The use of oral ganciclovir in the treatment of cytomegalovirus retinitis in patients with AIDS

Clive Ward-Able, BPharm, MB, ChB; Peter Phillips, MD, FRCPC; Christos M. Tsoukas, MSc, MD, FRCPC, FACP

Canadian Medical Association Journal 1996; 154: 363-368


Members of the medical advisory board: John M. Gill, MB, ChB, ABIM, FACP, FRCPC, medical director, Southern Alberta HIV Clinic and associate professor of microbiology and infectious disease, University of Calgary, Calgary, Alta.; Janette I. Lindley, MD, FRCSC, St. Paul's Hospital, Vancouver, BC; Kenneth J. Logue, MD, BSc, clinical associate, University of Toronto, Toronto, Ont.; Anita R. Rachlis, MD, FRCPC, Sunnybrook Health Science Centre, North York, Ont.; Walter F. Schlech, MD, FACP, ABIM, FRCPC, Victoria General Hospital, Halifax, NS; Alice Tseng, PharmD, lecturer, Faculty of Pharmacy, University of Toronto, and HIV primary care pharmacist, Wellesley Health Centre, Toronto, Ont.; Sharon Walmsley, MD, FRCPC, assistant director, Immune Deficiency Clinic, Toronto General Hospital, and assistant professor, Department of Medicine and Microbiology, University of Toronto, Toronto, Ont.

Dr. Ward-Able is the medical director of the BioMed Business Unit of Hoffmann-La Roche (Canada), Mississauga, Ont.; Dr. Phillips is an assistant clinical professor at the University of British Columbia and on staff at St. Paul's Hospital, Vancouver, BC; Dr. Tsoukas is associate director of the McGill AIDS Centre, Immune Deficiency Treatment Centre, Montreal General Hospital, Montreal, Que.


Paper reprints of the full text may be obtained from: Dr. Clive Ward-Able, BioMed Business Unit, Hoffmann-La Roche Ltd, 2455 Meadowpine Blvd., Mississauga ON L5N 6L7
Abstract
Introduction
CMV infection
Treatment
Adverse effects
Precautions
Contraindications and drug interactions
Recommendations for monitoring patients receiving oral therapy following initial stabilization
Costs
References
Guidelines for use of oral ganciclovir in treatment of CMV retinitis

Abstract

Objective: To recommend the appropriate use of oral ganciclovir as an alternative to intravenous (IV) maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS.
Options: IV infusion of ganciclovir and foscarnet have been the only approved choices for maintenance therapy until the introduction of oral ganciclovir.
Outcomes: Ease of administering maintenance therapy and improved quality of life for patients with AIDS.
Values: The medical advisory group comprised physicians treating patients with AIDS, an ophthalmologist with expertise in CMV retinitis and a pharmacist with expertise in AIDS therapy. Ease of administration of maintenance therapy and quality of patients' lives were considered important.
Benefits, harms and costs: Oral ganciclovir is a safe and convenient alternative to IV maintenance therapy for patients with CMV retinitis. However, its low bio-availability precludes its use for induction therapy and necessitates careful monitoring for compliance. Compared with IV administration of ganciclovir, oral maintenance therapy is cost effective.
Evidence: Evidence for the guidelines was gathered from data presented at a symposium on CMV retinitis and oral ganciclovir, clinical trials of oral ganciclovir and input from a visiting expert. It was presented at a meeting of the advisory board whose members are involved in the care of patients with AIDS and the management of CMV retinitis. The guidelines were approved by each member of the advisory board.
Recommendations: Diagnosis, treatment and follow-up of CMV retinitis should always be in consultation with an ophthalmologist who is experienced in treating this disease. The patient should be fully informed about the limitations of the oral form of ganciclovir; he or she should be involved in decision making and carefully monitored. Oral ganciclovir should not be used for induction therapy or for maintenance therapy in high-risk patients.
Validation: Similar guidelines have been produced in England, where the drug has been available since January 1995.
Sponsor: The deliberations of the advisory board and the preparation of this report were funded through an educational grant from Hoffmann-La Roche (Canada).

Top of document

Introduction

Cytomegalovirus (CMV) retinitis commonly threatens the eyesight of patients in the late stages of AIDS.(1-3) Until recently, treatment of CMV retinitis has been limited to intravenous (IV) infusions of ganciclovir or foscarnet once or twice daily for the remainder of the patient's life.(4,5) However, daily infusions require permanent in-dwelling central catheters, which are potential sources of infection, especially in an immunocompromised patient.

