5 mg/kg body weight IV every other week with saline hydration and probenecid as above (AI)
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The choice of initial therapy for CMV retinitis should be individualized, based on location and severity of the lesion(s), level of immunosuppression, and other factors such as concomitant medications and ability to adhere to treatment (AIII)

Initial therapy in patients with CMV retinitis, esophagitis, colitis, and pneumonitis should include initiation or optimization of ART (BIII)

In patients with CMV neurological disease, localized morbidity might occur because of IRIS, a brief delay in initiation of ART until clinical improvement might be prudent (CIII)

Maintenance therapy for CMV retinitis can be safely discontinued in patients with inactive disease and sustained CD4+ count (>100 cells/mm3 for ≥3-6 months); consultation with ophthalmologist is advised (BII)

Patients with CMV retinitis who discontinued maintenance therapy should undergo regular eye examination, optimally every 3 months, for early detection of relapse or immune recovery uveitis (IRU) (AIII) IRU might develop in the setting of immune reconstitution. Treatment of IRU: periocular corticosteroid or short courses of systemic steroid
Preferred therapy for CMV esophagitis or colitis
transparent gifgrey bulletGanciclovir IV or foscarnet IV for 21-28 days or until resolution of signs and symptoms (BII)
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transparent gifgrey bulletOral valganciclovir may be used if symptoms are not severe enough to interfere with oral absorption (BII)
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transparent gifgrey bulletMaintenance therapy is usually not necessary, but should be considered after relapses (BII)
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Preferred therapy CMV pneumonitis
transparent gifgrey bulletTreatment should be considered in patients with histologic evidence of CMV pneumonitis and who do not respond to treatment of other pathogens (AIII)
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transparent gifgrey bulletThe role of maintenance therapy has not been established (CIII)
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Preferred therapy CMV neurological disease Treatment should be initiated promptly
transparent gifgrey bulletCombination of ganciclovir IV + foscarnet IV to stabilize disease and maximize response, continue until symptomatic improvement (BII)
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transparent gifgrey bulletMaintenance therapy (with valganciclovir PO + IV foscarnet) should be continued for life unless evidence of immune recovery is evident (BII)
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References

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