Management of cytomegalovirus disease with antiviral drugs.

REVIEWS OF INFECTIOUS DISEASES • VOL. 12, SUPPLEMENT 1 • SEPTEMBER-OCTOBER 1990 © 1990 by The University of Chicago. All rights reserved. 0162-0886/90/1205-0056$02.00

Management of Cytomegalovirus Disease with Antiviral Drugs Henry H. Balfour, Jr.

From the Departments of Laboratory Medicine and Pathology and of Pediatrics, University of Minnesota Health Sciences Center, Minneapolis, Minnesota

Cytomegalovirus (CMV) has been recognized as a neonatal pathogen for many years. More recently, this virus has been identified as a major cause of infectious disease in patients with cancer, recipients of organ and bone marrow transplants, and persons with AIDS. At the University of Minnesota Health Sciences Center in Minneapolis, we have been grappling for nearly two decades with the problem of CMV disease in our immunosuppressed patients. CMV has been so pervasive that we nicknamed it the "troll of transplantation." As the number of transplant recipients and AIDS patients grows, the need for effective anti-CMV compounds will become even more apparent. This is a review of clinical trials designed to assess treatment or suppression of CMV disease. The presentation is limited to trials of antiviral drugs and begins with those designed for treatment because protocols for treatment historically

This work was supported in part by grants no. AM 13083from the National Institute of Arthritis and Metabolic Diseases and no. AI 27661 from the National Institute of Allergy and Infectious Diseases and grants from Burroughs Wellcome Company and the Minnesota Medical Foundation. The author appreciates the skilled editorial assistance of Carol J. Andersen, Ralph C. Heussner, and Courtney V. Fletcher. Please address requests for reprints to Dr. Henry H. Balfour, Jr., Box 437 UMHC, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455.

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preceded those designed for prevention of the expression of CMV disease. Treatment of CMV Disease Initial Work with Pyrimidine Nucleosides

In the early days of CMV therapy, several anticancer drugs with uncertain antiviral mechanisms of action or activity were employed in desperate attempts to treat CMV disease. The structures of three of these compounds are shown in figure 1. Five leukemic children were treated with floxuridine for presumed CMV pneumonia [1]. The dosage given for CMV disease was the same as that used for treatment of leukemia. The patients showed prompt clinical responses with complete resolution of their pneumonitis. Unfortunately, laboratory confirmation of CMV disease was not well documented in this report. Intravenous administration of idoxuridine (total dose, 600-800 rug/kg infused over 5-7 days) was associated with a decrease in viruria in two of three infants with cytomegalic inclusion disease [2]. However, a clinical response was not apparent. Intravenous cytarabine (cytosine arabinoside) at dosages of 2-8 mg/Ikg-d) for 5-11 days was associated with decreased excretion of CMV in three infants with cytomegalic inclusion disease, but the drug was without clinical benefit [3]. These studies taken in aggregate were not sufficiently encouraging to stimulate controlled trials.

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Treatment of cytomegalovirus (CMV) disease met with limited success until the development of ganciclovir.Favorable clinicalresponses to ganciclovirhave been reported in ~80OJo of immunocompromised patients with CMV retinitis or gastrointestinal disease. CMV pneumonia is more difficult to treat, with therapy benefiting 10%-72% of patients. Ganciclovir must be given parenterally; the dose-limiting adverse event is neutropenia. Patients with AIDS frequently experience relapse and require maintenance therapy. Foscarnet is an attractive anti-CMV drug but must be given parenterally and is completely dependent on renal clearance for elimination. Prevention of CMV disease with antiviral drugs may be possible. Five weeks of intravenous acyclovir (500 mg/m" three times a day) significantly reduced the risk of CMV infection and disease in seropositive allogeneic bone marrow transplant recipients. The prophylactic benefit of acyclovir has recently been confirmed and extended by a placebo-controlled trial in renal allograft recipients at the University of Minnesota. A 12-week course of high doses of oral acyclovir (3,200 mg/d) was safe and significantly reduced the incidence of CMV infection and disease.

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Idoxuridine 0

01)'

~ HO

NH2

N:)

O~N

H~ HO

HO

HO O~N 0

F

I

~ HO

Vidarabine

N5c) ~N HO~ N

HO

HO

Figure 1. Chemical structures of three pyrimidine nucleosidesused in early efforts to treat CMV disease compared with the structure of the purine nucleoside vidarabine.

