REVIEWS OF INFECTIOUS DISEASES • VOL. 12, SUPPLEMENT 7 • SEPTEMBER-OCTOBER 1990 © 1990 by The University of Chicago. All rights reserved. 0162-0886/90/1205-0052$02.00
Cytomegalovirus in the Setting of Infection with Human Immunodeficiency Virus Robert T. Scbooley
From Harvard Medical School; and the Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts
Cytomegalovirus (CMV) is a ubiquitous human herpesvirus that contributes directly and indirectly to morbidity and mortality among patients infected with human immunodeficiency virus (HIV). CMV plays at least four possible roles in the pathogenesis of AIDS. These include direct CMV-induced morbidity associated with distinct clinical syndromes. Less direct roles for CMV in the pathogenesis of AIDS include interactions by which CMV may potentiate the immunomodulation induced by HIV or enhance HIV replication by trans-activation at the cellular level. Finally, gastrointestinal mucosal involvement of CMV infection may predispose to other infections by contributing to destruction of integumentary barriers. Previously it had been hypothesized that CMV played a role in Kaposi's sarcoma. However, recent data suggest that Kaposi's sarcoma is the result of proliferation of endothelial cells stimulated by growth factors elaborated by CD4+ cells infected with human T cell leukemia virus I or II or HIV-l or HIV-2 [1, 2]. Thus, this review will not include a discussion of the possible relation between CMV and Kaposi's sarcoma. Prevalence of CMV Infection in Patients with DIV Infection Serologic and isolation studies have documented an extremely high prevalence of CMV infection in most HIV-infected patient populations (table 1) [3-8]. The author gratefully acknowledges the editorial assistance of Ms. Janet Steele. Please address requests for reprints to Dr. Robert Schooley, Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
Rates of seropositivity to CMV in studies of healthy American homosexual men are usually >90070. In homosexual patients with AIDS, rates of CMV seropositivity approach 100070. CMV seropositivity also is common among African patients with AIDS [7] but is less prevalent among hemophiliacs with HIV infection [8]. Among hemophiliacs with HIV infection, rates of CMV seropositivity appear to parallel closely those among age-matched control populations. Excretion of CMV increases with increasing HIVrelated immune dysfunction [4, 5]. Attempts to isolate CMV from cultures of urine, throat, and blood of homosexual men are often successful [4]. Excretion of CMV in semen is exceedingly common, with isolation rates of up to 40% in homosexual men [6]. It has been hypothesized that excretion of CMV in semen plays a major role in the transmission of CMV among homosexual men. Although much of the CMV activity among HIV-infected individuals reflects reactivation of latent virus, superinfection with multiple strains of CMV has been documented by Southern blot hybridization [9]. As noted above, the ubiquity of CMV infection among homosexual men is a reflection of both increased rates of sexual transmission and decreased immunologic control of latent CMV. Immunologic control of latent infection with viruses of the herpes group is mediated primarily by cellular immune mechanisms [10-13]. Defects in natural killer cell activity,in CMV-and Epstein-Barr virus (EBV)-specific cytotoxic T lymphocyte effector function, and in CMV-induced lymphocyte proliferation and interferon generation have been documented. In general, loss of herpesvirus-specific effector functions occurs parallel with decreases in other aspects of the cell-
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Human cytomegalovirus (CMV) has several possible roles in the pathogenesis of AIDS. CMV causes a number of clinical syndromes, including retinitis, pneumonitis, and gastroenteritis in patients infected with human immunodeficiency virus type 1 (HIV-l). In addition, CMV may potentiate the cellular immunodeficiency observed in patients with HIV infection either directly or through enhancement of HIV replication. Finally, CMV may predispose the host to bacterial or fungal infection by compromising the integrity of mucosal barriers to infection. Therapy with ganciclovir for CMV infection may result in a decrease in morbidity related to the virus, but problems with drug toxicity and resistance to the agent mandate the development of additional therapeutic approaches.
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mediated immune response as measured by the total number of circulating cells of the CD4+ surface phenotype [13]. Partial or complete restoration of natural killer activity and of the ability to generate CMV- or EBV-specific cytotoxic T cells has been demonstrated in vitro with interleukin-2 but not with interferon-a [13, 14]. The ability of such immunomodulating agents to restore CMV- or EBV-specific immune mechanisms in vivo has not yet been adequately addressed.
With the initial description of AIDS, it was noted that several of the immune abnormalities in patients with AIDS appeared to bear a superficial resemblance to abnormalities observed in patients with primary CMV or EBV infection. These abnormalities included, but were not restricted to, changes in the relative distribution of lymphocyte surface phenotypes in the peripheral blood and a great decrease in responses to mitogens and antigens [15-17]. In addition, it has been demonstrated that reactivation of herpesvirus in the setting of immunosuppression may also be associated with a return of the immunoregulatory abnormalities exhibited during primary infection with the herpesvirus [18]. These superficial similarities, coupled with the ubiquity of herpesvirus infection among patients with AIDS, led to early speculation that herpesviruses might even play an etiologic role in the pathogenesis of AIDS. Interaction of CMY and DIY at the Cellular Level HIV replication is regulated by a complex array of HIV-encoded regulatory gene products [19-22]. In addition to being activated by viral promotors, the long terminal repeat segments of HIV have been shown to be responsive in vitro to cellular transcription activators [23, 24]. This has led to speculation that immunologic activation of an HIV-infected CD4+ cell might also lead to enhancement of HIV replication [25]. Other groups have investigated possible direct interactions between herpesvirus promotors and the regulatory long terminal repeat sequence of HIV [26, 27]. Such in vitro studies have demonstrated that regulatory elements of CMV, herpes simplex virus (HSV), and EBV are capable of activating the long terminal repeat sequence of HIV. The mechanisms responsible for this activation might not be the same for retrovirus and herpesvirus gene prod-
CMV seropositivity Patient population Homosexual men in the U.S. With AIDS or ARC HIV seronegative HN seropositive Patients with AIDS Africans Men in the U.S. Hemophiliacs 20 y of age Overall NOTE.
