AD IS PHARMACOECONOMIC DRUG EVALUATION

Ganciclovir

Phormacoeconomics 1997 Aug; 12 (2 PI 1): 209-228 1170-7690/97 /OCOS-G209/S 10.00/0

© Adis International Umited. All rights reserved.

A Pharmacoeconomic Review of its Use as Intravenous or Oral Maintenance Therapy in the Management of Cytomegalovirus Retinitis in Patients with AIDS

Caroline M. Perry and Rick Davis

Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: w.L. Drew, University of California, Mt Zion Medical Center, San Francisco, California, USA; M. Hardens, The Lewin Group, Leiden, The Netherlands; F.J. Hellinger, Agency For Health Care Policy and Research, Rockville, Maryland, USA; D.A. Jabs, The Johns Hopkins University and Hospital, The Wilmer Ophthalmic Institute, Baltimore, Maryland, USA; M.A. Jacobson; University of California at San Francisco AIDS Program, San Francisco General Hospital, San Francisco; California, USA; E.S. Johnson, Epidemiology Resources, Inc., Newton Lower Falls, Massachusetts, USA; P.e. Langley, Center for Pharmaceutical Economics, College of Pharmacy, University of Arizona, Tucson, Arizona, USA; A.P. Luckie, Melbourne, Victoria, Australia; E. Mozaffari, Palo Alto, California, USA; S.R. Norrby, University of Lund, Department of Infectious Diseases, University Hospital of Lund, Lund, Sweden; S.B. Palmer, Centre for Health Economics, University of York, York, England; J-M.G. von den Schulenburg, University of Hannover, North German Center for Health Services Research, Hannover, Germany; M. Stoll, Department of Clinical Immunology, Medical School of Hannover, Hannover, Germany; S.D. Sullivan, School of Pharmacy, University of Washington, Health Sciences Center, Seattle, Washington, USA.

Contents Summary ................ . 1. Overview of Cytomegalovirus Retinitis

1 .1 Epidemiology . . . . . . . . . . . . 1.2 Treatment Options ... . .... .

2. Pharmacoeconomic Considerations in the Treatment of Cytomegalovirus Retinitis . . . . . . . . . . . . . . . . . . .

3. Rationale for Use of Ganciclovir in Cytomegalovirus Retinitis 3.1 Pharmacology 3.2 Efficacy .......... . . ... . ... . 3.3 Tolerability .................. .

4. Pharmacoeconomic Evaluation of Ganclclovir 4.1 Cost Analyses . . . . . . . . . . . . . . . . . 4.2 Health State Utility Analysis . . . ..... . 4.3 Ganciclovir Resource Utilisation and Treatment Pattern Study .

5. Pharmacoeconomic Positioning of Intravenous and Oral Ganciclovir .

209 213 213 213

214 216 216 216 217 218 218 224 225 225

Summary Synopsis Cytomegalovirus retinitis, an opportunistic infection caused by the herpesvirus

cytomegalovirus, is a major cause of illness in patients with advanced AIDS. As infected patients require long term drug treatment to delay disease progression

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Overview of Cytomegalovirus Retinitis

Perry & Davis

and minimise loss of vision, the disease is associated with substantial treatment costs which considerably increase overall expenditure on AIDS-related health care.

During the last decade, intravenous ganciclovir has been a mainstay of treat­ment for patients with cytomegalovirus retinitis. However, notwithstanding its demonstrated efficacy as maintenance therapy for this condition, long term in­travenous drug administration is both inconvenient and uncomfortable for many patients. Moreover, neutropenia and catheter-related infections have been re­ported commonly in patients receiving ganciclovir via the intravenous route. To overcome the limitations of intravenous ganciclovir, an oral formulation of the drug has been developedfor use as maintenance therapy. In comparative clinical trials, both intravenous and oral ganciclovir maintenance therapy slowed disease progression and preserved visual acuity in patients with stabilised cytomegalo­virus retinitis, although there was evidence that the intravenous formulation was more effective in terms of delaying recurrence of active disease. This suggests that oral ganciclovir use should be limited to the treatment of patients without evidence of immediately sight-threatening cytomegalovirus retinitis.

Three published cost analyses, which were based on efficacy and tolerability data derived from 2 randomised, comparative clinical trials, have shown that oral ganciclovir maintenance therapy offers cost advantages over intravenous maintenance therapy, despite the higher acquisition cost of the oral formulation. The higher overall costs of intravenous maintenance treatment, compared with oral therapy, were attributed to higher drug administration and adverse event treatment costs. In one analysis, estimated lifetime treatment costs of oral main­tenance therapy were 25.2% lower than those of intravenous maintenance treat­ment. As yet, no formal cost-effectiveness evaluations of oral and intravenous ganciclovir have been published.

Few published data are available regarding the relative effects of intravenous and oral ganciclovir on quality of life. However, in a health state utility analysis, there was a large overall preference among HIV-infected individualsfor oral over intravenous maintenance treatment.

