Cytomegalovirus

VIROLOGY

Human cytomegalovirus (CMV, HCMV, HHV-5) is a ubiquitous beta herpesvirus that only infects humans and human cells. As with all herpes viruses, CMV is a large, double-stranded DNA virus that contains 162 capsomeres, a tegument between the capsid and envelope, and an envelope containing lipids and glycoproteins that are sensitive to lipid solvents and detergents (164). Once an individual is infected with CMV, the virus establishes latency and may reactivate in persons with normal immune systems and commonly during immunosuppression. In normal immune competent individuals, reactivation of CMV results in local reactivation in urine, saliva, the cervix in women and in semen of men. However, CMV reactivation in the immunocompromised host often results in viremia, and can cause severe and life-threatening infections in persons with deficient cell mediated immunity. The virus commonly crosses the human placenta and is the most common congenital infection in developed countries.

EPIDEMIOLOGY

Human CMV is transmitted from human to human; there is no animal reservoir. The virus has a worldwide distribution and infects all ethnic and socioeconomic groups. CMV is the most common cause of congenital infection found in from 0.4% to 2.5% of infants at birth. After the newborn period, person-to-person transmission occurs most commonly through salivary or sexual contact. Contact with urine can also result in transmission. Mother-to-infant transmission can occur in utero resulting in congenital infection, intrapartum as the infant passes through an infected cervix or through breast milk. From 20% to 40% of healthy women shed CMV into their breast milk and results in infection of 30 to 70% of nursing infants. In the healthy, full-term infant acquisition of CMV via this route rarely results in complications, and the potential of transmitting CMV to infants through human milk is outweighed by the benefits of breastfeeding. Thus, women should be encouraged to nurse their infants without regard to their CMV serostatus. The acquisition of CMV by premature infants may result in symptomatic infection with CMV including fever, pneumonia, gastrointestinal disease and hepatitis (201). In these situations when the use of breast milk is desired, the milk should be expressed and freeze-thawed or heated to decrease the potential infectivity of the milk. It should be noted, however, that freeze-thawing may not be 100% effective in eliminating CMV transmission through breast milk (111).

CMV is commonly transmitted among young toddlers and children in day care centers and has reached up to 70% in some day care settings. CMV may also be transmitted from an infected donor to a recipient through transfusion of blood and blood products, and bone marrow and solid organ transplantation. Staff members working in day care and pre-school settings are at increased risk for CMV infection. Nosocomial transmission of CMV to health care workers is uncommon. The CDC has provided the following recommendations for individuals caring for infants and children: 1) Female employees should be educated about CMV and how it is spread, and also hygienic practices, such as handwashing, that reduce the risk of CMV infection. 2) Non-pregnant women of childbearing age who have never been infected with CMV and who are working with infants and children should not be routinely moved to other work situations to avoid CMV infection. 3) Pregnant women working with infants and children should be informed of the risk of getting CMV infection, the possible effects on the unborn child, and appropriate prevention strategies. 4) Routine laboratory testing for CMV antibody (immune protein) in female workers is not currently recommended. However, female workers who are pregnant or planning a pregnancy should be informed that a CMV antibody test can help them assess their risk. Whenever possible, CMV seronegative (without CMV antibodies) pregnant women should consider working in a setting with less exposure to young children.  The CDC suggests steps that can be taken to reduce the risk of CMV transmission through exposure to saliva and urine that might contain CMV (http://www.cdc.gov/cmv/prevention.html).  These include: Wash hands often with soap and water for 15-20 seconds after changing diapers, feeding a young child, wiping a young child’s nose or drool and handling children’s toys; Do not share food, drinks or eating utensils used by young children; Do not share a toothbrush with a young child; Avoid contact with saliva when kissing a child; Clean toys, countertops, and other surfaces that come into contact with children’s urine or saliva.

CLINICAL MANIFESTATIONS

CMV causes a broad spectrum of clinical diseases. It is the major cause of non-Epstein-Barr virus infectious mononucleosis in immunocompetent individuals and is an important cause of disease in immunocompromised individuals including in addition to congenitally infected infants, persons with malignancies, organ transplant recipients and persons with AIDS and other severe diseases that impact on cellular immunity. Major diseases associated with CMV include pneumonia, colitis, esophagitis, hepatitis, central nervous system (CNS) disease including encephalitis and polyradiculitis. Other common manifestations, including leukopenia, adrenalitis and oral ulcers have also been described particularly in persons with AIDS. Reactivation of CMV in persons with AIDS in the pre-HAART (highly active antiretroviral therapy) era not only impacted on the development of CMV-specific diseases but on survival; in persons with advanced AIDS without effective antiretroviral therapy, the presence of CMV in blood is an independent predictor of survival (197, 203).

Congenital CMV Infection

CMV is a major cause of birth defects affecting approximately 1% (.5 to 2%) of all babies born in the United States and other developed countries. Of those infants congenitally infected, approximately 5% are symptomatic at birth. Infants born with symptoms at birth are at highest risk for developing neurological problems including sensorineural deafness. However, between 5-17% of infants with asymptomatic congenital infection will develop hearing loss (39). Put in other terms, of the approximate 4 million births annually in the United States, 40,000 infants are born with congenital CMV and 8,000 will develop sensorineural hearing deficits or other sequelae associated with their infection. The auditory deficits associated with congenital CMV may not be stable, so that infants who have normal hearing in the newborn period may be identified as having hearing loss several years after birth. Infants born small for gestational age with manifestations including petechiae, jaundice hepatosplenomegaly, microcephaly and hearing loss are termed to have cytomegalic inclusion disease and are at greatest risk for having severe long-term neurologic deficits. In such cases, thrombocytopenia is also present in 75% at birth.

Chorioretinitis occurs in approximately 10-20% of infants with symptomatic congenital CMV. The presence of periventricular calcifications seen on CT scan are typical of congenital CMV and are often associated with severe neurological deficits. However, calcifications may not always be periventricular and need not be present for an infant to develop mental retardation or hearing impairment. Findings of microcephaly, periventricular calcifications, an abnormal neurological examination or signs of disseminated infection increase the likelihood of long-term CNS sequelae. Although it had been thought that primary CMV infection of the pregnant mother was more likely to be associated with serious congenital infection, recent studies indicate that symptomatic infection occurs with similar frequency in infants born to women regardless of their CMV serostatus prior to becoming pregnant.  Thus, infants born with congenital CMV to women previously seropositive for the virus are at equivalent risk of serious complications including sensoineurall hearing loss as those born to women who have experienced a primary infection during pregnancy (15, 16, 135, 166, 229).  Although the data are uncertain, it appears that women who give birth to infants with symptomatic congenital CMV experience reinfection during pregnancy. For this reason, pregnant women whether seropositive for CMV or not are encouraged to follow the CDC recommendations described above.

Perinatal and Acquired CMV Infection of Children

Healthy infants may acquire CMV infection through exposure to infected maternal genital secretions or postnatally through ingestion of CMV containing breast milk. The incubation period between exposure and symptoms when present is 3 to 12 weeks. Most full term infants exposed to CMV experience asymptomatic infection. However, interstitial pneumonia, paroxysmal cough, petechial rash, hepatosplenomegaly and thrombocytopenia may occur. Hepatitis when it occurs is usually mild and self-limited. Typically, the alkaline phosphatase is elevated out of proportion to the enzyme aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

When premature infants acquire CMV infection either through intrapartum exposure, breast milk or transfusion of CMV positive blood products, there is a greater risk of symptomatic infection including interstitial pneumonia, hepatitis, thrombocytopenia, hepatopslenomegaly and hemolytic anemia. Whether CMV infection contributes to the risk for development of chronic lung disease associated with premature remains a topic of debate. Long-term sequelae, however, including mental retardation and hearing deficits are rarely associated with postnatal acquisition of CMV.

CMV Infection of Immunocompetent Adults

Symptomatic primary CMV infection of the adolescent or adult usually results in a mononucleosis-like syndrome. Wreghitt and colleagues reviewed the clinical presentations of 124 adults with primary CMV infection (228). Of the patients with primary CMV infections, clinical and laboratory findings included abnormal liver function tests in 69%, malaise 67%, sweats 46%, fever 46%, muscle aches 36%, respiratory symptoms 28%, lymphadenopathy 24%, arthralgias 17% and headache 14%. A relapsing illness was reported in 15% of patients and the mean duration of symptoms was 7.8 weeks (range 1-20 weeks). All patients recovered without long-term complications. Of the patients studied by Wreghitt, 15% required hospitalization. In a study of hospitalized patients only diagnosed with CMV disease, 99% of patients were febrile, 51% reported headaches and 36% had splenomegaly (2). The duration of illness was 21 days. Numerous other clinical syndromes have been associated with CMV infection including Guillian-Barre syndrome, meningoencephalitis, myocarditis, colitis, and Menetrier's disease among others. The causal role of CMV with these other diseases is unclear.

CMV Retinitis

Involvement of the retina by CMV was only rarely identified in immunocompetent individuals and was uncommon even in severely immunocompromised persons prior to AIDS in adults (54, 63,153). Chorioretinitis was most commonly observed in infants congenitally infected with CMV with the cytomegalic inclusion disease syndrome (29). Prior to the availability of HAART, CMV retina was a common complication identified in persons with advanced AIDS (CD4+ lymphocyte counts < 50 cells/µL) (82). CMV retinitis was one of the original AIDS-defining infections. It can be diagnosed on ophthalmologic examination by characteristically confluent, yellow-white white retinal infiltrates often with a granular appearance or a more fulminant appearance with retinal hemorrhages. Without treatment, and with continued immunosuppression, retinitis progresses to retinal necrosis and permanent loss of vision especially when it involves the macula and optic nerve.

CMV disease occurred in 21% to 44% of patients with AIDS prior to the introduction of HAART (64, 141). Of patients with CMV disease, approximately 85% had CMV retinitis, especially those with CD4+ lymphocyte counts below 50 cells/µL (189). In contrast the incidence of CMV retinitis in the HAART era was an estimated 0.36/100 person-years based on 29 incident cases among 1600 HIV-infected patients without CMV retinitis at initial exam who were followed for at least one year (8134 person-years of follow-up) (206). A CD4+ lymphocyte count below 50 cells/µL in 26 of the 29 patients at the 3-month visit prior to diagnosis was the most important risk factor for CMV retinitis with a hazard ratio of 136 (95% C.I. 30 to 605) (206).  A longitudinal study of 503 patients with both prevalent and incident CMV retinitis, corrected for length of follow-up, revealed 9 times fewer deaths, 28 times less retinitis progression, 4 times few retinal detachments, and 2 times less moderate or severe vision loss in patients who entered the study with preexisting CMV retinitis (91). Progression and complications do not completely cease even with improved immune status. Most vision loss in CMV retinitis was attributable to retinitis involvement of the posterior pole of the eye among 379 HAART-era patients (494 eyes) (208).  Cataract also caused vision loss in some patients but retinal detachment carried the worst prognosis: 100% of eyes with retinal detachment had moderate vision loss and 42% had severe vision loss (208). 

