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Maintenance therapy for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: Foscarnet
Maintenance Therapy for Cytomegalovirus Retinitis in Patients with Acquired Immunodeficiency Syndrome: Foscarnet MARK
A. JACOBSON,
M.D.,
San Francisco, Ca/fma
The use of ganciclovir in the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) is limited by marrow toxicity and by the development of resistance to this agent in CMV strains capable of causing progressive disease. Foscarnet retains activity against ganciclovirresistant CMV and has an adverse effect profile different from that of ganciclovir. Preliminary data from studies conducted under the AIDS Clinical Trials Group (ACTG) program indicate that intravenous foscarnet maintenance therapy at 60, 90, and 120 mg/kg/day in AIDS patients with CMV retinitis successfully completing foscarnet induction therapy is associated with median times to retinitis progression of 90, 95, and >123 days, respectively. An ACTG trial of foscarnet in patients failing ganciclovir therapy has been initiated, as has a trial jointly sponsored by the National Eye Institute and the National Institute of Allergy and Infectious Diseases comparing the safety and efficacy of foscarnet and ganciclovir. Also underway is a trial evaluating the effects of combination and alternating regimens of these two agents.
ytomegalovirus (CMV) retinitis occurs in approximately 5-20% of patients with acquired immunodeficiency syndrome (AIDS) [1,21. Treatment of CMV retinitis with ganciclovir has been associated with a high rate of initial response in the form of stabilization or regression of CMV lesions [3]. However, use of this agent is limited by its marrow-suppressive effects. Ganciclovir administration has been associated with dose-limiting neutropenia in approximately 15% of AIDS patients (Data on file, Syntex Corporation); the potential for such an effect is of particular concern in these patients, who already have some degree of marrow suppression in association with AIDS and who must frequently receive other marrow-suppressive therapies. Studies of the concomitant administration of ganciclovir and zidovudine have shown that only a small proportion of patients can receive the two agents for any appreciable period without development of severe toxicity [4-61. Although the availability of recombinant granulocyte-macrophage and granulocyte colony-stimulating factors may reduce problems with profound neutropenia in some patients receiving ganciclovir alone or in combination with zidovudine [7], treatment with these agents currently is costly. The use of ganciclovir may be further limited by the problem of CMV resistance. Clinical CMV isolates resistant to ganciclovir have been reported, and it has been found that such strains can cause disease progression
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[VI.
From the Department of Medicrne, Diwsion of AIDS, Infectious Drsease and Clrnical Pharmacology, University of California, San Francisco, Calrfornra. Reouests for reorints should be addressed to Mark A. Jacobson, M.D.. Division of AIDS, Infectious Disease and Clinical Pharmacology, University of Califorma at San Francisco, Ward 84, Buildrng 80, 995 Potrero, San Francisco, 1 Calrfornra 94110.
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Foscarnet, a pyrophosphate analogue with activity against the human herpesviruses and human immunodeficiency virus [lo, 111, is a promising alternative to ganciclovir in patients experiencing hematologic toxicity on ganciclovir or in whom disease is found or suspected to be caused by ganciclovir-resistant CMV. Foscarnet induction therapy also has been associated with a high rate of response [12]. However, the finding that the median time to retinitis progression among ganciclovir-treated patients not receiving maintenance therapy is on the order of 2-4 weeks [13] indicates that antiviral treatment aimed at maintaining functional vision must take the form of chronicessentially, lifelong-therapy. We have initiated
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several studies in the AIDS Clinical Trials Group (ACTG) program examining the effects of foscarnet maintenance therapy at different dosages, both in patients with previously untreated retinitis and in those with retinitis refractory to ganciclovir therapy. The data gathered in these studies to date, as well as other findings on the effectiveness and safety of foscarnet therapy, are reviewed herein. More definitive data on the potential role of foscarnet as first-line therapy in the treatment of CMV retinitis are expected from a large multicenter randomized prospective trial comparing the efficacy and safety of foscarnet and ganciclovir, jointly sponsored by the National Eye Institute and the National Institute of Allergy and Infectious Diseases [14]. Preliminary analysis of data from this trial suggests that foscarnet maintenance therapy at a dose of 90 mglkglday results in efficacy equivalent to standard ganciclovir maintenance regimens for preventing retinitis progression.