In conclusion, oral ganciclovir appears to be a cost-saving and patient­preferred alternative to its intravenous counterpart for the maintenance therapy of AIDS patients with stabilised cytomegalovirus retinitis in whom there is no evidence of sight-threatening disease.

The most common manifestation of cytomegalovirus infection in patients with AIDS is cytomegalovirus retinitis, a disease that leads to visual deterioration and eventual blindness in untreated patients. Currently, more than 20 million indivi­duals worldwide are estimated to be infected with HIV Although it has been suggested that up to 45% of these individuals will eventually develop cytome­galovirus retinitis, this percentage may well be an overestimate for HIV-infected individuals in developing countries.

The incidence of AIDS-related cytomegalovirus retinitis has gradually in­creased over the last decade, as a result of improved antiretroviral drug therapy and better management of opportunistic infections. These factors contributed to improved survival and resulted in a larger population of patients with advanced AIDS at high risk of developing cytomegalovirus retinitis. However, a decrease in the incidence of cytomegalovirus retinitis has recently become evident. This

© Adis International Umited. All rights reserved. Pharmacoeconomics 1997 Aug; 12 (2 PI 1)

GancicIovir: A Pharmacoeconomic Review

Pharmacoeconomic Considerations in the Treatment of Cytomegalovirus Retinitis

Rationale for Use of Ganciclovir in Cytomegalovirus Retinitis

Pharmacoeconomic Evaluation of Ganciclovir

is probably due to the use of highly effective 2- and 3-drug combinations of antiretroviral agents.

Intravenous ganciclovir has been established for several years as a treatment for patients with AIDS-related cytomegalovirus retinitis. It is initially adminis­tered as induction therapy (generally as 5 mg/kg twice daily for 2 to 3 weeks) to stop retinal lesion progression and then as long term maintenance therapy in a dosage of 5 mg/kg/day. Recently, oral ganciclovir (3000 mg/day, administered in 3 or 6 divided doses after food) has also been approved as maintenance therapy.

Other agents used to treat patients with cytomegalovirus retinitis include in­travenous foscamet and cidofovir. As yet, no formal pharmacoeconomic evalua­tions have compared these agents with intravenous or oral ganciclovir.

Patients with cytomegalovirus retinitis require costly, lifelong maintenance ther­apy to slow progression of retinal lesions and to minimise loss of vision. Treat­ment costs of this disease have been reported to substantially increase overall expenditure on AIDS-related health care.

In addition to the acquisition costs of drug therapy, direct costs incurred in the treatment of cytomegalovirus retinitis include drug administration costs, which vary according to the route used, and costs associated with the management of treatment-related adverse events. Other direct healthcare costs include those of nursing time and physician consultations.

The maintenance treatment of patients with cytomegalovirus retinitis also involves several nonmedical direct and indirect societal costs. Among these are the costs of work absence and lost productivity, as well as travel expenses. How­ever, these costs may not have a significant effect on overall costs of treatment, given that cytomegalovirus retinitis generally occurs in patients with advanced AIDS who are no longer able to work.

Both intravenous and oral ganciclovir have demonstrated efficacy as maintenance therapy for patients with stabilised AIDS-related cytomegalovirus retinitis. In 2 major comparative clinical trials, assessments of the primary efficacy end-point of time to disease progression by masked assessment of retinal photographs showed no significant advantage for intravenous over oral ganciclovir therapy. Assessments by unmasked funduscopy, reflecting typical clinical practice but subject to observer bias, revealed a significant efficacy advantage for intravenous over oral ganciclovir in terms of time to disease progression.

Neutropenia and thrombocytopenia have been reported as the most common adverse events in patients receiving intravenous ganciclovir. In 2 comparative trials, neutropenia occurred in 23 and 37% of patients on intravenous therapy, compared with 14 and 24% of patients who received the oral formulation. In the same trials, sepsis was reported in 8.5 and 19% of intravenous ganciclovir reci­pients compared with 3 and 8% of patients who received the oral formulation .

Cost analyses conducted using data from the US, UK and Germany have shown that direct healthcare costs of oral ganciclovir maintenance therapy are generally lower than those of intravenous maintenance therapy. Models, based on efficacy and tolerability data from comparative clinical trials and nontrial resource usage data, were used to assess the economic effect of both types of treatment. All cost analyses were conducted from the perspective of the healthcare payer.

In a US evaluation, which examined the direct costs of treatment from the pers­pective of the state Medicaid payer, costs of intravenous induction and maintenance

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212 Perry & Davis

therapy were included in the main analysis, whereas reinduction treatment costs were not estimated. On the basis of photographic assessments of clinical efficacy (57 and 62 days free of disease progression for oral and intravenous treatment, respectively) direct healthcare costs of oral ganciclovir treatment were estimated to be about 42% lower than those of intravenous treatment [$US4938 vs $US8587 (1993 dollars)]. In addition, compared with intravenous ganciclovir, estimated lifetime treatment costs (which included estimates of reinduction costs) were 25.2% lower for the oral formulation ($US25 007 vs $US33 453), based on pho­tographic assessments. Sensitivity analysis indicated that oral ganciclovir re­mained less costly than the intravenous drug when funduscopy data were substituted for photographic data.