(% )
93.5
Reference
3 4 6
100 80 100
6
100 100
7 7
26
8
59 43
8
ARC = AIDS-related complex.
ucts, but the net result in culture is the same, i.e., increased expression of the long terminal repeat segment of HI V [26]. Recently, Skolnik et al., extended these observations, which were made primarily with plasmids, to preparations of whole virus in T cell lines [28]. The possible role of such regulatory interactions between herpesviruses and HIV in the pathogenesis of AIDS is dependent on dual infection of individual cells in vivo. Although dual viral isolation from single-cell preparations has not been demonstrated, dual infection of B cells by HIV and EBV has been demonstrated in vitro [29, 30]. Recently, Nelson et al. have demonstrated dual infection of brain cells with CMV and HIV in patients with HIV infection in studies in which in situ nucleic acid hybridization and indirect immunofluorescence were used simultaneously [31]. The role, if any, of additive immunosuppression and of trans-activation mediated by herpesviruses in the pathogenesis of AIDS remains to be conclusively demonstrated. Although evidence has accumulated that herpesvirus activity increases with increasing HIV-induced immune dysfunction, and although prospective cohort studies have suggested that an elevated titer of CMV antibody is an independent risk factor for clinical progression to AIDS, such studies suffer from the familiar cart-and-horse problem [4, 5, 32]. It is not possible to distinguish betweenincreased herpesvirus activity due to progressive HIV-induced immune dysfunction and accelerated HIV-induced dysfunction due to increased herpesvirus activity. In addition, the occurrence of occasional transfusion-associated cases with no evi-
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CMY-Induced Immunomodulation
Table 1. Seroprevalence of CMV infection in selected populations at risk for AIDS.
CMVinAIDS
dence of prior herpesvirus infection indicates that development of AIDS is not dependent on herpesvirus infection per se. Further investigation of these interactions at the cellular level with the use of molecular biological techniques will provide useful insights into viral and cellular regulatory mechanisms. The assessment of the potential clinical impact of such interactions requires the development of therapeutic strategies that will influence these regulatory mechanisms before the development of frank AIDS.
CMV is ubiquitous during life [4-7, 33] and at autopsy in patients with AIDS [34]. CMV-induced morbidity has been reported in patients with AIDS, with involvement of the eye and of the gastrointestinal, pulmonary, nervous, and reproductive systems (table 2) [35-61]. In patients with AIDS, CMV-induced morbidity is most easily demonstrable in the eye and in the gastrointestinal tract. With CMV retinitis, patients usually present with painless progressive loss of vision, which initially may involve only one eye but usually progresses to both eyes if untreated. Ophthalmoscopic findings are usually characteristic, appearing as a hemorrhagic process that heals with hypopigmented scarring. CMV-associated morbidity throughout the gastrointestinal tract has been reported, with lesions involving the oral mucosa, the esophagus, the intestine, the rectum, as well as the biliary tree [38-51]. In the case of oral or esophageal lesions, the involvement may be painful and progressive. In addition to the direct morbidity that such involvement induces, eating may be difficult for these patients, thus exacerbating a marginal nutritional status. Finally, CMV may compromise mucosal barriers and predispose to infection with other pathogens. Gastric and intestinal involvement may be associated with gastrointestinal bleeding, perforation, malabsorption, and/or intractable diarrhea. In addition, occasional cases of antral obstruction have been reported [42, 43]. Biliary involvement has also been reported, with clinical manifestations including cholangitis, papillary stenosis, and acalculous cholecystitis [46-49]. Encephalitis and pneumonia due to CMV are frequently reported. In each situation, however, it is often difficult to distinguish CMV colonization from pathogenic involvement of the organism [52]. The diagnosis of CMV pneumonia often is made in the
Table 2. AIDS.
Manifestations of CMV infection in patients with
Ophthalmic Retinitis Conjunctivitis CNS Encephalitis Myelitis Gastrointestinal Stomatitis Esophagitis Gastritis Antral obstruction Cholecystitis/cholangitis/papillary stenosis Hepatitis Ileitis/colitis Proctitis Miscellaneous Pneumonia Adrenalitis Epididymitis Cervicitis
setting of concomitant pneumonia due to Pneumocystis carinii solely on the basis of isolation of CMV from bronchial washings. Given the ubiquity of CMV in patients whose immunodeficiency is profound enough to have permitted the development of R carinii-pneumonia, it is particularly difficult to ascribe pneumonia to CMV solely on the basis of the isolation of CMV. Although histologic involvement of the brain suggestive of CMV infection frequently is noted in patients who die of AIDS and although nucleic acid sequences and antigens of CMV have been demonstrated in neural tissue obtained from patients with AIDS [31], the problems involved in ascribing a pathogenic role for CMV in the brain are similar to those involving the lungs. This is further compounded by the demonstrable neurotropism of HIV [62-65]. Nonetheless, patients have been reported in whom encephalitis, myelitis, and polyneuropathy have been attributed to CMV infection [56-61]. Adrenal involvement of CMV has also been reported [35, 66-68]. This involvement may simply be noted histologically at autopsy or may be clinically apparent as adrenal insufficiency [35, 68]. CMV has also been reported to cause epididymitis, uterine cervicitis, and thrombophlebitis [53, 55]. Thus, although patients with AIDS are at risk for morbidity due to a wide variety of pathogens, few, if any, of these organisms are capable of producing
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Clinical Impact of CMV Infection in Patients with HIV Infection
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such widespread disease as is CMV. The clinical manifestations of CMV infection are protean in this patient population, and unlike the situation in other immunocompromised patients, in whom the immunodeficiency may improve with marrow engraftment or the like, once established, CMV-related morbidity in patients with AIDS tends to follow a progressive, relentless course in the absence of effective therapeutic intervention.