The US Public Health Service recommended in 1999 the discontinuation of antiviral therapy in patients with healed CMV retinitis and CD4+ T lymphocyte counts greater than 50-100 cell/microliter for 3- 6 months with suppressed HIV RNA levels (211). In a cohort of 71 patients meeting these criteria, approximately half discontinued therapy.  During longitudinal follow-up, there was no statistical difference between groups in mortality, retinitis progression, or loss of visual acuity (81). There are no similar guidelines for restarting secondary prophylaxis in patients with retinitis who have deterioration of immune status; resumption if CD4+ lymphocytes fall to less than 50-100 cells/microliter seems reasonable.  Ophthalmologic surveillance and home monitoring for vision changes is usually conducted at least every 3 months for patients at highest risk. Patients with CMV retinitis may have floaters, flashes of light, blurred vision, or blind spots in addition to loss of vision. Mild anterior uveitis, vitritis, and retinal vasculitis may occur even in early stages of disease.

With immune recovery, an estimated 17.6% (95% C.I. 12.3%-24.1%) of patients with CMV retinitis are at risk for intraocular inflammatory complications of uveitis, macular edema, epiretinal membrane and vision loss (103).  Immune recovery uveitis is more likely to occur with large CMV lesions. It does not respond to antiviral therapy as the retinitis is not active. Ocular complications related to the immune response to CMV retinitis may also occur in immunocompetent patients with active CMV retinitis, especially the elderly and patients with relative immunocompromise from medication or disease. These patients may develop atypical or chronic retinal infections that are complicated by retinal ischemia and vascular occlusion (37, 171) Diagnosis is typically delayed or patients are treated with ineffective antiviral therapy with acyclovir or valacyclovir (171) leading to a high risk of severe vision loss from the vasculitic complications (37).

Lumbosacral Polyradiculopathy and Myelitis

Of the various syndromes that involve CMV in the CNS, CMV polyradiculopathy is the most frequent and characteristic. Patients experience a subacute onset of weakness, loss of reflexes, and variable sensory loss, usually in the legs, in association with bladder and anal sphincter dysfunction (Table 1). Pathologically, there is CMV infection of the ventral and dorsal roots of the cauda equina and often the adjacent spinal cord, with severe inflammation and axonal necrosis. CSF examination typically shows pleocytosis, often with a preponderance of polymorphonuclear leukocytes and hypoglycorrhachia (32).

CMV Encephalitis

There are two types of CMV encephalitis in patients with AIDS. The first is a diffuse, multifocal, micronodular CMV encephalitis that is difficult to distinguish from dementia complex caused by HIV (3, 61). In a retrospective autopsy study, Holland et al. (84) reported that of 220 autopsies done on patients with AIDS, 14 showed CMV encephalitis, and 17 showed HIV dementia without involvement of CMV in the CNS. Both disorders exhibit cognitive and motor disturbances such as confusion, forgetfulness, apathy and withdrawal, unsteadiness, impaired memory, and diffuse hyperreflexia. CMV encephalitis was not associated with typical abnormalities or positive cultures for CMV in the spinal fluid. CMV PCR of CSF is almost always positive and is the diagnostic assay of choice when CMV infection of the CNS is suspected (30, 73, 78, 184, 226). CMV dementia may be associated with serum hyponatremia and signs of Addison s disease.

The second type of CMV encephalitis is CMV ventriculoencephalitis. These patients often have a characteristic ventriculitis demonstrable by magnetic resonance imaging (MRI) with gadolinium enhancement of the periventricular areas (156). Ventriculitis is associated with ependymal and subependymal necrosis. Patients are usually in advanced stages of AIDS, with CD4+ lymphocyte counts below 50 cells/µL. They have acute onset of apathy, disorientation, cranial nerve palsies, and nystagmus, and usually progress rapidly. Ventricular enlargement is usually seen. CSF is usually abnormal, often with a predominance of neutrophils.

As with other CNS complications associated with AIDS, the availability of effective combination antiretroviral therapy has made CMV encephalitis uncommon.

Mononeuritis Multiplex

CMV mononeuritis, the least common of the CMV CNS disorders, results from focal necrotizing vasculitis of epineural arteries, characterized by polymorphonuclear leukocytic infiltration. Patients present with multifocal or asymmetric sensory and motor deficits in major peripheral or cranial nerves in a setting of severe immunosuppression. Laryngeal nerves may be especially involved (181). This syndrome may coexist with CMV retinitis, polyradiculitis, or encephalitis. Electrophysiologic studies may show axonal neuropathy and CMV DNA is detected in CSF.

Gastrointestinal Disease

The gastrointestinal tract including the mouth, esophagus, stomach, small intestines, colon, and rectum may be involved with CMV disease in immunosuppressed patients including transplant recipients and persons with AIDS (69). As noted earlier, CMV disease at these sites requires demonstration of the virus as well as local histologic evidence of lesions specific for CMV. Manifestations of CMV include painful erosions or ulcers of the mouth, epiglottis, or pharynx. Odynophagia is a common symptom. The esophagus may be involved with a solitary ulcer or diffuse esophagitis associated with upper gastrointestinal bleeding. Esophageal strictures may occur after healing. Stomach ulcers may cause bleeding, gastric obstruction, or perforation. Involvement of the small bowel includes progressive diarrhea associated with ulcerated necrosis that may be complicated by perforation. Terminal ileal disease may mimic Crohn's disease clinically, and may be associated with massive gastrointestinal bleeding. Patients who have colonic disease may have diarrhea, hematochezia, spasms, and abdominal pain associated with constitutional symptoms such as fever, anorexia, and weight loss. Acute bleeding has been reported, especially from cecal ulcers in transplant patients. The colon may show diffuse ulcerations, focal ulcerations with skip areas, or less commonly pseudopolyps and pseudomembranes. The most common site of gastrointestinal involvement in AIDS patients is the colon, particularly in the rectosigmoid region (46). Hematochezia is seen in a minority of AIDS patients (40, 46).

The frequency of CMV disease of the gastrointestinal tract in transplant recipients varies from 2% to 15% in various reports (26). It appears to vary with the frequency of CMV disease in general, of which one determinant is the type of transplantation (79). In kidney and liver recipients, the frequency varies from 2% to 6% (87, 100, 125, 151). In heart and heart-lung recipients, it is 3% to 16% (100, 125, 128). The frequency is even higher in marrow recipients, although specific diagnosis is not always possible because of coexisting graft-versus-host disease (28).

Central Nervous System Infections

CMV is associated with specific syndromes of the central nervous system (CNS) in patients with AIDS and other immunocompromised persons (126). As with CMV retinitis, these syndromes are most common in advanced AIDS when the CD4+ lymphocyte count is below 50 cells/µL and effective antiretroviral therapy is not being administered. However, CNS manifestations including meningitis, encephalitis and transverse myelitis have also been observed in immunocompetent patients (158).

LABORATORY DIAGNOSIS

The diagnosis of CMV disease is dependent on the disease suspected, the age of the patient and the clinical background. For example, an infant suspected of congenital infection who has CMV detected by any assay within 2-3 weeks of life can be assumed to be congenitally infected. Similarly, a person with AIDS and a CD4+lymphocyte count below 50 cells/µL with retinitis diagnosed by an experienced ophthalmologist, will almost invariably have CMV retinitis. In contrast, because almost all seropositive immunocompromised persons will reactivate CMV in their urine or saliva, detection of CMV at these sites is not indicative of disease. In many cases a definitive diagnosis requires the identification of CMV in the specific organ involved and the exclusion of other potential pathogens.

Serology

Serologic assays are most useful for the identification of past infection; a positive assay for CMV specific IgG indicates previous infection. Conversion from seronegative status to IgM positive is indicative of recent infection, and suggests that an acute illness may be associated with CMV. However, when both CMV IgM and IgG are positive, primary infection from reactivation cannot be definitively determined unless the patient's previous CMV status is known. Although the detection of CMV IgM antibody has been used for the diagnosis of congenital CMV, as many as 30% of infected infants will be CMV IgM negative; false positive IgM assays may also occur. Thus, identification of infectious CMV from urine, antigen detection or detection of CMV-specific nucleic acid is recommended for the identification of a congenitally infected infant.

More recently, assays that measure the avidity of antibody to CMV have become commercially available.  These assays are based on the principle that within the first few months of infection, antibodies have low avidity and over time the avidity of specific antibody increases.  These assays have been particularly targeted toward the evaluation of pregnant women where it is often important to differentiate primary from recurrent infection.  However, the ability of these assays to differentiate primary infection remains uncertain and such tests should be used with caution.

Culture

Although culture is still an important tool for the diagnosis of CMV infection, in most situations culture has been replaced by more sensitive and rapid tests including antigen detection and nucleic acid detection assays. High titers of CMV are present in the urine and saliva of congenitally infected infants or immunocompromised persons. In such cases, viruses can be isolated in culture within a few days. However, many cultures take from 3 to 6 weeks to demonstrate viral specific cytopathic effect. Cultures of urine, saliva and buffy-coat can be enriched by centrifugation and when combined with immunodetection of CMV using monoclonal antibodies specific for immediate early or early proteins can often result in the detection of CMV in culture within 24-72 hours (67, 146, 157).

Detection of pp65 Antigen

The use of a monoclonal antibody directed toward the CMV matrix protein, pp65, has been used to detect CMV directly in peripheral blood polymorphonuclear leukocytes (74, 107, 146, 230). This assay is generally more sensitive than culture, is useful for the rapid identification of acute CMV infection, and is commercially available. The quantity of antigen positive cells has been associated with the presence and risk for subsequent development of CMV disease in immunocompromised persons including transplant recipients and persons with AIDS. The major disadvantages to the antigenemia assay are that samples should be processed within a few hours of being obtained and fresh blood must be distributed onto a slide potentially increasing the risk of transmission of an infectious agent to laboratory personnel.

Nucleic Acid Detection Methods

A number of different approaches are available for detecting either CMV DNA or RNA in clinical specimens that either amplify the target or probe allowing for high assay sensitivity and specificity. Of these assays polymerase chain reaction (PCR) assays, qualitative or quantitative, are most commonly used (4, 19, 20, 195, 200, 203, 227). PCR is highly sensitive and may detect the presence of CMV in clinical specimens when the risk for development of CMV disease is relatively low. Quantitative PCR assays for CMV have demonstrated that the risk for development of CMV disease increases as the quantity of CMV detected in blood specimens (plasma or cells) increases if no effective antiretroviral therapy is available. Additionally, in persons with untreated AIDS as the quantity of CMV DNA present in plasma increases, there is a concomitant risk not only for the development of CMV disease but also mortality. In fact, in persons with advanced, untreated AIDS (CD4+lymphocyte counts below 50 cells/µL), the presence and quantity of CMV DNA present in plasma are more predictive of survival than the quantity of plasma HIV-1 RNA (197, 203). Detection of CMV by PCR in cerebrospinal fluid (CSF) is the noninvasive diagnostic procedure of choice for the diagnosis of CMV-related CNS disease (30, 73, 174, 226).

PATHOGENESIS

During natural infection, CMV appears to enter through the epithelium lining the respiratory, gastrointestinal or genitourinary tract. However, infection may also occur through other direct routes including through hematogenous transmission as occurs with transfusion of blood and blood products, and through transplantation of seropositive donor bone marrow and solid organs. During acute infection, CMV can be detected in polymorphonuclear leukocytes and monocytes (35). Currently, the best evidence suggests that CMV establishes latency in myeloid progenitor cells and in endothelial cells of solid organs; the virus can also be detected in circulating monocytes of seropositive individuals.