Oral ganciclovir can be administered more easily, avoids the development of catheter-related infections and allows the patient more freedom of movement. However, bio-availability of the oral form is 6% to 9%, and a dose of 3 g daily has an area under the curve of about 70% of the IV formulation given at the dose of 5 mg/kg daily.(6,7) Randomized, open-label, parallel group trials comparing oral and IV ganciclovir have shown that the oral formulation is a safe alternative in maintenance therapy for CMV retinitis.(8-10) However, the ease of administration of the oral form may tempt physicians to prescribe it instead of the preferred IV route for induction therapy. It may also tempt physicians to use the oral form in patients who are at high risk of losing their eyesight. Careful monitoring of all patients taking the drug is critical to check for disease progression and drug toxicity.

Oral ganciclovir maintenance therapy should be instituted only after a minimum of 3 weeks induction therapy with the IV form and after lesions are stable.(8) Also, compliance is critical to the success of oral therapy. Given these caveats, it was decided that guidelines were needed for the use of oral ganciclovir in maintenance therapy for patients with CMV retinitis.

Hoffmann-La Roche formed an advisory board of eight physicians with special expertise and experience with AIDS, CMV retinitis and the use of oral ganciclovir, plus a HIV primary care pharmacist with a special interest in ganciclovir. The board members were also chosen to represent the centres where AIDS is concentrated in Canada.

The first meeting of this board was held in Washington on Jan. 29, 1995, during a symposium, "The role of oral ganciclovir for CMV retinitis and CMV disease," sponsored by the University of Alabama School of Medicine Division of Continuing Medical Education at the 2nd National Conference on Human Retroviruses and Related Infections. At its second meeting, on Aug. 28, 1995, in Toronto, a visiting expert, Dr. Kathleen Squires, associate professor of medicine and associate director, Outpatients AIDS Clinic, at the University of Alabama, gave an overview of clinical trials with oral ganciclovir and relevant experience in the United States where the drug is being used in clinical practice.

To aid the board's deliberations, a literature search was carried out through the Hoffmann-La Roche corporate library using MEDLINE and EmBase databases. The board also consulted guidelines that had been drawn up in England.(11)

After an outline of the proposed document was agreed upon, each section was discussed at length until consensus was reached. Input was provided by Dr. Squires, who was a principal investigator in one of the studies comparing oral and IV ganciclovir.(9)

Dr. Ward-Able, with the assistance of the other two principal authors, collated the recommendations and drafted the guidelines, which were then sent to all board members for comments and changes. After revision, a second draft was circulated and approved.

Top of document

CMV infection

Seroprevalence studies suggest that about 50% of adults in developed countries and over 90% of patients who are seropositive for HIV have been infected with CMV.(12) Primary infection is usually asymptomatic, but reactivation may occur if the patient's immune system is compromised, for example through HIV infection.(13)

Clinical evidence of CMV retinitis occurs in 25% to 30% of patients with AIDS, usually at a late stage when the CD4+ count is less than 50 cells/mm3.(1-3,14,15) The infection may be asymptomatic and diagnosed only on routine funduscopy, or it may be accompanied by floaters or flashes, decreased visual acuity, visual blurring, visual-field defects or distorted vision.(4) Typically, with funduscopy large creamy or yellowish white granular areas appear on the retina with perivascular exudates and hemorrhages -- the so-called "cottage cheese and ketchup" appearance.(4)

Prompt referral to an ophthalmologist, within 72 hours, is essential for confirmation of the diagnosis, particularly if macular disease is suspected. Untreated, lesions progress and new ones develop, resulting ultimately in blindness.

Top of document

Treatment

Clinical studies have shown that effective treatment involves an induction period of 2 to 3 weeks using a high IV dose of ganciclovir or foscarnet.(5,16-20) Once control of the disease is confirmed by an ophthalmologist, maintenance therapy is instituted to delay relapse. Progression is defined as an extension or spread of a previously stable margin of retinitis by 750 µm or more (about one-half the diameter of an optic disc) or the development of a new lesion.(8) Progression is not necessarily associated with an immediate decrease in visual acuity or a change in other symptoms.

Although both ganciclovir and foscarnet may be associated with significant adverse effects, their toxicity profiles are different. Ganciclovir may cause myelosuppression and dose-limiting neutropenia; foscarnet is associated with nephrotoxicity and metabolic disturbances.(5,20-22) Until recently, both agents required IV administration and the insertion of in-dwelling catheters, which resulted in the treatment being expensive, inconvenient for the patient and associated with sepsis. A new oral formulation of ganciclovir may now be used as an alternative to the IV form in maintenance therapy for certain patients.