Therapy for CMV infection in patients with AIDS represents both a challenge and an opportunity. As noted above, in patients with AIDS there is no opportunity to ameliorate the immunodeficiency by the sacrifice of an allograft, by bone marrow transplantation, or by induction of a neoplastic remission. Thus, in the setting of AIDS, antiviral agents can get little help from host immune mechanisms in overcoming CMV infection. This creates the challenge of developing therapeutic strategies that permit the maintenance of the antiviral effect and, conversely, an opportunity to evaluate antiviral agents in the absence of potentially confusing variables such as changing immune competence. In addition, successful treatment of CMV infection in the setting of AIDS often provides extremely gratifying results regarding the organ-system involvementthat prompted therapeutic intervention as well as an improvement in systemic manifestations of CMV infection such as fever, weight loss, and inanition. A number of therapeutic modalities for CMV infection have been suggested (table 3). The modalities proposed have included therapy with classic antiviral agents such Table 3. Potential therapeutic modalitiesfor treatment of CMV infection. Nucleoside analogues Ganciclovir Intravenous Oral Intravitreous Others Foscarnet
Table 4. Response of CMV infection to therapy with ganciclovir. Reference 76 74
77
Biologic response modifiers Interferons
Interleukin-2 Isoprinosine Immunoglobulins Zidovudine
78
Organ system Retinitis Colitis Retinitis Colitis Pneumonia Retinitis Gastrointestinal CNS Colitis Esophagitis Proctitis Ileitis
No. responded/ no. treated 6/7
111 11113 5/8 3/7 52/57 9/13 0/2 23/31 4/4 3/4 011
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Therapy for CMV Infection in Patients with AIDS
as ganciclovir and foscarnet as well as therapy with immunomodulating agents such as interferons and interleukin-2. Although interleukin-2 has been shown to partially restore CMV-specific cell-mediated immune responses in vitro [13, 14],it has not been studied extensively as a form of therapy for CMV. Attempts to treat established CMV infection with interferon-a in the setting of either CMV infection or allograft transplantation have been unsuccessful [69-71]. Successful therapy for CMV retinitis and for the gastrointestinal manifestations of CMV infection with the acyclovir analogue ganciclovir has been reported by several groups [72-79]. These studies havedemonstrated initial rates of partial or complete response of 700/0-900/0 for patients with ophthalmic or gastrointestinal disease (table 4) [74, 76-78]. Response rates in patients with other manifestations of CMV infection are difficult to assess because of the more sporadic nature of the case reports delineating these syndromes. Therapy involves an initial induction phase in which 7.5-15 mg of ganciclovir/kg is administered iv daily split into two or three equal doses. The current regimen recommended by Syntex (Palo Alto, California) involvesinitial induction with a dose of 5 rug/kg every 12 hours. As noted above, this regimen results in a clinical response in (\)800/0 of patients. The toxicity of ganciclovir is considerable (table 5). The most significant acute toxic reaction is bone . marrow suppression. Depending on the patient population tested, the duration of therapy, and the other drugs being administered, dose reduction or interruption may be necessary in up to 500/0 of patients because of anemia, neutropenia, or throm-
CMVin AIDS
Table S. Problems remaining with ganciclovir therapy. Toxicity Hematologic Neutropenia Thrombocytopenia Anemia Other CNS (disorientation, psychosis) Hepatitis, anorexia, nausea Thrombophlebitis Azoospermia
Route of administration Interactions with other drugs Zidovudine Pyramethamine/trimethoprim/sulfonamides
bocytopenia. Other toxic reactions that have been reported are CNS or gastrointestinal dysfunction, thrombophlebitis, and azoospermia. Hematologic toxicity appears to be exacerbated in some patients by concomitant administration of zidovudine. Once an initial response has been achieved (usually within 10-14 days), maintenance therapy is required. Most investigators administer the drug in a single daily dose of 2.5-5 mg/kg 3-7 days per week. Maintenance therapy is complicated by observation of the same acute toxic effects and usually requires the use of an indwelling central venous line. The risk, expense, and inconvenience associated with daily iv infusions of ganciclovir are considerable. Unfortunately, failure to continue ganciclovir therapy in this patient population is always associated with relapse. Recently, attempts have been made to circumvent the hematologic toxicity of the drug by administering it intravitreally for retinal disease or as an aerosol for pneumonia. Pilot studies of the pharmacokinetics of orally administered ganciclovir may provide alternatives to long-term iv administration [80-82]. Recently, resistance to ganciclovir was demonstrated in CMV isolates obtained from three patients undergoing prolonged treatment with ganciclovir [83]. This resistance, coupled with the toxic effects of the drug and the difficulties entailed in administering the drug parenterally essentially for the lifetime of the patient, should provide a strong impetus for the development of alternative agents with activity against CMV. Foscarnet (trisodium phosphonoformate hexahy-
Table 6. Response of patients with CMV retinitis to therapy with foscarnet. Response
No. of patients
No. treated Clinical response Resolution Improvement Relapse Toxic reactions Increase in creatinine level Anemia Tremor Thrombophlebitis NOTE.
13 13 6 7 8/12 10 6
5 3 2
Data are from [85].
drate) has been under study for treatment of herpesvirus infections in Scandinavia for several years. Recently, studies of foscarnet for the treatment of CMV infection in patients with AIDS have been undertaken [84, 85]. Although no controlled trials comparing ganciclovir to foscarnet have been reported, the initial rates of response to foscarnet therapy appear to be in the same range as those for ganciclovir [85]. Foscarnet is less likely to cause granulocytopenia than is ganciclovir but is also not without toxicity (tables 6 and 7). Maintenance therapy also is required with foscarnet, and its absorption following oral administration is limited [86]. Although the field of therapeutics for CMV retinitis in the setting of HIV infection is currently in a state of flux, a reasonable approach is presented in figure 1. If a patient has a peripheral involvement of the retina that appears to be stationary or progressing only slowly, it is reasonable to observe the patient ophthalmoscopically on a weekly basis. Objective assessment of progression is facilitated by the use of ophthalmoscopic photography. If the disease has not progressed, initiation of zidovudine therapy should be considered for those not already receiving the drug. Zidovudine therapy may result in a tem-
Table 7. Problems associated with foscarnet therapy. Toxicity Renal dysfunction Hematologic (anemia) Thrombophlebitis Nausea Tremor Route of administration How much is enough?
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How much is enough? Induction Maintenance
8815
8816
Schooley
Retinitis is sight-threatening, rapidly progressive, or assOciated with systemic manifestations
YES
I
"
NO
J
~
Gancidovir therapy (withhold zidovudine)
Observe
I I Maintenance 5 days/week Retinitis controlled
\
I
I
Decrease dose frequency as tolerated
Add zidovudine
~
NO
Observe
\
r: '0," Increase to 7 days/week
NO
YES
~
Add zidovudine
Figure 1. Approach to therapy for CMV retinitis in patients with AIDS.