CMV-specific latency-associated genes have not been clearly identified. Whether CMV establishes true latency or expresses a small number of latency transcripts remains under active investigation. How a cell that is carrying the virus genome but not actively replicating can switch from latency to active replication is also unknown. Remarkably, however, 50% to 100% of CMV seropositive transplant recipients reactivate CMV during immunosuppression which is highest with the greatest immunosuppression and when seronegative recipients receive a transplant from a seropositive donor (79). After primary infection and reactivation in the immunocompromised host, CMV can be detected in the blood during acute infection. Infectious virus is present in circulating monocytes and polymorphonuclear leukocytes, and viral DNA is present within plasma. CMV dissemination occurs during acute infection and when uncontrolled by the host immune system may spread to virtually all organs.

Considerable evidence indicates that natural killer cells, humoral antibody responses and cell-mediated immunity all play an important role in the control of CMV infection. However, the fact that almost all major and life-threatening CMV related diseases occur in persons with impaired cellular immunity including transplant recipients and AIDS patients emphasizes the importance of cellular immunity in controlling acute CMV infection. A striking example of the success of the immune system’s ability to control CMV is demonstrated in persons with advanced AIDS who prior to the availability of HAART frequently developed serious CMV disease. However, the same patients with severe CMV disease when treated with HAART and have elevations in their CD4+ lymphocyte counts above 100-150 cells/µL are able to control their infection without the continued need of anti-CMV therapy (see below).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Single Drug

At present there are three drugs (ganciclovir, foscarnet and cidofovir) approved for the treatment of CMV infections. Of these agents, only ganciclovir and foscarnet are routinely used for treatment of the broad spectrum of CMV diseases and for prevention of disease. Ganciclovir, foscarnet and cidofovir all inhibit the CMV DNA polymerase.

Ganciclovir ((9-(1,3-dihydroxy-2-propoxy)methyl)-guanine, DHPG), a nucleoside analog, inhibits CMV and also has activity against other herpesviruses including herpes simplex virus, varicella zoster virus, Epstein-Barr virus, human herpes virus type 6 and human herpes virus type 8. It is the treatment of choice for CMV, but is also effective in immunocompromised hosts for the prevention and treatment of herpes simplex and varicella zoster infections and in some studies in decreasing the risk of EBV-associated lymphoproliferative disease and in treatment of oral hairy leukoplakia. Ganciclovir is phosphorylated to its monophosphate form by a phosphokinase encoded within the UL97 region of CMV and further phosphorylated to its active triphosphate form by cellular kinases. The effective inhibitory concentration (IC50) of ganciclovir for CMV ranges from 0.3 to 8 µM. Most isolates have an IC50 of 1.5 µM or higher. Peak plasma concentration of ganciclovir after a dose of 5 mg/kg given as a 1-h intravenous infusion is 6.6 µg/mL (4 µM = 1 µg/mL). Trough levels were 1 µg/mL after 11 h (192). The usual dose of ganciclovir for intravenous induction is 5 mg/kg twice daily for 10 to 21 days. Maintenance dose is 5 mg/kg daily.

Foscarnet is a pyrophosphate analogue that also inhibits the DNA polymerase of CMV. IC50S (µM) for CMV, HSV-1 and HSV-2, varicella zoster virus and Epstein-Barr virus (EBV) are 50 to 800, 10 to 130, 48 to 90, and less than 500, respectively. Foscarnet penetrates the blood-cerebrospinal fluid (CSF) barrier with a coefficient of 0.05 to 0.72. After a single intravenous infusion of 90 mg/kg, Cmax at steady state is a mean of 623 µM (1 µM equals 0.3 mg/mL). Corresponding CSF levels are approximately two-thirds of plasma levels (75).

Cidofovir (HPMPC, (S)-1-(3-hydroxy-2-(phosphonylmthoxy)propyl) cytosine is a nucleotide analogue that inhibits the CMV DNA polymerase. In vitro, cidofovir has also been found to have activity against VZV, EBV, HSV-1 and 2, and herpesviruses 6, 7 and 8, papillomavirus, Molluscum contagiosum virus, adenovirus and poxviruses (including smallpox). The ID50 is 0.5 to 2.8 µM for wild isolates. Cellular enzymes are responsible for serial conversion to the diphosphate form, the active intracellular antimetabolite (78). The diphosphate form has a long intracellular half-life, exceeding 48 h (22).

Acyclovir is the most commonly used treatment for infections with herpes simplex virus and varicella zoster virus with IC50s of 0.1 to 0.2 µM for most HSV strains and 4 to 20 µM for VZV strains. Both HSV and VZV encode a thymidine kinase that effectively phosphorylates acyclovir to its monophosphate form which is then further phosphorylated to its active triphosphate form by cellular kinases. CMV does not encode a thymidine kinase and is sensitive to acyclovir at concentrations approximating 100 µM (110, 141) (1 µg/mL acyclovir is equivalent to 4.4 µM).

The high ID50 of acyclovir for CMV precludes its use for therapy of CMV infections clinically. However, it has been used for prophylaxis against CMV disease in solid organ and bone marrow transplant recipients with some success (but is inferior to both ganciclovir and foscarnet for prevention of CMV disease; see below).

Combination Drugs

Limited research has examined the combination of antivirals against CMV in vitro. Most studies have found that the combination of ganciclovir and foscarnet are usually additive and in some cases synergistic. Similar findings have been found for the combination of cidofovir with either ganciclovir or foscarnet. Clinical treatment approaches examining the combination of ganciclovir and foscarnet have in some settings demonstrated modest benefit of the combination but is associated with additive toxicities.

ANTIVIRAL THERAPY

Drug of Choice

Ganciclovir

The drug of choice for the treatment of CMV is ganciclovir. Therapy of the immunocompromised host usually requires induction daily therapy of twice daily dosing followed by maintenance therapy of once daily ganciclovir (Table 2). Intravenous ganciclovir is excreted almost exclusively by the kidneys while with the standard oral formulation ~ 85% is eliminated in stool. Dose adjustment of ganciclovir is required for patients in renal failure (Table 3).

Cerebrospinal fluid levels of ganciclovir range from 24% to 70% of plasma levels with intravitreal concentrations approximating 10% to 15% of plasma levels. Neutropenia is a common complication of ganciclovir treatment occurring in 25% to 40% of those receiving treatment. The neutropenia is usually responsive to granulocyte-colony stimulating factor (G-CSF); however, following bone marrow/stem cell transplantation, ganciclovir may slow engraftment which has made foscarnet the drug of choice for some transplant services.

In a direct comparison between ganciclovir and foscarnet in the treatment of CMV retinitis in persons with AIDS, foscarnet was as effective as ganciclovir but was associated of greater toxic reactions (189, 190). Of interest, AIDS patients, in one study, treated with foscarnet in the pre-HAART era had a lower mortality than those receiving ganciclovir (perhaps due to the modest antiretroviral activity of foscarnet; see below).

Oral Ganciclovir

Valganciclovir

Because ganciclovir has poor oral bioavailability, the valene ester valganciclovir is the oral formulation of choice. Valganciclovir is a monovalyl ester prodrug of ganciclovir. When administered orally, the valene ester is rapidly hydrolyzed to ganciclovir. The bioavailability of valganciclovir to ganciclovir is approximately 60%. A dose of 900 mg of valganciclovir provides similar levels to those obtained with the 5-mg/kg intravenous dosage (Table 2). Valganciclovir can be used for induction therapy as well as maintenance treatment of CMV retinitis and has been found equivalent of intravenously administered ganciclovir (122).

Alternative Therapy

Foscarnet

Foscarnet sodium is an inorganic pyrophosphate that inhibits replication of CMV as well as other herpesviruses by selective inhibition at the pyrophosphate binding site of virus-specific DNA polymerase. Foscarnet also inhibits the reverse transcriptase of HIV. Unlike most nucleosides, foscarnet does not require phosphorylation by viral or cellular encoded kinases for its activity. Cerebrospinal levels range from 55% to 75% of plasma concentrations.

Foscarnet requires intravenous induction followed by maintenance therapy, and is associated with a number of potential serious complications. Induction treatment with foscarnet is given as 90 mg/kg intravenously every 12 hrs. Maintenance therapy is 90-120 mg/kg given intravenously daily (Table 2). In persons with AIDS time to retinitis relapse and survival were improved with the 120 mg/kg maintenance dose when compared to the 90 mg/kg dosage (83, 94). Controlled infusion of foscarnet is required with ≤ 24 mg/mL (undiluted) when given by a central line or < 12 mg/mL (diluted in 5% dextrose or saline) via peripheral line. The 90-120 mg/kg dosage should be administered over at least 2 hours via infusion pump. Patients should remain well-hydrated during therapy. The drug is excreted exclusively through the kidneys and patients receiving inadequate hydration have developed cervical or penile ulcers. Foscarnet levels must be adjusted for renal failure (Table 4).

Cidofovir

Cidofovir is a nucleotide analog with activity against CMV as well as other viruses. It has a long half-life (t1/2 = 17 to 65 hrs) permitting a weekly or longer dosing schedule. It is excreted 70% to 85% in urine. Preclinical studies demonstrated that the major toxicity of cidofovir was a dose-dependent nephrotoxicity, characterized by degeneration and necrosis of cells of the proximal convoluted renal tubules (108). Probenecid, which is thought to compete with cidofovir uptake in proximal tubular cells, protects against nephrotoxicity in animals and is critical when administering cidofovir systemically to humans. A 5 mg/kg weekly dose of cidofovir given intravenously is the maximum tolerated dose of the drug (152). For treatment of CMV retinitis the drug is administered weekly for 2 weeks for induction and once every 2 weeks for maintenance (Table 2). Probenecid (2 g) must be given orally 3 hrs. before each intravenous dose.

Considerable evidence indicates that cidofovir is inferior to either ganciclovir or foscarnet for the treatment or prevention of systemic disease with CMV. Failure to clear CMV viremia is common during cidofovir treatment, and patients successfully treated for their CMV retinitis are at risk for development of other CMV diseases.

Combinations of Antiviral Agents

In controlled clinical trials, combination of ganciclovir  and foscarnet has been shown to be effective in persons with AIDS with CMV retinitis who have failed monotherapy with either drug but who have not developed resistance. This combination has also been given anecdotally in other CMV diseases including gastrointestinal disease and polyradiculopathy in AIDS patients. Although the combination has had modest success, the prolonged time required for intravenous administration and the additive toxicities have limited its use (see below).

Resistance to Antiviral Agents Used for Treatment and Prevention of CMV

The development of resistance to ganciclovir, foscarnet and cidofovir is well described and is an almost inevitable consequence of acute CMV infection associated with prolonged immunosuppression. Considerable research has established the genotypic and phenotypic patterns of resistance to ganciclovir, foscarnet and cidofovir (14, 27, 28, 48, 49, 50, 51, 56, 92, 182,198, 225). Low level resistance to ganciclovir (ID50 between 8 and 30 µM) is associated with mutations in the UL97 region of CMV that encodes for the phosphokinase involved in ganciclovir phosphorylation (184). High level ganciclovir resistance (> 30 µM) is usually associated with both UL97 mutations and a mutation within UL54 (the DNA polymerase). Although isolates with low level resistance to ganciclovir remain sensitive to cidofovir, isolates with high level ganciclovir resistance are usually also resistant to cidofovir. Most DNA polymerase mutations that confer resistance to ganciclovir and cidofovir remain sensitive to foscarnet. However, in the author’s experience, patients with CMV strains with high level resistance to ganciclovir within months develop resistance to foscarnet as well if they remain significantly immunosuppressed. There is no clinical evidence that resistant virus is less pathogenic than sensitive CMV strains.

