antiviral therapy for cytomegalovirus retinitis in aids with dihydroxy propoxymethyl guanine

AMERICAN JOURNAL OF OPHTHALMOLOGY®

VOLUME 101 NUMBER 4 APRIL, 1986

Antiviral Therapy for Cytomegalovirus Retinitis in AIDSWith Dihydroxy Propoxymethyl Guanine

Lauren R. Rosecan, M.D., Celine M. Stahl-Bayliss, M.D., Concetta M. Kalman, R.N.,and Oscar 1. Laskin, M~ D.

Six patients (all male, five homosexual andone bisexual, 23 to 48 years old) with theacquired immune deficiency syndrome (AIDS)who had cytomegalovirus retinitis were treated with a new antiviral drug as a part of aprospective open-labeled trial for serious cytomegalovirus infections. The drug, 9-[2hydroxy-l-(hydroxymethyl)ethoxymethyl]guanine (referred to as dihydroxy propoxymethyl guanine), a new acyclic nucleoside antiviral agent similar in structure to acyclovir,produced positive results. These patientstreated with dihydroxy propoxymethyl guanine (2.5 mg/kg of body weight every eighthours) showed regression and often disappearance of the lesions of cytomegalovirus retinitisdurin6 and for several weeks after therapy,usually with concomitant resolution of viralshedding. The cytomegalovirus retinitis recurred in four patients (the other two were lostto follow-up), but retreatment usually led to

Accepted for publication Jan. 10, 1986.From the Department of Ophthalmology (Dr.

Rosecan) and the Division of Clinical Pharmacology,Departments of Medicine and Pharmacology (Drs.Stahl-Bayliss and Laskin and Ms. Kalman), Cornell University Medical College, New York, New York. Thisstudy was supported in part by a grant from the Burroughs Wellcome Company; Dr. Stahl-Bayliss is a recipient of a Pharmaceutical Manufacturers AssociationFoundation Careers in Clinical Pharmacology Fellowship; Dr. Laskin is a recipient of a John A. HartfordFoundation Fellowship Award and a recipient of anAndrew W. Mellon Teacher-Scientist Award.

Reprint requests to Oscar L. Laskin, M.D., Division ofClinical Pharmacology, Cornell University Medical College, New York, NY 10021.

remission. Adverse drug toxicity (reversiblegranulocytopenia) occurred in two patients.

CYTOMEGALOVIRUS INFECTION of the eye is awell-known cause of devastating retinal inflammation. The first case of cytomegalovirus chorioretinitis in an adult was reported as recentlyas 19591; this was followed by only two morecase reports in the next decade.Y By 1980 approximately 40 adult patients with cytomegalovirus retinitis had been described, primarily asa result of immunosuppression in organ transplant recipients.v? In recent years, cytomegalovirus retinitis has become increasingly important because of the rising incidence of' theacquired immune deficiency syndrome (AIDS)in which there is severe suppression of cellmediated immunity.v" In two recent autopsyseries of patients with AIDS, cytomegalovirusretinitis was present in 34%8and 40%,12 respectively. The retinitis is often the first clinical signof disseminated cytomegalovirus infection. 5

The ophthalmoscopic manifestations of cytomegalovirus retinitis are distinctive and havebeen well described in patients without5,7,13,14

and with AIDS.8-11.15-20 In patients with AIDS,cytomegalovirus retinitis inevitably leads to irreversible retinal necrosis from severe immunosuppression. 8-12.15-22 All previous attempts attreating cytomegalovirus retinitis in AIDSpatients with antiviral agents, such as acyclovir,9.11.17,18.23 alpha-interferon.v-s-" and vidarabineI8.20-22 have been unsuccessful. Broadspectrum antibiotics, corticosteroids, and antifungal agents have also been tried withouttherapeutic benefit.":"

©AMERICAN JOURNAL OF OPHTHALMOLOGY 101:405-418, APRIL, 1986 405

406 AMERICAN JOURNAL OF OPHTHALMOLOGY April, 1986

9-[2-Hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine, also referred to as dihydroxy propoxymethyl guanine, is a new acyclicnucleoside antiviral drug that has potent invitro activity against human cytomegalovirus. 25,26 Dihydroxy propoxymethyl guanine isstructurally similar to acyclovir. However, acyclovir has little in vitro activity against humancytomegalovirus. The mechanism of action ofdihydroxy propoxymethyl guanine againsthuman cytomegalovirus has not been fullyelucidated. Unlike acyclovir, dihydroxy propoxymethyl guanine is phosphorylated incytomegalovirus-infected cells by some unknown pathway to its active form which inhibits the cytomegalovirus deoxyribonucleic acidpolymerase. We report the therapeutic response to the treatment of cytomegalovirusretinitis in AIDS patients with dihydroxy propoxymethyl guanine.