Vidarabine

Vidarabine (adenine arabinoside, ara-A; chemical name, 9-J3-n-arabinofuranosyladenine monohydrate) is a purine nucleoside with a molecular weight of 285.27 (figure 1). In the 1960s the compound was shown to have activity against human herpesviruses, including CMV [4]. Vidarabine has been shown to be randomly incorporated in its monophosphate form into herpes simplex viral and mammalian cellular DNA [5]. Vidarabine has multiple potential mechanisms of action, including inhibition of the DNA polymerases of herpesviruses. It was reasonable, therefore, to evaluate vidarabine as therapy for CMV disease. Twelve patients were treated with 5-20 mg of vidarabine/kg iv for 6-18 days [6]. Five children had congenital CMV infections, five had CMV disease following renal transplantation, and two had CMV mononucleosis. Viruria decreased in some children, but the clinical benefits of the drug were not clear. Rytel and Kauffman treated three renal transplant recipients with vidarabine at doses of 5-10 mg/(kg·d) for 4-6 days

[7]. Two patients experienced hematologic toxicity, and none experienced a clinical benefit. Pollard et a1. treated seven patients with CMV retinitis with doses ofvidarabine as high as 20 mg/(kg·d) for 5-14 days [8]. Five patients showed ophthalmologic improvement, but therapy was associated with significant gastrointestinal, hematologic, and neurologic adverse effects [8]. Weconducted the only placebo-controlled, doubleblind study of vidarabine for CMV disease [9]. After treating four renal allograft recipients with vidarabine to establish safety and tolerance, we began to enter additional renal transplant recipients in the double-blind portion of the trial. Patients assigned to the vidarabine group received 10 mg/kg iv for 7 days. The study was stopped abruptly when it became apparent that some patients were developing neurologic symptoms, including intention tremors, myoclonus, and decreased levels of consciousness. When the code for the 10 patients who completed the protocol was disclosed, it was learned that vidarabine was without therapeutic benefit and that neurologic toxicity had occurred only in patients assigned to the vidarabine group. Three of the four patients who experienced neurologic toxicity had very high serum creatinine levels (389-796 umol/L), Although we could not conclusively prove that the neurologic symptoms were due to vidarabine, the probability was high enough that we were reluctant to give this drug to any patient with compromised renal function. Acyclovir

Acyclovir(figure 2) is an acyclicanalogue of the natural nucleoside 2'-deoxyguanosine. The molecular weight of acycloviris 225.21 and the molecular weight of its iv formulation, acyclovir sodium, is 247. Mechanism of action. Acyclovir is inactive as a nucleoside and must be phosphorylated to the nucleotide form, acyclovir triphosphate, to exert its antiviral activity [10, 11]. The drug is selectively phosphorylated to acyclovir monophosphate by a virusspecific deoxypyrimidine kinase, commonly called thymidine kinase. Viral thymidine kinase is induced in cellsinfected by herpes simplex virus and varicellazoster virus but not by those infected with CMV. Acyclovir monophosphate is converted to acyclovir diphosphate by cellular guanosine monophosphate (guanylate) kinase and then by additional host-cell enzymes to acyclovir triphosphate [12]. Acyclovir


Cytarabine

Floxuridine

Antiviral Drugs for Cytomegalovirus Disease

Acyclovir

Ganciclovir

S8S1

Table 1. In vitro sensitivities of human herpesvirus to acyclovir and ganciclovir. ID50 (umol/L)" Acyclovir Virus CMV Herpes simplex type 1 Herpes simplex type 2 Varicella-zoster Epstein-Barr

triphosphate is both an inhibitor of and a substrate for viral DNA polymerase [10, 11, 13]. Acyclovir inhibits replication of at least five human herpesviruses in cell culture, and those data are summarized in table 1 [14-17]. The actual median inhibitory dose (1D50 ) values should be applied with caution to the clinical setting because there are no standard laboratory methods for antiviral sensitivity testing. The large quantities of acyclovir triphosphate produced in cells infected with herpes simplex virus account for the exquisite sensitivity of herpes simplex strains to acyclovir [11]. Varicella-zoster virus strains are not as sensitive as herpes simplex virus isolates. CMV strains do not induce production of virus-specific thymidine kinase, but the DNA polymerase of CMV is inhibited by acyclovir [18]. It is possible that the small amount of acyclovir triphosphate formed by host-cell enzymes is sufficient to halt replication of CMV under certain conditions. Resistance ofCMVstrains. CMV strains are relatively insensitive to acyclovir by in vitro plaque reduction assays [15, 16, 19, 20]. An increase in resistance to acyclovir has been demonstrated in conjunction with resistance to ganciclovir [20]. The mechanism for resistance is not known but could be the result of a mutation at the DNA polymerase gene locus that renders the DNA polymerase of CMV insensitive to acyclovir. Adverse effects. The maximal solubility of acyclovir in urine is 1.7mg/mL at 37°C. When this concentration is exceeded, the drug may crystallize in the renal collecting system, causing temporary but potentially profound renal dysfunction. With the iv

