Increased survival of a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis who received sodium phosphonoformate (Foscarnet)

Increased Survivalof a Cohort of Patieuts with Acquired Iumumlefi&ncy Syudrome and CytomegalovirusReti~itis Who Received Sodium Phosphonoformate(Foscarnet)” MICHAELA.POLIS,M.D.,M.P.H.,MARKD.DESM~,M.D.,BARBARAF.BAIRD,R.N., SUSANMELLOW,R.N.,JUDITHFALLOON,M.D.,RICHARDT.DAVEY,J~.,M.D., JOSEPHA.KOVACS,M.D.,ALANG.PALESTINE,M.D.,ROBERTB.NUSSENBLATT, M.D., HENRYMASUR,M.D.,H.CLIFFORDIANE,M.D.,Bethesda,hfary/and

PURPOBEZTo evaluate the impact of foacarnet on the longevity of persona with human immunod&&ncy virus, type 1 (HIV-l) infection and cytomeealovirue (Clw) retinitil3. PATIENTS AND MEIBOIB A cohort of 24 patients with acquired immunodeficiency syndrome(AIDs)andcMvretinitisrelceivedBodium phwphonoformate (fowrnet )aspartofa controlled eff&acy trial at the National II&tutee ofHealth. Fwaa continued for a8 long as it was toleratwL AnW&wiral therapy w8s given to the patient9 as tolerated. Long-term follow-up was available on all patients. Ew3uLTscSeJventeenpatients receked zidovudineduringorafterrtw&ingfoecarn et,2patients receked didssxyiaoains, 2 patients ddovudineanddkk&ne&e,and3patientsreceiwd no epeeifk an&&ro&al agent. Patients received foncarwt for a menn of 6.2 months (median, 4 monthq range, 10 days to 22 months). Ten patienta required a change to ganciclovir therapy at Bornetime &ax rec8iving frmcarnet. The ntedkntimefromthediagnotsisofCMVrethdtia untildeathwas13.6months(rang~3to34 months). Patient-8lived longer than untreated or g&lovir-treated historical controls with AIDS and ClMVret&&k There was no d&rence in the muvival of patients treated with foscametatthethueofdiagnosisandthawpatie& treat& with f-et only after pro@ea&moftheircMv-

*This is a rapidpublicationmanuscript. Fromths Laboratoryof Immunoregulation. NationalInstituteof Allergy and infectiousDiwasas (MAP, JF, RTD, HCL), the Laboratoryof Immuno&v. Natbnat Eve Instftute(MOD. SM. AGP, RBN), and the Critical Care-kdldneet, warren Grant Magnus& ClinicalCenter (BFB. JAR. HM), NationalInstitutesof Health, Bethesda,Maryland. Requests&reprints shouldba addressedto Mil A. Polls, M.D.. M.P.H., Laboratoryof Immunoregulation,National Instituteof Allergy and InfectiousDiseases.Buikling10. Room11813, NationalInstitutesof Health, 0ethesda.Matyfand20892. ManuscriptsubmittedMay 29, 1992. and accepted in revisedform October26,1992.

CONCLUSION& These data sug$@ut that fouwwnetmayprolongtheswvivalofpe~with AIDSandCMV retin&andshouldbetheinitial treatment of choice in theee patients.