Subjects and Methods

These patients were participants in a prospective open-labeled clinical study to evaluatethe therapeutic response, pharmacology, andtoxicity of dihydroxy propoxymethyl guaninein AIDS patients. All patients had AIDS according to the criteria of the Centers for DiseaseControl." and were hospitalized and examinedat the New York Hospital-Cornell UniversityMedical Center. Each patient was tested for theextent of cytomegalovirus infection by culturing all available bodily fluids, including blood,urine, sputum, feces, and pleural or cerebrospinal fluid if indicated. These cultures wereobtained pretreatment, at thrice-weekly intervals during treatment, and at weekly intervalsafter treatment. Each patient underwent standard blood and urine tests before treatmentand two to three times a week during treatmentand weekly after therapy. This battery of bloodtests included complete blood count with differential, platelet count, reticulocyte count,electrolytes, tests of renal function (blood ureanitrogen and creatinine), liver function tests(serum glutamic oxaloacetic transaminase,serum glutamic pyruvic transaminase, alkalinephosphatase, and total and direct bilirubin),cholesterol, triglycerides, amylase, glucose,calcium, phosphorus, uric acid, and erythrocyte sedimentation rate. Urinalysis with microscopy was also performed. During treatment, patients were queried daily for anyadverse drug reaction.

For inclusion in the study, each patient wasrequired to have clinical and virologic evidenceof cytomegalovirus infection (positive viral culture or colon or lung biopsy specimen confirming the presence of giant cells with cytomegalovirus inclusions by light microscopy) as well asthe absence of alternate causes. Also requiredwas ophthalmoscopic evidence of cytomegalovirus retinitis (periphlebitis and perivascularhemorrhages and exudates), documented byfundus photographs. Patient 3 was initiallybeing treated only for cytomegalovirus colitisand was visually asymptomatic. When evidence of cytomegalovirus retinitis was detectedduring a routine ocular examination on day 6 oftherapy, he was then studied for cytomegalovirus retinitis. The patients underwent visualacuity testing, slit-lamp examinations, and indirect ophthalmoscopic examinations after dilation of the pupils with tropicamide 1% andphenylephrine hydrochloride 2.5% beforetreatment and at regular weekly intervals during and after treatment. Slit-lamp examinationswere not performed if a patient was too ill toleave his bed. Fundus photographs were takenwhen possible after every ophthalmoscopicevaluation. The patients were examined dailyto assess the clinical course of their cytomegalovirus infection.

We excluded patients with either renal orhepatic dysfunction. No patient had receivedany antiviral or immune-modulating drugswithin two weeks before entry into this study.Written informed consent was obtained fromeach patient before the study was initiated.

The lyophilized sterile sodium salt of dihydroxy propoxymethyl guanine was supplied invials containing 500 mg of drug. Dihydroxypropoxymethyl guanine was reconstituted with10 ml of sterile water, and the calculated dosewas added to 100 ml of normal saline andinfused intravenously over one hour. Patientsreceived 1 mg/kg of body weight or 2.5 mg/kg ofbody weight every eight hours for five to 24days. One patient (Patient 2) received outpatient maintenance therapy of 2.5 mg/kg of bodyweight administered intravenously once dailyMonday through Friday for five weeks.

Case Reports

Case 1The patient, a 48-year-old bisexual man with

AIDS, had a 13-month history of fever, a 40-lbweight loss, lymphadenopathy, increased fa-

Vol. 101, No. 4 Antiviral Therapy for Cytomegalovirus Retinitis 407

tigue, and diarrhea. The patient was admittedto New York Hospital on March 12, 1985, forfurther testing. On March 26 bronchoalveolarwashings from his right and left lungs werepositive for cytomegalovirus; on April 3, aurine culture was positive for cytomegalovirus.From April 9 to April 29, the patient received125 mg of dihydroxy propoxymethyl guanine(2.5 mg/kg of body weight) every eight hoursfor 20 days (61 doses).

On day 0 of drug therapy, his visual acuitywas R.E.: 20/50 and L.E.: 20/20, with normalexternal and anterior segment findings. Ophthalmoscopy of the right eye disclosed a largepatch of white exudate in the temporal midperipheral retina, scattered white exudates, andperiphlebitis with perivascular sheathing of exudate along the superior and superotemporalvascular arcades. The left fundus showed scattered patches of white exudate. These findingswere consistent with cytomegalovirus retinitis.Another examination performed three daysafter treatment with dihydroxy propoxymethylguanine ended gave the same findings. Thepatient was discharged at that time. Urine cultures became negative for cytomegalovirusduring this course of treatment and remainednegative. The gastric mucosa biopsy specimenobtained on April 26 was positive for cytomegalovirus inclusions.

The patient did well until three weeks later,when he complained of decreased vision in hisright eye. On May 21, his visual acuity wasR.E.: light perception and L.E.: 20/20. Ophthalmoscopy of the right eye showed severe vitritis,periphlebitis, and cytomegalovirus retinitiswith extensive perivascular exudates and hemorrhages, consistent with marked worsening ofcytomegalovirus retinitis in that eye (Fig. 1).Findings in the left eye were unchanged. Thepatient was readmitted to New York Hospital,and from May 29 to June 21 he received 130 mgof dihydroxy propoxymethyl guanine (2.5mg/kg of body weight) every eight hours (70doses). A sputum culture obtained on May 30was positive for cytomegalovirus althoughurine and blood cultures remained negativeduring this course. On May 31 his visual acuitywas R.E.: 20/400 and L.E.: 20/40. There wasslight clearing of the vitritis in the right eye,although the appearance of the retina was similar to that seen ten days previously. The lefteye had developed moderately severe periphlebitis with perivascular exudates and hemorrhages, although the vitreous remained clear.The impression at that time was of stabilizationand possible slight improvement of the cyto-

megalovirus vitritis and retinitis in the righteye but of worsening of the cytomegalovirusretinitis in the left eye.