Median

Range

Median

Range

63.1 0.1 0.4 4.1

17-146 0.02-14 0.13-3 1.5-17.5 0.3-25

2.15

0.8-11 0.2-3 0.2-13.2 4.4-8.8

0.05

NOTE. Data are from [14-17]. * 1D50 = median inhibitory dose.

formulation of acyclovir, nausea, vomiting, caustic burns around infusion sites if drug solution extravasates, and CNS dysfunction have been reported. Oral acyclovir is remarkably free of adverse effects [14]. Pharmacology. In animal studies iv acyclovir rapidly enters all tissues, including the aqueous humor and brain [21]. The lowest concentrations of drug are found in the CNS. The volume of distribution of acyclovir at steady state is 70070 of total body weight ( rv50 L/1.73 m'), a volume that essentially corresponds to the total body water [22]. The average amount of plasma protein binding is 15070 of the administered dose [23]. Levelsof acyclovirin human CSF are rv50070 of the concomitant plasma concentrations [23]. Orally administered drug is poorly absorbed from the gastrointestinal tract, with plasma concentrations reaching peak levels 1.5-2 hours after ingestion of the drug [23]. The bioavailability of the oral formulations is rv15%. Approximately 70% of acyclovir is excreted unchanged in the urine [22]. In patients with normal renal function, 10070 of the acyclovirdose is recovered in the urine as 9-carboxymethoxymethylguanine, the only significant metabolite [24]. The renal clearance of acycloviris substantially greater than the estimated creatinine clearance, indicating that not all excretion is due to glomerular filtration [24]. Laskin et al. [25] showed that probenecid significantly enhanced plasma concentrations of acyclovir, indicating that the drug is eliminated by renal tubular secretion at least in part via the organic acid secretory system. Elimination of iv acyclovir conforms to a two-compartment model [23]. The l3-phase has a plasma half-life of 2.5-3.0 hours in patients >1 year of age who have normal renal function [26]. In infants 6 hours, with ""40010 of the initial level of the triphosphate persisting 24 hours after the removal of the drug from the medium [18]. Ganciclovir triphosphate appears to function both as an inhibitor of and as a faulty substrate for CMV DNA polymerase. Ganciclovir is actually less efficient than acyclovir at inhibiting CMV DNA polymerase [18]. Ganciclovir, like acyclovir, is active against at least five of six human herpesviruses. The ID so values of ganciclovir and acyclovir for human herpesviruses as determined in several laboratories are shown in table 1. As previously mentioned, the values may not be directly applicable to the clinical setting because methods for antiviral sensitivitytesting have not been standardized. Nevertheless, ganciclovir appears to be 25- to loo-fold more active than acyclovir against clinical isolates of CMV [15, 16, 20].


Clinical trials. CMV disease was one of the indications for enrollment in the first national randomized, placebo-controlled, double-blind trial of acyclovir therapy in immunocompromised patients. Between April 1980 and June 1981, we enrolled 18 patients in Minnesota with CMV disease [28]. 1\\'0 patients were excluded from final data analysis because their CMV disease was not well documented or was chronic. Results were based on 16 immunocompromised patients with acute CMV disease, 11 of whom were renal allograft recipients. Acyclovir was given iv (500 mg/m" three times a day) for 1 week. Recipientsof acyclovirdefervescedand showed clinical improvement significantly sooner than did patients receiving placebo. Although CMV was recovered from the throat and urine of acyclovir recipients throughout the study, viremia ceased after the first day of drug administration. Encouraged by the results of this trial, we conducted a second placebo-controlled study on renal allograft recipients. This study was a 2-week rather than a l-week dosing protocol because viremia had recurred rather promptly after acyclovir was discontinued in the first study. We commenced the second study in April 1982, at which time we estimated that 40 patients could be enrolled during a 2-year period. Costcontainment policies precluded the admission of some patients or forced the discharge of others before they could complete the study. We reluctantly closed the protocol in September 1983 because patient enrollment and retention were unacceptably low. Fifteen patients who had the more severe cases ofCMV disease could be evaluated [29]. There were no significant differences among these patients in time to cessation of virus shedding, defervescence, or clinical improvement. Two deaths due to CMV disease occurred in placebo recipients, but the difference in mortality between the two groups of patients was not significant. Nunan et ale treated three febrile renal allograft recipients who had serologic evidence of concurrent CMV infection [30]. Acyclovir (5-10 mg/Ikg-d[) was given iv for 5-10 days. The patients defervesced and were reported to be well after 8-12 months of follow-up. Bone marrow allograft recipients treated with acyclovir for CMV disease have fared poorly. Acyclovir alone or combined with interferon was unsuccessful for treatment of CMV pneumonia in that patient population [31, 32]. Plotkin et ale treated four children with congenital CMV disease [33].Three of the