FOSCARNETMAINTENANCETHERAPY DOSAGESTUDIES In our initial ACTG study [X,16] of foscarnet in AIDS patients with previously untreated CMV retinitis, patients successfully completing induction therapy with intravenous foscarnet 60 mgikg thrice daily for 14 days received foscarnet maintenance therapy at 60 mglkg for 5 and subsequently 7 days per week, with the dosage being adjusted daily during induction and weekly during maintenance, based on serum creatinine levels. Patients underwent biweekly fundus examinations and retinal photography for detection of retinitis progression, defined as a new retinal lesion, an increase in size of the original lesion by at least 750 ,um in the posterior retina, or an increase in size of the original lesion resulting in encroachment into a new “clock hour” sector in the anterior retina. Among 16 evaluable patients receiving treatment 7 days per week, retinitis progression occurred in 10 after Z24 weeks. In the remaining six patients, retinitis remained stable at the time of last examination after 8-28 weeks of maintenance therapy. Five patients received concomitant foscarnet and zidovudine treatment. Subsequently enrolled patients have received foscarnet induction therapy as above with the dosage being modified thrice weekly based on serum creatinine levels. Patients completing the induction course were then randomized to receive foscarnet 90 mglkgiday or 120 mgfkglday via 2-hour infusion together with 1 liter of saline, with the dosage being adjusted weekly based on serum creatinine concentration. Patients in the two groups for whom data were available at the time of this analysis were
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evenly matched with regard to mean age, prior zidovudine therapy, mean Karnofsky performance score, prior occurrence of Pneumocystis carinii pneumonia, mean duration from first occurrence of P. carinii pneumonia, mean CD4+ lymphocyte count, and mean serum creatinine concentration at entry. According to preliminary data, the median times to progression were >123 days among patients receiving 120 mgikglday, 95 days among those receiving 90 mglkglday, and 90 days among those receiving 60 mglkgiday. In other experience with foscarnet maintenance therapy, Palestine and colleagues [17] reported a median time to retinitis recurrence of 93 days among patients receiving 90 mglkglday, with this analysis including patients failing foscarnet induction therapy. Katlama and colleagues [18] reported a median time to progression of 100 days among patients receiving 100 mgl kg/day. Overall, these figures compare favorably with the reported times to progression of 32-58 days among patients receiving maintenance therapy with ganciclovir at a dosage of 5 mg/kglday 5 days per week and 75 days among those receiving ganciclovir maintenance at a dosage of 5 mglkglday 7 days/week [13,19,20].
FOSCARNETTHERAPYIN GANCICLOVIR TREATMENTFAILURE In a trial of foscarnet as salvage therapy in AIDS patients with CMV retinitis, patients with ganciclovir intolerance (defined as an absolute neutrophi1 count of ~750 cells/pL or a platelet count of ~25,000 cells/pL at the time of initial evaluation) and’patients with retinitis due to ganciclovir-resistant CMV or rapid progression of retinitis despite adequate ganciclovir therapy have received foscarnet induction therapy at a dosage of 60 mgikg thrice daily for 14 days. Initially, patients were then randomized to maintenance therapy at a dosage of either 60 mglkglday or 90 mglkglday; with the availability of data suggesting the superiority of a maintenence regimen of 120 mgikgiday, all patients subsequently enrolled received maintenance therapy at this higher dosage. Data from this trial are currently under analysis. The precise mechanism of resistance to ganciclovir in CMV and the exact magnitude of the problem with such resistance in the clinical arena have yet to be ascertained. Biron and colleagues showed that phosphorylation of ganciclovir was decreased in vitro in the presence of a laboratory ganciclovir-resistant strain [211 and subsequently documented such an effect on the part of several clinical isolates [22]. Whether this alteration is due to a mutation deleting the function of a virusspecific ganciclovir-phosphorylating enzyme or to a
February 14, 1992
The American Journal of Medicine
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mutation altering the ability of the virus to induce host cell phosphorylation is unclear. An initial report of cases in which resistant CMV strains were isolated from patients with rapid retinitis progression despite optimal ganciclovir therapy [8] was followed by a report of the results of a prospective survey of clinical CMV isolates indicating that the prevalence of ganciclovir-resistant strains is indeed substantial. In this survey, Drew and colleagues [91 found that 8% of AIDS patients with CMV retinitis receiving ganciclovir therapy excreted ganciclovirresistant CMV after >3 months of treatment. Foscarnet, which does not require phosphorylation to exert its antiviral effect, has thus far proved to remain active in vitro against ganciclovir-resistant CMV [22]. We [23] recently found a strong correlation between documented CMV resistance to ganciclovir in vitro and rapid progression of retinitis in two of our patients who had received long-term ganciclovir therapy. In both patients, the development of new lesions or advancement of the border of the initial lesion was documented ophthalmologically at examination intervals of 52 weeks while the patients were receiving high-dose ganciclovir. During ganciclovir therapy, both patients shed CMV with ganciclovir 50% effective doses of 9.5-14.5 pmol, with these isolates remaining susceptible to foscarnet. Foscarnet thepapy resulted in stabilization of retinitis for 12 and 25 weeks, with cessation of viremia and viruria, in the two patients.