Oral ganciclovir has a bio-availability of 5% under fasting conditions and between 6% and 9% with food. Therefore, it is important to tell patients to take their medication with meals.(7)

Because the drug is excreted renally, the dosage should be adjusted according to creatinine clearance rates (Table 1).(7)

Three randomized, open-label, parallel group studies were used to compare maintenance treatment with oral (3000 mg/d) versus IV (5 mg/kg daily) ganciclovir in patients with CMV retinitis following stabilization with IV ganciclovir (Table 2).(8-10) The Kaplan-Meier estimate of mean times to first progression of the retinitis was 5 to 12 days shorter in the groups taking ganciclovir orally than in the IV-treated groups (determined by masked reading of fundus photographs). This difference was not statistically significant in any of the studies; however, the clinical significance of these findings is still undetermined. Visual acuity, overall patient survival and rate of CMV shedding were similar in both groups. Based on this photographic analysis, the authors concluded that oral ganciclovir at 3 g/d is an effective alternative to IV ganciclovir in maintenance therapy for CMV retinitis.

Top of document

Adverse effects

Data collected from the three studies showed that the patients treated with oral ganciclovir had a significantly lower incidence of neutropenia (29% v. 41%, p = 0.024) and anemia (19% v. 25%, p = 0.027) than did the IV-treated group.(23) The orally treated group also had, predictably, fewer sepsis and catheter-related problems and required less use of hematopoietic growth factors for the treatment of neutropenia. For all other categories of measured toxicity, the oral and IV treatments were similar.

Top of document

Precautions

Oral ganciclovir is not to be used for induction therapy. CMV retinitis lesions must be stable after at least 3 weeks of induction treatment with IV ganciclovir before oral maintenance therapy is initiated.

The ease of prescribing and administering the oral formulation must not substitute for close clinical and ophthalmologic follow-up. All decisions regarding the use of oral ganciclovir must be made in conjunction with an ophthalmologist experienced in the treatment of CMV retinitis.

Education of the patient with respect to the disease, its treatment and the limitations of oral ganciclovir is important. Full discussion must take place between the clinician and the patient to enable informed decisions concerning efficacy and ease of administration.

Due to the low bio-availability of the oral form, compliance is critical to the maintenance of plasma levels and to the success of oral ganciclovir maintenance therapy. Often, patients will also be taking prophylaxis medications for other opportunistic infections along with antiretrovirals. It must be emphasized that the alternative to oral ganciclovir is IV maintenance therapy, and, as soon as progression of CMV retinitis is noted, the patient will be placed on IV treatment again. Patients must be advised that they must not stop oral ganciclovir therapy without first discussing it with their attending physician.

We recommend the use of periodic visual field assessment and fundus photography, where possible, as adjuncts to ophthalmologic examination.

Guidelines for the use of oral ganciclovir in maintenance treatment of CMV retinitis were devised by the advisory board and are included on page 366. [Guidelines.]

Top of document

Contraindications and drug interactions

Pregnancy, lactation and hypersensitivity to ganciclovir, acyclovir or famciclovir are absolute contraindications for the use of IV or oral ganciclovir.

Patients with retinitis that encroaches on the macula or optic disc (i.e., zone 1), extraocular CMV disease, severe chronic diarrhea, blindness in the other eye, frequently relapsing retinitis or patients in whom poor compliance is suspected are to be considered at high risk for early progression and should be maintained on IV therapy.

An absolute neutrophil count (ANC) below 500 cells/µL or fewer than 25 000 platelets per µL should be considered relative contraindications to the use of ganciclovir.

Drug interactions with the oral formulation are the same as those for the IV form of ganciclovir.

Top of document

Recommendations for monitoring patients receiving oral therapy following initial stabilization

Because time to progression may be shorter with oral ganciclovir and because there is a need to detect toxicities early, a clinical and laboratory evaluation, including a complete blood count and assessment of serum creatinine, should be carried out every 4 weeks. Similarly, an ophthalmologic evaluation with indirect ophthalmoscopy should be performed every 4 weeks. The importance of compliance must be reinforced. It should be emphasized that the patient must not interrupt therapy before discussion with the prescribing doctor as ganciclovir is virustatic and, if plasma levels fall below minimum inhibitory concentrations for CMV, the disease will progress.

In cases of renal impairment, the dose of ganciclovir must be altered as necessary. If neutropenia (ANC below 500 cells/µL) develops, consider hematopoietic growth factors, such as GM-CSF (granulocyte-macrophage colony stimulating factor) or G-CSF (granulocyte colony stimulating factor), or the elimination of other myelosuppressive drugs.

The recommendations may have to be adapted to the needs of individual patients. Insist that the patient seek medical help as early as possible if any change in visual function or new floaters occur, as this may indicate progression of the CMV retinitis.