Table 2. Phannacokinetic properties of ganciclovir. Pharmacokinetic property tY2a tY2P

Range

Mean

0.23 h 2.53 h VD 15.3 Ll1.73 m2 Vss 32.8 Ll1.73 m2 CI 208 mL/(min·1.73 2) % recovery* 91 % % protein binding NDt % oral bioavailability Cpmax 20.3 ~mol/Lt 1.5 umol/Ll' CpmiD

0.12-0.4 h 1.76-6.8 h 11-22.5 Ll1.73 m2 17-45 Ll1.73 m2 67-363 mLl(min·1.73 2) 78%-102% ND 3%-4%

NOTE. Data are from [35,37,41,42]. Abbreviations: tY2aand tY2P = half-life in the a and p phases; VD = volume of distribution; CI = clearance; C pmax and CpmiD :-= maximal and minimal plasma concentrations. * 24-hour urinary recovery of unchanged ganciclovir. t No data available. t Mean plasma concentration at steady state following l-hour infusions of 2.5 mg/kg every 8 hours.

described [38, 40, 44, 45]. Ganciclovir has a large volume of distribution, which indicates tissue uptake. The drug exhibits biexponential decay, with a terminal half-life of rv2.5 hours. Concentrations in CSF ranged from 1.96 to 2.66 umol/L (ratio of CSF to plasma concentration, 0.24-0.67) in four CSF samples obtained between 0.25 hours and 5.7 hours after an infusion of 2.5 mg/kg [44]. Although the oral bioavailability of ganciclovir is poor, peak and trough plasma concentrations after oral administration of 20 mg/kg every 6 hours were 2.96 umol/L and 1.05 umol/L, respectively [45], values that exceed the ID so for some strains of CMV. Clearance of ganciclovir is dependent upon renal elimination. Urinary recovery averages >90% in 24 hours [38, 40]. The total body clearance of ganciclovir is related to and exceeds creatinine clearance [40, 44], which suggests that tubular secretion as well as glomerular filtration is involved. No metabolites of ganciclovir have been detected. These data indicate that ganciclovir undergoes little nonrenal elimination and that its half-life in patients with renal insufficiency is prolonged. Indeed, in two patients whose creatinine clearances were 46 and 22 mL/ (min· 1.7Jl), the terminal half-lives of ganciclovir were 9.5 and 29 hours, respectively [40]. Hemodialysis has been reported to remove ganciclovir, and a terminal dialysis half-life of 4 hours was observed in one heart transplant recipient [46].


Resistance ofCMVstrains. Ganciclovir-resistant strains of CMV could eventually become troublesome. A ganciclovir-resistant human CMV mutant derived from the laboratory strain AD169 has been isolated and characterized [17]. The mechanism of resistance appears to be a reduction in phosphorylation since cells infected with this mutant accumulated 10% the amount of ganciclovir triphosphate accumulated by cells infected with the wild-type parent. Ganciclovir-resistant strains of CMV have been recovered from three immunosuppressed patients receiving long-term ganciclovir therapy [35], indicating that surveillance for ganciclovir-resistant clinical CMV isolates may be necessary. Adverse effects. Uninfected cells are capable of producing only low levels of ganciclovir triphosphate [18], but accumulation of ganciclovir triphosphate by host cells could result in myelosuppression. In vitro studies of the effect of ganciclovir on normal human hematopoietic progenitor cells have demonstrated dose-dependent toxicity. The concentration of ganciclovir required for ,50070 inhibition of granulocyte-macrophage colony formation was 2.7 ± 0.5 (SD) umol/L and for erythroid burst-forming units was 1.6 ± 0.2 umol/L [36]. These toxicity data imply that there is a threshold for ganciclovir cytotoxicity in normal human myeloid cells in vivo. Indeed, neutropenia appears to be the most important doselimiting adverse effect. The incidence of significant neutropenia (absolute count 50 umol/L and >10 umol/L, respectively, but others have observed neutropenia with lower plasma concentrations [39-41]. Neutropenia may be both dose-related and idiosyncratic. Recipients of allogeneic bone marrow appear to be more susceptible to ganciclovir-related neutropenia: a 60% incidence was observed in marrow transplant recipients vs, 35% in other immunosuppressed patients [39]. Neutropenia appears to be reversible, occurring a mean of 14.3 days after the start of therapy and resolving a mean of 22.8 days after its discontinuation [39]. Other adverse effects of ganciclovir therapy include hepatocellular dysfunction [42], thrombocytopenia, infusion site reactions, and gastrointestinal and CNS abnormalities [43]. Pharmacology. The pharmacokinetic properties of ganciclovir (summarized in table 2) have been well