FOSCARNETSAFETYISSUES The most frequently reported major adverse effect associated with foscarnet administration is nephrotoxicity, with dose-limiting toxicity occurring in approximately lo-20% of patients and cases of acute renal failure having been observed [12,16,24] (unpublished data). The second, most common serious adverse effect is symptomatic hypocalcemia [25]. Decreases in levels of ionized calcium appear to occur transiently in all patients at foscarnet doses 290 mg/kg. This effect may be responsible for arrhythmias and seizures observed in the context of acute overdose or excessively rapid infusion of foscarnet; changes in mental status and other neurologic effects have also been associated with hypocalcemia in some cases. Benign selflimited hyperphosphatemia has been described [16], and a mild exacerbation of anemia appears to be common. One case of nephrogenic diabetes insipidus has been associated with foscarnet administration [26]. The nephrotoxicity associated with foscarnet use appears to be due to acute tubular damage, although the precise mechanism has yet to be ascer2A-28s
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tained. Increases in serum creatinine concentration are commonly observed. To minimize the incidehce of nephrotoxicity, the foscarnet dose should be frequently recalculated, based on estimated creatinine clearance and patient weight. In examining the effect of saline loading on development of nephrotoxicity in patients receiving foscarnet, Deray and colleagues [27] found that 30 courses of continuously infused foscarnet accompanied by administration of 2.5 liters of saline were associated with a mean peak serum creatinine level of 1.1 mg/dL, a value significantly lower than the mean peak level of 2.2 mg/dL associated with 56 courses of foscarnet not. accompanied by saline loading. Hypocalcemia appears to be the result of the complexing of foscarnet with ionized calcium in the blood and can be observed in cases in which total calcium levels remain unchanged [25]. In a study in which patients receiving foscarnet maintenance therapy had ionized calcium levels measured immediately before and after dosing, we found that the mean level decreased by 0.17 mmol in six patients receiving 90 mg/kg tind by 0.28 mmol in 11 patients receiving 120 mg/kg. In 24-hour urine studies in seven patients receiving a 1Cday foscarnet induction regimen, we observed no changes in calcium or phosphate metabolism. Practical guidelines for the use gf foscarnet have evolved and continue to evolve with increasing experience with the agent. Primary among these is the necessity of administering the agent via infusion pump in order to avoid the potentially serious consequences of overdose or too rapid infusion. Serum creatinine levels should be monitored two to three times per week during induction therapy and once per week during maintenance therapy, with the foscarnet dosage being recalculated at these times. The same schedule should be followed in monitoring serum magmesium and potassium levels and hemoglobin concentrations. Ionized calcium levels should be obtained if patients develop symptoms of hypocalcemia or unexplained ,neurologic or cardiac abhormalities. Adequate hydration of patients should be maintained; as noted, saline loading may reduce the risk of nephrotoxicity. Administration of other potentially nephrotoxic agents should be avoided during foscarnet treatment.
POTENTIALROLEOF COMBINEDOR ALTERNATINGFOSCARNETAND GANCICLOVIR The potential utility of combined reduced-dose or alternating foscarnet and ganciclovir regimens is suggested by the difference between the adverse effect profiles of the two agents and by findings indicating that the combination of the two agents has an additive or synergistic effect in vitro against
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CMV. Manischewitz and coworkers [28] and Freitas and coworkers [29] have reported mean fractional inhibitory concentrations for this combination against CMV of 0.72 and 0.64, respectively. Under the ACTG program, we recently have initiated a study of combined and alternating regimens of foscarnet and ganciclovir in AIDS patients with CMV retinitis. In this trial, patients completing induction therapy with ganciclovir are to be randomized to receive foscarnet 120 mg/kg every other day and ganciclovir 6 mglkg every other day on alternate days or sequential daily infusions of foscarnet 60 mglkglday and ganciclovir 3. ‘75 mglkgl day. The primary objectives of the study are to evaluate tolerance of the regimens and evidence of pharmacokinetic interaction of the two agents. Secondary objectives include assessment of time to retinitis progression and evaluation of the emergence of viral resistance.
