Cytomegalovirus Retinitis and Response to Therapy with Ganciclovir

Cytomegalovirus Retinitis and Response to Therapy with Ganciclovir DALE E. HENDERLY, MD,*t WILLIAM R. FREEMAN, MD,*t DENNIS M. CAUSEY, MD,t NARSING A. RAO, MD*t

Abstract: A 15-month prospective study of 109 patients with the acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) was con­ ducted. Cytomegalovirus (CMV) retinitis developed in 18 of these patients; they were treated with ganciclovir. Five other patients with CMV retinitis who were not part of the prospective study were also treated with ganciclovir. CMV retinitis frequently involved the peripheral retina. All 23 patients treated with ganciclovir showed clinical regression of retinitis, although breakthrough recurrence ofCMV retinitis occurred in seven patients (30.4%) while on maintenance therapy with ganciclovir. During treatment, neutropenia (<1000 leukocytesjmm3 ) developed in three patients (13%). Ganciclovir is an effective means of therapy for CMV retinitis, but it must be given chronically to prevent reactivation. Breakthrough recurrences while on maintenance therapy are not uncommon, but can be successfully treated with more aggressive treatment with ganciclovir. In addition, the prognosis for survival of AIDS patients being treated with ganciclovir is improved when compared with that of untreated patients.[ Key words: acquired immune deficiency syndrome, cytomegalovirus, dihydroxy propoxymethyl gua­ nine, ganciclovir, retinitis.] Ophthalmology 94:425-434, 1987

Cytomegalovirus (CMV) retinitis is the most frequent ophthalmic opportunistic infection seen in patients with the acquired immune deficiency syndrome (AIDS), 1•2 and has been estimated to occur in 15 to 40% of patients with AIDS. J-s It is frequently bilateral and, if untreated, is almost always progressive, often leading to blindness. The clinical appearance of CMV retinitis varies from patient to patient. The typical posterior pole appearance is that ofa dense, white area ofretinal necrosis, frequently first developing along the vascular arcades (Fig 1). There may also be associated areas of retinal hemorrhages either within the area of the retinitis or along its leading edge. 6 •7

From the Departments of Ophthalmology* and Medicine,+ Los Angeles County/University of Southern California Medical Center, and the Estelle Doheny Eye Center,t Los Angeles. Presented at the Ninety· first Annual Meeting of the American Academy of Ophthalmology, New Orleans, Louisiana, November 9-13, 1986. Reprint requests to Dale E. Henderly, MD, Northwestern University School of Medicine, Department of Ophthalmology, 303 East Chicago Avenue, Chicago, IL 60611.

CMV retinitis also occurs in the peripheral retina where it tends to have a less intense white appearance with areas of granular, white retinitis that may or may not have as­ sociated retinal hemorrhages (Fig 2). As the retinitis pro­ gresses, an area of atrophic, avascular retina may remain with underlying retinal pigment epithelial (RPE) atrophy and/or hyperplasia. 8•9 CMV retinitis is a sign of systemic CMV infection 10 •11 and signifies profound immune compromise and poor prognosis for vision and survival. Holland and colleagues 12 reported that none ofseven patients in whom the diagnosis of AIDS and clinical CMV retinitis had been made lived longer than 6 weeks after the diagnosis of CMV retinitis was established. Other authors 3•6 •13 •14 have described slightly longer survival times, but none reported any pa­ tients who survived longer than 4 months after the di­ agnosis of CMV retinitis was made; the average survival of the 14 patients described in those studies was slightly more than 2 months. Ganciclovir (formerly known as dihydroxy propoxy­ methyl guanine, DHPG, 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine, and BW-759U) is a new acyclic 425

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Fig. 1. Patient 21, top left. CMV retinitis presenting as an area of dense, white retinitis along the superotemporal vascular arcade. Fig 2. Patient 7, top center. CMV presenting as granular peripheral retinitis. Patient 6, top right. Peripheral CMV retinitis. Fig 3. Patient 15, second row left. Hemorrhagic peripheral CMV retinitis. Second row right. the same area after 2 months of treatment with ganciclovir. Patient 9, third row left. CMV retinitis involving the inferior retina. Third row right, the same area after 2 months of treatment with ganciclovir. Pa­ tient 20, fourth row left. Diffuse CMV reti­ nitis with optic nerve involvement. Fourth row right, after 2 months of treatment with ganciclovir, there has been regression of ret­ initis with a marked improvement in visual acuity. Fig 4. Patient I, bottom left. CMV retinitis involving the superotemporal vas­ cular arcade. Bottom center, regression of retinitis after 2 months oftherapy with gan­ ciclovir. Bottom right, marked reactivation and progression after ganciclovir was dis­ continued for I month.

nucleoside antiviral that is related to acyclovir. It has been shown to be effective in halting the progression of CMV retinitis and frequently leads to regression ofretinitis. 9•15­ 18 Cessation of therapy, however, usually results in reacti­ vation of the infectionY- 17 In this article, we describe the clinical manifestations of CMV retinitis in 23 patients with AIDS and report the results of treatment with ganciclovir. 426

