608

AIDS COMMENTARY

Cytomegalovirus Infection in Patients with AIDS W. Lawrence Drew

From the Departments ofClinical Microbiology and lnfectious Diseases, Siskind Pathology Research Laboratory, Mount Zion Hospital and Medical Center, and The Departments of Laboratorv Medicine and Medicine, University of California, San Francisco, California

Cytomegalovirus (CMV) infection is acquired throughout life, By age 50 years, -50% of the population in a developed country is seropositive for CMV. The clinical impact of infection differs according to the time of acquisition. Beyond the neonatal period, infection in the healthy patient is asymptomatic in -90% of cases. If clinical illness occurs, it is usually manifested as an infectious mononucleosis-like syndrome, complete with atypical lymphocytosis but lacking a heterophil antibody. Although primary infection with CMV is usually benign, the virus remains latently present within the host thereafter, a property this virus shares with all other herpesviruses. Under conditions ofimmune compromise, especially impairment of cell-mediated immunity, latent virus may reactivate to produce a variety of clinical syndromes, including chorioretinitis, esophagitis, colitis, pneumonia, encephalitis, and adrenalitis [I]. Primary CMV infection is also severe in immunocompromised patients, but the overwhelming majority of patients with AIDS, especially homosexual men, are seropositive for CMV antibody before becoming infected with human immunodeficiency virus (HIV) and, therefore, are more likely to experience reactivation ofCMV [2]. Autopsy and clinical studies indicate that 90% of patients with AIDS

Reprints or correspondence: Dr.'W. Lawrence Drew, Mount Zion Medical Center of UCSF. 1600 Divisadero Street. San Francisco. California 94115. Clinical Infectious Diseases 1992;14:608-15 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1402-0033$02.00

develop active CMV infection during their illness, and up to 40% may experience life- or sight-threatening infections due to this virus.

Chorioretinitis Clinical evidence of CMV retinitis occurs in as many as

25% of patients with AIDS, and autopsy studies have revealed that CMV retinitis is present in up to 30% of patients. Retinitis is occasionally the presenting manifestation of AIDS, but it more commonly presents months to years after the diagnosis of AIDS has been established. Systemic CMV infection is also frequently present, and other viscera may be simultaneously diseased. Retinitis usually begins unilaterally, but progression to bilateral involvement is common due to the associated viremia. Unilateral "floaters" or decreased visual acuity is often the presenting complaint. Ophthalmologic examination typically reveals large white-colored areas with perivascular exudates and hemorrhages (referred to as a "cottage cheese and catsup" appearance; figure I). Initially, these abnormalities may be found at the periphery of the fundus, but, if left untreated, lesions often progress to involve the macula and the optic disk. Histological examination reveals coagulation necrosis and microvascular abnormalities [3]. Differentiating suspected CMV retinitis lesions from cotton-wool spots is essential because the latter are common in patients with AIDS. Cotton-wool spots result from ischemic atrophy of the nerve fiber layer of the retina, and they appear as small, fluffy, white lesions with indistinct margins, unasso-

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Advances in the field of antiviral therapy are now occurring with increasing frequency and rapidity and often generate varying degrees of confusion among those of us whose practices are focused primarily on therapy with antibacterial agents. How to treat cytomegalovirus infections in patients infected with the human immunodeficiencyvirus constitutes one ofthe best examples of the quandaries engendered by these advances, and the topic is reviewed in this first AIDS Commentary update. Given the U.S. Food and Drug Administration's recent approval of'foscarnet, this discussion is very timely; it is particularly relevant for clinicians to be made aware of current lines of thought regarding induction versus maintenance therapy, the benefits of efficacy versus adverse effects of drug-related toxicity, and the interactions between antiretroviral drugs and ganciclovir or foscarnet. Dr. W. Lawrence Drew's career in this area has been long-standing and productive, and he is one of the leading experts in the field. In this update he addresses these perplexing issues, -Merle A. Sande

cm 1992;14 (February)