Oral ganciclovir treatment was also associated with substantially lower direct medical care costs than intravenous therapy in a German economic evaluation that was based on efficacy and tolerability data from the Oral Ganciclovir Eu­ropean and Australian Cooperative Study. Maintenance and reinduction nondrug treatment costs were included, but first induction and maintenance drug acquisi­tion costs were excluded. Estimated direct costs of intravenous induction in the hospital (for inpatients) and intravenous maintenance therapy administration in the physician's office or at home were OMI7 448 and OM20 284 (in 1993 cur­rency), based on photographic data. Lower costs were estimated for intravenous induction in the hospital plus oral maintenance therapy; these costs were, respec­tively, OMI4 438 and OM8609, based on data from photographic or funduscopic assessments. The lower estimated costs of oral therapy were attributed to the avoidance of costs associated with long term intravenous administration, such as placement of a central venous catheter. Sensitivity analyses showed that the re­sults of the primary cost analysis were robust to a wide range of independent variables, including different adverse event probabilities, and different mean times to disease progression.

Expected costs of oral ganciclovir maintenance therapy were also lower than those of intravenous maintenance treatment in an evaluation conducted in the UK. As in the German study, drug acquisition costs were not available for inclu­sion in this model, but both reinduction and induction costs were incorporated. In the main analysis, the mean total expected cost per patient was 9% lower with oral therapy than with intravenous maintenance therapy [£7414 vs £8147 (in 1993/94 currency)]. Subsequent application of drug acquisition cost data for maintenance therapy to the model showed that oral ganciclovir was less costly than intravenous ganciclovir maintenance therapy when high unit costs of re­sources or home intravenous infusion pumps were used; however, for all other scenarios total costs of oral treatment were estimated to be £ 126 per patient to £ 1350 per patient higher than intravenous treatment. According to the investiga­tors, underestimates of intravenous treatment costs may have been used in this study.

A health state utility analysis assessed differences in patient preference for the 2 formulations and showed that most interviewed patients with HIV infection would prefer treatment with oral ganciclovir to intravenous treatment in the event of their developing cytomegalovirus retinitis.

A survey of ganciclovir resource utilisation and treatment patterns in 5 Euro­pean countries showed that protocols for intravenous maintenance therapy varied widely between countries. On the basis of findings of this investigation, it was

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Ganciclovir: A Pharmacoeconomic Review 213

concluded that the use of oral ganciclovir maintenance therapy had the potential to reduce healthcare resource use in the countries surveyed.

Cytomegalovirus retinitis, caused by the ubi­quitous herpesvirus cytomegalovirus, is an AIDS­defining opportunistic infection and is a major cause of morbidity in this patient population.l I.2] From a health economics standpoint, cytomegalo­virus retinitis is an illness associated with high treatment costs,[3] which substantially increase overall expenditure on AIDS-related health care.[4]

Over the last decade, intravenous ganciclovir has become an established treatment for patients with AIDS-related cytomegalovirus retinitis.l5.6]

However, suppression of cytomegalovirus disease can be achieved only if the drug is administered as lifelong maintenance therapy.l7,8] To overcome the impracticalities and complications of long term in­travenous drug therapy, an oral formulation of ganciclovir has been developed and has recently been approved for the long term maintenance treat­ment of cytomegalovirus retinitis in patients with AIDS.[9]

Because of the increasing need to justify AIDS­related treatment expenditure to healthcare payers and to society in general, pharmacoeconomic eval­uations have been conducted in the US, the UK and Germany to determine the relative effects of oral and intravenous ganciclovir treatment on health­care costs of cytomegalovirus retinitis. This article reviews these pharmacoeconomic evaluations and, from an economic perspective, positions both for­mulations of the drug in the management of pa­tients with AIDS-related cytomegalovirus retinitis. Ganciclovir is also available as a sustained release intraocular implant and as an intraocular injec­tion,[IO,II] but few pharmacoeconomic data regar­ding these formulations are currently available.

1. Overview of Cytomegalovirus Retinitis

1 .1 Epidemiology

Cytomegalovirus retinitis, the most common manifestation of cytomegalovirus infection in pa­tients with AIDS, occurs more frequently in pa-

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tients with advanced HIV disease (CD4+ counts ::;50 cells/I.d) than in individuals with higher CD4+ cell counts.l 12-14] In many patients, the initial pre­senting symptom of the disease is, typically, pain­less unilateral visual loss. Infected patients who do not receive drug treatment experience gradual reti­nal destruction and eventual unilateral or bilateral blindness.[I, 13, 15-19]

Recent estimates indicate that more than 20 mil­lion people worldwide are infected with HIV;[20] of these, it has been reported that up to 45% may de­velop cytomegalovirus retinitis.l I,14,15] This figure may, however, be an overestimate given that few AIDS patients in developing countries live long enough to develop the condition.