MATERIALS AND METHODS We performed a 15-month prospective evaluation of 109 male patients, the majority of whom were homosex­ ual, seen originally by the AIDS clinic of the Los Angeles County/University of Southern California Medical Cen­ ter. All patients with persistent generalized lymphade­

HENDERLY et al •

CMV RETINITIS AND GANCICLOVIR

nopathy/AIDS-related complex (ARC) or AIDS seen in that clinic were recruited to be part of the prospective study. Of those patients who agreed to participate in the study, 27 had persistent generalized lymphadenopathy/ ARC and 82 patients had been diagnosed as having AIDS. All patients had a complete ophthalmic examination. Fif­ teen patients with AIDS and three with ARC either had CMV retinitis at the time of presentation or it subse­ quently developed. In addition, five other patients who were referred to the Estelle Doheny Eye Center with the diagnosis of CMV retinitis were included in this study. All patients were treated with ganciclovir (obtained from Burroughs Wellcome Company, Research Triangle Park, NC). They were initially treated as inpatients with an induction intravenous dosage of 2.5 mg/kg every 8 hours for 10 days, and then as outpatients with a mainte­ nance intravenous dosage of 5 mg/kg/day given 5 days per week. Recurrences of the retinitis were treated with a reinduction dosage of 2.5 mgjkg every 8 hours for 10 days; these patients were subsequently maintained on 5 mg/kg/day given 7 days per week.

RESULTS The clinical features of the 23 patients with retinitis are summarized in Table 1. Of these 23 patients, 11 had unilateral CMV retinitis and 12 had bilateral involvement. Ofthe 35 eyes with retinitis, 3 (8.6%) had retinitis confined to the posterior pole, 18 (51.4%) had only peripheral ret­ inal involvement, and 14 eyes (40.0%) had diffuse retinitis involving both the peripheral retina and posterior pole. Nine of the patients had other manifestations of sys­ temic CMV infection: two patients had liver involvement, five had CMV colitis, and two had CMV pneumonitis. Three patients in this group also had dementia that re­ sponded to therapy with ganciclovir, suggesting the di­ agnosis of CMV encephalitis. All patients showed regression of retinitis after initiating treatment with ganciclovir (Fig 3), but 14 recurrences oc­ curred in 13 patients (56.5%) (Fig 4); there were seven recurrences while the patients were on maintenance ther­ apy and seven recurrences after discontinuation of gan­ ciclovir. Of the recurrences that followed discontinuation of therapy, three occurred after neutropenia developed of less than 1000 leukocytes/mm 3 necessitating withholding the drug. One patient had reactivation of retinitis after venous access problems led to a temporary cessation of therapy, one patient refused maintenance therapy entirely, and a recurrence developed in one patient after he stopped taking the ganciclovir while on vacation. One patient stopped treatment after induction therapy and signs of recurrence developed after initial regression of retinitis. Signs of recurrence developed I0 to 21 days after stopping treatment in all seven patients who discontinued therapy with ganciclovir. Neutropenia occurred in three patients, and was directly attributable to ganciclovir in two cases. Neutropenia de­ veloped in the third patient while simultaneously receiving

ganciclovir and chemotherapeutic agents for Kaposi's sarcoma. Dementia developed in one patient while on ganciclovir. Four patients presented with CMV retinitis as an initial manifestation of AIDS. Two of these patients presented without any evidence of other opportunistic infections or Kaposi's sarcoma, one presented with simultaneous CMV colitis, and one patient presented with simultaneous oral Kaposi's sarcoma. Two patients survived longer than 1 year after the initial diagnosis ofCMV retinitis and 12 patients (52.2%) have survived 6 months or longer. The average survival of pa­ tients after the initial diagnosis of CMV retinitis has been slightly more than 6 months (range, 2 weeks to 15 months).