CMV Infection in Patients with AIDS

ciated with exudates or hemorrhages. These lesions are asymptomatic, do not progress, and undergo spontaneous regression. Therefore, in questionable cases, reexamination of the fundus should be performed at frequent intervals (e.g., every other day). The diagnosis of CMV retinitis must be made clinically because it is impractical to obtain fluid or tissue from the eye for culture or microscopic examination. It is customary to perform a culture of blood, urine, or semen to document active CMV infection in the patient, but the relevance of these cultures is questionable, because many patients without retinitis have positive cultures. In contrast, negative cultures of body fluid from patients with suspected CMV retinitis should prompt consultation with an experienced ophthalmologist to confirm the clinical impression. All patients with AIDS should have a thorough ophthalmologic examination (including pupillary dilation) at regular intervals. Patients with suspected or confirmed CMV chorioretinitis should be treated with ganciclovir (Cytovene; Syntex Labs, Palo Alto, CA) or foscarnet (Foscavir; AB Astra, Sodertalje, Sweden) (see below). It has become clear that the approach to treatment of CMV retinitis in patients with AIDS is analogous to the therapy for a responsive, but not curable, malignancy. Thus, it has become customary to have an initial period of "induction" therapy followed by lifelong maintenance therapy. This approach is similar to the treatment of several other opportunistic infections in patients with AIDS, e.g., toxoplasmosis and cryptococcosis. There is no proof, however, that a period of induction therapy is necessary in the treatment ofCMV disease.

Gastrointestinal Infection Colitis. CMV colitis occurs in at least 5%-10% of patients with AIDS. Diarrhea, abdominal pain, weight loss, anorexia, and fever are frequent signs and symptoms. The differential

diagnosis includes infection due to other gastrointestinal pathogens (including Cryptosporidium, Giardia, Mycobacterium avium complex, Entamoeba, Shigella, Salmonella, Campylobacter, or Clostridium difJicile), although the prominence ofabdominal pain may suggest the possibility of diverticulitis, intraabdominal abscess, or mesenteric ischemia. Sigmoidoscopy reveals diffuse areas of erythema, submucosal hemorrhages, and diffuse mucosal ulcerations, although a grossly normal-appearing mucosa may be encOl.intered in up to 10% of those with histologic evidence of CMV colitis. Biopsy reveals vasculitis, neutrophilic infiltration, and nonspecific inflammation. The presence of CMV inclusions is the most important evidence to support the diagnosis of CMV colitis, especially in the absence of any other pathogen histologically or in culture. The presence of CMV antigen, and/or the positivity of cultured biopsy tissue can help to substantiate the diagnosis when such characteristic inclusions are not found. Colonic perforation or hemorrhage, as well as peritonitis, may occur as complications. If the pathogens listed above are not detected by routine microscopic examination of smears (including acid-fasttested smears), by cultures, by examinations for ova and parasites, or by assays for C. difJiciletoxin, then sigmoidoscopy or colonoscopy in addition to biopsy and culture for detecting the virus should be performed. Colitis due to CMV may improve with ganciclovir therapy, although a recent study revealed that 14 days of ganciclovir therapy was only marginally more effective than administration of placebo [4]. This study was confounded in part by the effects of antidiarrheal therapies that were used in both arms ofthe study. For gastrointestinal infection, the dosage of ganciclovir should probably be 5 mg/kg twice daily for 21 days (depending upon clinical response). It is not clear whether maintenance therapy is necessary, although relapses or recurrences do occur. There has not been a placebo-controlled study of foscarnet in the treatment of CMV gastrointestinal disease. Esophagitis. Clinically evident esophagitis in patients with AIDS is most commonly due to either Candida albicans or herpes simplex virus (HSV), but CMV may also cause esophagitis. Patients with esophagitis in whom CMV but not Candida organisms or HSV is detected by endoscopy with microscopy and culture should probably be treated with ganciclovir. Gastritis. CMV gastritis may also occur and may be signified by severe, continuous epigastric pain. Gastric ulcers may be seen on radiographs or with gastroscopy. The diagnosis is made by means of biopsy with use of the same techniques described for colitis and esophagitis. Hepatitis. Histologic evidence of CMV hepatitis is seen in one-third to one-half of patients with AIDS who have evidence ofCMV infection in other organs. The clinical impact of hepatitis is usually minimal; alkaline phosphatase levels are elevated, but bilirubin levels are rarely increased.

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Figure 1. Fundoscopic appearance of retinitis due to CMV.