When treating immunocompromised patients with any of the three antivirals approved for the treatment of CMV disease, CMV resistance may develop at a localized site while virus within the circulation or urine remains sensitive. This is particularly true for persons with AIDS and CMV retinitis where although there is viral suppression within blood, retinitis progresses. Genotypic analyses by Smith et al. have demonstrated that in such cases resistant virus can be detected in vitreous or aqueous humor removed from the involved eye (183).

Special Infections

Retinitis

With treatment prior to the availability of HAART, CMV retinitis could be arrested or contained but not cured. The time to progression of retinal lesions could be prolonged from a median of 3 weeks to 180 days or longer (120, 189) as long as maintenance therapy was continued. There are five FDA-approved treatments for CMV retinitis (intravenous ganciclovir, oral valganciclovir, intravenous foscarnet, intravenous cidofovir, and an ocular device containing ganciclovir) approved for induction and maintenance treatment of CMV retinitis. Two other drugs are approved for either maintenance treatment (oral ganciclovir) or salvage treatment (intravitreal formivirsen injection). Salvage treatment may also be undertaken with intravitreal injection of ganciclovir, foscarnet or cidofovir. In the case of cidofovir, caution must be taken because of the risk of hypotony (loss of ocular pressure) associated with the injections. Oral ganciclovir reduces new CMV retinitis lesions and systemic CMV disease in patients who remain immunosuppressed. Maintenance treatment with valganciclovir will likely replace administration of oral ganciclovir in such patients with persistently low CD4+lymphocyte counts.

Intravenous Ganciclovir

Prior to the licensure of intravenous ganciclovir considerable anecdotal experience had demonstrated the efficacy of ganciclovir against CMV retinitis (7, 60, 61, 85, 86). However, the common experience was that the disease occurred after cessation of treatment and that maintenance treatment was necessary for an indefinite time period (132). Spector et al. (202) demonstrated the efficacy of intravenous ganciclovir therapy for CMV retinitis in a randomized controlled trial. During a 16 week follow-up period, retinitis progressed in 10 of 13 study participants randomized to deferred treatment compared to 20 of 22 randomized to immediate intravenous ganciclovir induction therapy (5 mg/kg twice daily for 14 days) followed by 5 mg/kg maintenance. The median time to progression in the immediate treatment group was 49.5 days, compared to 13.5 days for deferred treatment. Although strict criteria for retinitis progression were used in this study and ganciclovir was found to be efficacious, the treatment benefit was relatively short lived demonstrating the necessity of immune restoration if persons with AIDS were to fully recover from their CMV retinitis.

Intravenous Foscarnet

Foscarnet was evaluated by Palestine et al (145) in a randomized controlled trial in persons with AIDS and CMV retinitis. The mean time to progression was 3.2 weeks in the deferred treatment group compared to 13.3 weeks in patients who received immediate foscarnet induction (180 mg/kg/day divided in three doses) followed by maintenance therapy of 90 mg/kg daily.

In a comparative trial of foscarnet versus ganciclovir for the treatment of CMV retinitis in the pre-HAART era, no significant difference was observed for the two treatments; the median time to disease progression was 56 days in the ganciclovir group compared to 59 days in the foscarnet group. However, mortality in the ganciclovir group was 77% higher than that in the foscarnet group. Median survival times were 5 months in the ganciclovir group and 12.5 months in the foscarnet group. The best explanation for this difference was the modest antiretroviral activity of foscarnet which was supported by the foscarnet treated patients experiencing higher CD4+ lymphocyte counts at weeks 4 and 16 after initiation of treatment. In this trial, jointly conducted by the Adult AIDS Clinical Trials Group (ACTG) and the Studies of Ocular Complications of AIDS (SOCA), neutropenia was more common in patients who received ganciclovir (34% vs. 14%). However, patients receiving foscarnet experienced a greater number of infusion-related complications (58% vs. 24%), more genital urinary symptoms in male patients (56% vs. 16%), and more nephrotoxicity and electrolyte abnormalities (13% vs. 6 %). Additionally, patients assigned to initially receive foscarnet were more likely to switch to ganciclovir treatment because of toxicity (46% vs. 11%). The incidence of seizures was the same in both groups (9% to 12%). Toxic effects were reversible, and no permanent disability or death resulted (180). Thus, although foscarnet was demonstrated to have equal efficacy to ganciclovir for the treatment of CMV retinitis in persons with AIDS and possibly improved survival (although this has not been confirmed in subsequent studies and would likely have no impact when CMV treatment is combined with HAART), the increased toxicity associated with foscarnet and the relative ease of administration of ganciclovir has resulted in ganciclovir being the drug of choice at most centers for the treatment of AIDS-related CMV retinitis.

Intravenous Cidofovir

Cidofovir, the third drug approved for the treatment of CMV retinitis was evaluated during the era of increased availability of different nucleoside reverse transcriptase inhibitors and the nucleoside reverse transcriptase inhibitor, nevirapine. In a randomized controlled trial, Lalezari and colleagues (109) found that retinitis progression occurred in patients assigned to deferred treatment a median of 22 days compared to 120 days in those assigned to immediate treatment. However, treatment needed to be discontinued in 24% of patients because of the development of 2+ proteinuria or creatinine levels of 2 g/dL or greater. A second study comparing deferred treatment to an initial induction of 5 mg/kg once weekly for 2 weeks followed by high-dose maintenance (5 mg/kg once weekly) or a low-dose maintenance (3 mg/kg once weekly) found similar results to the Lalezari study with no difference between the two treatment arms. It should be noted that in both studies, probenecid at 5 mg/kg was administered with all doses to decrease the frequency and seriousness of nephrotoxicity.

Although cidofovir has been found to be useful for the treatment of CMV retinitis and has the advantage of infrequent dosing, failure of the drug to clear viremia and the high risk of nephrotoxicity have generally resulted in cidofovir being second line therapy behind ganciclovir and foscarnet for treatment of CMV retinitis. Iritis and hypotony secondary to intravenous cidofovir administration can be sight threatening and usually require dose interruption or alternative therapy (36).

Combination of Ganciclovir and Foscarnet

In situations where a single anti-CMV agent has failed, the combination of ganciclovir and foscarnet has been found to be modestly successful. In a study of persons with AIDS in the pre-HAART era who had persistently active or relapsed CMV retinitis, patients were randomized to three different treatment groups consisting of high-dose foscarnet (120 mg/day maintenance), high-dose ganciclovir (10 mg/kg/day maintenance) or foscarnet (90 mg/kg/day maintenance) plus ganciclovir (5 mg/kg/day maintenance) (189, 190). Survival rates were equivalent in all three groups. Time to retinitis progression was 1.3 months for the foscarnet group, 2.0 months for the ganciclovir group and 4.3 months in the combination group. Interestingly, patients who remained on monotherapy but whose treatment was switched showed no apparent benefit in time to first progression compared with patients who were not switched. These data support the concept that drug resistance may not have accounted for all relapsed CMV retinitis.

In the SOCA study described above, the combination group also had the lowest rate of change in retinal area involved by CMV and visual field loss. Combination therapy was superior and was not associated with more toxic effects than either monotherapy.

However, combination therapy had the greatest negative impact on quality-of-life measures. It was associated with more frequent treatment changes and longer infusion times than the monotherapies.

In conclusion, the combination of ganciclovir and foscarnet demonstrated superior suppression of CMV retinitis in persons with advanced AIDS prior to the availability of HAART. The disadvantages of the combination therapy including inconvenience, higher cost and less patient acceptance have made it an uncommon combination except in severely debilitating or life-threatening infections where monotherapy has failed. With the recent availability of valganciclovir, it is possible that the combination of foscarnet and ganciclovir (using valganciclovir) will become a more popular first line therapy in certain life-threatening or high-morbidity CMV infections when the patient can take oral medication. However, with the availability of HAART, the combination of ganciclovir treatment with effective antiretroviral therapy will lead to treatment success in most cases of retinitis.

Oral Ganciclovir as Maintenance Treatment

Despite the low bioavailability of oral ganciclovir, considerable data support its use for maintenance therapy for CMV retinitis in patients in the pre-HAART era with advanced AIDS (49, 144, 196). The mean number of days to retinitis progression in clinical trials has been found to be similar between the oral formulation and intravenous form. However, the data also demonstrate the superiority of the intravenous form in regards to retinitis progression. Despite the benefit of intravenous maintenance, oral ganciclovir is most frequently used for maintenance of stable retinitis because of increased convenience and fewer adverse events. Diarrhea and neutropenia are common adverse events with oral ganciclovir as well as the intravenous form.

Valganciclovir

Valganciclovir is a monovalyl ester prodrug of ganciclovir that when administered orally is rapidly hydrolyzed to ganciclovir. Once the drug has been hydrolyzed the pharmacokinetics are identical to the parent compound. The absolute bioavailability of ganciclovir from valganciclovir is approximately 60% (99, 122). A dose of 900 mg of valganciclovir achieves equivalent levels to the 5 mg/kg intravenous administration of ganciclovir. Recent data indicate that treatment of CMV retinitis with an induction dose of valganciclovir 900 mg twice daily for three weeks followed by 900 mg daily maintenence is equivalent to ganciclovir 5 mg/kg induction intravenously followed by maintenance of 5 mg/kg intravenously. Adverse events were similar in the two groups. Valganciclovir is rapidly replacing intravenous ganciclovir in patients with CMV disease who are able to take oral medications. Moreover, valganciclovir is replacing oral ganciclovir for maintenance therapy as well as disease prevention/pre-emptive therapy in most cases except when there is liver disease and concern for altered metabolism of valganciclovir.

Intraocular Administration of Drugs

Intravenous therapy with currently approved drugs against CMV retinitis is complicated by a high frequency of side effects, the inconvenience of intravenous administration, and high cost of administering daily intravenous drug. Experience with local therapy has accumulated since intraocular injection of ganciclovir was initially reported in 1987 (58, 76). Originally described doses were 200 µg in 0.1 ml of ganciclovir sodium and 1.2 mg in 0.05 ml to 2.4 mg in 0.1 ml of foscarnet. Concentrated ganciclovir sodium solutions can be made to deliver 2000 micrograms in 0.1 or 0.05 ml with good safety and efficacy (230). Induction therapy typically consists of injections twice weekly for two to three weeks followed by weekly injections.

Another approach to the intraocular administration of ganciclovir has been the placement of a commercially available intravitreal device, which consists of diffusion cells lined by permeable polyvinyl membranes and contains ganciclovir that is surgically implanted into the vitreous. Using this approach, CMV retinitis can be successfully controlled (121, 134, 189). In the pre-HAART era, times to retinitis recurrence were significantly prolonged using the intravitreal implants when compared to any other treatment modality in patients with advanced AIDS. Whereas the median time to progression with the intravenous formulation was found to be approximately 70 days, retinitis progression occurred after 220 days in two studies administering 1 µg/ml through intravitreal implants. Of note, however, the risk of developing retinitis in the uninvolved eye or other systemic CMV disease was lower in advanced AIDS patients receiving intravenous ganciclovir than those with the implant. For this reason in patients who remain immunocompromised, systemic ganciclovir should be administered concomitantly with the implant to prevent the development of CMV disease at a new site. With HAART, patients who respond to their HIV therapy with an increasing CD4+ cells count above 100 cells/ µL may not require systemic therapy.