Top of document

Costs

Although the oral form of ganciclovir costs more than the IV formulation, a pharmacoeconomic study has shown that the cost of overall maintenance treatment of CMV retinitis with oral ganciclovir is lower.(24) The savings are mainly due to a decrease in the number of central line placements, fewer treatments for neutropenia and sepsis and a reduction in drug-delivery costs such as home care associated with IV administration.(23)

Top of document

References

  1. Palestine AG, Rodrigues MM, Macher AM et al: Ophthalmic involvement in acquired immunodeficiency syndrome. Ophthalmology 1984; 91: 1092-1099
  2. Jabs DA, Enger C, Bartlett JG: Cytomegalovirus retinitis and acquired immunodeficiency syndrome. Arch Opthalmol 1989; 107: 75-80
  3. Jabs DA, Green WR, Fox R et al: Ocular manifestations of acquired immune deficiency syndrome. Ophthalmology 1989; 96: 1092
  4. Drew WL, Buhles W, Erlich K: Management of herpes virus infections (CMV, HSV, VZV). In Sande MA, Volberding PA (eds): The Medical Management of AIDS, 3rd ed, WB Saunders, Philadelphia: 359-382
  5. Jacobson LA, O'Donnell JJ, Mills J: Foscarnet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 1989; 33: 736-741
  6. Spector SA, Busch DF, Follansbee S et al: Pharmacokinetic, safety, and antiviral profiles of oral ganciclovir in persons infected with human immunodeficiency virus: a phase I/II study. J Infect Dis 1995; 171: 1431-1437
  7. Cytovene Product Monograph. Hoffman-LaRoche (Canada). Oct 3, 1995
  8. Drew WL, Ives D, Lalezari JP et al: Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. N Engl J Med 1995; 333: 615-620
  9. Squires KE, Stempien MJ, Shadman A et al: Oral ganciclovir versus intravenous ganciclovir maintenance therapy for cytomegalovirus retinitis in patients with AIDS: preliminary results of a phase III study [abstract 540]. In The First National Conference on Human Retroviruses and Related Infections, Dec 12-16, 1993, Washington (unpublished, Apr 1995)
  10. Oral Ganciclovir European and Australian Cooperative Study Group: Intravenous versus oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS 1995; 9: 471-477
  11. Jefferiss Wing Therapeutics and Protocols Group: New developments in HIV therapy: oral ganciclovir, a rational approach to prescribing. St Mary's Hospital, London (unpublished observations, Apr 1995)
  12. Katlama C: Cytomegalovirus infection in acquired immune-deficiency syndrome. J Med Virol 1993; 1 (suppl): 128-133
  13. Drew WL: Cytomegalovirus infection in patients with AIDS. Clin Infect Dis 1992; 14: 608-615
  14. Pepose JS, Holland GN, Nestor MS et al: Acquired immune deficiency syndrome: pathogenetic mechanisms of ocular disease. Ophthalmology 1985; 92: 472-484
  15. Holland GN, Pepose JS, Pettit TH et al: Acquired immune deficiency syndrome: ocular manifestations. Ophthalmology 1983; 90: 859-873
  16. Laskin OL, Cederberg DM, Mills J et al: Ganciclovir for the treatment and suppression of serious infections caused by cytomeaglovirus. Am J Med 1987; 83: 201-207
  17. 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: 801-805
  18. Jacobson MA, O'Donnell JJ, Brodie HR et al: Randomized prospectice trial of ganciclovir maintenance therapy for cytomegalovirus retinitis. J Med Virol 1988; 25: 339-349
  19. Spector SA, Weingeist T, Pollard RB et al: A randomized, controlled study of IV ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. J Infect Dis 1993; 168: 557-563
  20. . 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: 665-673
  21. Holland GN, Sidikaro Y, Kreiger AE et al: Treatment of cytomegalovirus retinopathy with ganciclovir. Ophthalmology 1987; 94: 815-823
  22. Jabs DA, Newman C, De Bustros S et al: Treatment of cytomegalovirus retinitis with ganciclovir. Ophthalmology 1987; 94: 824-830
  23. Follansbee S, Stempien MJ, and Syntex Cooperative Oral Ganciclovir Study Group: Safety of oral ganciclovir for maintenance treatment of CMV retinitis [abstract H29]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Fla, Oct 1994
  24. Rachlis A, Smaill F: Incremental cost-effectiveness analysis of IV ganciclovir versus oral ganciclovir in maintenance treatment of CMV retinitis in patients with AIDS. Personal communications, Dr. A. Rachlis, Sunnybrook Health Science Centre, North York, Ont, Nov 24, 1995

| CMAJ February 1, 1996 (vol 154, no 3) | Clinical practice guidelines |