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rarely undergo spontaneous remission. Ganciclovir at doses of 3-15 mg/(kg·d) has produced improvement or stabilization of CMV retinitis. Favorable clinical responses to ganciclovir have been observed in >80010 of individuals with CMV retinitis [39-41, 43,53,54]. A therapeutic range for plasma concentrations of ganciclovir in the treatment of CMV retinitis has not yet been defined; a starting dose of at least 7.5mg/(kg·d) seems reasonable [41]. The majority of patients with AIDS require maintenance therapy because they relapse after the discontinuation of initial therapy. A randomized prospective trial showed that progression of retinitis occurred sooner in patients not given maintenance therapy [55]. For some patients, especially those who cannot tolerate iv infusions because of neutropenia, intravitreal administration of ganciclovir is a viable alternative. Cantrill et al. have described the long-term results of this method [56]. Treatment ofgastrointestinal CMV disease. Gastrointestinal CMV disease responds well to ganciclovir regardless of the underlying cause of immunosuppression. In the series presented by Buhles et al., the condition of 35 (83010) of 42 patients with gastrointestinal CMV disease improved or stabilized [43]. Thirty-nine of those 42 patients had AIDS. All four transplant recipients with gastrointestinal CMV disease whom we treated experienced stabilization or improvement [39]. Dieterich et al. described clinical improvement in 52 (75070) of 69 AIDS patients with CMV gastrointestinal disease who were treated with ganciclovir [57]. Treatment ofCMVpneumonia. CMV pneumonia is a very serious disease. However, renal transplant recipients may survive this infection, especially if they are treated with ganciclovir within a few days of the diagnosis [58]. Nine of 10 bone marrow allograft recipients with biopsy-proven CMV pneumonia who were treated by Shepp et al. died [38]. Our experience [39] and that of Crumpacker et al. [59] with the treatment of CMV pneumonia in bone marrow transplant recipients has been slightly better. Five (45010) of our 11 patients with CMV pneumonia improved during ganciclovir therapy [39]. However, the ultimate prognosis for our group was dismal. Only three of the 11 survived for more than 100days after transplantation. In the series by Crumpacker et al., eight (38070) of 21 patients survived for at least 90 days [59]. The improved survival in that series could have been due to the concomitant administration of CMV immune globulin. This combination has been


Ganciclovir has been given to patients at doses of 3-15 mg/(kg·d). Within this range, dose-independent kinetics are observed, and no accumulation of ganciclovir occurs in patients with normal renal function [40, 44]. Peak plasma concentrations observed with dosages of 1, 2.5, and 5 mg/kg every 8 hours average 9.4, 20.3, and 44.5 umol/L, respectively. Trough concentrations observed with the same dosages average 0.9, 1.9, and 4.4 umol/L, respectively. When given iv, ganciclovir achieves intraocular concentrations that reach and even exceed ID 5 0 for most strains of CMV [47, 48]. In an effort to achieve therapeutic intraocular concentrations, intravitreal administration of ganciclovir has been investigated. Intravitreal doses of up to 400 IJg were found to be nontoxic in a rabbit model [49], in which the elimination half-life of ganciclovir from the vitreous was estimated to be 8.5 hours [50]. A dose of 400 IJg maintained concentrations in the vitreous greater than the ID 5 0 for CMV for >60 hours after dosing. Henry et al. administered ganciclovir intravitreally to an AIDS patient with CMV retinitis [51]. Five 200IJgdoses of ganciclovir were administered in the left eye over a IS-day period. Concentrations of ganciclovir in the vitreous were 4.6 umol/L and 0.41 umol/L 51.4hours after the first dose and 97.3 hours after the fourth dose, respectively. The estimated elimination half-life from the vitreous was 13 hours. The 200-lJgdose appeared to maintain vitreous concentrations above the target concentration (2.6 umol/L, the ID 5 0 for CMV) for 62 hours. Clinical trials. Use of compassionate-plea protocols led to treatment of literally thousands of immunocompromised patients suffering from various forms of CMV disease. Although this militates against effective conduct of properly controlled clinical investigations, several randomized, placebocontrolled, double-blind protocols are in progress. The three most common forms of CMV disease in immunocompromised hosts are retinitis, gastrointestinal disease, and pneumonia. Because these CMV syndromes are quite distinct, they will be dealt with separately. The clinical response to ganciclovir appears to be directly related both to the CMV syndrome and to the underlying immunocompromised state. Treatment of CMV retinitis. CMV retinitis develops in f\J15OJo-45070 of patients with AIDS [52]. It also occurs, but at a much lower frequency, in transplant recipients. Patients with CMV retinitis

Balfour


o

II -0- P-C

I

~0

"0-

0-

Figure 3. Foscarnet, a pyrophosphate analogue, which is structurally different from the other anti-CMV drugs discussed in this review.