Intravitreal cidofovir has been given to patients with advanced AIDS and CMV retinitis (105). After a single injection of 10 mg, median time to retinitis progression in the pre-HAART era was approximately 55 days which compared favorably with the systemic use of ganciclovir or foscarnet. Multiple injections with cidofovir further prolong the time to retinitis progression. Mild to moderate iritis develops in approximately 35% of eyes inoculated with cidofovir. Additionally, decreased intraocular pressure (hypotony) is observed with the administration of intraocular cidofovir, and currently intraocular administration of cidofovir is not recommended.

In summary, intraocular administration of antivirals is effective in controlling CMV retinitis. The advantage is that a high concentration of drug is delivered locally while avoiding the toxicity of intravenous drug therapy and the inconvenience of intravenous drug catheters. The disadvantages of local therapy are that the treatment does not prevent development of retinitis in the other eye or of CMV disease elsewhere in the body. For patients in whom systemic antiviral therapy is inadequate to control progression of the retinitis, combined therapy with a ganciclovir-containing intraocular device and either oral ganciclovir (120) or oral valganciclovir would seem to be the best strategy to provide highly efficacious control of the retinal infection while reducing risk of systemic disease or second eye involvement. Choice of initial therapy for CMV retinitis is a multifactorial decision that incorporates the patient’s immune status and prior history of antiretroviral therapy (119). Patients who are HAART naïve or recently started on HAART have an excellent chance of responding to therapy with oral valganciclovir alone without the need for intravitreal therapies. Patients with retinitis progression while taking systemic anti-CMV therapy should be rapidly moved to intravitreal therapy.

CMV Retinitis in the HAART Era

With the availability of effective antiretroviral therapy, the patient with AIDS and a CD4+ lymphocyte count below 50 cells/µL has the opportunity to significantly lower their viral load and increase their CD4+ cells. Considerable data indicate that maintenance therapy for CMV retinitis can be safely discontinued when patients have quiescent retinitis and CD4+ lymphocytes have risen above 100-150 cells/µL for at least 3 months (33, 210, 216, 218). It is essential that all patients who have their CMV maintenance therapy discontinued have their CD4+ lymphocyte count monitored routinely as part of their HIV/AIDS care and undergo regular ophthalmologic examinations to ascertain that the retinitis remains inactive. A syndrome associated with immune reconstitution in patients with CMV retinitis, immune uveitis, has been described (101, 136, 193). In such cases of immune activation, anecdotal reports of systemic and periocular corticosteroid therapy have been useful in controlling the uveitis. CMV maintenance therapy should be reinstituted with any recurrence of CMV retinitis without regard to lymphocyte count or when CD4+ lymphocytes have declined below 100 cells/µL.

Lumbosacral Polyradiculopathy and Myelitis

Although there have been no controlled trials, clinical improvement has been reported after induction and maintenance therapy with intravenous ganciclovir (32, 38, 104). In one study (32), 6 of 16 patients with polyradiculopathy treated with ganciclovir responded with clinical improvement and stabilization. Factors associated with lack of response to therapy were persistence of polymorphonuclear leukocytes, low glucose levels in the CSF, and severe paraparesis prior to initiation of therapy (38). Patients who developed polyradiculopathy while on anti-CMV therapy also frequently did not respond. Lack of response is likely related to irreversible damage in the nervous system or the presence of resistant virus (224). Treatment of patients with the polyradiculopathy syndrome with foscarnet or a combination of ganciclovir and foscarnet has resulted in similar results to those treated with ganciclovir alone. In the author's experience, unless the diagnosis is made within days of clinical symptoms, usually by the characteristic presentation in a patient with advanced AIDS confirmed by a positive PCR for CMV DNA from cerebrospinal fluid, stabilization of the polyradiculopathy without significant improvement is the norm.

CMV Encephalitis

Treatment of AIDS patients with CMV encephalitis with either ganciclovir and/or foscarnet has met with variable success. In some reports, treatment with ganciclovir has resulted in radiologic improvement of ventriculitis and conversion of positive CMV cultures but little objective clinical neurologic improvement (156). Salazar et al. (167) reported four autopsy-proven cases of CMV ventriculitis with clinical and radiologic responses to treatment. Three patients received ganciclovir and two foscarnet. One patient showed marked neurologic improvement and radiologic resolution by MRI after 4 weeks of ganciclovir therapy. Two other patients on ganciclovir and two on foscarnet deteriorated and died. CMV encephalitis may occur while patients with advanced AIDS are receiving maintenance ganciclovir or foscarnet therapy for CMV retinitis, even when retinitis is being controlled (11). In such cases, failure of sufficient drug levels to reach the CNS or the selection for resistant virus within the CNS may contribute to the development of encephalitis. As with the polyradiculopathy syndrome, the early suspicion of disease with PCR confirmation in CSF and early institution of antiviral treatment has the highest probability of improving patient outcome.  Treatment of CMV encephalitis in the immunocompetent patient is of unclear benefit; however in the setting of encephalitis, if CMV DNA is detected within the cerebrospinal fluid, treatment with gancicovir is recommended.

Mononeuritis Multiplex

Temporary relapse or improvement of neuritis may follow ganciclovir or foscarnet therapy (165).

Cytomegalovirus Pneumonia

The lung is one of the most common sites of CMV disease. CMV pneumonia may result from different mechanisms of pathogenesis. Hence the treatment of CMV pneumonias differs, depending upon the type of patient. CMV pneumonia has been described rarely in immunocompetent patients, in association with CMV mononucleosis (121). The mortality of this condition is negligible, and antiviral therapy is highly effective (although usually not necessary). The most severe type of pneumonia with the highest mortality occurs in bone marrow recipients. Untreated, the mortality is 70 to 85% (129). Used alone, ganciclovir suppresses the virus but is not effective in reducing morbidity or mortality. Combination therapy of ganciclovir with immune globulin is now used widely (55,161). Reed et al. (55) reported that mortality was reduced to 30% in 10 patients who received ganciclovir and intravenous immune globulin. None of the 11 patients treated with either ganciclovir or intravenous immune globulin alone survived. The course of the patient may be complicated: some resolve after 14 days of treatment, others remain symptomatic and require maintenance treatment, and still others may have a relapse after remission that requires treatment reinduction. Neutropenia is often associated with repeated treatment with ganciclovir (160, 161), but usually responds to treatment with G-CSF.

In conclusion, CMV pneumonia in marrow recipients is highly fatal if left untreated. Neither ganciclovir or immune globulin alone is effective treatment. Mortality has been reduced by the combination but is still significant. For this reason, prophylaxis/pre-emptive therapy is preferable than treating CMV pneumonia in this population.

In solid organ transplantation, the course and treatment of CMV pneumonia is less well documented. Mortality varies for different types of transplanted organs, from 48% in an early series of renal recipients (151) to 75% in heart and heart-lung recipients (52). More recent data suggest that mortality associated with CMV pneumonia is generally lower in solid organ recipients than in bone marrow recipients (97, 172) likely due to the level of immunosuppression among the different groups of transplant recipients. Duncan et al. (53) reported that 48% of a group of 124 lung recipients developed CMV pneumonia. The ganciclovir-treated group had a significantly higher 1-year survival than the untreated group (86% vs. 38%). However, survivors had clinically significant chronic complications, compared with those who did not have CMV pulmonary infection. The need for immune globulin addition has not been documented in solid organ recipients remains controversial, although the combination has been reported effective in anecdotal reports (34, 66 and see below).

Despite the common occurrence of CMV disease and infection of the lungs demonstrated at post-mortem in persons with AIDS, CMV pneumonia is uncommon. The infrequency of CMV pneumonia associated with AIDS even prior to the availability of HAART likely reflects differences in the pathogenesis of CMV pneumonia in AIDS patients in comparison to the pneumonia observed following transplantation. Whereas CMV pneumonia following transplantation reflects infection of the lung with a concomitant local immunologic response often temporally associated with graft versus host disease, CMV pneumonia in persons with AIDS is the result of overwhelming infection with CMV (77, 133).

In persons with AIDS, CMV is frequently present in association with other opportunistic pathogens especially Pneumocystis carinii. Treatment of Pneumocystis alone frequently results in clinical improvement without the need to treat the CMV (21, 95, 98). However, numerous reports in the pre-HAART era documented cases of CMV pneumonia in persons with AIDS (6, 47, 68, 204, 215) so that the diagnosis must be considered in patients with advanced AIDS who are not responding to traditional antimicrobial therapy for Pneumocystis carinii and common bacterial pathogens (127).

Gastrointestinal Disease

In an uncontrolled report of ganciclovir treatment of 41 AIDS patients with gastrointestinal involvement in the pre-HAART era, clinical improvement occurred in 30 and virologic response in 32 (26). In a randomized placebo-controlled trial of persons with AIDS and CMV colitis, those treated with ganciclovir (10 mg/kg daily for 14 days) experienced a significant reduction of CMV-positive colon and urine cultures when compared to placebo which was associated with significant improvement in 63% of the treated group compared to 33% for those randomized to placebo (43). The treated group maintained body weight, but the placebo group lost weight. Diarrhea improved equally in both groups.

In additional uncontrolled reports, AIDS patients with CMV gastrointestinal disease who failed ganciclovir therapy (defined as progression of CMV disease) benefited from foscarnet. Dieterich et al. (44) administered foscarnet to 19 such patients and observed histopathologic improvement in 67% and clinical improvement in 74%. In a randomized comparison of the two drugs, no difference was observed between ganciclovir and foscarnet in treatment of gastrointestinal disease (12). Survival in both treatment groups (in the pre-HAART era) was less than 40 weeks and was unaffected by maintenance treatment therapy. Thus either ganciclovir or foscarnet was effective as first-line treatment for gastrointestinal CMV disease. Maintenance therapy did not prevent progression of the disease. The combination of ganciclovir and foscarnet has also been used successfully for treatment of CMV gastrointestinal disease (45).

Ganciclovir therapy in case reports resulted in symptomatic improvement of gastrointestinal CMV disease in as many as 93% to 100% of solid organ transplant recipients (100, 125). Mayoral et al. (125) used ganciclovir to treat 14 solid organ transplant recipients with gastrointestinal CMV disease (all but one endoscopically proven); 13 improved, 4 required additional treatment for recurrent disease. Kaplan et al. (104) reported that gastrointestinal disease was the most common infection in heart and heart-lung transplant recipients. An incidence of 9.9% included gastritis, 9;gastric ulceration, 4;duodenitis, 3;esophagitis, 1;pyloric perforation, 1;and colonic hemorrhage, 1. They were treated with ganciclovir 5 mg/kg twice daily for 2 to 8 weeks. Relapses occurred in 4 of 9 patients who were followed for a median of 18 months.

Reed et al. (162) conducted a controlled trial in marrow recipients who had gastrointestinal CMV disease; 14 patients were treated with ganciclovir and 19 received placebo. The most common involvement was the esophagus. Ganciclovir was given at a dosage of 2.5 mg/kg every 8 h for 14 days. No patient had resolution of all symptoms after treatment with ganciclovir. Partial improvement was observed in both treated and placebo control groups. The only significant difference was virtual elimination of the virus from both systemic and local cultures in the treated group; 73% of the treated and 79% of the placebo group showed some improvement. This study showed no clear advantage of treatment, although higher doses of ganciclovir (i. e. 5 mg/kg twice daily) may have demonstrated an advantage.