The increase in incidence of cytomegalovirus retinitis in developed countries over the last decade is largely the result of improved antiretroviral drug therapy and more effective management of oppor­tunistic infections, particularly Pneumocystis car­inii pneumonia. [9] This progress in patient manage­ment improved survival, but resulted in a large population of patients with advanced AIDS at high risk of developing cytomegalovirus retinitis.l9] More recently, the use of highly effective 2- and 3-drug combinations of antiretroviral drugs ap­pears to have led to a decline in the incidence of cytomegalovirus retinitis.

1 .2 Treatment Options

First-line treatment options for cytomegalovi­rus retinitis in patients with AIDS have, until re­cently, consisted of either intravenous ganciclovir or intravenous foscarnet, each administered as long term maintenance therapy.[21] Some patients expe­riencing virological or clinical relapse during ganciclovir therapy and/or ganciclovir-related haematological toxicity have been shown to bene­fit from switching to foscarnet. In most clinical tri­als conducted in patients with cytomegalovirus retinitis, ganciclovir and foscarnet were similarly effective treatments; however, in one comparative

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trial, recipients of intravenous ganciclovir had a significantly higher rate of mortality than foscar­net-treated patients (51 vs 34%; p = 0.007).f22.23] Despite the findings of this trial, foscarnet is widely perceived to be associated with a more marked adverse effect on quality of life than ganciciovir.[13]

Ganciclovir and foscarnet have been used in combination as second-line treatment for patients with AIDS-related cytomegalovirus retinitis.[21] Recently, cidofovir has been developed a third parenterally administered agent[24] and has been used as an alternative treatment for patients with cytomegalovirus retinitis.

7.2. 7 Intravenous Ganciclovir Traditionally, ganciclovir treatment for patients

with newly diagnosed cytomegalovirus retinitis has consisted of an intravenous induction phase [generally 5 mg/kg twice daily (administered as a I-hour infusion) for 14 to 21 days] to achieve dis­ease stabilisation (defined as nonprogressing or in­active retinal lesions). This is followed by lifelong maintenance intravenous therapy (5 mg/kg daily or 6 mg/kg for 5 days each week[231) to delay the spread of retinal lesions and preserve vision. Indi­viduals who experience clinical or virological re­lapse generally require reinduction therapy either with ganciclovir (generally 5 mg/kg twice daily for 14 to 21 days[4J) or with foscarnet before mainte­nance therapy is resumed. Reinduction therapy may be required after a mean time of 2 to 4 months.[l8,25J Although intravenous ganciclovir is a well-established maintenance treatment for cyto­megalovirus retinitis, administration via this route is often inconvenient and may cause considerable patient discomfort. In addition, long term intrave­nous ganciclovir administration is associated with several life-threatening complications, such as in­dwelling intravenous catheter infection and/or blockage, sepsis and dose-limiting neutropenia (re­sulting in interruption of ganciclovir and other haematotoxic drug therapy related to HIV disease) [see section 3.3].l18,25]

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Perry & Davis

7.2.2 Oral Ganciclovir Despite initial concerns that the low bioavaila­

bility of oral ganciclovir would limit its clinical potential (see section 3.1), clinical evidence has shown that oral ganciclovir is an effective mainte­nance treatment for patients with AIDS-related cyto­megalovirus retinitis.f7] Based on the findings of re­cent clinical trials, the recommended dosage of oral ganciclovir maintenance therapy is 3000 mg/day, administered after food in 3 or 6 divided do­ses. [18.25] As ganciclovir induction and reinduction therapy must be given intravenously, periphe­ral [26J or central venous catheter placement may be required for patients given the oral drug during times of intravenous induction or reinduction.f8] As with standard intravenous ganciclovir regimens, catheter-related problems and neutropenia may oc­cur in patients requiring intravenous induction treatment while receiving an oral regimen. How­ever, the incidence of these events tends to be lower than with a standard intravenous regimen (see sec­tion 3.3).

2. Pharmacoeconomic Considerations in the Treatment of Cytomegalovirus Retinitis

The mean cost of treating each of the 609 pa­tients with AIDS who survived the sixth time pe­riod of the AIDS Costs and Service Utilization Sur­vey (each time period was 3 months) was estimated to be $US 1680 per month, whereas the mean cost of treating each of the 79 patients who died during the same period was $US5840 per month (costs derived from 1991/92 data).[27J The mean cost of treating all patients was $US2137 per patient per month. Analysis of expenditure on the treatment of cytomegalovirus retinitis, as a proportion of the mean total cost, was not included in this estimate; however, overall costs of this infection are known to represent a substantial proportion of overall healthcare expenditure on AIDS. In a recent study, the projected annual cost of treating AIDS-related cytomegalovirus retinitis was $US 100 337 per pa­tient (1995 dollars). Costs of drug treatment, diag­nosis and laboratory monitoring were included in this estimate.[3J

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Ganciclovir: A Pharmacoeconomic Review