Foscamet

Foscarnet is also known as trisodium phosphonoformate, phosphonoformate, phosphonoformic acid, PFA, and foscarnet sodium (figure 3). The drug is a pyrophosphate analogue with a molecular weight of 191.95. The drug interferes with a number of viral polymerases, including the RNA polymerase of influenza virus, the reverse transcriptases of mammalian retroviruses, and DNA polymerases of animal and human herpesviruses [67]. Mechanism ofaction. Foscarnet reversibly and noncompetitively inhibits the activity of CMV DNA polymerase. In a study of 16 pyrophosphate analogues, Ericksson et aI. found foscarnet to be the most effective [68]. A concentration of foscarnet of 0.3 umol/L caused 50070 inhibition of the DNA polymerase activity of CMV strain AD 169. The sensitivities of 18clinical CMV isolates and of strain AD 169 were investigated in human embryonic fibroblasts with use of an ELISA system for detection of the production of CMV antigen [69]. The ID so of foscarnet for CMV strain AD 169 was 113 umol/L, The mean ID so for 16sensitive clinical isolates was 323 ± 192 (SD) umol/L. 1\vo clinical isolates were resistant (ID so > 800 umol/L). Pharmacology. Plasma concentrations during and after iv infusion are described by a threecompartment modeL The disposition of foscarnet is triphasic, with mean half-lives of 0.45, 3.3, and 18 hours, respectively, as was seen in six patients infected with human immunodeficiency virus (HIV) type 1 [70]. In that study the highest plasma concentrations were consistently found at the end of a 72-hour continuous iv infusion of 16,000 mg/d.


shown to reduce the morbidity of CMV pneumonia in two other uncontrolled studies [60, 61]. In the report by the Collaborative DHPG Study Group, four of seven patients with CMV pneumonia died of respiratory failure before completing a 14-day course of ganciclovir [62].In contrast, Buhles et al. reported that the condition of 26 (72070) of 36 patients with CMV pneumonia improved or stabilized with treatment [43].The clinical responses wereactually better among AIDS patients than among transplant recipients: 18 (78070) of 23 AIDS patients responded as compared with six (60070) of 10transplant recipients. The virologic response to ganciclovir therapy has been dramatic. Except for the rare patient who harbors a ganciclovir-resistant CMV strain, the drug ablates viremia in transplant recipients within 5 days [39]. The median time to cessation of viremia in 41 patients treated by Buhles et al. was 8 days [43]. Treatment ofrecurrent CMVdisease. The majority of patients with AIDS relapse within a month of the discontinuation of ganciclovir [39, 40, 43, 45, 53]. Therefore, recurrent CMV,disease is usually managed with maintenance therapy on an outpatient basis. Doses from 2.5 to 6 mg/Ikg-d) are given three to seven times a week. Maintenance therapy is not uniformly effective, and break-through infections have occurred [63, 64]. A maintenance regimen of 5 mg/kg administered iv five to seven times weekly may be superior to lower dosages in preventing relapses. No relapse occurred in eight patients receiving the 5-mg/kg regimen as opposed to 11 relapses (73070 ) in 15 patients receiving the 2.5-mg/kg regimen two to five times weekly [40]. Maintenance therapy with ganciclovir appears to be associated with increased survival in patients with AIDS. In a study of 122 AIDS patients with severe CMV infections, 62 patients received maintenance therapy (6 mg/Ikg-dl). The probability of survival in those receiving maintenance therapy was 33 weeks as compared with 18 weeks for those who did not receive maintenance therapy (P < .001) [65]. Ganciclovir therapy in children. According to a report by Gudnason et al., ganciclovir appears to be welltolerated by children [66].The uncontrolled clinical results for our pediatric patients are similar to those for adult patients. Clinical improvement was associated with ganciclovir therapy in seven (58070) of 12 children. Results were better for recipients of solid organs than for recipients of bone marrow allografts. CMV shedding ceased during ganciclovir therapy in nine (75070) of 12 patients.

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Prevention of CMV Disease Vidarabine

Forty bone marrow allograft recipients participated in a study of vidarabine for the prevention of CMV disease [76]. 1\venty-two patients were randomized to receive vidarabine while 18patients who received no antiviral drugs served as the control group. Patients assigned to the vidarabine group were given a 5-day course of the drug (5 mg/kg iv over 6-12 hours) followed by a 10-day rest period. Additional 5-day courses of vidarabine interspersed with I5-day rest periods were continued until the patients relapsed, developed pneumonia, or reached the l00th day posttransplantation. This drug regimen was nontoxic, but interstitial pneumonia and CMV shedding occurred with equal frequencies among treated and control patients. The authors concluded that vidarabine did not prove to be beneficial in this setting [76].