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Drew

Pneumonia

CNS Infection Subacute encephalitis caused by CMV probably occurs in patients with AIDS, but this syndrome more commonly results from neural invasion by HIV [5]. Fever, altered mental states, personality changes, difficulty concentrating, headaches, confusion, and somnolence are frequent symptoms. The diagnosis can be suspected from results of CSF cultures

but is confirmed only by brain biopsy resulting in evidence of periventricle necrosis, giant cells, and intranuclear and intracytoplasmic inclusions and the isolation of the virus or its identification by means of the finding of antigen or nucleic acid. CMV may also cause myelitis, presenting as a spinal cord syndrome with lower-extremity weakness, spasticity, and urinary retention. Areflexia, hypoaesthesia, and a sensory deficit may also occur. The cerebrospinal abnormalities, namely polymorphonuclear pleocytosis and a moderately low glucose concentration, are very unusual for viral infection [5a J. Administration ofganciclovir should be considered for treatment of patients who have AIDS and CMV neurologic disease, although no data on ganciclovir's efficacy in such cases are available.

Adrenal Gland Infection Adrenal infection by CMV is a common autopsy finding in patients with AIDS and may occasionally be associated with adrenal insufficiency [6, 7]. Patients who have postural hypotension, low-grade fever, and fatigue should be monitored for hypoadrenalism, especially ifunexplained evidence of sodium loss or potassium retention are noted.

What Procedures Can Be Used to Diagnose CMV Infection? Cytology/histology. Microscopically, the hallmark of CMV infection is the large (cytomegalic) 25-35-jlm cell containing a large central, basophilic intranuclear inclusion. The inclusion is referred to as an "owl's eye" because it is separated from the nuclear membrane by a halo. These inclusions are clearly seen with Papanicolaou's or hematoxylineosin stain. Clusters of small intracytoplasmic inclusions may also be seen in CMV-infected cells and are best visualized with Wright's and Giemsa stains. Cytological and histologic observations are insensitive measures of CMV infection. For example, cytological examination of urine is one-third to one-fourth as sensitive as culture for virus. Histologic examination of a small piece of lung biopsy tissue obtained transbronchoscopically may also be less sensitive than culture, partly because of sampling error. Cytological examination and/or culture of BAL specimens may be superior to lung biopsy because the primary sites of CMV infection in the lung are alveolar lining cells that are easily recovered by lavage. Cytocentrifugation may also facilitate concentration of these cells. CMV antigen detection. In an effort to provide a rapid diagnosis, investigators have used antibodies, especially monoclonal antibodies, to directly detect CMV antigens in tissues by immunofluorescence. Eighty percent to 100% of culture-positive biopsy specimens are also positive by immunofluorescence [8]. Virtually all studies ofCMV antigen de-

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Isolation of CMV from pulmonary secretions or lung tissue ofpatients with AIDS and pneumonia who undergo bronchoscopy and/or biopsy is common, but a true pathogenic role of the virus in the disease process is rarely apparent. Many patients with pulmonary disease who have CMV isolated from their lungs have concomitant infection with other pathogens, especially Pneumocystis carinii. Many of the patients respond to therapy directed at P. carinii pneumonia alone, a result raising the question ofwhether or not CMV is a true pulmonary pathogen. When CMV causes pulmonary disease in patients with AIDS, the syndrome is that of interstitial pneumonia. Patients often complain of gradually worsening shortness of breath; dyspnea on exertion; and a dry, nonproductive cough. The heart and respiratory rates are elevated, and auscultation of the chest often reveals minimal findings and no evidence of consolidation. Chest radiographs show diffuse interstitial infiltrates similar to those present in patients with P. carinii pneumonia. Hypoxemia is invariably present. The diagnosis ofCMV pneumonia is made on the basis ofa combination of factors: (I) CMV-positive cultures of lung tissue or bronchoalveolar lavage (BAL) specimens; (2) the presence in tissue of (a) pathognomonic cells with intranuclear inclusion bodies and (b) CMV antigen or nucleic acid; and (3) the absence of other pathogenic organisms. Patients with CMV-positive cultures of lung tissue or fluids and in whom no other pathogens are identified with diagnostic bronchoscopy may have invasive CMV pneumonia, but the diagnosis is more secure if tissue involvement is documented by the presence of inclusions, antigens, or viral nucleic acid within cells. Therapy with ganciclovir should be considered when a patient has documented pulmonary infection, when CMV is the only pathogen identified, and when his or her condition is deteriorating. In patients with AIDS, ganciclovir is less effective in treating pneumonia than it is in treating retinitis; - 50%-60% of patients respond to an initial course of therapy. The usual treatment is 5 mg/kg twice daily, although a higher dosage may be necessary. Unlike therapy for retinitis, therapy for pneumonia may be stopped once the pneumonia has resolved. Perhaps hyperimmune globulin to CMV should be given also, as it is to bone marrow transplant recipients who develop CMV pneumonia.