DISCUSSION The diagnosis of CMV retinitis was made on the basis ofits characteristic clinical appearance as an area ofwhite retinitis, frequently with associated retinal hemorrhages. The clinical appearance varied somewhat, however, de­ pending on its location: posterior pole retinitis tended to be well demarcated with a dense, white appearance and frequently appeared along the vascular arcades. Peripheral retinitis had a more granular, less intense white appear­ ance and was less well demarcated. Some previous reports ofCMV retinitis have described predominantly posterior pole retinitis, 8•12 although later studies have also described peripheral retinitis. 4 •9 In our experience, peripheral CMV retinitis, alone or in com­ bination with posterior pole infection, is the most com­ mon form in patients with AIDS and was seen in 32 of 35 eyes (91.4%). Retinitis confined to the peripheral retina was seen in 18 eyes (51.4%), and diffuse retinitis involving both the peripheral retina was seen in 18 eyes (51.4%) and diffuse retinitis involving both the peripheral retina and the posterior pole was noted in 14 eyes (40.0%). Ret­ initis limited to the posterior pole was rare in this series and occurred in only three eyes (8.6%). The reason for our high incidence of peripheral CMV retinitis, especially that confined to the peripheral retina, may relate to the fact that most of the patients in this study were seen on a prospective basis, and the diagnosis of CMV retinitis was made in early stages of the disease process. Because CMV retinitis is often asymptomatic or causes only mild symptoms in the early stages, it may go unrecognized until it has become more advanced and is detected in the posterior pole by the patient's primary care physician or until it causes changes in visual acuity. Although CMV retinitis is often thought to be a late opportunistic infection in patients with AIDS, our eval­ uation of these patients led in many cases to the diagnosis ofCMV retinitis early in the course ofAIDS. Four patients in this study presented with CMV retinitis as an initial manifestation of AIDS, whereas I I of23 patients (47.8%) had the diagnosis ofCMV retinitis made within 6 months after the diagnosis of AIDS. These findings suggest that 427

Table 1. Clinical Features of

Patient No.

Initial Vision

Date CMV Retinitis Diagnosed

Final Vision

Age

Past Medical History

00

26

3/85 Pneumocystis pneumonia, 5/85 Mycobacterium gordonae (lung), 6/85 CNS toxoplasmosis 6/84 idiopathic thrombocytopenic purpura

20/20

LP

20/800

NLP

20/40

20/70

20/100

OS

DO

OS

ou

00

OS

Location of Retinitis

ou

00

OS

10/85

Posterior pole

Diffuse

20/100

6/85

Peripheral

Peripheral

1/200

7/85

Diffuse

Diffuse

2

52

3

37

10/84 Bell's palsy secondary to cutaneous herpes zoster, 4/85 P. pneumonia

LP

HM

HM

4

45

20/20

HM

20/20

LP

10/85

Peripheral

Diffuse

5

31

8/85 gastrointestinal isosporiasis, 8/85 stomach Kaposi's sarcoma 12/84 P pneumonia, 1/85 herpes simplex proctitis

20/20

LP

20/400

NLP

11/85

Diffuse

Diffuse

6

36

5/85 cutaneous Kaposi's sarcoma, 9/85 CMV colitis, 10/85 gastrointestinal Kaposi's sarcoma, 10/85 CMV pneumonia

20/400

20/20

20/800

20/200

10/85

Diffuse

Diffuse

7

45

20/70

20/25

LP

20/25

1/86

Peripheral

Peripheral

8

33

12/84 candida esophagitis, 11/85 gastrointestinal shigella 7/85 CNS toxoplasmosis

20{30

20/20

20/200

20/20

12/85

Peripheral

Peripheral

9 10

44 31

20/20 20/20

20/20 20/20

20/20 20/20

20/20 20/20

1/86

11

37

20/20

20/20

20/30

20/25

1/86

12

38

20/20

20/20

20/20

20/20

13

36

10/85 intestinal cryptosporidiosis, 11/85 oral Kaposi's sarcoma

20{20

20/20

20/20

20/20

14

55

No history of prior opportunistic infections or Kaposi's sarcoma

20/20

20/40

20/20

NLP

15

32

7{85 P. pneumonia

20/20

20/20

20/20

20/20

16

26

1/85 P. pneumonia. 10/85 herpes simplex proctitis

20/25

20/25

20/25

20/25

428

9/85 CNS toxoplasmosis No history of prior opportunistic infections or Kaposi's sarcoma 3/85, 11/85, 1/86 P. pneumonia, 1/86 CMV pneumonitis, 2/86 CMV colitis 2/85, 9/85 P. pneumonia, 1{86 cutaneous Kaposi's sarcoma

1/86

Diffuse

12/85

Peripheral

Peripheral

2/86 2/86

6/86

Peripheral

Posterior pole

3/86

3/86 3/86

Peripheral

Peripheral Diffuse

Peripheral

Patients Treated with Ganciclovir Location of Systemic CMV Infections

Date of Initiating Ganciclovir

Complications Related to Treatment with Ganciclovir

Date of Recurrences

Date of Rein­ ductions

2/86 (intravenous access problems) None

2/86

? brain

10/85

None

None

8/85

None

None

7/85

None

12/85 (possible recurrence of CMVoptic neuritis OS)

Liver

10/85

None

2/86 (break­ through)

None

11/85

Neutropenia

Multiple (neutropenia)

Multiple

Colon. lung

10/85

Neutropenia, ? dementia

12/85 (breakthrough) 1/86 (neutropenia)

12/85

Response to Ganciclovir

Subsequent Opportunistic Infections or Kaposi's Sarcoma

Eventual Outcome

Regression after each induction

None

Died 4/86

None

Regression OU

None

12/85

Regression OU after initial treatment; slight im­ provement in vision OS after rein­ duction 12/85 Regression OU after each induction Regression while on ganciclovir with recurrences whenever drug was discontinued Regression after each induction