Several recent pharmacoeconomic evaluations of ganciclovir (see section 4) have provided useful information regarding costs of disease treatment from the perspective of the healthcare payer. In these evaluations, direct medical costs of cytomega­lovirus retinitis varied according to the route of administration of the drug selected for mainte­nance treatment. As mentioned in section 1.2.1, there are several medical complications, which have both quality-of-life and economic ramifica­tions , associated with long term intravenous ganciclovir therapy. From an economic viewpoint, treatment of these complications markedly in­creases the overall direct costs of cytomegalovirus retinitis treatment. [4,28] Ganciclovir-related neu­tropenia is also an important pharmacoeconomic issue, as expensive haematopoietic growth factors, such as recombinant granulocyte colony-stimulat­ing factor (rG-CSF), may be required as adjunctive treatment to ameliorate neutropenia before ganciclovir and other HIV disease-related thera­pies are resumed.l4,28.31 1 Since intravenous ganciclovir is associated with a higher incidence of neutropenia than the oral formulation (see section 3.3), the overall costs of intravenous treatment are potentially higher than those of oral treatment.

Several other expenditures related to intrave­nous and/or oral ganciclovir maintenance therapy affect the overall direct medical costs of cytome­galovirus retinitis.[4,32,331 These include drug ac­quisition costs, home care company fees, phar­macy dispensing fees and expenditures related to intravenous administration, such as costs of nee­dles, syringes, intravenous ports, butterflies and in­travenous line flushing . Other costs, such as charges for nursing time, hospital admission, time spent in hospital, and physician consultations in­crease the direct costs of treating AIDS-related cy­tomegalovirus retinitis. Nonmedical direct costs and indirect societal costs, including those of work absence, lost productivity and travel expenses, are also incurred during maintenance treatment of cy­tomegalovirus retinitis. However, as many patients with cytomegalovirus disease are already disabled before the disease is diagnosed, work absenteeism

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215

Table I. Costs associated with treatment of cytomegalovirus retinitis with intravenous and/or oral ganciclovir in several Eu­ropean countriesl321

Direct medical costs

Physician visits

Diagnostic tests

Drug acquisition

Hospitalisation, outpatient or home care costs for intravenous drug administration

Nursing time

Treatment of adverse events (e.g. granulocyte colony-stimulating factor for neutropenia, catheter-related complications)

Direct nonmedical costs

Travel/transportation

Special diets

Caregiving

Indirect costs

Work absenteeism

Underemployment or unemployment

is not necessarily a relevant issue in this patient population. An overview of direct medical, non­medical and indirect cost factors associated with intravenous and/or oral ganciclovir treatment of cytomegalovirus retinitis in patients with AIDS in several European countries is shown in table I.£321 Based on currently recommended dosages of gan­ciclovir, daily acquisition costs of oral ganciclovir maintenance treatment are higher than those of in­travenous maintenance treatment[41

Despite a shortage of published evidence, it is accepted that both cytomegalovirus retinitis per se and its treatment affect quality of life. [8] Since the type and magnitude of quality-of-life improve­ments in patients receiving either oral or intrave­nous ganciclovir have economic implications, ad­justment for quality-of-life differences (such as differences in patient preferences on the basis of risk and benefit data) between the 2 treatments should ideally be performed in pharmacoeconomic evaluations.

Few instruments have been designed to measure quality of life and visual function in patients with AIDS-related cytomegalovirus retinitis. However, Wu and colleagues[81 have recently developed a

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brief self-administered questionnaire to determine the effects of cytomegalovirus retinitis, and the treatment of this disease, in patients with AIDS. Questionnaire respondents (26 patients who had participated in a trial comparing intravenous ganciclovir with intravenous foscamet) indicated that the most common visual problems associated with cytomegalovirus retinitis were impaired pe­ripheral vision, and difficulties driving at night and reading small print. Intravenous treatment was found to interfere with social activities, affect daily living activities and affect body image in 40, 24 and 28% of respondents, respectively. It was revealed that patients spent an average of 2.3 hours per day receiving intravenous drug treatment. This ques­tionnaire has been used as a means of determining general health status and visual function in patients receiving intravenous or oral ganciclovir mainte­nance treatment in 2 clinical trials which have not yet been published.

3. Rationale for Use of Ganciclovir in Cytomegalovirus Retinitis

This section provides an overview of relevant clinical data reviewed previously in Drugs,[SI sup­plemented with results of more recent clinical trials of intravenous and oral ganciclovir in patients with AIDS-related cytomegalovirus retinitis. The pur­pose of this section is to provide information rele­vant to the pharmacoeconomic evaluation of gan­ciclovir.