\I
Remission or stabilization YES
\
NO
Observe
I
\
Gancidovir therapy
Consider alternative therapies: foscarnet intravitreal gancidovir
porary improvement in some patients as the result of its indirect immunomodulating activity through inhibition of HIV replication [87]. When the lesion is sight-threatening or rapidly progressive, ganciclovir therapy should be initiated. It is generally recommended that zidovudine be withheld during the induction phase of ganciclovir therapy. If the disease is controlled by an initial induction regimen, conversion to a 5-day-a-week maintenance regimen is indicated. If the disease remains stable with this dose for 4-6 weeks, it is reasonable to attempt to decrease the frequency of administration of ganciclovir to 3 days per week; if reactivation of disease occurs with a 5-day-per-week regimen, an increase to a 7-day-a-week regimen is indicated. Most patients require 5-7 days of ganciclovir per week for adequate maintenance of remission [77]. Once a staTable 8. Problems remaining in the diagnosisof and therapy for CMV infection in patients with AIDS. Diagnostic precision Speed Distinction between colonization and morbidity Development and techniques for monitoring therapeutic efficacy Therapeutics Development of agents with decreased toxicity Development of manageable maintenance regimens
ble ganciclovir regimen has been established, it is reasonable to reintroduce zidovudine. If the disease is not controlled by ganciclovir or if bone marrow toxicity precludes the use of optimal doses of the drug, foscarnet and/or intravitreal ganciclovir are available alternatives.
Remaining Problems in Diagnosis of and Therapy for CMV Infection in Patients with AIDS Although much progress has been made in the recognition of CMV-related clinical syndromes, in diagnostic techniques, and in therapeutic modalities, significant problems remain in the management of CMV infections in patients with AIDS (table 8). Diagnostic techniques that distinguish morbidity from colonization more precisely and that allow rapid quantitation of viral load are essential for early diagnosis and assessment of therapeutic efficacy. The results with ganciclovir and foscarnet have clearly established that antiviral chemotherapy for CMV infection is possible. Nonetheless, the significant acute and chronic toxic reactions associated with these agents, coupled with the requirement for long-term maintenance therapy and the lack of reliable oral dosing regimens, mandate the development of a wider array of less toxic forms of therapy.
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YES
Receiving zidovudine YES NO
CMVinAIDS
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lymphadenopathy associated virus (LAV) to replication in EBV-transformed B lymphoblastoid cell lines. Science 1984;225:63-6 Blumberg RS, Paradis TJ, Crawford D, Byington RE, Hirsch MS, Schooley RI. Effects of human immunodeficiency virus (HIV) on the cytotoxic response to Epstein-Barr virus (EBV) transformed B lymphocytes. AIDS Res Hum Retroviruses 1987;3:303-15 Nelson JA, Reynolds-Kohler C, Oldstone MBA, Wiley CA. HIV and HCMV coinfect brain cells in patients with AIDS. Virology 1988;165:286-90 Polk BF, Fox R, Brookmeyer R, Kanchanaraksa S, Kaslow R, Visscher B, Rinaldo C, Phair J. Predictors of the acquired immunodeficiency syndrome developing in a cohort of seropositive homosexual men. N Engl J Med 1987; 316:61-6 Lerner CW, Tapper ML. Opportunistic infection complicating acquired immune deficiency syndrome. Clinical features of 25 cases. Medicine (Baltimore) 1984;63:155-64 Macher AM, Reichert CM, Straus SE, Longo DL, Parrillo J, Lane HC, Fauci AS, Rook AH, Manischewitz JF, Quinnan GV Jr. Death in the AIDS patient: role of cytomegalovirus [letter]. N Engl J Med 1983;309:1454 Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988;108:585-94 Holland GN, Gottlieb MS, YeeRD, Schanker HM, Pettit TH. Ocular disorders associated with a new severe acquired cellular immunodeficiency syndrome. Am J Ophthalmol1982; 93:393-402 Friedman AH, Orellana J, Freeman WR, Luntz MH, Starr MB, Tapper ML, Spigland I, Rotterdam H, Mesa Tejada R, Braunhut S, Mildvan D, Mathur U. Cytomegalovirus retinitis: a manifestation of the acquired immune deficiency syndrome (AIDS). Br J Ophthalmol 1983;67:372-80 Kanas RJ, Jensen JL, Abrams AM, Wuerker RB. Oral mucosal cytomegalovirus as a manifestation of the acquired immune deficiency syndrome. Oral Surg Oral Med Oral Pathol 1987;64:183-9 Gertler SL, Pressman J, Price P, Brozinsky S, Miyai K. Gastrointestinal cytomegalovirus infection in a homosexual man with severe acquired immunodeficiency syndrome. Gastroenterology 1983;85:1403-6 Levine MS, Woldenberg R, Herlinger H, Laufer I. Opportunistic esophagitis in AIDS: radiographic diagnosis. Radiology 1987;165:815-20 Villar LA, Massanari RM, Mitros FA. Cytomegalovirus infection with acute erosive esophagitis. Am J Med 1984;76: 924-8 Elta G, Turnage R, Eckhauser FE, Agha F, Ross S. A submucosal antral mass caused by cytomegalovirus infection in a patient with acquired immunodeficiency syndrome. Am J Gastroenterol 1986;81:714-7 Victoria MS, Nangia BS, Jindrak K. Cytomegalovirus pyloric obstruction in a child with acquired immunodeficiency syndrome. Pediatr Infect Dis 1985;4:550-2 Kavin H, Jonas RB, Chowdhury L, Kabins S. Acalculous cholecystitis and cytomegalovirus infection in the acquired immunodeficiency syndrome. Ann Intern Med 1986;104: 53-4 Hinnant KL, Rotterdam HZ, Bell ET, Tapper ML. Cytomeg-
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J, Stevens G, Fujikawa L, Macher AM, Nussenblatt R, Baird B, Megill M, Wittek A, Quinnan GV, Parrillo JE, Rook A, Eron LJ, Poretz OM, Goldenberg RI, Fauci AS, Gelmann EP. Effect of 9-(l,3-dihydroxy-2-propoxymethyl) guanine on serious cytomegalovirus disease in eight immunosuppressed homosexual men. Ann Intern Med 1986; 104:41-4 Laskin OL, Cederberg OM, Mills J, Eron LJ, Mildvan D, Spector SA, Gancidovir Study Group. Gancidovir for the treatment and suppression of serious infections caused by cytomegalovirus. Am J Med 1987;83:201-7 Chachoua A, Dieterich 0, Krasinski K, Greene J, Laubenstein L, Wernz J, Buhles W, Koretz S. 9-(l,3-dihydroxy-2propoxymethyl) guanine (gancidovir) in the treatment of cytomegalovirus gastrointestinal disease with the acquired immunodeficiency syndrome. Ann Intern Med 1987;107: 133-7 Bach MC. Breakthrough of cytomegalovirus infection despite 9-(1,3-dihydroxy-2-propoxymethyl) guanine therapy [letter]. Ann Intern Med 1986;104:587 Cantrill HL, Henry K, Melroe NH, Knobloch WH, Ramsay RC, Balfour