None

11 /85 retinal detachmen! OD 12/85 retinal detachmen! OS Vision before detach­ ments: OD, 20/25; OS, 20/30 Alive 9/86 Presented 8/86 with bilateral retinal detachments; ganci­ clovir started else­ where

2/86

None

1/86

None

5/86 (breakthrough)

5/86

None

1/86

None

6/86 (breakthrough)

6/86

Colon Liver

2/86 2/86

None None

None 6/86 (breakthrough)

None 6/86

Lung , colon

1/86

None

None

None

Colon. ? brain

2/86

None

None

None

3/86

None

Colon

3/86

None

None

4/86

None

None

3/86

None

Died 7/86

12/85 candida esophagitis

Died 4/86

3/86 recurrent herpes simplex proctitis

Alive 9/86 Progression of CMV because neutro­ penia necessitated repeatedly stopping and restarting drug

Neutropenia and dementia possibly related to drug; reactivation of retinitis after drug discontinued 1/86 Alive 9/86 Optic atrophy OD causing marked visualloss Alive 9/86 3/86 retinal detachment OD

12/85 conjunctival Kaposi's Died 2/86 sarcoma

Regression after each induction Regression after each induction Regression Regression after each induction Regression

None 12/85 gastrointestinal Kaposi's sarcoma

Died 5/86 Alive 9/86

None

Died 4/86

None

Early signs of regression

2/86 Disseminated M. avium-intracellulare

Died 2/86

6/86 (refused drug)

6/86

Regression after each induction

3/86 candida esophagitis

Alive 9/86

4/86, 5/86 (refused maintenance therapy) 6/86 (breakthrough)

4/86

Regression after each induction

3/86 CMV colitis 5I86 P. pneumonia

Died 8/86

6/86

Regression after each induction Regression

None

Alive 9/86

None

Alive 9/86

None

Miscellaneous

None

4/86 disseminated Mycobacterium avium- intra­ cellu/are complex None

Reactivation occurred after patient discontinued drug to take vacation

(Table 1 continues)

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Table 1

Initial Vision Patient No.

Age

17

37

18

35

19

35

20

28

21

50

22

35

23

34

Past Medical History 10/82, 6/83, 11/83 P.

pneumonia 2/86 P. pneumonia, 2/86 oral

Kaposi's sarcoma 3/84 cutaneous Kaposi's sarcoma, 6/84 oral Kaposi's sarcoma, 5/85 P. pneumonia, 9/85 herpes simplex encephalitis 4/85 P. pneumonia, 7/85 oral Kaposi's sarcoma, 8/85 cutaneous Kaposi's sarcoma, 2/86 pulmonary Kaposi's sarcoma 5/85 cutaneous Kaposi's sarcoma, 3/86 P. pneumonia, 5/86 viral encephalitis, ? herpes zoster versus CMV 10/85 P. pneumonia No history of prior opportunistic infection or Kaposi's sarcoma

OD = right eye; OS perception.

=

left eye; OU

=

OD

OS

OD

20/400

LP

HM

20/20

20/20

NLP

20/20

20/20

20/400

20/20

HM

HM

20/20

20/60

20/20

20/20

20/20

20/20

20/20

20/20

20/20

20/20

20/20

20/20

20/20

20/20

20/20

=

cytomegalovirus; CNS

CMV retinitis may be a frequent, early, asymptomatic opportunistic infection that can initially go unrecognized without indirect ophthalmoscopic examination ofthe pe­ ripheral retina. This demonstrates the importance of fre­ quent ophthalmologic examination of all patients with ARC or AIDS. Ganciclovir was very effective in the treatment of CMV retinitis in our patients, all of whom showed regression of retinitis within 10 to 14 days after initiation oftherapy. Ten patients had sustained regression with no recurrences while on the drug. As the retinitis began to regress, the dense granularity or whiteness of the lesion began to fade; fading continued with therapy and the size of the lesions diminished slowly. The retinitis became more patchy and eventually the white areas of retinitis regressed completely, leaving areas of atrophic, markedly thinned retina with ghost vessels and underlying RPE changes, including hy­ perplasia and/or atrophy. The hemorrhages associated with the retinitis also regressed, but at a slower pace than did the retinitis itself. Reactivation of the viral retinitis was not uncommon while the patients were on maintenance therapy with gan­ ciclovir. This breakthrough reactivation was seen in 7 of 23 patients (30.4% ), all ofwhom originally showed regres­ sion of retinitis. Recurrences occurred at an average of 4.6 months (range, 2-7 months) after initiation of treat­ ment. They appeared as new, white lesions at the edges 430