Hepatitis

Tissue invasive CMV disease in any immunocompromised host can manifest as CMV hepatitis. In liver transplant recipients however, CMV hepatitis occurs in 2-17% of the patients and is the most common organ specific manifestation of CMV infection (112, 173).Virtually all patients with CMV hepatitis have viremia. However, CMV viral load or antigenemia levels may be variable (112). Definitive diagnosis requires demonstration of CMV in liver tissue by immunohistochemical analysis or in situ hybridization. Viral inclusions are often absent on histopathologic examination. Microabscesses and ballooning of hepatocytes, while not specific for CMV are the most frequently observed histopathological findings (112). In most patients, CMV hepatitis represents isolated organ involvement without evidence of disseminated disease.

Intravenous ganciclovir 5 mg/kg twice daily (adjusted for renal dysfunction) for 2-4 weeks is the recommended therapy (154). In patients with documented viremia, ganciclovir should be continued for at least a week beyond the resolution of viremia. Valganciclovir is an alternative therapeutic option in stable patients able to take oral medications. Virologic and clinical outcomes with valganciclovir in transplant recipients with tissue-invasive CMV disease, including CMV hepatitis were comparable to those in patients who received intravenous ganciclovir (89). Routine addition of CMVIG to antiviral therapy for CMV hepatitis is not recommended. However, adjunctive CMVIG may be considered in patients with severe gastrointestinal disease or in those with hypogammaglobulinemia (154).

Liver transplant recipients with CMV hepatitis were at a higher risk for the subsequent development of biliary complications (112). However, in appropriately treated patients, long-term outcomes are not compromised.

Congenital CMV Infection

Uncontrolled trials (137) and a randomized, controlled study done through the Collaborative Antiviral Study Group (CASG) have suggested for infants born with symptomatic congenital CMV that the administration of ganciclovir 12 mg/kg /day intravenously divided in two doses for six weeks when administered within the first month of life may be associated with a decline in hearing deficits (217).   Follow up of the infants in the CASG study, demonstrated that infants receiving ganciclovir had fewer developmental delays at 6 and 12 months compared to untreated controls (142).  A recent study completed by the CASG presented, to date, only in abstract form examined 6 weeks versus 6 months of valganciclovir in infants with symptomatic congenital CMV.  A dosage of VGCV 16 mg/kg given twice daily was given to all study participants.  Participants were then randomized to continue VGCV at the same dose or to placebo.  At 12 and 24 months, infants who received 6 months of VGCV were more likely to have improved or normal hearing than those who had received 6 weeks of treatment.  Additionally, at 24 months there was improvement in language and receptive communication in the group receiving 6 months of treatment.  Of importance, there was no difference in neutropenia, thrombcytopenia or nephrotoxicity between the two treatment groups.

ADJUNCTIVE THERAPY

The major adjunctive therapies that have been studied for the treatment and prevention of CMV disease are IVIG and CMVIG. As noted earlier, the combination of IVIG with ganciclovir in a number of studies seems to modestly improve outcome in the treatment of bone marrow transplant recipients and CMV pneumonia. Snydman and colleagues have championed the use of CMVIG to prevent/ ameliorate CMV disease in solid transplant recipients (185).

The use of CMVIG given in conjunction with ganciclovir has been evaluated in patients following cardiothoracic transplantation (212). In the study by Valantine et al. patients following heart, heart-lung or lung transplant were given ganciclovir plus CMVIG and compared to matched historical controls. At 3 years, there was a significant decrease in CMV disease (76% versus 39%), the proportion of rejection free patients (34% versus 11%) and overall survival (91% versus 63%) for the ganciclovir plus CMVIG group versus ganciclovir matched controls, respectively. Fewer cardiothoracic recipients also experienced obliterative bronchiolitis, 86% in the ganciclovir plus CMVIG versus 59% for those receiving ganciclovir only. The major problem with these data is the use of historical controls as the comparison group and the potential that other factors may have significantly impacted on disease outcome. Thus, the impact of CMVIG on heart, heart-lung, and lung transplant patients initiated early after transplantation requires a randomized controlled trial before definitive recommendations can be made.

The use of CMVIG for persons with HIV/AIDS has generally been unsuccessful. CMVIG was found to be unsuccessful in the prevention of CMV disease. Additionally, CMVIG when given in conjunction with ganciclovir for the treatment of CMV retinitis failed to prolong the time to retinitis progression in persons with advance AIDS prior to the availability of HAART.

As noted earlier, the use of CMVIG to prevent congenital infection is controversial and awaits controlled clinical trials before its use during pregnancy can be recommended.

ENDPOINTS FOR MONITORING THERAPY

Ganciclovir Toxicity

Ganciclovir use requires monitoring the neutrophil count because neutropenia is the most important of the severe adverse reactions that limit the use of ganciclovir. Neutropenia or an absolute neutrophil count below l000/µL occurs in ~ 30% of patients receiving ganciclovir (62), but may occur in as many as 70% when administered with zidovudine (80). Severe neutropenia (< 500/µL) occurs in ~ 20% of patients. Neutropenia usually resolves with discontinuation of therapy and may be prevented by concomitant administration of granulocyte-or granulocyte macrophage colony-stimulating factor (G-CSF or GM-CSF). Thrombocytopenia is a less common but potentially serious complication of ganciclovir, particularly in patients with AIDS, and further indicates its bone marrow suppressive effect. Other side effects of ganciclovir include rash, nausea, fever, vomiting, anemia, diarrhea, eosinophilia, confusion, seizures, and psychotic reactions in a small number of patients (25).

Foscarnet Toxicity

The major toxicity of foscarnet is renal impairment, which occurs to some degree in most treated patients. Approximately 33% of 189 patients with AIDS and CMV retinitis who received intravenous foscarnet treatment developed impairment manifested as a serum creatinine concentration of 2 mg/dL or higher. Such elevations are usually, but not always, reversed on discontinuation of the drug. Because foscarnet chelates divalent cations, it has also been associated with serum electrolyte imbalance such as hypocalcaemia (15%), hypomagnesemia (50%), and hypokalemia (16%). Foscarnet has been associated with seizures in AIDS patients. Hypocalcemia may play a role in cases of unexplained seizures or arrhythmia. Anemia has been reported in 33% of patients receiving foscarnet. This has been manageable, and less than 1% required discontinuation of the drug for this reason. Granulocytopenia has been reported in 17% of patients, but only 1% was terminated from studies because of neutropenia. Penile ulceration may result from exposure of the glans penis to unchanged foscarnet in urine (5, 93). Patients receiving foscarnet must remain well hydrated in order to prevent such complications.

VACCINES

Although congenital infection with CMV remains the major infectious cause of birth defects in the developed world, there is still no vaccine available for protection against CMV. Considerable research is ongoing in this area; however, it is unlikely that a vaccine for CMV will be licensed and widely available within the next several years.

PREVENTION

Bone Marrow Transplant Recipients

Immunoglobulin

Although a number of early studies reported that use of immunoglobulin reduced CMV disease in marrow transplant recipients, other trials failed to demonstrate a benefit (17, 18, 106,131,143,220). In a study of 97 seronegative marrow recipients, Bowden et al. (18) examined four assigned groups: (a) intravenous CMV immunoglobulin and seronegative blood products, (b) seronegative blood products alone, (c) CMV immunoglobulin alone, and (d) neither treatment. CMV infection in the four respective groups was 5, 13, 54, and 40%, respectively. The main conclusion of this study was that among 57 patients with seronegative donors, those who received seronegative blood products had significantly less infection (1 in 32) than those who received the standard blood products (8 of 25; P < .007). Immunoglobulin alone had no effect. This study showed that CMV infection and disease could be prevented in seronegative recipients who had seronegative donors by providing CMV-free blood products. The remaining question was whether immunoglobulin could prevent infection and disease in seronegative recipients with seropositive donors. Bowden et al. (17) showed in a randomized controlled study in 120 such patients that it could not.

In a study of seropositive bone marrow recipients (207), among 308 seropositive recipients evaluated, 22% of control patients and 13% of immunoglobulin recipients developed interstitial pneumonia. The incidence of acute graft-versus-host disease (GVHD) was reduced from 51% in controls to 30% in immunoglobulin recipients. Whether the reduction of pneumonia was a direct effect of immunoglobulin or a secondary effect of the reduction of GVHD by immunoglobulin is unclear. These findings were not confirmed in a subsequent study (163).

In summary, there are currently no compelling data that demonstrate benefit of immune globulin or hyperimmune globulin for the prevention or amelioration of CMV disease following in bone marrow recipients and this treatment is not recommended in such settings.

Antiviral Agents

Patients who are CMV seropositive before marrow transplantation are at greater risk for developing CMV disease after transplantation than seronegative recipients. Regardless of the donor serologic status, the frequency of infection in the first 100 days after transplantation is about 70% (129). This group of patients has been primarily targeted for testing antiviral prophylaxis and therapy.

Meyers et al.  (130) found that intravenous acyclovir (500 mg/m2 given every 8 h starting 5 days before transplantation of CMV seropositive subjects and continued until day 30 thereafter) reduced the incidence of CMV disease from 38% to 22% and the incidence of CMV infection from 75% to 59%. Transplantation-associated mortality was reduced from 54% to 29%. The European Acyclovir Study Group (155) evaluated intravenous acyclovir at a dose of 500 mg/m2 thrice daily or oral acyclovir for the first 30 days after transplantation and then oral acyclovir or placebo until day 210. The rate of CMV infection, frequency of viremia, and mortality were lower in the group that received intravenous acyclovir. However, the frequency of CMV disease was similar in the two groups. Boeckh et al. (13) evaluated intravenous acyclovir from 5 days before autologous transplantation to day 100 in a retrospective study. There was no difference in the incidence of CMV disease or pneumonia. Thus, although some studies have established a benefit of acyclovir (including valacyclovir) for prevention of CMV disease, its benefits are inferior to ganciclovir or foscarnet and its use is not recommended for prevention of CMV disease.

There are two approaches to the use of ganciclovir in CMV seropositive marrow recipients. The first is early treatment or pre-emptive therapy where patients identified as having active CMV infection historically by surveillance cultures or currently usually by direct CMV antigen or PCR detection in blood are then given ganciclovir. The second approach is to administer ganciclovir after engraftment to all seropositive patients.

Following the first approach, Schmidt et al. (170) performed bronchoalveolar lavage (BAL) surveillance cultures at the median day of engraftment (day 22) and enrolled those with CMV-positive cultures. Twenty patients were randomized to the placebo group and 20 to the treatment group, who received ganciclovir from day 35 after transplantation to day 120. CMV pneumonia was reduced from 70% to 25%. Of the 55 patients who were not positive by BAL (and thus not eligible for the study), 22% developed CMV pneumonia. Goodrich et al. (71) selected patients for prophylaxis by screening for positive CMV cultures from blood, throat washes, or urine. Patients received either ganciclovir until day 100 after transplantation or placebo. Results were obtained on 102 patients. CMV disease was reduced from 43% (15 of 35) in the placebo group to 3% (1 of 37 patients) in the treatment group during the first 100 days after transplantation.

Following the second approach, Goodrich et al. (70) gave ganciclovir to all 33 patients, from engraftment to 100 days after transplantation; 45% of the placebo recipients (14 of 31) developed CMV infection 100 days after transplantation compared with 1 (3%) ganciclovir recipient. Neutropenia occurred in 30% of the ganciclovir recipients. Mortality did not differ between the two groups. Winston et al. (219) gave ganciclovir for 1 week before marrow infusion and then starting after engraftment until day 100 after transplantation. CMV infection was reduced from 56% to 24%.