3.1 Pharmacology

Ganciclovir, an analogue of the nucleoside 2'­deoxyguanosine, exhibits good antiviral activity against human cytomegalovirus in vitro and in

vivo.[SI Cytomegalovirus resistance to ganciclovir is uncommon in viral isolates from untreated pa­tients,[34) but the gradual emergence of viral resis­tance has been seen in 7.6% of 72 patients recei­ving long term (:2 3 months) intravenous treatment with the drugJ3S)

The oral bioavailability of ganciclovir is low, with mean absolute bioavailability values of about 9% reported after multiple doses of 500mg 6 times

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Perry & Davis

daily or 1000mg 3 times daily after food in 18 cy­tomegalovirus-infected patients with AIDSJ36) However, although oral ganciclovir was originally thought to have only limited clinical potential be­cause of its low bioavailability, the steady-state area under the plasma concentration-time curve in patients receiving an oral dosage of 3000 mg/day was only 30% less than that achieved after a single intravenous 5 mg/kg dose)36) Importantly, during treatment with oral dosages of 3000 mg/day, mean plasma ganciclovir concentrations are sufficient (>0.5 mg/L) to produce in vitro inhibition of most clinical isolates of cytomegalovirus.[37·38)

3.2 Efficacy

Clinical trials of intravenous or oral ganciclovir maintenance therapy in patients with stable AIDS­related cytomegalovirus retinitis have shown that both types of treatment prolonged time to recur­rence of acti ve disease. [S.6.18,2S,39-41)

In randomised studies comparing oral and in­travenous ganciclovir, the maintenance dosages were 3000 mg/day (in 3 or 6 divided doses) and 5 mg/kg/day, respectively. Maintenance therapy was administered after the disease had been stabilised (defined as the presence of inactive or nonprogressing lesions) by a course of intravenous ganciclovir induction therapy, which was generally administered for 14 to 21 days. In the event of cli­nical and/or virological relapse, intravenous reinduction therapy (sections 1.2.1 and 1.2.2) was administered to both intravenous and oral gan­ciclovir recipients. The primary clinical efficacy end-point was the number of days from the start of ganciclovir maintenance therapy to progression of cytomegalovirus retinitis, as assessed by masked assessment of retinal photographs or by unmasked funduscopic examination) 18,2S)

Results of 2 recent trials, from which clinical and tolerability data were derived for cost analyses, are shown in table II.

In the trial reported by Drew et al.,[18) times to first cytomegalovirus retinitis progression, de­termined by masked photographic assessment, were 57 and 62 days, respectively, for patients who

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Ganciclovir: A Pharmacoeconomic Review 217

Table II. Summary 01 2 major multicentre, nonblind, randomised trials comparing intravenous and oral ganciclovir (GCV) as maintenance treatment for cytomegalovirus retinitis in patients with AIDS; data from both trials were used in pharmacoeconomic evaluations of oral and intravenous GCV

Reference No. of pts Induction regimen Maintenance regimen Mean (median) time to Tolerability enrolled in (duration in days) progression of retinitis maintenance (days) phase retinal lunduscopic

photographic examination assessment

The Oral 47 NA" 5 mgJkgJday IVb 62 (60) 109" (137) Higher incidence of Ganciclovir (up to 140) neutropenia, sepsis, IV European and 112 NAa 500mg 6x/day poe 51 (41) 86 (84) site infections in IV GCV Australian (up to 140) treatment group than in Cooperative oral GCV recipients Study Groupl2SJ

Drew et al. I18J 60 10 mg/kgJday x 14 days, 5 mgJkgJday IVb 62 (49) 96' (105) Higher incidence of then 5 mgJkgJday x 7 days (up to 140 - mean 116) neutropenia",

63 10 mg/kgJday x 14 days, 500mg 6x/day poe 57 (29) 68 (48) anaemia", IV

then 5 mg/kgJday x 7 days (up to 140 - mean 100) catheter-related events'" and sepsis in IV GCV treatment group than in oral GCV recipients

a In the trial reported by The Oral Ganciclovir European and Australian Cooperative Study Group,12SJ patients were enrolled after comple-tion of IV GCV induction therapy (5 mg/kg twice daily for 14 to 21 days).

b Administered as an infusion over 1 hour.

c Preferably administered with food.

Abbreviations and symbols: IV = intravenous(ly); NA = not applicable (see footnote a); PO = orally; pts = patients; 'p = 0.03, "p = 0.02, '''p = 0.006 versus oral treatment group.

received treatment with either oral (evaluable n = 60) or intravenous ganciclovir (evaluable n = 57).[181 All study participants had newly diag­nosed, stabilised cytomegalovirus retinitis.

Assessment by funduscopy showed a sig­nificant efficacy advantage for intravenous over oral ganciclovir therapy (table II). However, this assessment was subject to observer bias, since it was conducted by unmasked evaluators. Analysis of other clinical outcomes showed no between­group differences in the duration of viral shedding, changes in visual acuity, subjective assessment of functional vision or survivaJ.f181 Of the 161 pa­tients initially enrolled in this trial, 38 (24%) were unable to participate in the maintenance therapy phase; the most common reasons for this were un­stable retinitis after 3 weeks' induction therapy (n = 18), and abnormal laboratory results (n = II).

The European and Australian multicentre trial of intravenous (n = 47) versus oral ganciclovir

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(n = 112) in patients with AIDS and stable cytome­galovirus retinitis also showed that both formula­tions slowed progression of the latter.l25] In concor­dance with the findings reported by Drew et aJ.f181 masked retinal photographic assessments indi­cated that, on average, recipients of intravenous ganciclovir maintenance therapy experienced more days free of disease progression (62 days) than pa­tients treated with the oral drug (51 days),[25] al­though this between-group difference did not at­tain statistical significance. However, unmasked clinical assessments by funduscopy revealed that disease progression occurred significantly more slowly in the intravenous ganciclovir treatment group than in the oral ganciclovir recipients (table II).