HH Jr. Treatment of cytomegalovirus retinitis with intravitrea1 gancidovir: long-term results. Ophthalmology 1989;96:367-74 Jacobson MA, de Miranda P, Cederberg OM, Burnette T, Cobb E, Brodie HR, Mills J. Human pharmacokinetics and tolerance of oral gancidovir. Antimicrob Agents Chemother 1987;31:1251-4 Debs RJ, Montgomery AB, Brunette EN, DeBruin M, Shanley JD. Aerosol administration of antiviral agents to treat lung infection due to murine cytomegalovirus. J Infect Dis 1988;157:327-31 Erice A, Chou S, Biron KK, Stanat SC, Balfour HH Jr, Jordan MC. Progressive disease due to gancidovir-resistant cytomegalvirus in immunocompromised patients. N Engl J Med 1989;320:289-93 Singer DRJ, Fallon TJ, Schulenburg WE, Williams G, Cohen J. Foscarnet for cytomegalovirus retinitis [letter]. Ann Intern Med 1985;103:962 Walmsley SL, Chew E, Read SE, Vellend H, Salit I, Rachlis A, Fanning MM. Treatment of cytomegalovirus retinitis with trisodium phosphonoformate hexahydrate (foscarnet). J Infect Dis 1988;157:569-72 Sjovall J, Karlsson A, Ogenstad S, Sandstrom E, Saarimaki M. Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus. Clin Pharmacol Ther 1988; 44:65-73 Fischl MA, Richman DO, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan 0, Schooley RT, Jackson GG, Durack OT, King 0, AZT Collaborative Working Group. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind placebocontrolled trial. N Engl J Med 1987;317:185-91
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HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science 1985;227:177-82 Ho DD, Rota TR, Schooley RT, Kaplan JC, Allan JD, Groopman JE, Resnick L, Felsenstein 0, Andrews CA, Hirsch MS. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Eng! J Med 1985;313:1493-7 Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 1986;233:1089-93 Gabuzda DH, Ho DO, de la Monte SM, Hirsch MS, Rota TR, Sobel RA. Immunohistochemical identification of HTLV-III antigen in brains of patients with AIDS. Ann NeuroI1986;20:289-95 Reichert CM, O'Leary TJ, Levens DL, Simrell CR, Macher AM. Autopsy pathology in the acquired immune deficiency syndrome. Am J PathoI1983;112:357-82 Tapper ML, Rotterdam HZ, Lerner CW, Al'Khafaji K, Seitzman PA. Adrenal necrosis in the acquired immunodeficiency syndrome. Ann Intern Med 1984;100:239-41 Greene LW, Cole W, Greene JB, Levy B, Louie E, Raphael B, Waitkevicz J, Blum M. Adrenal insufficiency as a complication of the acquired immunodeficiency syndrome. Ann Intern Med 1984;101:497-8 Chou S, Dylewski JS, Gaynon MW, Egbert PR, Merigan rc, Alpha-interferon administration in cytomegalovirus retinitis. Antimicrob Agents Chemother 1984;25:25-8 Meyers JD, McGuffin RW, Bryson YJ, Cantell K, Thomas ED. Treatment of cytomegalovirus pneumonia after marrow transplant with combined vidarabine and human leukocyte interferon. J Infect Dis 1982;146:80-4 Meyers JD, McGuffin RW, Neiman PE, Singer JW, Thomas ED. Toxicity and efficacy of human leukocyte interferon for treatment of cytomegalovirus pneumonia after marrow transplantation. J Infect Dis 1980;141:555-62 Felsenstein 0, D'Amico OJ, Hirsch MS, Neumeyer DA, Cederberg OM, de Miranda P, Schooley RT. Treatment of cytomegalovirus retinitis with 9-[2-hydroxy-l-(hydroxymethyl)ethoxymethyl] guanine. Ann Intern Med 1985;103:377-80 Bach MC, Bagwell SP, Knapp NP, Davis KM, Hedstrom PS. 9-(I,3-dihydroxy-2-propoxymethyl)guanine for cytomegalovirus infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1985;103:381-2 Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-(l,3-dihydroxy2-propoxymethyl) guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1986;314:801-5 D'Amico OJ, Talamo JH, Felsenstein 0, Hirsch MS, Albert OM, Schooley RT. Ophthalmoscopic and histologic findings in cytomegalovirus retinitis treated with BW-B759U. Arch Ophthalmol 1986;104:1788-93 Masur H, Lane HC, Palestine A, Smith PO, Manischewitz
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Cytomegalovirus in the Setting of Infection with Human Immunodeficiency Virus Robert T. Scbooley
From Harvard Medical School; and the Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts
Cytomegalovirus (CMV) is a ubiquitous human herpesvirus that contributes directly and indirectly to morbidity and mortality among patients infected with human immunodeficiency virus (HIV). CMV plays at least four possible roles in the pathogenesis of AIDS. These include direct CMV-induced morbidity associated with distinct clinical syndromes. Less direct roles for CMV in the pathogenesis of AIDS include interactions by which CMV may potentiate the immunomodulation induced by HIV or enhance HIV replication by trans-activation at the cellular level. Finally, gastrointestinal mucosal involvement of CMV infection may predispose to other infections by contributing to destruction of integumentary barriers. Previously it had been hypothesized that CMV played a role in Kaposi's sarcoma. However, recent data suggest that Kaposi's sarcoma is the result of proliferation of endothelial cells stimulated by growth factors elaborated by CD4+ cells infected with human T cell leukemia virus I or II or HIV-l or HIV-2 [1, 2]. Thus, this review will not include a discussion of the possible relation between CMV and Kaposi's sarcoma. Prevalence of CMV Infection in Patients with DIV Infection Serologic and isolation studies have documented an extremely high prevalence of CMV infection in most HIV-infected patient populations (table 1) [3-8]. The author gratefully acknowledges the editorial assistance of Ms. Janet Steele. Please address requests for reprints to Dr. Robert Schooley, Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
Rates of seropositivity to CMV in studies of healthy American homosexual men are usually >90070. In homosexual patients with AIDS, rates of CMV seropositivity approach 100070. CMV seropositivity also is common among African patients with AIDS [7] but is less prevalent among hemophiliacs with HIV infection [8]. Among hemophiliacs with HIV infection, rates of CMV seropositivity appear to parallel closely those among age-matched control populations. Excretion of CMV increases with increasing HIVrelated immune dysfunction [4, 5]. Attempts to isolate CMV from cultures of urine, throat, and blood of homosexual men are often successful [4]. Excretion of CMV in semen is exceedingly common, with isolation rates of up to 40% in homosexual men [6]. It has been hypothesized that excretion of CMV in semen plays a major role in the transmission of CMV among homosexual men. Although much of the CMV activity among HIV-infected individuals reflects reactivation of latent virus, superinfection with multiple strains of CMV has been documented by Southern blot hybridization [9]. As noted above, the ubiquity of CMV infection among homosexual men is a reflection of both increased rates of sexual transmission and decreased immunologic control of latent CMV. Immunologic control of latent infection with viruses of the herpes group is mediated primarily by cellular immune mechanisms [10-13]. Defects in natural killer cell activity,in CMV-and Epstein-Barr virus (EBV)-specific cytotoxic T lymphocyte effector function, and in CMV-induced lymphocyte proliferation and interferon generation have been documented. In general, loss of herpesvirus-specific effector functions occurs parallel with decreases in other aspects of the cell-