Acyclovir

Bone marrow allograft recipients. Despite the discouraging results of acyclovir therapy for CMV disease in bone marrow transplant recipients, we believedthat the drug might still prove useful in preventing the development of active CMV disease if given to an asymptomatic patient. This approach has the theoretical advantage of providing systemic levelsof acyclovir before viral replication begins or accelerOates. Also, assuming that the treatment of recurrent genital herpes is an analogous situation, less drug would be required to suppress CMV disease than to treat it. To test this hypothesis, we conducted a multicenter protocol in which acyclovirwas administered iv from 5 days before to 30 days after allogeneic bone marrow transplantation. Because of the demonstrated suppressive benefit of acyclovir in mucocutaneous herpes simplex infections in bone marrow transplant recipients [77],the study was not placebocontrolled. Patients were tested before transplantation, and those seropositive for both CMV and herpes simplex virus were assigned to the acyclovir group. Patients who were seropositive for CMV but seronegative for herpes simplex virus served as controls. Patients seropositive for herpes simplex virus were not assigned to the control group because, according to our reasoning, the majority of them would be removed from our study prematurely. They would


Plasma concentrations during the infusions were 75-265 umol/L, Intermittent 2-hour infusions of 60 mg/kg three times a day produced peak and trough serum levelsof 557 umol/L and 155umol/L, respectively, after 2 weeks of therapy [71]. Foscarnet is not metabolized but appears to be eliminated by both tubular secretion and glomerular filtration since the renal clearance of the drug (176 mL/[min·1.73m2 ]) exceeds creatinine clearance. The apparent nonrenal clearance reflects sequestration of foscarnet in bone, where it can be deposited for many months. When 4,000 mg of foscarnet was given orally ina water solution every 6 hours for 3 days, peak plasma concentrations were below the limit of detectability in four of six patients. 1\vo patients had plasma concentrations between 35-50 umol/L, Calculated oral bioavailability varied from 12070 to 22070. It was estimated that 10070-28070 of the cumulative dose may have been deposited in bone. Adverse effects. The major adverse effect of foscarnet is renal dysfunction [71]. Renal toxicity is thought to result at least in part from dose-dependent inhibition of renal excretion of phosphate. Other adverse effects include phlebitis at the infusion site, gastrointestinal disturbances, lower back pain, decreases in hemoglobin concentrations, and electrolyte abnormalities that include hypocalcemia and hyperphosphatemia [72, 73]. Clinical trials. Foscarnet has been administered in continuous or intermittent infusions to transplant recipients and AIDS patients in uncontrolled trials [71-75]. Clinical improvement was seen in 69070 of treatment episodes in transplant patients with CMV infections reported by Ringden et at. [74]. However, all nine marrow allograft recipients with CMV pneumonia died. Favorable clinical responses were also reported in five of six transplant recipients with lifethreatening CMV disease [75]. Eleven HIV-infected patients with CMV retinitis weretreated with 2-hour infusions of foscarnet given every8 hours for 2 weeks [71].Four patients also received a maintenance regimen for an additional 2-16 weeks (60 mg/kg five times a week). A significant decrease in serum concentrations of HIV p24 antigen was observed, but the effect of the drug on CMV retinitis was not reported. A number of studies using foscarnet for the treatment of primary HIV infection or herpesvirus infections are being implemented through the National Institutes of Health AIDS Clinical Trials Group.

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During the first year after transplantation, four (7.5%) of 53 patients in the acyclovir group had CMV disease as compared with 15 (29070) of 51 in the placebo group (P = .002, Gehan test). The greatest prophylactic benefit was observed in seronegative recipients whose donors were seropositive. The incidence of CMV infection, as indicated by isolation of virus from any site cultured, was significantly lower in recipients of acyclovir than in recipients of placebo, as were the rates of viremia and viruria.

Future Priorities The next logical step in developing strategies for treatment of CMV disease is to conduct and complete controlled clinical trials of both ganciclovir and foscarnet. We do not want to be in the position of advocating the use of potentially toxic drugs unless they have proven clinical efficacy. Clinical and virologic data suggesting the anti-CMV effect of ganciclovir are abundant. However, neither the patient populations who will benefit from this drug nor its optimal dosage have been established. Foscarnet is an attractive but unproven therapeutic agent for CMV disease, HIV disease, or both. The drug clearly has the potential to be effective in certain patient populations with either or both of these viral diseases. A reasonable two-pronged approach would be the utilization of acyclovirfor prevention of CMV disease in high-risk patients. If CMV disease develops during administration of acyclovir, the patients could be treated under controlled protocols with ganciclovir, foscarnet, or neweranti-CMV drugs as they become available. An obvious but unavoidable conclusion is that we need more and better anti-CMV drugs. Several compounds with in vitro activity against CMV have not yet reached the point of clinical trials or have been withheld from patients because of potential toxicity. A good example is FIAC (2'-fluoro-5-iodoarabinosylcytosine), which is a drug developed by the Sloan-Kettering group [81] that has anti-CMV activity and may be suitable for oral administration. The search to identify and develop such drugs will intensify as more patients receive transplants and more HIV-infected persons develop AIDS. During the past two decades, we have made important advances in the management of CMV disease with antiviral drugs. Ganciclovir and foscarnet have emerged