oscarnet (trisodium phosphonoformate hexaF hydrate, Foscavir, Astra Pharmaceutical Products, Westborough, MA) is an antiviral drug that inhibits DNA and RNA polymerases of several human and animal viruses, including cytomegalovirus (CMV) and other human herpes viruses, as well as the reverse transcriptase of the human immunodeficiency virus, type 1 (HIV-l) [l]. In persons with acquired immunodeficiency syndrome (AIDS), foscarnet has been used extensively in clinical trials for the treatment of CMV retinitis [2-71, for acyclovirresistant herpes simplex virus [6-lo], and for acyclovir-resistant varicella zoster virus [ll] infections. Early studies of CMV retinitis associated with AIDS described it as a premorbid condition, with no patient surviving longer than 6 weeks after diagnosis [12].In September 1991, the United States Food and Drug Administration (FDA) approved the use of foscarnet for the treatment of CMV retinitis. Prior to the approval of foscarnet, ganciclovir (DHPG, Cytovene, Syntex Laboratories, Palo Alto, CA) was the only FDA-licensed treatment for CMV retinitis. Specific antiretroviral therapy with zidovudine has been shown to improve the survival of persons with HIV infection [X3-15].Although ganciclovir is effective for the treatment of CMV retinitis, its use often precludes the use of xidovudine because of their overlapping toxicities, particularly neutropenia [16].Zidovudine carr routinely be given with foscarnet without the occurrence of increased toxicity related to either agent 161.Foscarnet, in addition to its anti-CMV activity and its compatibility with zidovudine, has demonstrable intrinsic in vitro and in uivo activity against HIV [6,17-201. Previously reported studies have shown the median survival of persons with AIDS from a diagnosis of CMV retinitis to range from 1 to 13 months

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[7,21-261.These data have suggested improved survival in patients with a more recent diagnosis of CMV retinitis [25,26] and in those patients who have responded to ganciclovir therapy [24,25]. However, other studies have not been able to demonstrate an increased survival benefit related to either currently licensed anti-CMV therapy [26]. Most of the studies showing survival after diagnosis of CMV retinitis, however, have been limited to chart reviews [21,23-261. In addition, most were conducted prior to the routine use of antiretroviral therapy, Pneumocys tis carinii pneumonia prophylaxis, and the use of foscarnet for specific anti-C&IV therapy [21-251. Recently, a randomized study from the Studies of the Ocular Complications of AIDS (SOCA) Research Group demonstrated increased survival from the diagnosis of CMV retinitis among patients with AIDS initially randomized to receive foscarnet (12.6 months) compared with those patients initially randomized to receive ganciclovir (8.5 months) [7]. This is the report of the survival of a cohort of patients with AIDS and CMV retinitis that predates the SOCA trial who received foscarnet as their initial therapy for CMV retinitis. PATIENTS AND METHODS Subjects

The subjects included in this study had AIDS and previously untreated CMV retinitis characterized by the presence of progressive, white, fluffy, or granular retinal infiltrates, with or without associated hemorrhage, as previously described [S]. The retinal lesions were not immediately sight-threatening, i.e., (1) they were located at least 1,500 pm from the margin of the optic disc and at least 3,000 pm from the center of the fovea, or (2) they had already involved the retina to the extent that visual acuity was reduced to 20/400 or less. Additional entry criteria included a serum creatinine level less than 2.0 mg/dL, absolute neutrophil count greater than 500 cells/mms, platelet count greater than 25,000/mm3, and a Karnofsky performance score of at least 60. Concomitant therapy with zidovudine or dideoxyinosine was permitted but was not required by protocol. Experimental

Ddi

Subjects were randomly assigned to receive either immediate or delayed therapy with intravenous foscarnet at a dose of 60 mg/kg, adjusted for estimated creatinine clearance, every 8 hours for 3 weeks in the hospital (induction therapy) followed by daily infusions of intravenous foscarnet at a dose of 90 mg/kg (maintenance therapy), also adjusted