REFERENCES 1. Jabs DA, Green WR, Fox R, Polk BF, Bartlett JG. Ocular manifestations of acquired immunodeflciency syndrome. Ophthalmology 1989; 96: 1092-g. 2. Jacobson MA, O’Donnell JJ, Porteous D. Brodie HR, Feigal D, Mills J. Retinal and gastrointestinal disease due to cytomegalovirus in patients with the acquired immune deflctency syndrome: prevalence, natural htstory, and response to ganciclovlr therapy. Q J Med 1988; 67: 473-86. 3. Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-(1,3-dihydroxy-Z-propoxymethyl)guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1986; 314: 801-5. 4. Jacobson MA, de Miranda P, Gordon SM, Blum MR. Volberding P, Mills J. Prolonged pancytopenia due to combined ganclclovir and zldovudine therapy. J Infect DIS 1988; 158: 489-90. 5. Hochster H, Dieterich D, Bozzette S, et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group study. Ann Intern Med 1990; 113: 111-7. 6. Nussbaum J, Antoniskis D, Causey D, Leedom JM. Toxicity of combined AA/ ganciclovir (DHPG) therapy in AIDS patients [Abstr M.B.0.491. In: Proceedings of the Vth International Conference on AIDS, June 4-9, 1989, Montreal, Canada; 195. 7. Grossberg HS, Bonnem EM, Buhles WC Jr. GM-CSF with ganciclovir for the treatment of CMV retlnltis in AIDS. N Engl J Med 1989; 320: 1560. 8. Ence A, Chou S, Biron KK, Stanat SC, Balfour HH Jr, Jordan MC. Progressive disease due to ganciclovlr-resistant cytomegalovirus in lmmunocompromaed patients. N Engl J Med 1989; 320: 289-93. 9. Drew WL. Miner RC, Busch DF, et al. Prevalence of resistance in patients receiving ganclclovir for serious cytomegalovlrus infectlon. J Infect DIS 1991; 163: 716-9. 10. Oberg B. AntIviral effects of phosphonoformate. Pharmacol Ther 1983; 19: 387-415. 11. Sandstrom EG, Byington RE, Kaplan JE, Hirsch MS. Inhibition of human T-cell lymphotropic virus type III In vitro by phosphonoformate. Lancet 1985; i: 1480-2. 12. Walmsley SL, Chew E, Read SE, et al. Treatment of cytomegalovirus retinitis with
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tnsodium phosphonoformate hexahydrate (foscarnet). J Infect Dis 1988; 157: 56972. 13. Jacobson MA, O’Donnell JJ, Brodie HR, Wofsy C, Mills J. Randomized prospectlve trial of ganciclovir maintenance therapy for cytomegalovlrus retinitis. J Med Virol 1988; 25: 339-49. 14. Studies of Ocular Complications of AIDS Research Group, Mortality in patients with the acquired lmmunodeficiency syndrome treated with either foscarnet or ganclclovir for cytomegalovirus retinitis. N Engl J Med 1992, 326: in press. 15. Jacobson MA, Causey D, Polsky B, eta/. Dose-ranging study of daily intravenous (iv) maintenance foscarnet (PFA) therapy (rx) for cytomegalovirus (CMV) retinitis in AIDS patients [Abstr F.B.961. In: Proceedings of the Vlth International Conference on AIDS, June 20-24, 1990, San Francisco; 113. 16. Jacobson MA, O’Donnell JJ, Mills J. Foscarnet treatment of cytomegalovlrus retlnltis In patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 1989; 33: 736-41. 17. PalestIne AG, Polis MA, De Smet MD. A randomized controlled trial of foscarnet In the treatment of cytomegalovlrus retinitis in patients with AIDS. Ann Intern Med 1991; 115: 665-73. 18. Katlama C, Dohin E, Massin-Cocherau I, Fassin D, Le Hoang P, Gentilini M. Prophylaxis of CMV retinitis relapse: evaluation of foscarnet in maintenance therapy [Abstr M.B.P.117]. In. Proceedings of the Vth International Conference on AIDS, June 4-9, 1989, Montreal, Canada; 241. 19. Rozenbaum W, Gharakhanian S, Zazoun L, et al: Efficacy and toxicity of ganciclovir maintenance treatment in AIDS-related CMV retinitis [Abstr M.B.P.132]. In. Proceedings of the Vth International Conference on AIDS, June4-9, Montreal, Canada; 243. 20. Feinberg J, Katz D, Mastre B, De Armond B. Ganciclovir (GCV) in AIDS patients with immediately sight-threatening CMV retinitis (ISTCR): initial summary of “treatment IND” data [Abstr Th.B.4321. In: Proceedings of the Vlth International Conference on AIDS, June 20-24, 1990, San Francisco. 21. Biron KK, Fyfe JA, Stanat SC, et al. A human cytomegalovirus mutant resistant to the nucleoslde analog 9-{[2-hydroxy-l-(hydroxymethyl)ethoxy]methyl}guanine (BW B759U) induces reduced levels of BW B759U triphosphate. Proc Nat1 Acad Sci USA 1986; 83: 8769-73. 22. Biron KK, Stanat SC, Reardon J, Erice A, Balfour H, Jordan MC. Ganciclovir-resistant cllnical Isolates of CMV: antiviral susceptibility profiles and mode of resistance studies [Abstr]. In: Abstracts of the papers presented at the Second international Cytomegalovlrus Workshop, University of California, San Dlego, 1989; 65. 23. Jacobson MA, Drew WL, Feinberg J, et a/. Foscarnet therapy for ganciclovirresistant cytomegalovirus retinitis in patients with AIDS. J Infect Dis 1991; 163: 1384-51. 24. Cacoub P, Deray G, Baumelou A, et a/. Acute renal failure induced by foscarnet: 4 cases. Clin Nephrol 1988; 29: 315-8. 25. Jacobson MA, Gambertoglio JG, Aweeka FT, Causey DM, Portale AA. Foscarnetinduced hypocalcemia and effects of foscarnet on calcium metabolism. J Clin Endocnnol Metab 1991; 72: 1130-5. 26. Farese RV, Schambelan M, Hollander H, Stringari S, Jacobson MA. Nephrogenic diabetes inslpidus assoctated wtth foscarnet treatment of cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome. Ann Intern Med 1990; 112: 955-6. 27. Deray G, Martinez F, Katlama C, et al. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol 1989; 9: 316-21. 28. Manischewitz JF, Quinnan GV Jr, Lane HC, Wittek AE. Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother 1990; 34: 373-5. 29. Freitas VR, Fraser-Smith EB, Matthews TR. Increased efficacy of ganciclovir in combination with foscarnet against cytomegalovlrus and herpes simplex virus type 2 in vitro and In VIVO. Antivir Res 1989; 12: 205-12.