develop mucotaneous herpes simplex infections following transplantation and be treated with acyclovir. Between April 1984 and December 1985, 151 patients completed this protocol [78]. One hundred thirty patients underwent transplantation in Seattle and 21 receivedtransplants in Minneapolis. The characteristics of the acyclovir and control groups were similar except that the acyclovir recipients were significantly older, in accordance with serologic evidence of previous infection with herpes simplex virus. Patients assigned to the acyclovirgroup received 500 mg/m' three times a day iv for 36 days. Acyclovir recipients had significantly lower rates of CMV pneumonia, invasive CMV disease, and mortality during the first 100 days after transplantation. Acyclovir recipients also had a significantly lower probability of shedding CMV than did their counterparts who received placebo. However, acyclovir was not completely effective in preventing CMV disease. Three patients developed CMV disease while receiving acyclovir, and 14 (160/0) ultimately developed CMV pneumonia during the first-100days following transplantation. It should be mentioned that patients received no antiviral drugs after the first posttransplant month. It is entirely possible that a longer course of acyclovir would have resulted in even fewerbreakthrough cases of CMV disease. Renaltransplant patients. Shortly after the bone marrow transplant protocol was under way, we began a similar study of renal transplant recipients. Because iv acycloviris potentially nephrotoxic, we studied the oral formulation in renal allograft recipients. Acyclovir was given at doses of 800-3,200 mg/d for 12 weeks according to a dose-adjustment regimen based on estimated renal function. Patients received their first dose of acyclovir as an 800-mg tablet just before transplantation. Plasma concentrations of acyclovir were measured by radioimmunoassay on days 1 and 2 and 5, 6, or 7 after transplantation. The dosage-adjustment scheme and the pharmacokinetic model performed well, allowing us to safely administer these doses in the immediate posttransplant period [79]. Mean peak and trough acyclovir concentrations near the end of the first week of acyclovir dosing were25 umol/L and 18 umol/L, respectively. We then conducted a randomized, placebo-controlled, double-blind trial between August 1985and May 1988in 104recipients of cadaver kidneys. Acyclovir was found to be safe and significantly reduced the incidence of CMV infection and disease [80].

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as promising drugs for treatment of CMV disease. Acyclovir has prevented CMV disease in bone marrow and renal allograft recipients in controlled trials. If ganciclovir and foscarnet withstand the rigors of controlled treatment trials, a combined preventiontreatment plan for management of CMV disease will be at hand. References

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The clinical significance of infections with cytomegalovirus strains resistant to antiviral drugs.

Polymerase chain reaction to evaluate antiviral therapy for cytomegalovirus disease.

Antiviral drugs.

The clinical significance of in vitro cytomegalovirus susceptibility to antiviral drugs.

Diagnosis of viral disease and the advent of antiviral drugs.

New antiviral and antifungal drugs.

Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus.

Teratogenicities of ophthalmic drugs. I. Antiviral ophthalmic drugs.

Inhibition of immune functions by antiviral drugs.

Optimizing distribution of pandemic influenza antiviral drugs.

Resistance of viruses to antiviral drugs.

Failure of antiviral therapy in AIDS-associated cytomegalovirus cholangitis.

Effects of antiviral therapy for patients with inflammatory bowel disease and a positive intestinal biopsy for cytomegalovirus.

Cytomegalovirus antiviral resistance: characterization of results from clinical specimens.

Human cytomegalovirus (CMV) susceptibility to currently approved antiviral drugs does not impact on CMV terminase complex polymorphism.

Cytomegalovirus and ulcerative colitis: Place of antiviral therapy.

Systemic antiviral drugs used in ophthalmology.

Antiviral drugs for seasonal influenza 2014-2015.

Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients.

Antiviral drug resistance in herpesviruses other than cytomegalovirus.

Long-term outcome of inflammatory bowel diseases with cytomegalovirus colitis: effect of antiviral treatment.

Aminobisphosphonates Synergize with Human Cytomegalovirus To Activate the Antiviral Activity of Vγ9Vδ2 Cells.

Artesunate demonstrates in vitro synergism with several antiviral agents against human cytomegalovirus.

Targeting the latent cytomegalovirus reservoir with an antiviral fusion toxin protein.