OS

20/30

both eyes; CM

Date CMV Retinitis Diagnosed

Final Vision

=

ou

OD

OS

Location of Retinitis

ou

3/86

OD

OS

Diffuse

Diffuse

Peripheral

4/86

Peripheral

3/86

Diffuse

3/86

Peripheral

Posterior pole

5/86

Peripheral

5/86 Diffuse

6/86

central nervous system; LP

=

light perception; HM

=

hand motion; NLP

=

no light

ofthe previous retinitis and progressed toward the normal­ appearing retina. Patients who had such breakthrough CMV infections were all successfully treated with reinduction therapy (2.5 mgjkg every 8 hours for 10 days), after which they were placed on maintenance therapy 7 days per week. None of these patients has had a subsequent reactivation. There were few complications from treatment with ganciclovir. Neutropenia that was believed to be directly related to treatment developed in only two patients (8.7%); another patient had neutropenia that may have resulted from his simultaneous treatment with chemotherapeutic agents for Kaposi's sarcoma. Dementia developed in one patient while being treated with ganciclovir, but it was not clear if this was a side effect of the drug or a mani­ festation of recurrent CMV encephalitis. In some of the earlier patients treated with ganciclovir, we waited for definite signs ofadvancement of the retinitis before starting therapy. Because all of these patients showed progression of the retinitis, we started subsequent patients on ganciclovir shortly after the diagnosis ofCMV retinitis was made. The good response to treatment and the low incidence of side effects led us to believe that immediate treatment with ganciclovir was justified. The prognosis of patients undergoing treatment with ganciclovir is improved when compared with earlier re­ ports of patients who received different treatment. 3 •6 • 12­ 14

HENDERLY et al

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CMV RETINITIS AND GANCICLOVIR

(continued)

Location of Systemic CMV Infections

Date of Initiating Ganciclovir

Complications Related to Treatment with Ganciclovir

Date of Recurrences

Date of Reinductions

Response to Ganciclovir

Subsequent Opportunistic Infections or Kaposi's Sarcoma

Eventual Outcome

pneumonia

Died 7/86

None

3/86

None

None

None

Regression OU

4/85 P.

None

4/86

None

None

None

Regression

None

Alive 9/86

None

3/86

None

None

None

Slow regression

5/86 pulmonary Kaposi's sarcoma

Died 7/86

None

3/86

Possible neutropenia

6/86 (neutropenia)

6/86

Regression after each induction

None

Alive 9/86

Possibly brain

5/86

None

None

None

Regression

None

Alive 9/86

None

6/86

None

Alive 9/86

6/86

None

Regression after each induction Regression

None

None

7/86 7/86 (drug discontinued after induction) None None

None

Alive 9/86

Two of our patients lived longer than 1 year after the original diagnosis of CMV retinitis, and the average sur­ vival is now slightly greater than 6 months. Of the 23 patients in this study, 11 (47.8%) have died and 12 (52.2%) are still alive. Not only are patients living longer, but there is a sub­ jective improvement in the quality oflife for patients un­ dergoing treatment with ganciclovir. Many patients report an improved sense of well being and are able to resume many normal activities of daily living. The improved prognosis and quality of life are probably related to control of CMV infections elsewhere in the body. Previous reports have documented that CMV in­ fection is common in patients with AIDS, 19 and is often a multiorgan infection, most frequently affecting the ret­ ina, lungs, liver, brain, and gastrointestinal systems. 5 •11 When untreated, the progressive course ofCMV infections has led to rapid failure of these multiple organ systems and to death. Ganciclovir treatment for CMV retinitis can be assumed to also cause regression ofCMV infections elsewhere in the body. By controlling the infection in other organ systems, as well as in the eyes, patients are living longer and feeling better. In conclusion, CMV retinitis is a common opportu­ nistic infection in patients with AIDS and frequently ap­ pears first in the peripheral retina. CMV retinitis may present early in the course ofAIDS. Ganciclovir is effective

Miscellaneous 5/86 bilateral retinal detachments 5/86 retinal detachment OD Marked vitritis developed OS as retinitis regressed Neutropenia while on chemotherapy for Kaposi's sarcoma

in treating CMV retinitis and causes few complications. Breakthrough reactivation of retinitis while on mainte­ nance therapy with ganciclovir is not uncommon, but can be successfully treated with reinduction therapy and increased frequency of maintenance therapy. The survival of patients being treated with ganciclovir is longer than that previously reported for patients with untreated CMV infections. In addition, the patients report an im­ proved quality oflife while on treatment with ganciclovir. The improved prognosis and quality oflife may be related to suppression ofCMV infections elsewhere in the body.

REFERENCES 1. Freeman WR, O'Connor GR. Acquired immune deficiency syndrome retinopathy, pneumocystis, and cotton-wool spots. Am J Ophthalmol 1984; 98:235-7. 2. Holland GN, Gottlieb MS, Yee RD, et al. Ocular disorders associated with a new severe acquired cellular immunodeficiency syndrome. Am J Ophthalmol 1982; 93:393-402. 3. Freeman WR, Lerner CW, Mines JA, et al. A prospective study of the ophthalmologic findings in the acquired immune deficiency syndrome. Am J Ophthalmol1984; 97:133-42. 4. Pepose JS, Holland GN, Nestor MS, et al. Acquired immune deficiency syndrome: pathogenic mechanisms of ocular disease. Ophthalmology 1985; 92:472-84. 5. Reichert CM, O'Leary TJ, Levens DL, et al. Autopsy pathology in the

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8. 9.