By June 7 (day 9 of therapy), visual acuityhad improved to R.E.: 20/70 and L.E.: 20/25.Ophthalmoscopy of the right eye disclosed significant clearing of the vitritis and marked regression of the periphlebitis and perivascularexudates. Ophthalmoscopy of the left eye disclosed maintenance of a clear vitreous andmodest regression of the periphlebitis and perivascular exudates. The impression at that timewas of significant regression of cytomegalovirus vitritis and retinitis in the right eye andmodest regression of cytomegalovirus retinitisin the left eye during this treatment.

Examinations on June 13 and June 20 (days 16and 23, respectively, of this course of therapy)showed continued improvement in the cytomegalovirus retinitis in both eyes, with resolution of the vitritis in the right eye noted on June20. On June 27, six days after treatment withdihydroxy propoxymethyl guanine ended, thepatient's visual acuity was R.E.: 20/50 and L.E.:20/20 -3. Both fundi showed clear vitreous andcontinued marked regression of the periphlebitis and perivascular hemorrhages and exudates(Fig. 2). The overall impression was of remarkable regression of cytomegalovirus vitritis,periphlebitis, and retinitis (both exudative andhemorrhagic components) both during and immediately after treatment with dihydroxy propoxymethyl guanine.

Urine cultures for cytomegalovirus, whichhad remained negative during this treatment,became positive on July 3, 1985 (12 days aftertherapy ended). On July 11 (20 days after therapy ended), the patient had a repeat ocularexamination because of decreased vision inboth eyes for one week. Visual acuity at thattime was R.E.: 201100 and L.E.: counting fingers at 2 feet. There was recurrence of moderately severe vitritis and severe cytomegalovirusretinitis in the right eye and of severe cytomegalovirus vitritis and retinitis in the left eye.Further deterioration was noted on July 18 (27days after therapy ended), when the visualacuity was R.E.: 20/200 and L.E.: hand movements, with severe cytomegalovirus vitritisand retinitis in both eyes. The patient was lostto follow-up.

Case 2The patient was a 23-year-old homosexual

man with AIDS diagnosed in August 1984when he developed seizures. These were foundto be caused by central nervous system toxo-


plasmosis. At that time the patient was successfully treated with sulfonamides and pyrimethamine.

In February 1985, the patient complained ofprogressively decreasing vision in his righteye. Ophthalmoscopic findings were consistentwith cytomegalovirus retinitis (perivascularhemorrhages and exudates). Ocular examination on March 1 showed active cytomegalovirusretinitis in the right eye with extensive hemorrhages and confluent white exudates along themajor vascular arcades, extending into theoptic disk which had blurred margins andedema (Fig. 3). The posterior pole of the lefteye was largely unaffected, although tracewhite exudates were barely visible temporal tothe macula and in the midperipheral retina.

The patient was admitted to the New YorkHospital on April 10, 1985, for further testingand treatment with dihydroxy propoxymethylguanine. His medical history included 18months of diarrhea, malnutrition with progressive weight loss, anemia, three weeks of fever,and recent onset of shortness of breath. Medications at the time of admission included dapsone, pyrimethamine, and ketoconazole. Aphysical examination showed a cachectic appearance with a weight of 85 lbs, orthostatichypotension, and pharyngeal thrush. The pretreatment (day 0) visual acuity was R.E.: counting fingers (nasal visual field only) and 1. E.:20/20. In the right eye there was an afferentpupillary defect, optic disk pallor suggestive ofoptic neuritis, and perivascular confluent hemorrhages and exudates extending into the opticdisk margins.

From April 12 to April 30, the patient received 105 mg of dihydroxy propoxymethylguanine (2.5 mg/kg of body weight) every eighthours (55 doses). Urine cultures for cytomegalovirus were positive on April 15 and April 18,and then became and remained negative thereafter. A colonic biopsy specimen on April 16was positive for cytomegalovirus colitis. Onthe tenth day of therapy, the visual acuity wasR.E.: 20/400 and L.E.: 20/20, with an afferentpupillary defect in the right eye. Ophthalmoscopy showed regression of the hemorrhagicand exudative lesions along the major vasculararcades in the right eye. There was a focus ofhemorrhage and exudative cytomegalovirusretinitis superotemporal to the macula in theleft eye.

The patient was discharged from the hospitalon May 2. Ophthalmoscopy at that timeshowed continued marked regression of the

exudative and hemorrhagic cytomegalovirusretinitis lesions in the right eye as well asregression of the hemorrhagic and exudativefocus of cytomegalovirus retinitis superotemporal to the macula in the left eye. Ophthalmoscopy on May 14 (14 days after therapy ended)showed stabilization of the cytomegalovirusretinitis lesions in both eyes, with maintenanceof the same visual acuity (R.E.: 20/400 and 1.E.:20/20).