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A. JACOBSON,
M.D.,
San Francisco, Ca/fma
The use of ganciclovir in the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) is limited by marrow toxicity and by the development of resistance to this agent in CMV strains capable of causing progressive disease. Foscarnet retains activity against ganciclovirresistant CMV and has an adverse effect profile different from that of ganciclovir. Preliminary data from studies conducted under the AIDS Clinical Trials Group (ACTG) program indicate that intravenous foscarnet maintenance therapy at 60, 90, and 120 mg/kg/day in AIDS patients with CMV retinitis successfully completing foscarnet induction therapy is associated with median times to retinitis progression of 90, 95, and >123 days, respectively. An ACTG trial of foscarnet in patients failing ganciclovir therapy has been initiated, as has a trial jointly sponsored by the National Eye Institute and the National Institute of Allergy and Infectious Diseases comparing the safety and efficacy of foscarnet and ganciclovir. Also underway is a trial evaluating the effects of combination and alternating regimens of these two agents.
ytomegalovirus (CMV) retinitis occurs in approximately 5-20% of patients with acquired immunodeficiency syndrome (AIDS) [1,21. Treatment of CMV retinitis with ganciclovir has been associated with a high rate of initial response in the form of stabilization or regression of CMV lesions [3]. However, use of this agent is limited by its marrow-suppressive effects. Ganciclovir administration has been associated with dose-limiting neutropenia in approximately 15% of AIDS patients (Data on file, Syntex Corporation); the potential for such an effect is of particular concern in these patients, who already have some degree of marrow suppression in association with AIDS and who must frequently receive other marrow-suppressive therapies. Studies of the concomitant administration of ganciclovir and zidovudine have shown that only a small proportion of patients can receive the two agents for any appreciable period without development of severe toxicity [4-61. Although the availability of recombinant granulocyte-macrophage and granulocyte colony-stimulating factors may reduce problems with profound neutropenia in some patients receiving ganciclovir alone or in combination with zidovudine [7], treatment with these agents currently is costly. The use of ganciclovir may be further limited by the problem of CMV resistance. Clinical CMV isolates resistant to ganciclovir have been reported, and it has been found that such strains can cause disease progression
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[VI.
From the Department of Medicrne, Diwsion of AIDS, Infectious Drsease and Clrnical Pharmacology, University of California, San Francisco, Calrfornra. Reouests for reorints should be addressed to Mark A. Jacobson, M.D.. Division of AIDS, Infectious Disease and Clinical Pharmacology, University of Califorma at San Francisco, Ward 84, Buildrng 80, 995 Potrero, San Francisco, 1 Calrfornra 94110.
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The American Journal of Medtcine
Foscarnet, a pyrophosphate analogue with activity against the human herpesviruses and human immunodeficiency virus [lo, 111, is a promising alternative to ganciclovir in patients experiencing hematologic toxicity on ganciclovir or in whom disease is found or suspected to be caused by ganciclovir-resistant CMV. Foscarnet induction therapy also has been associated with a high rate of response [12]. However, the finding that the median time to retinitis progression among ganciclovir-treated patients not receiving maintenance therapy is on the order of 2-4 weeks [13] indicates that antiviral treatment aimed at maintaining functional vision must take the form of chronicessentially, lifelong-therapy. We have initiated
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several studies in the AIDS Clinical Trials Group (ACTG) program examining the effects of foscarnet maintenance therapy at different dosages, both in patients with previously untreated retinitis and in those with retinitis refractory to ganciclovir therapy. The data gathered in these studies to date, as well as other findings on the effectiveness and safety of foscarnet therapy, are reviewed herein. More definitive data on the potential role of foscarnet as first-line therapy in the treatment of CMV retinitis are expected from a large multicenter randomized prospective trial comparing the efficacy and safety of foscarnet and ganciclovir, jointly sponsored by the National Eye Institute and the National Institute of Allergy and Infectious Diseases [14]. Preliminary analysis of data from this trial suggests that foscarnet maintenance therapy at a dose of 90 mglkglday results in efficacy equivalent to standard ganciclovir maintenance regimens for preventing retinitis progression.