eID 1992; 14 (February)

eID 1992; 14 (February)

CMV Infection in Patients with AIDS

What Types of Treatment Are Available? Ganciclovir Ganciclovir is an acyclic nucleoside analogue of thymidine that is structurally similar to acyclovir. In vitro, ganci-

clovir shows activity against HSV and varicella-zoster virus at concentrations equivalent to those at which acyclovir is active but is 10- to 100-fold more active against CMV; 50% inhibition of CMV replication (measured by plaque- or yield-reduction assay) requires concentrations of 0.4-11.0 p,M (0.1-2.75 mg/ml.) (15]. Ganciclovir itself is inactive and must be converted to the triphosphate to inhibit viral DNA synthesis. The drug is phosphorylated to the monophosphate in virus-infected cells to a greater degree than in uninfected cells. It is then further converted to the triphosphate (the active form) by cellular enzymes, presumably deoxyguanosine kinases. HSV and varicella-zoster virus induce their own thymidine kinase in infected cells, and this enzyme efficiently phosphorylates ganciclovir. The mechanism by which monophosphorylation occurs in CMV- and Epstein-Barr virus-infected cells is obscure, however, because these viruses do not specify a thymidine kinase. It appears that the CMV genome encodes an enzyme that does phosphorylate ganciclovir, since virtually all resistant strains fail to phosphorylate the drug. Although ganciclovir functions like acyclovir as a selective inhibitor of viral DNA polymerase, unlike acyclovir, ganciclovir has a 5' hydroxy group and, thus, can be incorporated into DNA. Therefore, ganciclovir may be expected to be more toxic than acyclovir, and this theory has been supported in animal and clinical studies. Pharmacology and dosage. Intravenous ganciclovir is the only form currently available for clinical use. It is supplied as a lyophilized powder in vials containing 500 mg. It should be reconstituted only with 10 mL of sterile water for injection and then diluted in 50-120 mL of diluent. Acceptable diluents are normal saline (0.9% NaCl), 5% dextrose in water, and Ringer's or lactated Ringer's solution. The final volume for injection in adults should be 50-250 mL. When fluid volume is of concern, the ganciclovir may be infused in solutions containing up to 10 mg/mL; however, the pH of this solution is -11.0, and it must be infused by a pump over a l-hour period. When administered by intravenous infusion over I hour in the usual dose of 5 mg/kg, the mean peak blood level is -8 p,g/mL (32 p,M) in patients with normal renal function, and the serum half-life is 2.9-1.3 hours (16]. The drug is given twice daily during "induction" therapy, whereas maintenance therapy consists ofadministration of 5 mg/kg once daily. Because the drug undergoes renal excretion, the dosage must be reduced for patients with impaired renal function. A precise formula for dosage reduction has not been established, but suggested dosage guidelines for induction therapy are presented in table I. For maintenance therapy, these recommended dosages should be halved. Oral bioavailability is approximately 10%; studies ofan oral preparation are under way. Initial induction treatment for CMV retinitis consists of administration of 5 mg of ganciclovir/kg twice daily for 14 days. Initial response (consisting of improvement or stab ili-