On May 28 (28 days after therapy ended), thepatient returned because of decreasing visionin his left eye. Visual acuity at that time wasR.E.: 20/400 and L.E.: 20/200. Ophthalmoscopyshowed recent reactivation of hemorrhagic andexudative cytomegalovirus retinitis lesions inthe right eye along the temporal vascular arcades and in the papillomacular area, and inthe left eye superotemporal to the macula. Thelatter lesion had expanded approximatelythreefold with fresh hemorrhages and exudatesto involve the macula. The patient was readmitted and treated from May 30 to June 4 with 100mg of dihydroxy propoxymethyl guanine (2.5mg/kg of body weight) every eight hours forfive days (14 doses). On the second day oftherapy, the patient's visual acuity was R.E.:20/400, with an afferent pupillary defect, andL.E.: 201100. On June 4, the treatment wasdiscontinued and the patient was dischargedfrom the hospital because of severe neutropenia (granulocyte count, 693/cu mm). Visualacuity at that time was R.E.: 20/200 and L.E.:20/20. Ophthalmoscopy of the right eye disclosed marked regression of the hemorrhagicand exudative lesions of cytomegalovirus retinitis (Fig. 4). Ophthalmoscopy of the left eyealso showed regression of the large focus ofcytomegalovirus retinitis superotemporal tothe macula with clearing of the foveal hemorrhage and exudate, allowing the visual acuityto return to 20/20.. There was clearing of thecentral portion of the large lesion, giving theappearance of a ring of regressing cytomegalovirus hemorrhage and exudate.

On June 27, the patient's visual acuity wasR.E.: hand movements and L.E.: 20/40-3, witha continued afferent pupillary defect in theright eye. Ophthalmoscopy disclosed a paleoptic disk and stable, regressed cytomegalovirus retinitis in the right eye and reactivationand expansion of the hemorrhages and exudates of the focus of cytomegalovirus retinitissuperotemporal to the macula in the left eye.The patient was readmitted to New York Hospital and from June 28 to July 8, was retreated


Fig. 1 (Rosecan and associates). Case 1, May 21, 1985. Severe cytomegalovirus vitritis and retinitis withprominent perivascular sheathing with exudate. Left, Right eye temporal to optic disk. Right, Right eye nasal tooptic disk.

with 110 mg of dihydroxy propoxymethyl guanine (2.5 mg/kg of body weight) every eighthours. On July 8, the patient was dischargedfrom the hospital. At that time his visual acuitywas R.E.: light perception, with an afferentpupillary defect, and L.E.: 20/50. Ophthalmoscopy disclosed a pale optic disk and stable,regressed cytomegalovirus retinitis with apatch of white exudate temporal to the macula

in the right eye and continued regression of thelarge ring of cytomegalovirus retinitis superotemporal to the macula in the left eye.

From July 18 to Aug. 23, the patient wasmaintained on 110 mg of dihydroxy propoxymethyl guanine (2.5 mg/kg of body weight)administered intravenously once a day Monday through Friday. On July 23 the visualacuity was R.E.: light perception, with an affer-

Fig. 2 (Rosecan and associates). Case 1, June 27, 1985. Six days after cessation of 21-day course of treatment.Note resolution of vitritis and marked regression of cytomegalovirus retinitis and perivascular exudativesheathing, with complete disappearance of many lesions. Left, Right eye temporal to optic disk. Right, Right eyenasal to optic disk.


Fig. 3 (Rosecan and associates). Case 2, March I, 1985. Before treatment. Note hemorrhagic and exudativelesions. Left, Right eye temporal to optic disk. Right, Right eye nasal to optic disk.

ent pupillary defect, and L.E.: 20/60. Ophthalmoscopy of the right eye disclosed a pale opticdisk and stable, regressed cytomegalovirusretinitis with marked regression of the patchof white exudate temporal to the macula.Ophthalmoscopy of the left eye disclosed stabilization of the central portion of the ring configuration of the cytomegalovirus retinitissuperotemporal to the macula but there wasresidual hemorrhagic activity near the maculaand residual exudative activity at the temporal

periphery of the ring configuration. On July 30the visual acuity was R.E.: light perception andL.E.: 20/60, with continued afferent pupillarydefect in the right eye. Ophthalmoscopyshowed stabilization of the regressed cytomegalovirus retinitis in the right eye and stabilization of the cytomegalovirus retinitis in the lefteye. The treatment was discontinued on Aug.23 because of granulocytopenia. The patientdied four weeks later.