3.3 Tolerability

Neutropenia (defined as a neutrophil count of <500 cells/ill) and thrombocytopenia (defined as a

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platelet count <50 OOO/Jll) have been reported as the most common adverse events in patients recei­ving intravenous ganciclovir; these events oc­curred in 38 and 20% of patients, respectively, in the compassionate use programme.l5] Neutropenia was dose-limiting (absolute neutrophil count <500 cells/Jll) in 16% of patients.l42]

The incidence of neutropenia was higher in re­cipients of intravenous maintenance therapy than in patients who received oral therapy in the 2 randomised comparative clinical trials shown in ta­ble II (37 vs 24%[18] and 23 vs 14%[25]). Diarrhoea was experienced frequently by patients treated with either intravenous or oral ganciclovir, occur­ring in 21 to 54% ofpatients.[18.25]

There was an almost 3-fold higher incidence of sepsis (19 vs 8%[18] and 8.5 vs 3%[25]) in patients who received intravenous maintenance therapy than in oral therapy recipients. The incidence of catheter-related complications was significantly higher in the patients treated with intravenous ganciclovir than in the oral treatment group (31 vs 10%; P = 0.006).[18]

4. Pharmacoeconomic Evaluation of Ganciclovir

Data from comparative clinical trials of oral and intravenous ganciclovir maintenance therapy in patients with stabilised AIDS-related cytomegalo­virus retinitis have been integrated into phar­macoeconomic analyses of these formulations of the drug. It should be noted, however, that the oral ganciclovir data were derived from short term ($6 months) trials which included only those patients who had not relapsed while receiving previous in­travenous ganciclovir therapy. Indeed, no data are yet available regarding the clinical efficacy of oral ganciclovir administration after retinitis progres­sion or relapse.

Three published cost analyses have compared the effects on health care resources of oral and in­travenous ganciclovir maintenance treatment for patients with AIDS and stabilised cytomegalovirus retinitis.[4.26.28] Data are limited at present regar­ding the relative effects of oral and intravenous

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Perry & Davis

ganciclovir on quality of life in patients with AIDS­related cytomegalovirus retinitis; however, a single study has used health state utility as a means of evaluating quality-of-life differences in patients hypothetically treated with either intravenous or oral ganciclovir.[43] Intravenous ganciclovir treat­ment patterns and resource utilisation have also been assessed in several European countries with the aim of anticipating the effect of oral ganci­clovir maintenance therapy on healthcare resource use,l32]

4.1 Cost Analyses

The direct medical costs of intravenous and oral ganciclovir have been assessed in models using cost data from the US,[4] Germany[28] and the UK (table III)[26] and efficacy and tolerability data from published trials.l 18.25]

Direct nonmedical and HIV disease-related comorbidity costs were excluded, as were indirect societal costs, such as the cost of days missed from work during treatment with oral or intravenous ganciclovir. However, as mentioned in section 2, it is questionable whether the inclusion of indirect costs would have had a significant effect on overall treatment costs given that cytomegalovirus retinitis tends to occur in patients with advanced AIDS who may already be unable to work.

All 3 studies were conducted from a healthcare payer perspective and included only direct medical costs. Each evaluation was based on nontrial resource usage patterns derived from Delphi pa­nels, rather than trial-based resource and cost data. The US and UK studies used expert opinion to de­termine these patterns, whereas the German study estimated costs for several different treatment sce­narios.

The 3 analyses included costs associated with maintenance therapy, but only the UK and US stud­ies incorporated costs of first intravenous induc­tion. Intravenous reinduction costs were included in the main analyses in the UK and German studies, whereas these costs were included only in the esti­mated lifetime cost simulations in the US study (table III).l4.26.28J

Phormacoeconomics 1997 Aug; 12 (2 PI 1)

Ganciclovir: A Pharmacoeconomic Review 219

Table III. Overview of results from 3 cost analyses that estimated the mean expected direct medical costs of oral and IV ganciclovir maintenance therapy per patient with cytomegalovirus retinitis

Reference Healthcare payer Costs included in the model perspective (cost year)

Davies & Maynardl261 UK NHS (1993/94)

Sullivan et al. 141 US state Medicaid (1993)

von den Schulenburg German social et al.1281d health insurers

(1993)

Induction, maintenance and reinduC1ion therapy

Adverse events (neutropenia and catheter-related infection)

Medical care resource use estimated from 3 centres in the UK that treat patients with AIDS

Inpatient, hospital outpatient, home care visits. laboratory and diagnostic tests, nursing and medical staff time

Induction and maintenance therapy

Adverse events (neutropenia. catheter-related infection. sepsis)

Medical care resource use estimated from an 11-member expert panel and a national survey of AIDS primary healthcare providers; efficacy, adverse event and some treatment pattern data were also derived from the Clinical trial reported by Drew et al.[161