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tection in tissue have involved cases of CMV pneumonia. Since this entity is so rare in AIDS, such studies are less relevant in this patient population. Both culture and antigen detection are more sensitive than histologic examination for detecting CMV infection, but whether or not cases in which no inclusions are revealed by histologic examination are true instances of CMV pneumonia is disputed. BAL specimens have also been used to detect CMV antigen and to diagnose CMV pneumonitis with a high degree of accuracy [9]. A recent report [10] indicates that overnight shell-vial culture of BAL fluid is very sensitive (96%) compared with either conventional cultures ofBAL fluid or lung biopsy. Detecting CMV by DNA hybridization. Recent efforts have been directed at detecting CMV by in situ hybridization [II]. This procedure is currently available only in research settings but gives promise as a useful diagnostic technique. Culture. Culture has been generally regarded as the definitive method for detecting CMV infection. It is an especially reliable measure of infection in immunocompromised patients because these patients often have high titers of virus in their secretions. For example, patients with AIDS may have titers of viable virus of> 106 in semen. In contrast, a single, random urine culture may fail to detect CMV infection in patients if the titer of the virus in their urine is low. The recovery of CMV from urine is increased two- to threefold by the processing of several specimens. When urine samples are directly inoculated into diploid fibroblast tissue culture, CMV cytopathic effect can occasionally be detected within a few days. More-rapid culture results may be achieved by "culture amplification" ofa specimen by using the shell-culture technique [12]. Serology. Seroconversion is usually an excellent marker for primary CMV infection but almost never occurs in patients with AIDS because the overwhelming majority are seropositive before HIV infection occurs. Titers of IgG antibody to CMV antigen may be very high in patients with AIDS, but the height of the titer is not diagnostically useful. Theoretically, CMV-specific IgM antibody develops only during primary infection. In homosexual men, IgM antibody is so prevalent (>90% in a study by Mintz et al. [13]) that it is not useful as a diagnostic test for acute primary infection. The high prevalence ofigM antibody in the sera ofhomosexual men is presumably a result of reactivation of CMV, although repetitive exposure to differing strains of the virus may account for its presence in some individuals (14].

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Table 1. Proposed dosage adjustment for ganciclovir induction therapy in patients with impaired renal function. Level of renal function Normal Mild impairment Moderate impairment Severe impairment

=

100

Serum creatinine level (mg/IOO ILL)

Dosage of ganciclovir

80

(rng/kg)"

60

4.5

* For maintenance therapy these dosages should be halved [16]; b.i.d. twice a day.

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100

'0 .~

80

Parameter No. of patients Mean days to relapse" Median days to relapse"

None

Low

High

20 41 47

9 51 47

32 128 105

* Low dose, 10-15 mg/kg per week; high dose, 25-35 mg/kg per week. t Kaplan-Meier estimate [16].

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Days After Start of Induction Treatment

Figure 2. The effect of ganciclovir on CMVinfection (n = number of indicated cultures performed).

only in the treatment of acute CMV infection, but other herpesviruses (specifically HSV types I and 2 and varicella-zoster virus) are also susceptible to the drug in vitro. Because patients with AIDS and severe CMV infection frequently have illnesses due to other herpesviruses, a bonus of ganciclovir therapy may be an associated improvement of HSV and varicella-zoster virus infections. Ganciclovir is probably also active against Epstein-Barr virus, but this is not certain. Virological response to ganciclovir. The results of cultures for CMV of blood, urine, and throat-swab specimens from patients treated with ganciclovir are shown in figure 2 [19]. Most of these patients had CMV retinitis, although patients with AIDS and CMV infections of other organ systems are included. For 87% of these patients a complete virological response (conversions from positive to negative cultures or a

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Maintenance dosage of ganciclovir*

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Gl

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Table 2. Effect of ganciclovir maintenance therapy on clinical relapse ofCMV retinitis in patients with AIDS.

Urine (n = 107)

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zation in vision and/or ophthalmoscopic appearance) occurs in -80% of treated patients. By comparison, the disease is relentlessly progressive in 90% of patients if left untreated. Visual abnormalities due to hemorrhages or exudates frequently do not reverse, but a decrease in visual acuity due to edema of the macula may improve with treatment. Maintenance therapy for the remainder of the patient's life appears necessary, because the virus is only suppressed, not eliminated, by ganciclovir. Table 2 compares patients with CMV retinitis who received no maintenance therapy with those who received either low- or high-dose maintenance therapy [16]. The data suggest that maintenance therapy at a dosage of 30-35 mg/kg per week is required for sustained remission, although the optimal schedule for maintenance therapy remains to be established. Toxicity, especially neutropenia, may limit the dose and duration of maintenance therapy. Even with continued maintenance therapy, progression of CMV retinitis can occur. This can result from resistance of the virus to the drug or from the patient's continued immunologic deterioration as the HIV infection progresses [17]. Retinal detachment may occur in later stages ofCMV retinitis as the necrotic retina scars and thins. Intravitreal injection of ganciclovir has been used in patients whose neutropenia limited the amount of drug that could be administered systemically, but this approach does not provide therapy for the systemic CMV infection that is frequently present [18]. Clinical use. Administration of ganciclovir is indicated