FOSCARNETMAINTENANCETHERAPY DOSAGESTUDIES In our initial ACTG study [X,16] of foscarnet in AIDS patients with previously untreated CMV retinitis, patients successfully completing induction therapy with intravenous foscarnet 60 mgikg thrice daily for 14 days received foscarnet maintenance therapy at 60 mglkg for 5 and subsequently 7 days per week, with the dosage being adjusted daily during induction and weekly during maintenance, based on serum creatinine levels. Patients underwent biweekly fundus examinations and retinal photography for detection of retinitis progression, defined as a new retinal lesion, an increase in size of the original lesion by at least 750 ,um in the posterior retina, or an increase in size of the original lesion resulting in encroachment into a new “clock hour” sector in the anterior retina. Among 16 evaluable patients receiving treatment 7 days per week, retinitis progression occurred in 10 after Z24 weeks. In the remaining six patients, retinitis remained stable at the time of last examination after 8-28 weeks of maintenance therapy. Five patients received concomitant foscarnet and zidovudine treatment. Subsequently enrolled patients have received foscarnet induction therapy as above with the dosage being modified thrice weekly based on serum creatinine levels. Patients completing the induction course were then randomized to receive foscarnet 90 mglkgiday or 120 mgfkglday via 2-hour infusion together with 1 liter of saline, with the dosage being adjusted weekly based on serum creatinine concentration. Patients in the two groups for whom data were available at the time of this analysis were
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IN AIDS/JACOBSON
evenly matched with regard to mean age, prior zidovudine therapy, mean Karnofsky performance score, prior occurrence of Pneumocystis carinii pneumonia, mean duration from first occurrence of P. carinii pneumonia, mean CD4+ lymphocyte count, and mean serum creatinine concentration at entry. According to preliminary data, the median times to progression were >123 days among patients receiving 120 mgikglday, 95 days among those receiving 90 mglkglday, and 90 days among those receiving 60 mglkgiday. In other experience with foscarnet maintenance therapy, Palestine and colleagues [17] reported a median time to retinitis recurrence of 93 days among patients receiving 90 mglkglday, with this analysis including patients failing foscarnet induction therapy. Katlama and colleagues [18] reported a median time to progression of 100 days among patients receiving 100 mgl kg/day. Overall, these figures compare favorably with the reported times to progression of 32-58 days among patients receiving maintenance therapy with ganciclovir at a dosage of 5 mg/kglday 5 days per week and 75 days among those receiving ganciclovir maintenance at a dosage of 5 mglkglday 7 days/week [13,19,20].
FOSCARNETTHERAPYIN GANCICLOVIR TREATMENTFAILURE In a trial of foscarnet as salvage therapy in AIDS patients with CMV retinitis, patients with ganciclovir intolerance (defined as an absolute neutrophi1 count of ~750 cells/pL or a platelet count of ~25,000 cells/pL at the time of initial evaluation) and’patients with retinitis due to ganciclovir-resistant CMV or rapid progression of retinitis despite adequate ganciclovir therapy have received foscarnet induction therapy at a dosage of 60 mgikg thrice daily for 14 days. Initially, patients were then randomized to maintenance therapy at a dosage of either 60 mglkglday or 90 mglkglday; with the availability of data suggesting the superiority of a maintenence regimen of 120 mgikgiday, all patients subsequently enrolled received maintenance therapy at this higher dosage. Data from this trial are currently under analysis. The precise mechanism of resistance to ganciclovir in CMV and the exact magnitude of the problem with such resistance in the clinical arena have yet to be ascertained. Biron and colleagues showed that phosphorylation of ganciclovir was decreased in vitro in the presence of a laboratory ganciclovir-resistant strain [211 and subsequently documented such an effect on the part of several clinical isolates [22]. Whether this alteration is due to a mutation deleting the function of a virusspecific ganciclovir-phosphorylating enzyme or to a
February 14, 1992
The American Journal of Medicine
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ON HERPESVIRUS INFECTIONS
IN AIDS I JACOBSON
mutation altering the ability of the virus to induce host cell phosphorylation is unclear. An initial report of cases in which resistant CMV strains were isolated from patients with rapid retinitis progression despite optimal ganciclovir therapy [8] was followed by a report of the results of a prospective survey of clinical CMV isolates indicating that the prevalence of ganciclovir-resistant strains is indeed substantial. In this survey, Drew and colleagues [91 found that 8% of AIDS patients with CMV retinitis receiving ganciclovir therapy excreted ganciclovirresistant CMV after >3 months of treatment. Foscarnet, which does not require phosphorylation to exert its antiviral effect, has thus far proved to remain active in vitro against ganciclovir-resistant CMV [22]. We [23] recently found a strong correlation between documented CMV resistance to ganciclovir in vitro and rapid progression of retinitis in two of our patients who had received long-term ganciclovir therapy. In both patients, the development of new lesions or advancement of the border of the initial lesion was documented ophthalmologically at examination intervals of 52 weeks while the patients were receiving high-dose ganciclovir. During ganciclovir therapy, both patients shed CMV with ganciclovir 50% effective doses of 9.5-14.5 pmol, with these isolates remaining susceptible to foscarnet. Foscarnet thepapy resulted in stabilization of retinitis for 12 and 25 weeks, with cessation of viremia and viruria, in the two patients.