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for creatinine clearance. One liter of a saline solution was given with each infusion. Subjects were evaluated weekly with ophthalmologic examinations, including retinal photographs, and a battery of laboratory examinations. Patients who were assigned to delayed therapy were not hospitalized but were monitored weekly with the same ophthalmologic and laboratory examinations. Subjects were treated in the Warren Grant Magnuson Clinical Center of the National Institutes of Health (NIH), Bethesda, Maryland, and the study accrued patients between November 1988 and October 1989. This study was reviewed and approved by the Institutional Review Board of the National Institute of Allergy and Infectious Diseases, and all patients provided written informed consent prior to enrollment. All patients were followed at the NIH until they reached a study endpoint, defined as (1) the progression of a retinal lesion by 750 pm over a 750~pm front, or (2) the development of a new lesion at least l/16 of the disc area in size as determined by a masked retinal photograph reading center. When subjects on the delayed arm of the study reached a study endpoint, they received foscarnet on a schedule identical to that administered to the patients on the immediate treatment arm. Subjects on the immediate treatment arm of the study who reached a study endpoint received an increased dose of foscarnet until the retinal lesions were no longer active. Foscarnet was made available to all participants as long as continued administration appeared to be safe and tolerable. Follow-Up Care

Subjects were followed at the NIH until they reached a study endpoint, at which time their care was resumed by the referring physicians. Ascertainment of antiretroviral use, change in anti-CMV therapy, and death was made by frequent telephone contacts and consultations with the patients, their family members, and referring physicians. RESULTS As previously reported, patients enrolled were severely immunocompromised with a mean CD4+ count of 10 cells/mm3 (median, 9 cells/mm3; range, 0 to 39 cells/mm3) on the immediate treatment arm (n = 13) and 44 cells/mm3 (median, 41, range 6 to 85 cells/mm3) on the delayed treatment arm (n = 11). The time from diagnosis of CMV retinitis to entry into the study was a median of 2 weeks for both arms, with a mean of 3.9 weeks (range, 1 week to 3 months) for the immediate treatment arm and a mean of 3.3 weeks (range, 1 day to 4 months) for the delayed treatment arm. The mean Karnofsky score

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for all patients was 75. As previously reported, foscarnet significantly prolonged the time to progression of CMV retinitis. The mean time to progression of CMV retinitis was 3.2 weeks in the control group compared with 13.3 weeks in the treatment group (p 0.2). Subjects randomized to immediate therapy survived a mean of 14.6 months (median, 14 months; range, 3 to 26 months) while subjects on the delayed therapy arm survived a mean of 14.0 months (median, 10 months; range, 5 to 34 months). Notably, six patients (25%) survived at least 2 years after their diagnosis of CMV retini-

YOYTWB

Figure 1. Kaplan-Meier plot. Fraction of patients surviving from the time of diagnosis of CMV retinitis as a function of time.

tis. The patients requiring a change to ganciclovir therapy lived longer than the group as a whole, with a mean survival of 19.9 months (median, 21.5 months; range, 7 to 34 months). Those receiving ganciclovir had received foscarnet for a mean of 6.5 months (median, 5 months; range, 10 days to 16 months). COMMENTS CMV retinitis is the most common cause of blindness in persons with AIDS [27]. With increasing familiarity with the diagnosis of this condition and the availability of ganciclovir to treat this disease, survival after diagnosis of CMV retinitis increased from about 1 to 6 months prior to 1988 [21-23,251to 5 to 13 months for patients diagnoeed after 1987 [7,25,26] (Table I). Two of these studies have suggested a survival benefit in patients treated with ganciclovir compared with untreated patients or patients not responding to ganciclovir. Holland et al [25] report that patients treated with ganciclovir survived a median of 7 months compared with untreated patients, who survived a median of only 2 months. Jabs et al [24] report that patients who responded to treatment with ganciclovir had a median survival of 10.0 months, compared with a median survival of only 2.3 months among patients who did not have a complete response. Long-term survivors (i.e., those responding to ganciclovir) in that study, however, may have been persons who were less immunocompromised at study entry. In studies evaluating the effect of foscarnet on survival, Harb et al [26], in a retrospective study, found no difference in the median survival time from the diagnosis of CMV retinitis between patients treated with ganciclovir (8 months, n = 56) and those treat-

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TABLE I ReportedSurvival of PersonsWith AIDS and CMV Retinitis