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11.

12.

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acquired immune deficiency syndrome. Am J Pathol 1983; 112:357­ 82. Friedman AH, Orellana J, Freeman WR, et al. Cytomegalovirus retinitis: a manifestation of the acquired immune deficiency syndrome (AIDS). Br J Ophthalmol1983; 67:372-80. de Venecia G, Zu Rhein GM, Pratt MV, Kisken W. Cytomegalic inclusion retinitis in an adult: a clinical, histopathologic, and ultrastructural study. Arch Ophthalmol1971; 86:44-57. Nicholson DH. Cytomegalovirus infection of the retina. lnt Ophthalmol Clin 1975; 15(4):151-62. Akula SK, Mansell PWA, Ruiz R. Treatment of cytomegalovirus retinitis with dihydroxy propoxymethyl guanine. Am J Ophthalmol 1986; 101: 622. Fiala M, Chatterjee SN, Carson S, et al. Cytomegalovirus retinitis sec­ ondary to chronic viremia in phagocytic leukocytes. Am J Ophthalmol 1977; 84:567-73. Murray HW, Knox DL, Green WR, Susel RM. Cytomegalovirus retinitis in adults: a manifestation of disseminated viral infection. Am J Med 1977; 63:574-84. Holland GN, Pepose JS, Pettit TH, et al. Acquired immune deficiency syndrome: ocular manifestations. Ophthalmology 1983; 90:859-73.

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13. Bachman DM, Rodrigues MM, Chu FC, et al. Culture-proven cyto­ megalovirus retinitis in a homosexual man with the acquired immu­ nodeficiency syndrome. Ophthalmology 1982; 89:797-804. 14. Khadem M, Kalish SB, Goldsmith JA, et al. Ophthalmologic findings in acquired immune deficiency syndrome (AIDS). Arch Ophthalmol 1984; 102:201-6. 15. Rosecan LR, Stahi-Bayliss CM, Kalman CM, Laskin OL. Antiviral ther­ apy for cytomegalovirus retinitis in AIDS with dihydroxy propoxymethyl guanine. Am J Ophthalmol1986; 101:405-18. 16. Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-(1 ,3-dihydroxy-2-propoxymethyl) guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1986; 314:801-5. 17. Fauci AS, Masur H, Gelmann EP, et al. The acquired immunodeficiency syndrome: an update. Ann Intern Med 1985; 102:800-13. 18. Felsenstein D, D'Amico DJ, Hirsch MS, et al. Treatment of cytomeg­ alovirus retinitis with 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine. Ann Intern Med 1985; 103:377-80. 19. Macher AM, Reichert CM, Straus SE, et al. Death in the AIDS patients: role of cytomegalovirus. N Engl J Med 1983; 309:1454.

Discussion by William W. Culbertson, MD Henderly and co-workers have focused our attention on the management of the increasingly frequent problem of cytomeg­ alovirus (CMV) retinitis in patients with acquired immune de­ ficiency syndrome (AIDS). Earlier studies of untreated patients showed that CMV retinitis was relentlessly progressive, but un­ fortunately no firm data were collected on the rate of loss of central visual acuity. 1- 3 Therefore, the value of clinical studies which attempt to evaluate the efficacy of any treatment is limited by the fact that we do not know the natural history ofthe disease for comparison purposes. Another potential source of error is that the diagnosis of CMV retinitis is made by the ophthalmol­ ogist's observation of a "typical" CMV retinitis lesion in the fundus. In fact, a small percentage of AIDS patients with nec­ rotizing retinitis actually has toxoplasma, cryptococcal, syphilitic, or herpes simplex retinitis, or cotton-wool spots, all of which may be indistinguishable from CMV retinitis. Ganciclovir has been used by Dr. Henderly for the treatment ofCMV retinitis in AIDS because it has been shown to suppress CMV in vitro4 --Q and because other treatments including acyclovir have been ineffective. 3 The mechanism of action of ganciclovir depends on its structural similarity to guanosine, which is used by the cell to make both viral and cellular DNA (Fig 1). It is a modification of acyclovir in which another hydroxyl group has been added to the side chain. Acyclovir does not work in CMV infection because the viral thymidine kinase required to phos­ phorylate acyclovir is not produced by CMV-infected cells (Fig 2). Ganciclovir is phosphorylated by cellular enzymes prefer­ entially and therefore concentrates in CMV-infected cells where it works by inhibiting viral DNA polymerase. Unfortunately, uninfected cells such as in the bone marrow do phosphorylate small amounts of ganciclovir, which can inhibit cellular DNA polymerase resulting in neutropenia. Ganciclovir is very similar to acyclovir in its tissue distribution, easily crossing the blood­ brain barrier and being excreted by the kidney. The three imFrom the Bascom Palmer Eye Institute, Miami.