FOSCARNETSAFETYISSUES The most frequently reported major adverse effect associated with foscarnet administration is nephrotoxicity, with dose-limiting toxicity occurring in approximately lo-20% of patients and cases of acute renal failure having been observed [12,16,24] (unpublished data). The second, most common serious adverse effect is symptomatic hypocalcemia [25]. Decreases in levels of ionized calcium appear to occur transiently in all patients at foscarnet doses 290 mg/kg. This effect may be responsible for arrhythmias and seizures observed in the context of acute overdose or excessively rapid infusion of foscarnet; changes in mental status and other neurologic effects have also been associated with hypocalcemia in some cases. Benign selflimited hyperphosphatemia has been described [16], and a mild exacerbation of anemia appears to be common. One case of nephrogenic diabetes insipidus has been associated with foscarnet administration [26]. The nephrotoxicity associated with foscarnet use appears to be due to acute tubular damage, although the precise mechanism has yet to be ascer2A-28s
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The Amencan Journal of Medicine
tained. Increases in serum creatinine concentration are commonly observed. To minimize the incidehce of nephrotoxicity, the foscarnet dose should be frequently recalculated, based on estimated creatinine clearance and patient weight. In examining the effect of saline loading on development of nephrotoxicity in patients receiving foscarnet, Deray and colleagues [27] found that 30 courses of continuously infused foscarnet accompanied by administration of 2.5 liters of saline were associated with a mean peak serum creatinine level of 1.1 mg/dL, a value significantly lower than the mean peak level of 2.2 mg/dL associated with 56 courses of foscarnet not. accompanied by saline loading. Hypocalcemia appears to be the result of the complexing of foscarnet with ionized calcium in the blood and can be observed in cases in which total calcium levels remain unchanged [25]. In a study in which patients receiving foscarnet maintenance therapy had ionized calcium levels measured immediately before and after dosing, we found that the mean level decreased by 0.17 mmol in six patients receiving 90 mg/kg tind by 0.28 mmol in 11 patients receiving 120 mg/kg. In 24-hour urine studies in seven patients receiving a 1Cday foscarnet induction regimen, we observed no changes in calcium or phosphate metabolism. Practical guidelines for the use gf foscarnet have evolved and continue to evolve with increasing experience with the agent. Primary among these is the necessity of administering the agent via infusion pump in order to avoid the potentially serious consequences of overdose or too rapid infusion. Serum creatinine levels should be monitored two to three times per week during induction therapy and once per week during maintenance therapy, with the foscarnet dosage being recalculated at these times. The same schedule should be followed in monitoring serum magmesium and potassium levels and hemoglobin concentrations. Ionized calcium levels should be obtained if patients develop symptoms of hypocalcemia or unexplained ,neurologic or cardiac abhormalities. Adequate hydration of patients should be maintained; as noted, saline loading may reduce the risk of nephrotoxicity. Administration of other potentially nephrotoxic agents should be avoided during foscarnet treatment.
POTENTIALROLEOF COMBINEDOR ALTERNATINGFOSCARNETAND GANCICLOVIR The potential utility of combined reduced-dose or alternating foscarnet and ganciclovir regimens is suggested by the difference between the adverse effect profiles of the two agents and by findings indicating that the combination of the two agents has an additive or synergistic effect in vitro against
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SYMPOSIUM
CMV. Manischewitz and coworkers [28] and Freitas and coworkers [29] have reported mean fractional inhibitory concentrations for this combination against CMV of 0.72 and 0.64, respectively. Under the ACTG program, we recently have initiated a study of combined and alternating regimens of foscarnet and ganciclovir in AIDS patients with CMV retinitis. In this trial, patients completing induction therapy with ganciclovir are to be randomized to receive foscarnet 120 mg/kg every other day and ganciclovir 6 mglkg every other day on alternate days or sequential daily infusions of foscarnet 60 mglkglday and ganciclovir 3. ‘75 mglkgl day. The primary objectives of the study are to evaluate tolerance of the regimens and evidence of pharmacokinetic interaction of the two agents. Secondary objectives include assessment of time to retinitis progression and evaluation of the emergence of viral resistance.