The overall impression was of marked regres-

Fig. 4 (Rosecan and associates). Case 2, June 7, 1985. Three days after cessation of second course of treatment.Note marked regression and some disappearance of hemorrhagic and exudative lesions. Left, Right eyetemporal to optic disk. Right, Right eye nasal to optic disk.


sion of the hemorrhagic and exudative lesionsof cytomegalovirus retinitis both during andfor several weeks after cessation of treatmentwith dihydroxy propoxymethyl guanine, butwith recurrence of focal lesions of cytomegalovirus retinitis thereafter in the absence of treatment. With retreatment with maintenancedoses of dihydroxy propoxymethyl guanine,the newly active lesions regressed and becomequiescent.


man with AIDS and biopsy-proven Kaposi'ssarcoma diagnosed in December 1984. In lateAugust 1984, the patient developed diarrheacaused by cytomegalovirus colitis. Both stoolculture and a colon biopsy specimen were positive for cytomegalovirus. From September 1984through January 1985, the patient had a 37.5-lbweight loss, weakness, fatigue, and cutaneousspread of the Kaposi's sarcoma. There were novisual complaints. On Jan. 30, 1985, the patientwas admitted to the New York Hospital fortreatment of cytomegalovirus colitis with dihydroxy propoxymethyl guanine.

Physical examination disclosed normal ocular findings, cutaneous Kaposi's sarcoma, anddiffuse lymphadenopathy.

From Jan. 31 to Feb. 11, the patient received138 mg of dihydroxy propoxymethyl guanine(2.5 mglkg of body weight) every eight hours;this resulted in resolution of his gastrointestinal symptoms.

After therapy, the patient had a recurrence ofdiarrhea, and was readmitted to New YorkHospital ten weeks later for retreatment. FromApril 25 to May 15 he was treated with dihydroxy propoxymethyl guanine, 2.5 mglkg ofbody weight, every eight hours for 21 days (60doses). The patient had no visual complaints,and on day 6 of therapy his visual acuity was20/20 bilaterally and the anterior segmentswere normal. However, the right fundus contained an arcuate-shaped perivascular patch ofwhite exudate inferior to the macula with hemorrhagic activity at its periphery (Fig. 5), consistent with cytomegalovirus retinitis in anearly stage before development of more widespread hemorrhages and exudates. The leftfundus showed patches of white exudate andhemorrhagic activity along the superotemporaland inferotemporal vascular arcades in themidperipheral retina, also consistent with cytomegalovirus retinitis in an early stage of development.

On day 16 of therapy visual acuity and anterior segment findings were unchanged butthere was decreased density of the white exudative lesion below the macula in the right eye(Fig. 5) and decreased density of the whiteexudates in the left eye, signifying early regression of the lesions. On day 21 visual acuity andanterior segment findings were unchanged andthere was continued regression and decreaseddensity of the white exudative lesion below themacula in the right eye (Fig. 5) and continueddiminution and decreased density of the whiteexudates in the midperiphery of the left eye.The overall impression was of regression of thelesions of cytomegalovirus retinitis during thecourse of treatment with dihydroxy propoxymethyl guanine.

Blood, urine, and throat cultures, which hadbeen positive for cytomegalovirus during thefirst two days of treatment, became negativethroughout the course of treatment. The gastrointestinal symptoms improved during therapy with a decrease in the frequency of bowelmovements. The patient was lost to follow-upafter discharge from the hospital.


man with AIDS complicated by Pneumocystiscarinii pneumonia in July 1984. This was successfully treated with sulfamethazole-trirnethoprim. In November 1984 the patient developeddiarrhea, which was shown by colonoscopyand colon biopsy to be caused by cytomegalovirus colitis. In December 1984 the patient noteddecreased vision in his right eye, with a blindspot and metamorphopsia just below fixation inthat eye. In January 1985, a colonic biopsyspecimen was again positive for cytomegalovirus colitis. The patient was admitted to theNew York Hospital on Feb. 14, 1985, for treatment.

At admission his visual acuity was R.E.:20/200 and L.E.: 20/20, and external and anterior segment findings were normal. Ophthalmoscopy disclosed a ring configuration ofwhite exudate above and extending into themacula in the right eye with early hemorrhagicactivity on the nasal margin of that ring (Fig. 6).This lesion was consistent with cytomegalovirus retinitis, and its extension into the maculaaccounted for the recently decreased vision inthe right eye. The left fundus had a cotton-woolspot inferonasal to the macula and above theinferotemporal arcade. The vitreous was normal in both eyes. Urine cultures were positive


for cytomegalovirus. From Feb. 15 to Feb. 25,the patient received 149 mg of dihydroxy propoxymethyl guanine (2.5 mg/kg of bodyweight) every eight hours (31 doses). At theend of treatment (day 10L visual acuity wasstill R.E.: 20/200 and L.E.: 20/20 but there waspartial regression in the inferonasal portion ofthe ring of white exudate above the macula inthe right eye. Two weeks after cessation oftherapy visual acuity was still the same butthere was regression of two thirds of the ring Ofwhite exudate in the right eye despite continued macular involvement (Fig. 6). There was nochange in the cotton-wool spots in the left eye.

The overall impression was of regression ofthe exudative lesions of cytomegalovirus retinitis both during and for two weeks after treatment with dihydroxy propoxymethyl guanine.The symptoms of cytomegalovirus colitis alsoimproved during the course of therapy, asevidenced by a decreased frequency of bowelmovements and less diarrhea. The patient waslost to follow-up after discharge from the hospital.


man with AIDS and biopsy-proven Kaposi'ssarcoma that was first diagnosed in September1984. In February 1985, he noticed subtlechanges in his vision for one month, followedby a rapid decrease in vision in his left eye.