The studies cited above show that ganciclovir is effective in reducing CMV disease if administered (a) routinely to all patients or (b) selectively to those found to be positive by surveillance cultures. But if one avoids excess toxicity by restricting administration to patients at higher risk, there is the danger of missing those who become ill without positive surveillance cultures. At the moment there is no perfect solution to this problem. However, studies using antigenemia or quantitative PCR provide excellent although not perfect surveillance.

Prevention of CMV in Organ Transplant Recipients

Prevention of CMV in transplant recipients using antiviral agents is generally approached using one of two strategies: 1), preemptive therapy where the antiviral agent is targeted towards patients with early viral replication or viremia in an attempt to prevent the progression of asymptomatic infection to CMV disease, and 2), prophylaxis where the drug is administered to all patients for the period that they are deemed to be at risk for CMV, usually 90-100 days post-transplant (148, 176). Major advantages of the prophylactic approach include the fact that it obviates the need for frequent monitoring to detect early viral replication, is reliably protective against CMV during the time that the antiviral agent is employed, and likely provides protection against indirect sequelae or secondary outcomes associated with CMV. Disadvantages of this approach are that most patients while accruing the cost and possibly the risk of toxicity associated with antiviral agent, are unlikely to benefit from it. There is also a potential concern for the emergence of antiviral resistance. Additionally, accumulating data show that while CMV disease can be effectively prevented during the time that antiviral prophylaxis is employed (first 3 post-transplant months), a significant proportion of the patients, particularly in the recipient seronegative/donor seropositive (R-/D+) group, develop CMV disease upon discontinuation of prophylaxis (1, 96, 114, 147). Late-onset CMV disease, defined as CMV disease occurring after 100 days post-transplant, has emerged as a significant complication with the use of valganciclovir prophylaxis in the current era (1, 96, 114, 147, 176).

Advantages of the preemptive therapy approach are that the antiviral agent is directed only towards patients at high-risk for CMV disease, and therapy is employed for a defined and shorter duration. This strategy, including the costs of surveillance monitoring is associated with lower overall costs. Existing data have not documented late-onset CMV disease with valganciclovir used as preemptive therapy (41, 124,178). The proposed basis of this observation is that asymptomatic viremia implicit in preemptive therapy approach may facilitate CMV-specific immune responses that are critical in long-term protective immunity against the virus (178).

Antiviral agents for prophylaxis

Options for antiviral agents that can be employed as prophylaxis include acyclovir, valacyclovir, or ganciclovir derivatives. Acyclovir due to its poor in vitro activity against CMV and low oral bioavailability has not proven particularly effective for the prevention of CMV disease. Comparative studies have shown lower efficacy rates for acyclovir compared to ganciclovir containing regimens (222). Valacyclovir is a valyl ester of acyclovir with improved oral bioavailability. In a placebo controlled trial in renal transplant recipients, valacyclovir (2 g orally four times daily) significantly reduced the incidence of CMV disease and that of acute allograft rejection (117). Although not as effective as ganciclovir, valacyclovir represents a cost-effective alternative to ganciclovir in renal transplant recipients.

Intravenous ganciclovir employed for a prolonged period has proven effective for CMV disease. In a randomized trial that involved predominantly seropositive patients, prophylaxis with intravenous ganciclovir that was administered to liver transplant recipients for 100 days was associated with a CMV disease rate of 1% in all patients, and 10% in those at risk for primary CMV infection, i.e., seronegative recipients of seropositive allografts (222). However, this approach did not gain wide acceptance because of the requirement of prolonged vascular access for intravenous administration of the drug.     

Administration of oral ganciclovir for 100 days after liver transplantation reduced the rate of CMV disease to 5% among all patients, and to 15% among those at risk for primary CMV infection (65). However, given the poor oral bioavailability of oral ganciclovir, a potential concern in the setting of prolonged use of this agent is suboptimal suppression of the virus and the emergence of ganciclovir-resistant CMV. Patients at particular risk are those receiving intense immunosuppression and the R-/D+ group. At one institution that employed prolonged prophylaxis with oral ganciclovir, 10% of the patients who underwent solid organ transplantation developed CMV disease within the first year after transplantation (116). Of note, 20% of the patients with CMV disease had ganciclovir-resistant CMV (116). In another report, 11 infections with ganciclovir-resistant CMV in organ transplant recipients were documented, a majority of these patients had received prolonged oral ganciclovir prophylaxis (90).

Valganciclovir is a valine ester prodrug of ganciclovir. Following ingestion, a vast majority of valganciclovir, prior to reaching system circulation, is hydrolyzed to ganciclovir (150). The oral bioavailability of valganciclovir is such that ganciclovir levels achievable are comparable to those attained with intravenous ganciclovir (150). In a randomized trial comparing valganciclovir 900 mg once daily with oral ganciclovir 1000 mg tid administered for 100 days as prophylaxis in CMV recipient negative/donor positive organ transplant recipients, neither group experienced CMV disease during the treatment phase (147). By 12 months, however, the incidence of CMV disease in the valganciclovir and oral ganciclovir groups was 17.2% and 18.4%, respectively (147).

Approach to prophylaxis

Options for antiviral agents as prophylaxis include valganciclovir (900 mg qd), oral ganciclovir (1 g tid), or intravenous ganciclovir (5 mg/kg/d). Breakthrough CMV disease is a rare occurrence during the use of either of these agents. However, late-onset CMV disease may occur in 2.5 - 17% of the patients receiving oral ganciclovir, and 5.5 - 18% of those receiving valganciclovir (1, 10, 96,115, 147, 177). Valacyclovir (8 g/d) is an alternative in renal transplant recipients, particularly in the R+ subgroup. It should however be noted that 57% of all episodes of CMV disease in patients receiving valacyclovir were also late occurring. Based on a higher incidence of tissue invasive disease with valganciclovir compared to oral ganciclovir in liver transplant recipients in the PV-16000 trial, the FDA has cautioned against the use of valganciclovir in liver transplant recipients. In the clinical setting, however, valganciclovir has been used in liver transplant recipients (10, 96, 114, 178).

Valganciclovir and intravenous ganciclovir are rational choices for antiviral prophylaxis in lung transplant patients. Lung transplant recipients are at high-risk for the development of ganciclovir resistant CMV (113). Resistant virus has been documented in 1 - 4.4% of the R+, and 9-27% of the R-/D+ lung transplant recipients (113).  Given that most such cases have occurred after prolonged exposure to oral ganciclovir, this agent is a less desirable option, for CMV prophylaxis in lung transplant recipients, particularly in the R-/D+ subgroup.

The usual duration of antiviral prophylaxis is 90-100 days post-transplant. It has been proposed that in lung transplant recipients 180 compared to 100 days may be a more optimal duration of prophylaxis (231). Freedom from CMV infection and disease was greater in patients receiving 180 days (90%) compared to those receiving 100-170 days (64%) or < 100 days (59%) of prophylaxis (231).

Antiviral agents for preemptive therapy

The success of preemptive therapy hinges upon early and reliable detection of CMV viremia. Existing studies in organ transplant recipients have employed either CMV antigenemia or a CMV DNA based molecular assays to initiate preemptive therapy. The predictive value of various diagnostic assays for the early detection of CMV disease is outlined in Table 5. CMV antigenemia is easy to perform, has a rapid turn-around time, and can be quantitated. Although, CMV disease may precede detectable antigenemia, most studies in transplant recipients have validated antigenemia as a reliable tool for initiating preemptive therapy (178, 213). Potential disadvantages of the antigenemia test include the need for immediate processing of specimens and the requirement of a leukocyte count of ≥ 200 cells/ mm.

Nucleic acid based assays obviate the need for immediate processing of the samples. CMV-DNA detection by PCR in the leukocytes may be overly sensitive and does not reliable distinguish latent CMV infection from replicating CMV infection. Detection of CMV DNA by means of PCR of plasma, whole blood hybrid capture assay or CMV RNA (mRNA) is considered specific for replicating virus (72). A quantitative PCR that predicts CMV disease and could be used in a preemptive strategy has not been reliably defined. In one report, quantitative PCR in the range of 2000 - 5000 copies/ml was deemed to be the optimal cut-off for predicting CMV disease with a positive and negative predictive value of 50% and 96.6%, respectively (88).  At present, preemptive therapy for transplant recipients may be based on results of the antigenemia test or quantitative PCR, depending on the access to the test.

Approach to preemptive therapy

The underlying principle and the intent of preemptive therapy are to prevent the progression of asymptomatic viremia detectable by a sensitive assay, to CMV disease. Thus, CMV infection (viremia) would already have occurred prior to the initiation of antiviral therapy. Ideally, therefore, the antiviral agent employed should be able to completely suppress the replicating virus. Acyclovir or its prodrug valacyclovir, given their poor activity against CMV are largely unsuitable agents for preemptive therapy. Use of intravenous ganciclovir, while effective as preemptive therapy, is impractical and inconvenient because of the requirement of intravenous access. Preemptively administered oral ganciclovir at dosages ≥3 gm/day has also been shown to be effective in reducing the risk of CMV disease (149, 178, 209). In liver transplant recipients, preemptive oral ganciclovir was associated with a significantly lower risk of CMV disease (RR 0.11, 95% CI, 0.01 - 0.96, p = 0.04) compared to the control group that did not receive prophylaxis (209). Oral ganciclovir for 6 weeks initiated upon detectable CMV antigenemia was also effective in preventing CMV disease in liver transplant recipients in another report (178). Oral ganciclovir, however, may not be an optimal antiviral agent for preemptive therapy. Given its poor bioavailability and low achievable serum levels, oral ganciclovir may not only be suboptimal as preemptive therapy in the setting of high viral load, but may predispose to the emergence of ganciclovir resistance. CMV replication dynamics in liver transplant recipients have shown that viral growth in CMV-experienced host will be substantially inhibited by oral ganciclovir at a dose of 1 gm orally tid (57).  In CMV naïve host however, in whom an anti-CMV agent must have an efficacy of ≥ 93% in inhibiting viral replication, oral ganciclovir may not be optimal (57).  During preemptive therapy with oral ganciclovir in liver transplant recipients the maximum viral load attained was lower, but not significantly different compared to placebo (mean, 734 vs. 2603 copies/106 peripheral blood leukocytes, respectively, p = .19) (159). Two of 6 patients, both R-/D+, with persistent viral replication on oral ganciclovir subsequently developed CMV syndrome (159).

Although the FDA has cautioned against the use of valganciclovir in liver transplant recipients, this agent has been shown to be effective as preemptive therapy in organ transplant recipients, including those undergoing liver transplantation. Of 59 liver transplant recipients, including R-/D+ patients, 28.8% (17/59) received valganciclovir as preemptive therapy for CMV infection (antigenemia) (178). At a median follow-up of 3.1 person years, there were no episodes of CMV disease. Another report in solid organ transplant recipients compared the efficacy of preemptive therapy with valganciclovir employed as preemptive therapy with intravenous ganciclovir (124). There were no episodes of CMV disease or of late-onset CMV disease in either group at 12-month follow-up (124). Of 301 high-risk seropositive transplant recipients who received preemptive therapy with valganciclovir for CMV antigenemia, none had CMV disease when followed for a median of 14 months (42). The goal should be to reach an undetectable level of viremia by either antigenemia or PCR, whichever test prompted the initiation of preemptive therapy. The duration of preemptive therapy has typically ranged from 14-21 days. Antigenemia level with preemptive valganciclovir decreased by 99.5% at 2 weeks compared to baseline (178). In another study, the time to become PCR negative with preemptive valganciclovir was 15.5 days, the baseline CMV viral load being 3.8 log10 genomes/mL (124).