432

portant features ofganciclovir are: (I) it is virostatic against CMV virus; (2) its reversible bone marrow toxicity; and (3) the fact that it can only be given by intravenous (IV) administration at the current time. Six previously published articles showed that a limited in­ duction course of IV ganciclovir temporarily suppressed retinitis in 34 patients. 7- 12 Henderly and co-workers presented their work in which they were able to extend suppression of retinitis after high-dose induction therapy by continuing with ongoing, lower­ dose maintenance therapy in 23 patients. Recurrences were re­ treated according to the original induction schedule. Their pa­ tients came from routine screening examinations of all AIDS patients, and therefore included some asymptomatic patients with small or peripheral lesions. By specifying whether the ini­ tially observed lesions were posteriorly or peripherally located, Henderly et al have allowed us to determine the effect of the location of the lesion on the liklihood of central visual loss.

GUANOSINE

ACYCLOVIR

GANCICLOVIA (BW759U) (DHPG)

Fig 1. Acyclovir and ganciclovir are acyclic derivatives of guanosine. Ganciclovir has an additional hydroxyl group at the end of the side chain.

ACYCLOVIR

___N_o __v_I_R_A_L__~JNO THYMIDINE KINASE

PHOSPHORYLATION BY GANCICLOVIR CELLULAR ENZYMES

\

PHOSPHORYLATION BECAUSE ACYCLOVIR NEEDS VIRAL THYMIDINE KINASE

GANCICLOVIR TRIPHOSPHATE

INHIBITS VIRAL DNA POLYMERASE

TOXICITY TO BONE MARROW IN NORMAL CELLS (NEUTROPENIA)

CMV VIRAL INHIBITION (VIROSTATIC)

/

l

Fig 2. Acyclovir cannot be phosphorylated in CMV-infected cells because they do not produce the viral thymidine kinase necessary for acyclovir activation. Ganciclovir is preferentially phosphorylated by cellular enzymes in CMV-infected cells. Ganciclovir triphosphate is a competitive inhibitor of viral DNA polymerase causing CMV virostasis. Reversible bone marrow toxicity results from phosphorylation of small amounts of ganciclovir in normal cells and consequent inhibition of normal cellular DNA polymerase.

Fig 3. Top left, fundus photograph of patient maintained on ganciclovir showing clinically inactive CMV retinitis. Transmission electron micro­ graphs (Fig 3, bottom left and right) were obtained from the junction zone (arrow) between clinically unaffected and atrophic retina. Bottom left, culture-proven complete cytomegalovirus in inner retinal cells at junction (Fig 3, top left) between "normal" and atrophic retina (original magnification, Xl60,000). Bottom right, budding CMV in clinically in­ active retina in the same patient (original magnification, Xl60,000).

433

OPHTHALMOLOGY

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APRIL 1987

Table 1. Summary of Results after Induction Therapy for 23 Patients Results Suppression after induction Recurrence on maintenance therapy Bilateral Retinal detachment AIDS presenting with retinitis Neutropenia Time to death AIDS

=

1000/o 570/o 520/o 6 eyes 4 patients 3 patients 6 mos

acquired immune deficiency syndrome.

Table 2. Percentage of Eyes Retaining Central Vision (>20/100) on Maintenance Therapy (2B eyes)

% of Eyes (Visual Acuity >20/100) Overall Peripheral retinitis only Posterior ± peripheral retinitis

57 (15/26) 71 (11 /17) 36 (4/11)

These authors found that the retinitis appeared to regress in all patients after induction therapy (Table I). Although the ret­ initis may appear clinically inactive, it probably smolders along at a very slow rate. These electron micrographs were taken at the border zone between normal and atrophic retina in one of our patients who died while on maintenance treatment. He had no evidence of active retinitis anywhere in the eye at the time of death (Fig 3, top left). However, we were easily able to find substantial quantities of complete (Fig 3, bottom left) and bud­ ding CMV virus in the retina (Fig 3, bottom right) on electron microscopy and by viral isolation in cell culture. Fifty-seven percent of patients suffered recurrence of their retinitis during the period of study. Clinical recurrences were not new lesions, but rather reactivations at the leading edge of previous lesions. Regression of retinitis occurring on continuous maintenance therapy probably represents inadequate drug dosage rather than drug resistance. Henderly and associates give us added insight into the im­ portant question of how many patients retained their central (>20/100) vision throughout the study (Table 2). By additional computation ofthe data ofHenderly eta!, we find that 57% (15/ 28) of eyes having central vision (>20/ l 00) at the start oftherapy retained central vision throughout treatment. As we would ex­ pect, patients with peripheral lesions only were twice as likely (71 %, II/ 17) to retain central vision as those with posterior ret­ initis (36%, 4/ II). Approximately one half of the patients were followed up to the time of death. These treated patients survived an average of 6 months which is significantly longer than previously reported for untreated AIDS patients with CMV retinitis. 2•3• 13 In general, these patients lived longer and felt better after treatment probably because of the virostatic effects of the drug on other CMV-in­ fected organs including the lungs, brain, adrenal glands, bone marrow, and kidneys. Of the ten patients with central vision (>20/ 100) in at least one eye at the initiation of treatment and who ultimately died on treatment, 6 (60%) retained central vision in at least one eye until death. Paradoxically, ifganciclovir treat­ ment confers a longer life span, treated patients have more time to go blind from their retinitis than untreated patients. These authors have pointed out the difficulties encountered in ganci­ clovir treatment including the need for expensive indefinite daily