Ophthalmoscopy on March 18 disclosed cytomegalovirus retinitis that was more severe inthe left eye than in the right eye. The right eyecontained isolated foci of white exudate inferior to the optic disk, superior to the macula, andalong the superotemporal and inferotemporalarcades in the midperiphery where they wereaccompanied by early hemorrhagic activity. Inthe left eye the cytomegalovirus retinitis wasmore extensive, with coalesced areas of whiteexudate along the major temporal and nasalvascular arcades and a large patch of exudateinferotemporal to the macula. There were otherpatches of white exudate above and below theoptic disk. Most prominent was a focus ofrecent hemorrhage in a patch of exudate in thenasal perimacular area; this accounted for therecently decreased vision.

On March 23, the patient was admitted tothe New York Hospital for treatment withdihydroxy propoxymethyl guanine. Physicalfindings included cutaneous Kaposi's sarcoma,lymphadenopathy, slight edema of his left leg,and swelling of the suprapubic area. The pre-

treatment visual acuity was R.E.: 20/20 andL.E.: 20/200.

From March 25 to April 4, the patient wastreated intravenously with 71 mg of dihydroxypropoxymethyl guanine (1 mg/kg of bodyweight) every eight hours (31 doses). On thesecond day of therapy, an ocular examinationshowed worsening of the cytomegalovirus retinitis. Ophthalmoscopy of the right eye disclosed progression of the cytomegalovirus retinitis with coalescence and new hemorrhagicactivity of the previously isolated exudativelesions, especially along the superotemporalvascular arcade, and prominent periphlebitiswith perivascular sheathing of exudate alongthe inferoternporal, inferior, and superior vascular arcades (Fig. 7). Ophthalmoscopy of theleft eye also disclosed progression of the cytomegalovirus retinitis with similar coalescenceof and new hemorrhagic activity in the patchesof exudate along the temporal and nasal vascular arcades, accompanied by enlargement of theexudative patch with increased hemorrhage inthe focus of activity nasal to the macula.

On April 2, the patient's visual acuity wasR.E.: 20/20 and L.E.: 20/100. Ophthalmoscopyof the right eye showed stabilization and earlyregression of the exudative and hemorrhagiclesions along the superotemporal vascular arcade and marked regression and shrinkage ofthe periphlebitis and perivascular exudatealong the inferotemporal and inferior vasculararcades. The left eye showed marked shrinkageand regression of the exudative lesions alongthe temporal and nasal vascular arcades andresorption of the hemorrhagic component ofthe perimacular focus of cytomegalovirus retinitis.

From April 5 to April 17, the patient receivedan increased intravenous dose of 178 mg ofdihydroxy propoxymethyl guanine (2.5 mg/kgof body weight) every eight hours (37 doses).Ophthalmoscopy of the right eye on April 22(four days after therapy ended) showed continued regression of both the exudative and hemorrhagic components of cytomegalovirus retinitis along the superotemporal arcade (Fig. 8).The periphlebitis and perivascular exudativesheathing along the inferotemporal, inferior,and superior vascular arcades had disappearedcompletely. The left eye also showed markedregression, and in some areas elimination, ofboth the exudative and hemorrhagic components of the cytomegalovirus retinitis along thetemporal and nasal vascular arcades. The perimacular focus of activity was less dense in both


Fig. 5 (Rosecan and associates). Case 3, right eye. Left, May I, 1985, seven days after initiation of treatment.Note cytomegalovirus retinitis with patch of exudate and slight hemorrhages inferior to the macula. Right, MayIS, 1985 at end of 21-day course. Note regression of exudative lesion below macula.

the exudative and hemorrhagic components(Fig. 8).

Urine cultures for cytomegalovirus were positive on March 29 and then became and remained negative both during and after the twocourses of treatment with dihydroxy propoxymethyl guanine until May 6. At that time theyagain became positive, three weeks after cessation of the second course of therapy. The treatment was stopped on day 13 of the second

course of treatment because of granulocytopenia. The patient did not return for follow-upbut was hospitalized elsewhere with recurrence of the cytomegalovirus retinitis approximately three weeks after cessation of therapy.

Thus, there was marked improvement in thecytomegalovirus retinitis in both eyes duringand after treatment with dihydroxy propoxymethyl guanine, shown by regression and insome locations elimination of the exudative

Fig. 6 (Rosecan and associates). Case 4, right eye. Left, Feb. 14, 1985, cytomegalovirus retinitis with ring ofexudative lesions and slight hemorrhages before treatment. Right, On March 7,1985, there is marked regressionof nasal two thirds of ring exudate two weeks after cessation of ll-day course of treatment.


Fig. 7 (Rosecan and associates). Case 5, March 26,1985. One day after initiation of treatment, hemorrhagic and exudative lesions are apparent. Top left,Right eye. Note prominent perivascular sheathingwith exudate. Top right, Left eye temporal to opticdisk. Bottom left, Left eye nasal to optic disk.