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Human cytomegalovirus (CMV) has several possible roles in the pathogenesis of AIDS. CMV causes a number of clinical syndromes, including retinitis, pneumonitis, and gastroenteritis in patients infected with human immunodeficiency virus type 1 (HIV-l). In addition, CMV may potentiate the cellular immunodeficiency observed in patients with HIV infection either directly or through enhancement of HIV replication. Finally, CMV may predispose the host to bacterial or fungal infection by compromising the integrity of mucosal barriers to infection. Therapy with ganciclovir for CMV infection may result in a decrease in morbidity related to the virus, but problems with drug toxicity and resistance to the agent mandate the development of additional therapeutic approaches.
Schooley
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mediated immune response as measured by the total number of circulating cells of the CD4+ surface phenotype [13]. Partial or complete restoration of natural killer activity and of the ability to generate CMV- or EBV-specific cytotoxic T cells has been demonstrated in vitro with interleukin-2 but not with interferon-a [13, 14]. The ability of such immunomodulating agents to restore CMV- or EBV-specific immune mechanisms in vivo has not yet been adequately addressed.
With the initial description of AIDS, it was noted that several of the immune abnormalities in patients with AIDS appeared to bear a superficial resemblance to abnormalities observed in patients with primary CMV or EBV infection. These abnormalities included, but were not restricted to, changes in the relative distribution of lymphocyte surface phenotypes in the peripheral blood and a great decrease in responses to mitogens and antigens [15-17]. In addition, it has been demonstrated that reactivation of herpesvirus in the setting of immunosuppression may also be associated with a return of the immunoregulatory abnormalities exhibited during primary infection with the herpesvirus [18]. These superficial similarities, coupled with the ubiquity of herpesvirus infection among patients with AIDS, led to early speculation that herpesviruses might even play an etiologic role in the pathogenesis of AIDS. Interaction of CMY and DIY at the Cellular Level HIV replication is regulated by a complex array of HIV-encoded regulatory gene products [19-22]. In addition to being activated by viral promotors, the long terminal repeat segments of HIV have been shown to be responsive in vitro to cellular transcription activators [23, 24]. This has led to speculation that immunologic activation of an HIV-infected CD4+ cell might also lead to enhancement of HIV replication [25]. Other groups have investigated possible direct interactions between herpesvirus promotors and the regulatory long terminal repeat sequence of HIV [26, 27]. Such in vitro studies have demonstrated that regulatory elements of CMV, herpes simplex virus (HSV), and EBV are capable of activating the long terminal repeat sequence of HIV. The mechanisms responsible for this activation might not be the same for retrovirus and herpesvirus gene prod-
CMV seropositivity Patient population Homosexual men in the U.S. With AIDS or ARC HIV seronegative HN seropositive Patients with AIDS Africans Men in the U.S. Hemophiliacs 20 y of age Overall NOTE.
(% )
93.5
Reference
3 4 6
100 80 100
6
100 100
7 7
26
8
59 43
8
ARC = AIDS-related complex.
ucts, but the net result in culture is the same, i.e., increased expression of the long terminal repeat segment of HI V [26]. Recently, Skolnik et al., extended these observations, which were made primarily with plasmids, to preparations of whole virus in T cell lines [28]. The possible role of such regulatory interactions between herpesviruses and HIV in the pathogenesis of AIDS is dependent on dual infection of individual cells in vivo. Although dual viral isolation from single-cell preparations has not been demonstrated, dual infection of B cells by HIV and EBV has been demonstrated in vitro [29, 30]. Recently, Nelson et al. have demonstrated dual infection of brain cells with CMV and HIV in patients with HIV infection in studies in which in situ nucleic acid hybridization and indirect immunofluorescence were used simultaneously [31]. The role, if any, of additive immunosuppression and of trans-activation mediated by herpesviruses in the pathogenesis of AIDS remains to be conclusively demonstrated. Although evidence has accumulated that herpesvirus activity increases with increasing HIV-induced immune dysfunction, and although prospective cohort studies have suggested that an elevated titer of CMV antibody is an independent risk factor for clinical progression to AIDS, such studies suffer from the familiar cart-and-horse problem [4, 5, 32]. It is not possible to distinguish betweenincreased herpesvirus activity due to progressive HIV-induced immune dysfunction and accelerated HIV-induced dysfunction due to increased herpesvirus activity. In addition, the occurrence of occasional transfusion-associated cases with no evi-
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CMY-Induced Immunomodulation
Table 1. Seroprevalence of CMV infection in selected populations at risk for AIDS.
CMVinAIDS
dence of prior herpesvirus infection indicates that development of AIDS is not dependent on herpesvirus infection per se. Further investigation of these interactions at the cellular level with the use of molecular biological techniques will provide useful insights into viral and cellular regulatory mechanisms. The assessment of the potential clinical impact of such interactions requires the development of therapeutic strategies that will influence these regulatory mechanisms before the development of frank AIDS.