Organ transplant recipients receiving monoclonal or polyclonal antilymphocytic antibodies are at high-risk for CMV infection. These patients should receive a potent antiviral agent such as intravenous ganciclovir or valganciclovir initiated in conjunction with the antilymphocytic agent and continued for ~ 2 weeks. This form of CMV prevention triggered by a clinical event is termed targeted or selective prophylaxis.

Prophylaxis in HIV Patients

The most common and most debilitating form of CMV disease is CMV retinitis, which may eventually lead to blindness despite effective antiviral therapy if antiretroviral therapy is unable to raise the CD4+ lymphocyte count above 100-150 cells/µL. In the pre-HAART era, in a placebo-controlled study, Spector et al. randomized (in a 2:1 ratio) 486 patients who received 1000 mg oral ganciclovir three times daily and 239 controls (120, 199). Entry criteria were a CD4+ count of 50/µL or less or l00/µL or less and a history of an AIDS-defining event. The incidence of CMV retinitis after 18 months of observation was 39% in the placebo group and 18% in the treated group. Total CMV disease was significantly reduced by treatment (39% vs. 20%), including investigator-reported colitis (13% vs. 4%). Although there was a trend toward overall survival benefit for patients treated with oral ganciclovir (relative risk = 0.8), the difference was not statistically significant (P = 0.14). Patients in the treated group had more instances of neutropenia, were more frequently on granulocyte colony-stimulating factor, and had more frequent elevations of serum creatinine.

In a second study performed by the CPCRA, oral ganciclovir prophylaxis in persons with AIDS failed to demonstrate a benefit in decreasing CMV disease (23). However, several important differences existed between the two studies with the most important being the monitoring of retinitis in both studies. Whereas the earlier study by Spector and colleagues screened participants at baseline and every two months with a dilated eye examination performed by an experienced ophthalmologist, the second study did not have dilated eye examinations at their clinical site unless the study participant complained of visual disturbances. Although a trend in favor of ganciclovir was observed in the CPCRA study, the difference was not statistically significant. Of interest, however, in this additional study a trend toward improved survival was also observed in the ganciclovir treated group (relative risk = 0.84; P= 0.1).

Spector et al further examined the impact of viral load as determined by CMV DNA PCR of plasma in 1654 study participants. The development of CMV disease was directly correlated with the quantity of CMV DNA present at study entry. Importantly, however, for study participants randomized to receive ganciclovir, those who went from plasma PCR positive to negative developed significantly less CMV disease than those who remained PCR positive (20% versus 48%, respectively; relative risk 0.33, P< 0.001). Of note, overall survival was also predicted by the presence and quantity of CMV DNA in plasma. Moreover, study participants randomized to receive ganciclovir who went from CMV DNA positive to negative had significantly improved survival compared to those who remained PCR positive (24% versus 47%, relative risk, 0.36, P< 0.001).  Additionally, a more recent study performed in the HAART era failed to show a benefit of valganciclovir when given as pre-emptive therapy because of the low rate of organ disease in HIV-infected patients despite low CD4+ cell counts and CMV viremia (223).

In total, in the current recommendation of The U. S. Public Health Service/Infectious Diseases Society of America Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus does not recommend valganciclovir prophylaxis in HIV-infected patients regardless of CD4+ count, CMV viremia or antiretroviral treatment.  The guidelines recommend that the primary method for preventing severe disease is the recognition of early clinical symptoms of CMV with institution of appropriate therapy.

INFECTION CONTROL

No special precautions are necessary for hospitalized patients known to be actively infected with CMV. Patients do not require isolation or single rooms. It is important, however, that individuals adhere to strict handwashing after exposure to bodily secretions including saliva, urine and tears because infectious CMV can be present such fluids. Additionally, seronegative immunocompromised patients and uninfected preterm infants should be administered CMV seronegative blood and blood products to prevent transmission from donor to recipient. Universal precautions in handling blood, blood products and secretions are recommended in all patient care settings and are sufficient for control of CMV.

CONTROVERSIES

A number of important controversies remain regarding the optimal approaches to the prevention and treatment of the broad range of CMV diseases observed in diverse patient populations. To a great extent, the different underlying clinical conditions that are associated with CMV diseases have complicated treatment approaches. Generally, the underlying risk factor for serious CMV infection is immunosuppression, particularly of cell-mediated immunity. However, clearly the immunosuppression associated with AIDS versus marrow or stem cell transplantation versus solid organ transplantation differs considerably and appears to have a major impact on the pathogenesis of CMV diseases in these settings.

In CMV seropositive patients with organ transplant recipients either receiving a seropositive transplant or previously CMV positive, the use of pre-emptive therapy versus universal prophylaxis remains controversial (179). Issues including efficacy, logistics, duration, cost and the relative risk of disease in a given population and the adequacy of treatment impact on decision making. In the HAART era, patients begun on effective antiretroviral therapy usually do not require pre-emptive treatment. If pre-emptive therapy is the approach selected, the choice of screening tool becomes important. Most studies have found that antigenemia assays or PCR assays are comparable for screening patients. The experience at a given center is important in deciding on which of the numerous assays available are best for a given center. Additionally, for how long prophylaxis/pre-emptive therapy should be continued remains controversial. For persons with AIDS, if preventive treatment is initiated it should be continued until the patient is receiving HAART on has a CD4+ lymphocyte count above 100 cells/µL. When to discontinue prevention for transplant recipients is more problematic. Discontinuation of prophylaxis/pre-emptive therapy after 100-120 days has led to late onset CMV disease. In transplant settings the continuation of preventive therapy will be best determined by the clinical status of a given patient and the amount of immunosuppression required. In patients, who remain on high immunosuppression, the risk of CMV remains high and preventive therapy should probably be continued. In contrast, patients following transplantation who are on minimal immunosuppression who are not experiencing GVHD can likely have their CMV preventive treatment discontinued. Monitoring patients for CMV reactivation and increased risk for disease are warranted initially on a monthly basis when preventive treatment is discontinued.

Prevention of congenital infection is an important focus of CMV research.  With the lack of a vaccine, a number of interventions have been evaluated to identify the congenitally infected fetus in utero and prevent the sequelae associated with infection.  Of these strategies, the use of CMV hyperimmunoglobulin (HIG) has been most extensively studied and the most controversial.  To date, there are three studies that suggest that administration of HIG may decrease the risk of symptomatic congenital CMV (138, 139, 214).  However, there is no standard dosage nor duration of administration during pregnancy although most studies gave monthly doses of HIG until delivery.  While the use of HIG is expensive, proponents argue that the lifetime-care of symptomatic CMV congenitally infected infant far exceeds the cost.  Unfortunately, there are no randomized, controlled studies with long-term follow-up of infants exposed in utero to HIG.  The number of women who would need to be screened during such a study, the cost of HIG and the expense of long-term follow-up make such a study difficult; however, such a study will need to be conducted in the U.S. before HIG is widely recommended for use during pregnancy.

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Tables

Table 1.  Clinical and Laboratory Findings Associated with CMV Polyradiculopathy in Patients with AIDS*

CSF cell count, No./mm3	500 (0-1500)**
Polymorphonuclear cells, %	70 (40-95)**
Protein, mg/dL	275 (110-700)**
Glucose, mg/dL	30 (15-50)**
CMV culture positive,%	50
CMV PCR positive, %	100
CMV at autopsy, %	100
Acute denervation (electromyogram), %	90
Small evoked M waves, %	90
Progressive severe weakness, %	100
Early sacral paresthesia, %	100
Urinary retention, %	80
CMV retinitis, %	40
Sensory level, %	20
Duration of illness, days	30 (20-60)**

* from reference 156.

**Approximate mean values with ranges.

Table 2. Usual Dosages of Antiviral Drugs for Treatment of CMV Infections in Adults and Children with Normal Renal Function.

	Route	Adults		Children
Drug		Induction	Maintenance	Induction	Maintenance
Ganciclovir	IV	5 mg/kg/dose Q12h	5 mg/kg/dose once daily	5 mg/kg/dose Q12h	5 mg/kg/dose once daily
Valganciclovir	oral	900 mg Q12h	900 mg once daily	Not studied in children
Foscarnet	IV	90 mg/kg/dose Q12h	90 mg/kg Once daily	90 mg/kg/dose Q12h	90 mg/kg Once daily
Cidofovir + Probenecid	IV	5 mg/kg once per week for 2 weeks (probenecid 2 grams must be given 3 hrs before dose, 1 gram at 4 and 10 hours post dose)	5 mg/kg every 2 weeks (probenecid 2 grams must be given 3 hrs before dose, 1 gram at 4 and 10 hours post dose)	Not studied in children
Ganciclovir Implant	intraocular	N/A	Replace every 7-8 months if necessary	Not studied in children

Table 3.  Ganciclovir Dose Modification in Renal Failure

IV Form* (Induction)	Capsule Form (Valganciclovir)
CrCl >70 mL/min  ……5 mg/kg q12h  50-69 mL/min ………... 2.5 mg/kg q12h  25-49 mL/min …………2.5 mg/kg q24h  10-24 mL/min ………...1.25 mg/kg q24h  <10 mL/min……….1.25 mg 3 times/ week                                following hemodialysis	CrCl > 70 mL/min  ……..1000 mg tid  50-69 mL/min  ……….….1500 mg qd                                          500 mg tid  25-49 mL/min   ………….1000 mg/day                                          500 mg/day bid 10-24 mL/min…………….500 mg qd  <10 mL/min  ……….500 mg 3 times/week                                     post hemodialysis

Maintenance dose is 50% of induction dose

Table 4.  Foscarnet Dose Adjustment in Renal Failure

CrCl (mL/min/kg)	60 mg/kg dose (induction)	90 mg/kg dose induction/maintenance	120 mg/kg dose maintenance
>1.4 >1.0-1.4 >0.8-1.0 >0.6-0.8 >0.5-0.6 >0.4-0.5 <0.4	60 q8h 45 q8h 50 q12h 40 q12h 60 q24h 50 q24h not recommended	90 q12h          90 q24h 70 q12h          70 q24h 50 q12h          50 q24h 80 q24            80 q48h 60 q12h          60 q48h 50 q12h          50 q48h not recommended	120 q24h 90 q24h 65 q24h 105 q48h 80 q48h 65 q48h not recommended

Table 5.  Characteristics of Viral Markers in Predicting CMV Disease in Organ Transplant Recipients

Variable	Antigenemia	Plasma PCR	Quantitative   PBL*  PCR	bDNA	pp67m RNA	Hybrid capture CMV-DNA assay
Sensitivity (%)	95.2-100	55-100	91	100	64	87.5-100
Specificity (%)	55.3-63.2	47-74	47	42.1	79	34-42
Positive predictive value (%)	30-61.1	28-55	50	50	60	36-50
Negative predictive value (%)	73-100	74-100	90	100	76	100
Time from positivity to onset of CMV Disease (days)	9-18	6-21	10	9	0	12.5-14

*PBL = peripheral blood leukocyte

Table from (Singh, Liver Transplant 01)

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