Fig. 8 (Rosecan and associates). Case 5, April 22,1985. Five days after cessation of treatment. Notemarked regression and some disappearance of hemorrhagic and exudative lesions. Top left, Right eye.Note disappearance of perivascular exudativesheathing. Top right, Left eye, temporal to opticdisk. Bottom left, Left eye nasal to optic disk.


and hemorrhagic lesions of cytomegalovirusretinitis. The therapeutic response to antiviraldrugs frequently does not occur until severaldays after initiation of therapy. Thus, the initialworsening of the cytomegalovirus retinitisnoted on day 2 of therapy was not unusualgiven the subsequent response to therapy.


man with AIDS in whom central nervous system toxoplasmosis appeared in September1984. Treatment with sulfadiazine and pyrimethamine led to resolution of the toxoplasmosis. In December 1984, vision in the left eyebecame blurred. Evaluation at that time wasconsistent with cytomegalovirus retinitis. Thepatient also had cytomegalovirus colitis. Frommid-December until mid-January, the patientcomplained of progressively worsening visionin his right eye. He was admitted to the NewYork Hospital on Jan. 17, 1985, for treatmentwith dihydroxy propoxymethyl guanine.

From Jan. 18 to Jan. 28, the patient received110 mg of dihydroxy propoxymethyl guanine(2.5 mg/kg of body weight) every eight hours(31 doses). On Jan. 18, his visual acuity washand movements at 1 foot bilaterally and theexternal and anterior segment findings werenormal. Ophthalmoscopy of the right eye disclosed severe vitritis with vitreous veils andcytomegalovirus retinitis with an obscuredview of the optic disk. The left fundus showedmoderately severe vitritis and retinitis withextensive perivascular white exudates accompanied by moderate hemorrhages, indicative ofcytomegalovirus retinitis. The optic disk of theleft eye was normal. Urine culture was positivefor cytomegalovirus.

On Jan. 24, the patient's visual acuity wasR.E.: counting fingers at 5 feet and L.E.: lightperception. Ophthalmoscopy disclosed a modest decrease in vitritis in the right eye. On Jan.28 (at the end of dihydroxy propoxymethylguanine therapy) his visual acuity was R.E.:counting fingers at 5 feet and L.E.: hand movements at 5 feet. Ophthalmoscopy disclosedsignificantly decreased vitritis in each eye, butespecially in the right eye, allowing better visualization of the perivascular exudates and hemorrhages which were consistent with cytomegalovirus retinitis.

At a follow-up examination on Feb. 5, visualacuity was R.E.: 20/50 +2 and L.E.: light perception. External and anterior segmentfindings were normal. There was marked clear-

ing of the vitreous in the right eye. In the lefteye, there was a hazy vitreous with manyvitreous veils and much vitreal debris. Theright fundus demonstrated perivascular exudates and hemorrhages consistent with cytomegalovirus retinitis, as did the left fundus,although the view was hazy secondary to thevitritis in the left eye.

The overall impression was of improvementin the cytomegalovirus vitritis and retinitis inboth eyes, but more in the right eye. Thepatient was not treated with either topical orsystemic corticosteroids during or after treatment with dihydroxy propoxymethyl guanine.Urine cultures for cytomegalovirus becamenegative shortly after initiation of treatmentand remained negative during and after treatment.

On Feb. IS, his visual acuity was R.E.: 20/60and L.E.: light perception. The anterior chamber of each eye contained 2+ cells; the vitreousshowed increased cells in the right eye but nochange in the left eye; neither fundus showed agross change. The impression was of increasedinflammation, more severe in the right eye thanin the left eye. On Feb. 21, the patient wasreadmitted to the New York Hospital, and fromFeb. 22 to March 4, received 50 mg of dihydroxypropoxymethyl guanine (1 mg/kg of bodyweight) intravenously every eight hours (31doses). On Feb. 25, the visual acuity was R.E.:counting fingers at 2 feet and L.E.: light perception without projection. An afferent pupillarydefect in the left eye suggested optic neuritisand cytomegalovirus involvement of the opticnerve. Ophthalmoscopy showed confluentwhite retinal exudates in both eyes with noareas of uninvolved retina in either eye. Theoptic disk and vessels could not be visualizedbecause of the extensive exudates and vitrealopacities in both eyes. The impression was ofsevere, progressive cytomegalovirus retinitisin both eyes.

The patient's poor vision continued, and healso complained of tinnitus on March 1. Thepatient decided to leave the hospital on March4. On March 31, he was readmitted to the NewYork Hospital because of deterioration in hismental status and was found to be encephalopathic with severe ataxia. At that time his visualacuity was no light perception bilaterally, andthe pupils were fixed and dilated at 8 mm ineach eye. There was bilateral horizontal nystagmus, and the optic disks were obscured byhemorrhage and exudate. The patient died onApril 14, 1985.

416 AMERICAN JOURNAL OF OPillHALMOLOGY April, 1986

The overall impression was of significant improvement in the cytomegalovirus retinitis andvitritis with 2.5 mg/kg of body weight of dihydroxy propoxymethyl guanine every eighthours and of poor response with 1 mg/kg ofbody weight of drug every eight hours.