CMV is ubiquitous during life [4-7, 33] and at autopsy in patients with AIDS [34]. CMV-induced morbidity has been reported in patients with AIDS, with involvement of the eye and of the gastrointestinal, pulmonary, nervous, and reproductive systems (table 2) [35-61]. In patients with AIDS, CMV-induced morbidity is most easily demonstrable in the eye and in the gastrointestinal tract. With CMV retinitis, patients usually present with painless progressive loss of vision, which initially may involve only one eye but usually progresses to both eyes if untreated. Ophthalmoscopic findings are usually characteristic, appearing as a hemorrhagic process that heals with hypopigmented scarring. CMV-associated morbidity throughout the gastrointestinal tract has been reported, with lesions involving the oral mucosa, the esophagus, the intestine, the rectum, as well as the biliary tree [38-51]. In the case of oral or esophageal lesions, the involvement may be painful and progressive. In addition to the direct morbidity that such involvement induces, eating may be difficult for these patients, thus exacerbating a marginal nutritional status. Finally, CMV may compromise mucosal barriers and predispose to infection with other pathogens. Gastric and intestinal involvement may be associated with gastrointestinal bleeding, perforation, malabsorption, and/or intractable diarrhea. In addition, occasional cases of antral obstruction have been reported [42, 43]. Biliary involvement has also been reported, with clinical manifestations including cholangitis, papillary stenosis, and acalculous cholecystitis [46-49]. Encephalitis and pneumonia due to CMV are frequently reported. In each situation, however, it is often difficult to distinguish CMV colonization from pathogenic involvement of the organism [52]. The diagnosis of CMV pneumonia often is made in the
Table 2. AIDS.
Manifestations of CMV infection in patients with
Ophthalmic Retinitis Conjunctivitis CNS Encephalitis Myelitis Gastrointestinal Stomatitis Esophagitis Gastritis Antral obstruction Cholecystitis/cholangitis/papillary stenosis Hepatitis Ileitis/colitis Proctitis Miscellaneous Pneumonia Adrenalitis Epididymitis Cervicitis
setting of concomitant pneumonia due to Pneumocystis carinii solely on the basis of isolation of CMV from bronchial washings. Given the ubiquity of CMV in patients whose immunodeficiency is profound enough to have permitted the development of R carinii-pneumonia, it is particularly difficult to ascribe pneumonia to CMV solely on the basis of the isolation of CMV. Although histologic involvement of the brain suggestive of CMV infection frequently is noted in patients who die of AIDS and although nucleic acid sequences and antigens of CMV have been demonstrated in neural tissue obtained from patients with AIDS [31], the problems involved in ascribing a pathogenic role for CMV in the brain are similar to those involving the lungs. This is further compounded by the demonstrable neurotropism of HIV [62-65]. Nonetheless, patients have been reported in whom encephalitis, myelitis, and polyneuropathy have been attributed to CMV infection [56-61]. Adrenal involvement of CMV has also been reported [35, 66-68]. This involvement may simply be noted histologically at autopsy or may be clinically apparent as adrenal insufficiency [35, 68]. CMV has also been reported to cause epididymitis, uterine cervicitis, and thrombophlebitis [53, 55]. Thus, although patients with AIDS are at risk for morbidity due to a wide variety of pathogens, few, if any, of these organisms are capable of producing
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Clinical Impact of CMV Infection in Patients with HIV Infection
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Schooley
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such widespread disease as is CMV. The clinical manifestations of CMV infection are protean in this patient population, and unlike the situation in other immunocompromised patients, in whom the immunodeficiency may improve with marrow engraftment or the like, once established, CMV-related morbidity in patients with AIDS tends to follow a progressive, relentless course in the absence of effective therapeutic intervention.
Therapy for CMV infection in patients with AIDS represents both a challenge and an opportunity. As noted above, in patients with AIDS there is no opportunity to ameliorate the immunodeficiency by the sacrifice of an allograft, by bone marrow transplantation, or by induction of a neoplastic remission. Thus, in the setting of AIDS, antiviral agents can get little help from host immune mechanisms in overcoming CMV infection. This creates the challenge of developing therapeutic strategies that permit the maintenance of the antiviral effect and, conversely, an opportunity to evaluate antiviral agents in the absence of potentially confusing variables such as changing immune competence. In addition, successful treatment of CMV infection in the setting of AIDS often provides extremely gratifying results regarding the organ-system involvementthat prompted therapeutic intervention as well as an improvement in systemic manifestations of CMV infection such as fever, weight loss, and inanition. A number of therapeutic modalities for CMV infection have been suggested (table 3). The modalities proposed have included therapy with classic antiviral agents such Table 3. Potential therapeutic modalitiesfor treatment of CMV infection. Nucleoside analogues Ganciclovir Intravenous Oral Intravitreous Others Foscarnet
Table 4. Response of CMV infection to therapy with ganciclovir. Reference 76 74
77
Biologic response modifiers Interferons
Interleukin-2 Isoprinosine Immunoglobulins Zidovudine
78
Organ system Retinitis Colitis Retinitis Colitis Pneumonia Retinitis Gastrointestinal CNS Colitis Esophagitis Proctitis Ileitis
No. responded/ no. treated 6/7
111 11113 5/8 3/7 52/57 9/13 0/2 23/31 4/4 3/4 011
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Therapy for CMV Infection in Patients with AIDS
as ganciclovir and foscarnet as well as therapy with immunomodulating agents such as interferons and interleukin-2. Although interleukin-2 has been shown to partially restore CMV-specific cell-mediated immune responses in vitro [13, 14],it has not been studied extensively as a form of therapy for CMV. Attempts to treat established CMV infection with interferon-a in the setting of either CMV infection or allograft transplantation have been unsuccessful [69-71]. Successful therapy for CMV retinitis and for the gastrointestinal manifestations of CMV infection with the acyclovir analogue ganciclovir has been reported by several groups [72-79]. These studies havedemonstrated initial rates of partial or complete response of 700/0-900/0 for patients with ophthalmic or gastrointestinal disease (table 4) [74, 76-78]. Response rates in patients with other manifestations of CMV infection are difficult to assess because of the more sporadic nature of the case reports delineating these syndromes. Therapy involves an initial induction phase in which 7.5-15 mg of ganciclovir/kg is administered iv daily split into two or three equal doses. The current regimen recommended by Syntex (Palo Alto, California) involvesinitial induction with a dose of 5 rug/kg every 12 hours. As noted above, this regimen results in a clinical response in (\)800/0 of patients. The toxicity of ganciclovir is considerable (table 5). The most significant acute toxic reaction is bone . marrow suppression. Depending on the patient population tested, the duration of therapy, and the other drugs being administered, dose reduction or interruption may be necessary in up to 500/0 of patients because of anemia, neutropenia, or throm-