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IV administration through an indwelling IV line. The side effects of neutropenia, CNS symptoms, and phlebitis are bothersome but reversable. Alternate routes of delivery, such as orally (Burroughs-Wellcome, personal communication) or intraocu­ larly,14·15 would circumvent some ofthese problems. In conclusion, this study has shown that CMV retinitis is re­ tarded or suppressed by ganciclovir therapy, but reactivates in all patients whenever the drug is withdrawn and in over one half of patients on maintenance therapy. Treated patients possibly live longer than untreated patients. Lacking an untreated control group for comparison purposes, we still do not know how effective ganciclovir is in preventing visual loss and when we should consider initiating ganciclovir therapy, if ever. Should it be given prophylactically or only for vision-threatening lesions in one or both eyes? If the fact that ganciclovir probably prolongs the lives of AIDS patients is added to the equation, the decision if and when to begin treatment becomes very complex and may depend on other nonocular factors such as medical, social, and economic considerations. References 1. Holland GN, Gottlieb MS, Yee RD. et al. Ocular disorders associated with a new severe acquired cellular immunodeficiency syndrome. Am J Ophthalmol1982; 93:393-402. 2. Holland GN, Pepose JS, Pettit TH, et al. Acquired immune deficiency syndrome: ocular manifestations. Ophthalmology 1983; 90:859-73. 3. Palestine AG, Rodrigues MM. Macher AM, et al. Ophthalmic involve­ ment in acquired immune deficiency syndrome. Ophthalmology 1984; 91 :1092-9. 4. Mar EC, Patel PC, Huang ES. Effect of 9-(2-hydroxyethoxymethyl) guanine on viral-specific polypeptide synthesis in human cytomega­ lovirus-infected cells. Am J Med 1982; 73:82-5. 5. Tocci MJ, Livelli TJ, Perry HC, Field AK. Effects of the nucleoside analog 2: NOR-'Z-deoxyguanosine on human cytomegalovirus repli­ cation. Antimicrob Agents Chemother 1984; 25:247-52. 6. Plotkin SA, Drew WL, Felsenstein D, Hirsch MS. Sensitivity of clinical isolates of human cytomegalovirus to 9-(1 ,3-dihydroxy-2-propoxy­ methyl) guanine. J Infect Dis 1985; 152:833-4. 7. Felsenstein D, D'Amico DJ, Hirsch MS, et al. Treatment of cytomeg­ alovirus retinitis with 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine. Ann lnt Med 1985; 103:377-80. 8. Bach MC, Bagwell SP, Knapp NP, et al. 9-(1 ,3-dihydroxy-2-propoxy­ methyl) guanine for cytomegalovirus infections in patients with the acquired immunodeficiency syndrome. Ann lnt Med 1985; 103: 381-2. 9. Palestine AG, Stevens G, Lane HC, et al. Treatment of cytomegalovirus retinitis with dihydroxy propoxymethy1 guanine. Am J Ophthalmol1986; 101:95-101. 10. Masur H, Lane HC, Palestine A. et al. Effect of 9-(1 ,3-dihydroxy-2­ propoxymethyl) guanine on serious cytomegalovirus disease in eight immunosuppressed homosexual men. Ann lnt Med 1986; 104:41-4. 11. Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-(1 ,3-dihydroxy-2-propoxymethyl) guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1985; 314:801-5. 12. Rosecan LR, Stahi-Bayliss CM, Kalman CM, et al. Antiviral therapy for cytomegalovirus retinitis in AIDS with dihydroxy propoxymethyl guanine. Am J Ophthalmol1986; 101:405-18. 13. Macher AM. Reichert CM, Straus SE, et al. Death in the AIDS patient: role of cytomegalovirus (letter). N Engl J Med 1983; 309:1454. 14. Pulido J, Peyman GA. Lesar T, Verno! J. lntravitreal toxicity of hy­ droxyacyclovir (BW-759U): a new antiviral agent. Arch Ophthalmol 1985; 103:840-1. 15. Schulman J, Peyman G, Horton M, et al. Intraocular 9-((2-hydroxy-1­ (hydroxymethyl) ethoxy] methyl) guanine levels after intravitreal and subconjunctival administration. Ophthalmol Surg 1986; 17:429-30.