Discussion

All six patients treated with dihydroxy propoxymethyl guanine demonstrated significantregression of the exudative, hemorrhagic, andperiphlebitic lesions of cytomegalovirus retinitis. This clinical improvement was usually accompanied by an antiviral effect, shown by aconversion of cytomegalovirus cultures frompositive to negative during therapy. However,the cytomegalovirus retinitis recurred withinseveral weeks after stopping dihydroxy propoxymethyl guanine therapy in four of the sixpatients. The other two were lost to follow-up.In most patients, the reactivated cytomegalovirus retinitis responded to retreatment with dihydroxy propoxymethyl guanine. Outpatientmaintenance therapy with dihydroxy propoxymethyl guanine was given to one patient (Patient 2). During five weeks of such therapy, thepatient had no recurrence.

Both patients who demonstrated vitritis secondary to cytomegalovirus retinitis (Patients 1and 6) showed marked improvement, and inone patient (Patient 1) disappearance of thevitritis, during and shortly after treatment withdihydroxy propoxymethyl guanine. All six patients treated with 2.5 mg/kg of body weight ofdihydroxy propoxymethyl guanine showed regression of the cytomegalovirus retinitis during and for at least two or three weeks aftereach course of treatment. Of the two patientswho also received 1 mg/kg of body weight ofdihydroxy propoxymethyl guanine, one (Patient 5) showed regression of the lesions andthe other (Patient 6) showed worsening of thecytomegalovirus retinitis. It appears that thehigher dose is more effective. In two patientsgiven 2.5 mg/kg of body weight every eighthours, therapy had to be discontinued becauseof granulocytopenia (Patients 2 and 5). Thiswas reversible. This was the only toxic effectattributable to dihydroxy propoxymethyl guanine in our patients. Testicular atrophy hasbeen observed in animals receiving the drugbut has not been documented in humans.

In all but Patient 4, urine cytomegalovirus

cultures changed from positive to negative during treatment with dihydroxy propoxymethylguanine. In two patients who had pretreatmentfoci of perimacular exudates with trace hemorrhagic activity (Patients 3 and 4), treatmentwith dihydroxy propoxymethyl guanine appeared to prevent the more advanced phase ofthe disease, usually evidenced by expansion ofhemorrhages and exudates, and cause the lesions to regress.

In Patient 2 there was progressive optic nerveinvolvement suggestive of optic neuritis, resulting in no light perception in one eye despiteremarkable regression of the cytomegalovirusretinitis. In this patient an afferent pupillarydefect was present in that eye before treatmentwith dihydroxy propoxymethyl guanine, indicating that optic nerve damage was not a resultof the treatment. Similarly, Patient 6 had progressive cytomegalovirus involvement of bothoptic nerve heads coincident with the patient'srefusal of further treatment, progressive neurologic deterioration, and positive cytomegalovirus cultures of cerebrospinal fluid.

Optic nerve head involvement with cytomegalovirus has been documented in patientswith9•17,22 and without AIDS.2,28 Optic neuritiswas present in seven of 18 patients with AIDSwho had cytomegalovirus retinitis in one series. Twelve of these patients also had vitritis."Thus, the presence of optic nerve involvementin the two patients in our series was probablynot a toxic effect of treatment with dihydroxypropoxymethyl guanine but rather an indication of extensive cytomegalovirus involvement.

Although the six patients treated with dihydroxy propoxymethyl guanine showed significant improvement both during and for severalweeks after treatment, there was usually reactivation of the cytomegalovirus retinitis afterwards. The same positive results were obtainedwith outpatient maintenance therapy in Patient2. Because of recurrence of the disease aftercessation of therapy, long-term maintenancewill probably be necessary.

Although cytomegalovirus retinitis in a population of patients with organ transplants wasreported to follow a variable course dependingon the state of exogenously administered immunosuppression.v-P'" cytomegalovirus retinitis in patients with AIDS is invariably progressive because of the uniformly profoundsuppression of cellular immunity.8.12,15.22 Inthose with transplants the best form of treatment has usually been to reduce the dosage ofimmunosuppressive agents,5.7,13,14 whereas in


those with AIDS it been impossible to restorenormal cellular immunity. 8-12,15-22The direct relationship between the severity of cytomegalovirus retinitis and the degree of immunosuppression was noted before the advent of AIDS as aclinical entity. 5-7,13,14 Unfortunately, this relationship has continued to hold true, as theprogression of cytomegalovirus retinitis appears to correlate with the dim prognosis ofAIDS itself. 8-12,15-22

In patients with AIDS, cytomegalovirus retinitis invariably follows a progressively deteriorating course. The resolution seen in our patients treated with dihydroxy propoxymethylguanine is encouraging. Properly controlledtrials and long-term maintenance therapy arenecessary to evaluate this promising new therapeutic agent for cytomegalovirus retinitis.

ACKNOWLEDGMENT

The Burroughs Wellcome Co. supplied thelyophilized sterile sodium salt solution ofdihydroxy propoxymethyl guanine used in thisstudy.

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antiviral therapy for cytomegalovirus retinitis in aids with dihydroxy propoxymethyl guanine

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