CMVin AIDS
Table S. Problems remaining with ganciclovir therapy. Toxicity Hematologic Neutropenia Thrombocytopenia Anemia Other CNS (disorientation, psychosis) Hepatitis, anorexia, nausea Thrombophlebitis Azoospermia
Route of administration Interactions with other drugs Zidovudine Pyramethamine/trimethoprim/sulfonamides
bocytopenia. Other toxic reactions that have been reported are CNS or gastrointestinal dysfunction, thrombophlebitis, and azoospermia. Hematologic toxicity appears to be exacerbated in some patients by concomitant administration of zidovudine. Once an initial response has been achieved (usually within 10-14 days), maintenance therapy is required. Most investigators administer the drug in a single daily dose of 2.5-5 mg/kg 3-7 days per week. Maintenance therapy is complicated by observation of the same acute toxic effects and usually requires the use of an indwelling central venous line. The risk, expense, and inconvenience associated with daily iv infusions of ganciclovir are considerable. Unfortunately, failure to continue ganciclovir therapy in this patient population is always associated with relapse. Recently, attempts have been made to circumvent the hematologic toxicity of the drug by administering it intravitreally for retinal disease or as an aerosol for pneumonia. Pilot studies of the pharmacokinetics of orally administered ganciclovir may provide alternatives to long-term iv administration [80-82]. Recently, resistance to ganciclovir was demonstrated in CMV isolates obtained from three patients undergoing prolonged treatment with ganciclovir [83]. This resistance, coupled with the toxic effects of the drug and the difficulties entailed in administering the drug parenterally essentially for the lifetime of the patient, should provide a strong impetus for the development of alternative agents with activity against CMV. Foscarnet (trisodium phosphonoformate hexahy-
Table 6. Response of patients with CMV retinitis to therapy with foscarnet. Response
No. of patients
No. treated Clinical response Resolution Improvement Relapse Toxic reactions Increase in creatinine level Anemia Tremor Thrombophlebitis NOTE.
13 13 6 7 8/12 10 6
5 3 2
Data are from [85].
drate) has been under study for treatment of herpesvirus infections in Scandinavia for several years. Recently, studies of foscarnet for the treatment of CMV infection in patients with AIDS have been undertaken [84, 85]. Although no controlled trials comparing ganciclovir to foscarnet have been reported, the initial rates of response to foscarnet therapy appear to be in the same range as those for ganciclovir [85]. Foscarnet is less likely to cause granulocytopenia than is ganciclovir but is also not without toxicity (tables 6 and 7). Maintenance therapy also is required with foscarnet, and its absorption following oral administration is limited [86]. Although the field of therapeutics for CMV retinitis in the setting of HIV infection is currently in a state of flux, a reasonable approach is presented in figure 1. If a patient has a peripheral involvement of the retina that appears to be stationary or progressing only slowly, it is reasonable to observe the patient ophthalmoscopically on a weekly basis. Objective assessment of progression is facilitated by the use of ophthalmoscopic photography. If the disease has not progressed, initiation of zidovudine therapy should be considered for those not already receiving the drug. Zidovudine therapy may result in a tem-
Table 7. Problems associated with foscarnet therapy. Toxicity Renal dysfunction Hematologic (anemia) Thrombophlebitis Nausea Tremor Route of administration How much is enough?
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How much is enough? Induction Maintenance
8815
8816
Schooley
Retinitis is sight-threatening, rapidly progressive, or assOciated with systemic manifestations
YES
I
"
NO
J
~
Gancidovir therapy (withhold zidovudine)
Observe
I I Maintenance 5 days/week Retinitis controlled
\
I
I
Decrease dose frequency as tolerated
Add zidovudine
~
NO
Observe
\
r: '0," Increase to 7 days/week
NO
YES
~
Add zidovudine
Figure 1. Approach to therapy for CMV retinitis in patients with AIDS.
\I
Remission or stabilization YES
\
NO
Observe
I
\
Gancidovir therapy
Consider alternative therapies: foscarnet intravitreal gancidovir
porary improvement in some patients as the result of its indirect immunomodulating activity through inhibition of HIV replication [87]. When the lesion is sight-threatening or rapidly progressive, ganciclovir therapy should be initiated. It is generally recommended that zidovudine be withheld during the induction phase of ganciclovir therapy. If the disease is controlled by an initial induction regimen, conversion to a 5-day-a-week maintenance regimen is indicated. If the disease remains stable with this dose for 4-6 weeks, it is reasonable to attempt to decrease the frequency of administration of ganciclovir to 3 days per week; if reactivation of disease occurs with a 5-day-per-week regimen, an increase to a 7-day-a-week regimen is indicated. Most patients require 5-7 days of ganciclovir per week for adequate maintenance of remission [77]. Once a staTable 8. Problems remaining in the diagnosisof and therapy for CMV infection in patients with AIDS. Diagnostic precision Speed Distinction between colonization and morbidity Development and techniques for monitoring therapeutic efficacy Therapeutics Development of agents with decreased toxicity Development of manageable maintenance regimens
ble ganciclovir regimen has been established, it is reasonable to reintroduce zidovudine. If the disease is not controlled by ganciclovir or if bone marrow toxicity precludes the use of optimal doses of the drug, foscarnet and/or intravitreal ganciclovir are available alternatives.
Remaining Problems in Diagnosis of and Therapy for CMV Infection in Patients with AIDS Although much progress has been made in the recognition of CMV-related clinical syndromes, in diagnostic techniques, and in therapeutic modalities, significant problems remain in the management of CMV infections in patients with AIDS (table 8). Diagnostic techniques that distinguish morbidity from colonization more precisely and that allow rapid quantitation of viral load are essential for early diagnosis and assessment of therapeutic efficacy. The results with ganciclovir and foscarnet have clearly established that antiviral chemotherapy for CMV infection is possible. Nonetheless, the significant acute and chronic toxic reactions associated with these agents, coupled with the requirement for long-term maintenance therapy and the lack of reliable oral dosing regimens, mandate the development of a wider array of less toxic forms of therapy.
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YES
Receiving zidovudine YES NO
CMVinAIDS
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