1992; 14 (February)

em

1992; 14 (February)

CMV Infection in Patients with AIDS

frequent complaint (5%), followed by vomiting (4%), abnormal liver function (3%), and diarrhea (2%). (3) Toxic effects on gonads. In preclinical animal studies, ganciclovir was determined to be a potent inhibitor of spermatogenesis. Sperm counts before and during ganciclovir therapy have been obtained too infrequently to provide meaningful information on spermatogenesis in humans. Follicle-stimulating hormone and luteinizing hormone have been measured in patients treated with ganciclovir, and increases in the levels of these hormones have been noted in - 30% of patients. These data may suggest that toxic effects on end-organs are produced. Unfortunately, control patients not receiving ganciclovir must also be studied to accurately interpret these results. Nonetheless, patients wishing to reproduce should use ganciclovir only for the strongest indications. Approximately one-third of patients must discontinue or interrupt ganciclovir treatment. The most common causes of interruption of therapy are neutropenia (65%), adverse CNS reactions (11%), and thrombocytopenia (8%). Additional Considerations

Ganciclovir plus zidovudine. Studies are in progress to determine whether the combination of zidovudine and ganciclovir is more toxic than either agent alone. Until these results are available, the two drugs should be given concurrently with extreme caution and frequent hematologic monitoring. In the occasional event of serious drug toxicity, the physician (and patient) must decide which drug should no longer be administered. Each case must be considered individually, but sight-threatening disease usually mandates continuation of therapy with ganciclovir. In these instances, dideoxyinosine (ddI) or dideoxycytidine (ddC) should be substituted for the zidovudine. CMV immune globulin. CMV immune globulin (derived from plasma with a high titer ofCMV antibody) or high-dose human gamma globulin has been combined with ganciclovir to treat bone marrow transplant recipients with CMV pneumonia; however, since CMV pneumonia is so rare in AIDS patients, the use of this product should also be very rare. Moreover, there is no evidence that this product is of any added benefit in treating CMV syndromes other than pneumonia. Foscarnet

Foscarnet, also known as phosphonoformate, phosphonoformic acid, or PFA, is a pyrophosphate that inhibits the DNA polymerase ofCMV. Specifically, the drug blocks the pyrophosphate binding site of the viral DNA polymerase, preventing cleavage of pyrophosphate from deoxyadenosine triphosphates (figure 3) [21]. This action is relatively selective in that CMV DNA polymerase is inhibited at concentra-

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> 100-fold reduction in CMV titer) was detected in urine, and for 83% a complete response was detected by culture of blood. The median time until response was 8 days for both blood and urine cultures. Resistance to ganciclovir. Erice et al. [20] reported three patients in Minnesota whose clinical course suggested the emergence of resistance and whose CMV isolates required increases in the concentration of ganciclovir to be inhibited in tissue culture by 90% over baseline determinations [20]. Subsequently, my colleagues and I recently documented that after 3 months of continuous ganciclovir therapy, -10% of patients excrete resistant strains of CMV (arbitrarily defined as strains that are inhibited only by four times the median concentration of ganciclovir required to inhibit a group of pretherapy isolates [17]). These strains appear to remain sensitive to foscarnet, and patients excreting ganciclovir-resistant strains have been successfully treated with foscarnet [20a]. Toxicity. Toxic effects frequently limit therapy with ganciclovir. The primary types of adverse affects are as follows. (1) Hematopoietic effects. Neutropenia, defined as an absolute neutrophil count of < 1,000/mm3 , occurs in nearly 25% ofganciclovir recipients. Sixteen percent of patients receiving the drug develop neutrophil counts of

Cytomegalovirus infection in patients with AIDS.

Advances in the field of antiviral therapy are now occurring with increasing frequency and rapidity and often generate varying degrees of confusion am...
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