Reference

No.of Patients

Typeof Study

Treatment

’

Dates Entered

SurvivalFrom Diagnosisof CMV Retinitis (mo) (median)

SurvivalFrom Diagnosisof CMV Retinitis (range)

[I21

Retrospective

10

None

5/81 to lo/82

<11/2

[211

Retrospective

8

None

7181 to 12/83

4 (mean)

Longest, 10 mo

I221

Prospective

Ganciclovir

7’85 to 6’86

6 (mean)

Longest, 15 mo

Ganciclovir

1986

5.4

1983 to 4’88

5.5

18

Retrospective

5

[231

Retrospective

31

[241

Retrospective

46 ;? !29

[251

Retrospective

:: 55 43

57 Retrospective

I261

133 61 72 :: 21

[71

Prospective

Current study, from [61

127

None Ganciclovir Responders Nonresponden or partial responders

10.0 2.3

None Nonelganciclovir None’ganciclovir

5’84 to 12’85 l/86 to 12’87

; 4

lto19mo Oto24mo

None Ganciclovir

5’84 to 12187

1981 to 12’87

2

Oto18mo

Mixed Mixed Mixed

7’85 to 9’87 1o’8g 10’87 to 10’89

! 9

20% survival > 1 y 38% survival > 1 y

2’87 to lo/89 2’87 to 10’89 2’87 to lo/89

; 9

1981 to 4/84

None Ganciclovir Foscarnet

7

Ganciclovir Foscarnet

4/90 to 10’91

8.5

107 24

Foscarnet

1 l/88 to lo/89

13.5

Prospective

Oto2mo

1 to24mo

12.6 3to34mo 25% survival >2 y

ed with foscarnet (9 months, n = 21) whereas the SOCA prospective study found a significantly increased survival in the group randomized to foscarnet (12.6 months, n = 107) compared with the group randomized to ganciclovir (8.5 months, n = 127). In the present study, this cohort of persons with AIDS and non-sight-threatening CMV retinitis who received foscarnet as their initial therapy for CMV retinitis lived more than 50% longer than the longest surviving reported historical control subjects [26], prior to the SOCA trial. The study had several unique aspects: (1) this was the first cohort of patients treated with foscarnet and prospectively followed for an extended period of time, (2) followup of the patients was complete with respect to mortality, and (3) all patients received the same initial therapy with foscarnet and were initially treated by the same group of physicians at a single center. While recognizing the limitations of making comparisons with historical controls, the study suggests that foscarnet may contribute to survival in these

patients. There are several possible explanations for the observed increase in survival. Treatment with foscarnet may have controlled systemic CMV infections, which may contribute to mortality in persons with AIDS late in the course of their infection. The compatibility of foscarnet with zidovudine allowed more than half of the patients to receive this antiretroviral therapy during the study whereas many members of historical cohorts were unable to due to ganciclovir’s relative incompatibility with zidovudine. Finally, as demonstrated by decreasing circulating HIV p24 antigen levels both when used in combination with zidovudine and alone, foscarnet has marked intrinsic antiretroviral activity [6,17-201, which may contribute to increased survival. This antiretroviral effect appears to be at least additive and may be synergistic in uiuo [20]. The intrinsic antiretroviral activity of foscarnet may be an even more important factor when one considers that HIV appears to routinely become less sensitive to zidovudine with prolonged use of this agent [28]. Finally, a recent report demon-

