Canadian Medical Association Journal 1996; 154: 363-368
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.
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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.
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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.
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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.
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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.
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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.]
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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.
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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.
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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)