REFERENCES 1. Jabs DA, Green WR, Fox R, Polk BF, Bartlett JG. Ocular manifestations of acquired immunodeflciency syndrome. Ophthalmology 1989; 96: 1092-g. 2. Jacobson MA, O’Donnell JJ, Porteous D. Brodie HR, Feigal D, Mills J. Retinal and gastrointestinal disease due to cytomegalovirus in patients with the acquired immune deflctency syndrome: prevalence, natural htstory, and response to ganciclovlr therapy. Q J Med 1988; 67: 473-86. 3. Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-(1,3-dihydroxy-Z-propoxymethyl)guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1986; 314: 801-5. 4. Jacobson MA, de Miranda P, Gordon SM, Blum MR. Volberding P, Mills J. Prolonged pancytopenia due to combined ganclclovir and zldovudine therapy. J Infect DIS 1988; 158: 489-90. 5. Hochster H, Dieterich D, Bozzette S, et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group study. Ann Intern Med 1990; 113: 111-7. 6. Nussbaum J, Antoniskis D, Causey D, Leedom JM. Toxicity of combined AA/ ganciclovir (DHPG) therapy in AIDS patients [Abstr M.B.0.491. In: Proceedings of the Vth International Conference on AIDS, June 4-9, 1989, Montreal, Canada; 195. 7. Grossberg HS, Bonnem EM, Buhles WC Jr. GM-CSF with ganciclovir for the treatment of CMV retlnltis in AIDS. N Engl J Med 1989; 320: 1560. 8. Ence A, Chou S, Biron KK, Stanat SC, Balfour HH Jr, Jordan MC. Progressive disease due to ganciclovlr-resistant cytomegalovirus in lmmunocompromaed patients. N Engl J Med 1989; 320: 289-93. 9. Drew WL. Miner RC, Busch DF, et al. Prevalence of resistance in patients receiving ganclclovir for serious cytomegalovlrus infectlon. J Infect DIS 1991; 163: 716-9. 10. Oberg B. AntIviral effects of phosphonoformate. Pharmacol Ther 1983; 19: 387-415. 11. Sandstrom EG, Byington RE, Kaplan JE, Hirsch MS. Inhibition of human T-cell lymphotropic virus type III In vitro by phosphonoformate. Lancet 1985; i: 1480-2. 12. Walmsley SL, Chew E, Read SE, et al. Treatment of cytomegalovirus retinitis with
ON HERPESVIRUS INFECTIONS
IN AIDS I JACOBSON
tnsodium phosphonoformate hexahydrate (foscarnet). J Infect Dis 1988; 157: 56972. 13. Jacobson MA, O’Donnell JJ, Brodie HR, Wofsy C, Mills J. Randomized prospectlve trial of ganciclovir maintenance therapy for cytomegalovlrus retinitis. J Med Virol 1988; 25: 339-49. 14. Studies of Ocular Complications of AIDS Research Group, Mortality in patients with the acquired lmmunodeficiency syndrome treated with either foscarnet or ganclclovir for cytomegalovirus retinitis. N Engl J Med 1992, 326: in press. 15. Jacobson MA, Causey D, Polsky B, eta/. Dose-ranging study of daily intravenous (iv) maintenance foscarnet (PFA) therapy (rx) for cytomegalovirus (CMV) retinitis in AIDS patients [Abstr F.B.961. In: Proceedings of the Vlth International Conference on AIDS, June 20-24, 1990, San Francisco; 113. 16. Jacobson MA, O’Donnell JJ, Mills J. Foscarnet treatment of cytomegalovlrus retlnltis In patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 1989; 33: 736-41. 17. PalestIne AG, Polis MA, De Smet MD. A randomized controlled trial of foscarnet In the treatment of cytomegalovlrus retinitis in patients with AIDS. Ann Intern Med 1991; 115: 665-73. 18. Katlama C, Dohin E, Massin-Cocherau I, Fassin D, Le Hoang P, Gentilini M. Prophylaxis of CMV retinitis relapse: evaluation of foscarnet in maintenance therapy [Abstr M.B.P.117]. In. Proceedings of the Vth International Conference on AIDS, June 4-9, 1989, Montreal, Canada; 241. 19. Rozenbaum W, Gharakhanian S, Zazoun L, et al: Efficacy and toxicity of ganciclovir maintenance treatment in AIDS-related CMV retinitis [Abstr M.B.P.132]. In. Proceedings of the Vth International Conference on AIDS, June4-9, Montreal, Canada; 243. 20. Feinberg J, Katz D, Mastre B, De Armond B. Ganciclovir (GCV) in AIDS patients with immediately sight-threatening CMV retinitis (ISTCR): initial summary of “treatment IND” data [Abstr Th.B.4321. In: Proceedings of the Vlth International Conference on AIDS, June 20-24, 1990, San Francisco. 21. Biron KK, Fyfe JA, Stanat SC, et al. A human cytomegalovirus mutant resistant to the nucleoslde analog 9-{[2-hydroxy-l-(hydroxymethyl)ethoxy]methyl}guanine (BW B759U) induces reduced levels of BW B759U triphosphate. Proc Nat1 Acad Sci USA 1986; 83: 8769-73. 22. Biron KK, Stanat SC, Reardon J, Erice A, Balfour H, Jordan MC. Ganciclovir-resistant cllnical Isolates of CMV: antiviral susceptibility profiles and mode of resistance studies [Abstr]. In: Abstracts of the papers presented at the Second international Cytomegalovlrus Workshop, University of California, San Dlego, 1989; 65. 23. Jacobson MA, Drew WL, Feinberg J, et a/. Foscarnet therapy for ganciclovirresistant cytomegalovirus retinitis in patients with AIDS. J Infect Dis 1991; 163: 1384-51. 24. Cacoub P, Deray G, Baumelou A, et a/. Acute renal failure induced by foscarnet: 4 cases. Clin Nephrol 1988; 29: 315-8. 25. Jacobson MA, Gambertoglio JG, Aweeka FT, Causey DM, Portale AA. Foscarnetinduced hypocalcemia and effects of foscarnet on calcium metabolism. J Clin Endocnnol Metab 1991; 72: 1130-5. 26. Farese RV, Schambelan M, Hollander H, Stringari S, Jacobson MA. Nephrogenic diabetes inslpidus assoctated wtth foscarnet treatment of cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome. Ann Intern Med 1990; 112: 955-6. 27. Deray G, Martinez F, Katlama C, et al. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol 1989; 9: 316-21. 28. Manischewitz JF, Quinnan GV Jr, Lane HC, Wittek AE. Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother 1990; 34: 373-5. 29. Freitas VR, Fraser-Smith EB, Matthews TR. Increased efficacy of ganciclovir in combination with foscarnet against cytomegalovlrus and herpes simplex virus type 2 in vitro and In VIVO. Antivir Res 1989; 12: 205-12.
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The American Journal of Medicine
Volume 92 (suppl 2A)
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