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strates in uitro antagonism of the antiretroviral activity of zidovudine and dideoxyinosine by ganciclovir, suggesting that ganciclovir may have a deleterious effect on HIV-l-infected persons being treated with that agent [29]. The present study had several potential limitations: (1) we had no matched concurrently followed cohort of untreated or ganciclovir-treated patients and therefore do not know the survival experience of those matched groups, (2) care of the patients was administered by different physicians after the initial phase of the study was completed, (3) patients were selected for having only peripheral, i.e., non-sight-threatening CMV retinitis and may have represented relatively early CMV disease, (4) patients were selected for their ability to travel to the NIH and therefore all had a reasonable performance status at the initiation of the study, (5) patients were selected for having renal and hematologic parameters within defined limits, as specified in the Patients and Methods section, (6) all of these patients had access to good medical care and frequent medical follow-up, which may have favorably affected their HIV-l-related illnesses, and (7) the increased survival we observed may be reflecting the increase in survival among persons with AIDS and CMV retinitis over time as a consequence of improvements in HIV-l-related treatment strategies [25,26]. However, the observed increase in survival of more than 50%when compared with historical controls is difficult to attribute to these factors alone. One other study showed no difference in survival between patients with sight-threatening and non-sight-threatening lesions [25]. The mean performance score of 75 on our study was similar to the median of 70 reported in another [23]. Foscarnet was a newly available agent at the time and its lack of contribution to survival in earlier studies may have been due to unfamiliarity with its use [26]. Our survival data independently support the results of the SOCA trial, that foscarnet may provide a survival benefit compared with ganciclovir for the treatment of CMV retinitis in persons with AIDS. With improved treatments and prophylactic regimens for P. cariniipneumonia, fungal infections, and HIV infection itself, the incidence of CMVrelated disease will likely increase. Foscarnet provides an important therapeutic alternative to ganciclovir therapy for CMV infections and for other viral infections that may be resistant to standard therapies. However, foscarnet may have a narrow therapeutic window, and its toxicities, particularly nephrotoxicity and gastrointestinal disturbances, often make it a difficult agent to administer. These toxicities often necessitate a switch to ganciclovir.

In this study, possibly because of their prolonged survival and extended therapy with foscarnet, 42% of patients eventually required therapy with ganciclovir at some time after their initial foscarnet treatment. This is similar to the 36% of patients initially randomized to foscamet on the SOCA study who required switching to gancicloyir while only 12% of those randomized to ganciclovir required switching to foscarnet [7]. Nonetheless, foscarnet is clearly a valuable addition to the antiviral therapies currently available. Treatment for CMV retinitis has clearly improved the quality, and perhaps the duration, of survival in persons with AIDS and CMV retinitis. Only continued use and study will define the relative merits of foscarnet and ganciclovir in the treatment of CMV retinitis. The data presented in this report provide support of the SOCA data demonstrating enhanced survival with foscarnet. With its demonstrable activity in treating CMV retinitis, its intrinsic antiretroviral activity, and data suggesting that it may prolong survival in persons with HIV infection and CMV retinitis, foscarnet should become the initial treatment of choice for CMV retinitis in persons with AIDS. ACKNOWlEDWENT We thank the patients who participated

in the study, the nuning staff at the NIH.

the physicians who referred

to the Nlti, and Drs. Carl Kupfer and

patients

Anthony S. Fauci for their advice and support.

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569-72. 3. Lehoang P. Girard B. Robinet M, eta/. Foscarnet in the treatment of cytomegalovirus retinitis in acquired immune deficiency syndrome. Ophthalmology 1989; 96: 865-74. 4. Jacobson MA, O’Donnell JJ. Mills J. Foscamet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 1989; 33: 736-41. 5. Fanning MM, Read SE. Benson M. eta/. Foscarnet therapy of cytomegalovirus retinitis in AIDS. J Aquir

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6. Palestine AG. Polis MA. DeSmet MD. et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1991;115:665-73. 7. Studii of the Ocular Complications Trials Group. Mortality

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N Et@ J Med 1992; 326: 213-20. 8. Erlich KS. Jacobson MA. Koehler JE, et al. Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989:110:

710-3. 9. Safrin S. Assaykeen T, Follansbee S, Mills J. Foscarnet therapy for acyclovir resistant mucocutaneous

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preliminary data. J Infect Dis 1990;161:107844. 10.Safrin S. Crumpacker C, Chatis P, et al. A controlled trial comparing foscar-

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PHOSPHONOFORMATE (FOSCARNET) LONGEVITV / POLIS ET AL net with vidarabine for acydovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. N Engl J Med 1991;325:551-5. 11.Safrin S, Berger TG, Gilson I, et a/. Foscarnet therapy in five patients with AlDS and acyciovir-resistant varicella-zoster virus infection. Ann Intern Med 1991;115:19-21. 12.Holland GN, Pepose JS. Pettit Th. Gottlieb MS. Yee RD, Foos RY. Acquired immune deficiency syndrome. Ocular manifestations. Ophthalmology 1983; 90: 859-73. 13. Creagh-Kirk T. Doi R. Andrews E. et al. Survival experience among patients with AIDS receiving zidovudine. Follow-up of patients in a compassionate plea program. JAMA 1988; 260: 3009-15. 14. Fischl MA, Richman DD, Causey DM. et al. Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. JAMA 1989; 262: 2405-10. 15. Moore RD, Hidalgo J. Sugland BW, Chaisson RE. Zidovudine and the natural history of the acquired immunodeficiency syndrome. N Engl J Med 1991;324: 1412-6. 16.Hochster H, Dieterich D. Bonette S, et a/. Toxicity of combined gancidovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS clinical trials group study. Ann Intern Med 1990; 113: 11 l-7. 17. Sandstrom EG. Kaplan JC. Byington RE. Hirsch MS. Inhibition of human Tcell lymphotropic virus type Ill in vitro by phosphonoformate. Lancet 1985: 1: 1480-2. 18. Farthing CF, Dagleish AG, Clark A, McClure M, Chanas A, Gazzard BG. Phosphonoformate (foscarnet): a pilot study in AIDS and AIDS related complex. AIDS 1987; 1: 21-5. 19. Jacobson MA, Crowe S, Levy J, eta/. Effect of foscarnet therapy on infection with human immunodeficiency virus in patients with AIDS. J Infect Dis 1988;

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158:862-5. 20. Jacobson MA, van der Horst C. Causey DM. Dehlinger M, Hafner R, Mills J. In viva anti-retroviral effect of combined zidovudine and foscarnet therapy for human immunodefidency virus infection (ACTG Protocol 053). J Infect Dis 1991;163:1219-22. 21.Palestine AG, Rodrigues MM, Macher AM, et al. Ophthalmic involvement in acquired immunodeficiency syndrome. Ophthalmology 1984; 91: 1092-g. 22. Henderly DE, Freeman WR, Causey DM, Rao NA. Cytomegalovirus retinitis and response to therapy with ganciclovir. Ophthalmology 1987; 94: 425-34. 23. 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 deficiency syndrome: prevalence, natural history, and response to ganciclovir therapy. Q J Med 19%; 254: 473-86. 24. Jabs DA, Enger C, Bartlett JG. Cytomegalovirus retinitis and acquired immunodeficiency syndrome. Ophthalmology 1989; 107: 75-80. 25. Holland GN, Sison RF, Jatulis DE, eta/, the UCLA Retinopathy Study Group. Survival of patients with the acquired immune deficiency syndrome after development of cytomegalovirus retinopathy. Ophthalmology 1990; 97: 204-l 1. 26. Harb GE, Bacchetti P. Jacobson MA. Survival of patients with AIDS and cytomegalovirus disease treated with ganciclovir or foscarnet. AIDS 1991;5: 959-65. 27.Bloom JN, Palestine AG. The diagnosis of cytomegalovirus retinitis. Ann Intern Med 19%; 109: 963-g. 28. Larder BA. Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243: 1731-4. 29. Medina DJ. Hsiung GD, Mellon JW. Ganciclovir antagonizes the anti-human immunodeficiency virus activity of zidovudine and didanosine in vitro. Antimicrab Agents Chemother 1992; 36: 1127-30.

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