Inpatient, outpatient, home care visits, laboratory and diagnostic tests, nursing and medical staff time

Maintenance and reinduction therapy

Adverse events (neutropenia and catheter-related infection)

Inpatient, outpatient, home care visits, laboratory and diagnostic tests, nursing and medical staff time

Mean expected direct costs by assessment type"

funduscopy

E7414b (oral)

E8147b (IV)

$US5843 (oralr

$US11 004 (IV)

DM8609b (oral)

DM10 941 b (IV)

photography NAC

$US4938 (oralr

$US8587 (IV)

DM14 438b (oral)

DM17 448b (IV)

a To estimate these costs, the UK analysisl221 included pro-rated inpatient and outpatient resource use for induction, dependent on resource use at each centre questioned; the US analysisl41 used home care costs for IV induction, except for inpatient placement of the central line for patients receiving IV ganciclovir; the German studyl241 used treatment scenarios (see table IV).

b Does not include drug costs of oral or IV ganciclovir maintenance therapy because the cost of oral ganciclovir was not known at the time of the stUdy.

c Specific data were not provided; however, it was stated that, using photographic assessment, the expected total costs of the oral formu-lation would be E1430 less than that of the IV formulation.

d Results are for scenarios 2 and 5 for IV and oral maintenance cost groups, respectively (see table IV).

Abbreviations and symbols: DM = Deutschmarks; IV = intravenous; NA = not available; NHS = National Health Service; E = pounds sterling; $US = US dollars; .p < 0.0001 vs IV maintenance therapy.

Types of costs determined in these models in­cluded those of:

• hospitalisation • physician and ophthalmologist visits and clini­

cal assessments

• laboratory tests during induction, maintenance and reinduction phases

• central or peripheral intravenous line placement • nursing service costs associated with home or

outpatient drug administration

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• adverse events, including hospitalisation and drug therapy (for example, the cost of rG-CSF therapy for the treatment of neutropenia and an­timicrobial agents for catheter-related infec­tions). Because oral ganciclovir was unavailable in

Germany and the UK at the time the economic eval­uations were conducted, only the US study in­cluded drug acquisition costs associated with maintenance therapy in the primary analysis.

Phormacoeconomics 1997 Aug: 12 (2 PI 1)

220

Sensitivity analyses were performed in all of these models to verify the effects of different base­line assumptions on the validity of the results .

Results of these studies, which used simple modelling processes, generally showed that oral ganciclovir resulted in lower overall medical costs than intravenous ganciclovir maintenance therapy using results of either masked examination of reti­nal photographs (the optimal method in the 'artifi­cial' setting of the clinical trial) or unmasked funduscopy, which more realistically reflects clini­cal practice (table III) .

Efficacy and tolerability data from the clinical trial reported by Drew at aUIS] were used in the US economic evaluation of oral versus intravenous ganciclovir maintenance treatment for patients with AIDS and stabilised cytomegalovirus retinitis of recent onset.[4] The investigators conducted a statistical analysis of these clinical data which were

(j) :::> <I)

C') 0> 0> :::. C .~ iii a. a; a.

'" 1ii 0 u

C '" E iii ~ 'iii a; > 0 c: ., '" ::iE

3500

3000

2500

2000

1500

1000

Intravenous

Oral

IV induction • home care~ AE treatment costs • nursing Costs costs

• outpatient

Fig. 1. Comparison of estimated mean direct costs (1993 US dollars) of oral and intravenous (IV) ganciclovir treatment of patients with AIDS-related cytomegalovirus retinitis. Costs per patient were calculated over a mean of 83 days (21 days of IV induction therapy plus 62 days IV maintenance therapy) for the IV treatment group and over a mean of 78 days (21 days of IV induction therapy plus 57 days of oral maintenance therapy) for the oral treatment group.14J Abbreviation: AE = adverse event.

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Perry & Davis

augmented with minimal treatment pattern use and external unit cost information where necessary. As the primary end-point of the clinical trial was time to first reinduction as measured by retinal photo­graphy or funduscopy, the economic analysis cal­culated the cumulative cost to first reinduction, thus allowing for a direct link with the clinical data. The study was conducted in the US from the pers­pective of a state Medicaid payer (table III). Costs, estimated in 1993 US dollars, were calculated for induction therapy (intravenous ganciclovir 5 mg/kg twice daily for 14 days, then once daily for 7 days) and for maintenance treatment with intravenous (5 mg/kg daily) or oral ganciclovir (3000mg daily in divided doses). It was assumed that maintenance therapy would be administered until progression of cytomegalovirus retinitis, until patient withdrawal from the trial or until the end of the trial (week 20).

Acquisition costs of both ganciclovir formula­tions were calculated from the 1993 California State Medicaid reimbursement formula for pres­cription drugs. Reimbursement prices for weekly supplies of intravenous ganciclovir (prepared and distributed by a home care company) and oral ganciclovir (obtained from retail pharmacies) were estimated to be US$186.75 and US$315 .27, res­pectively.[4)

As assessments of disease progression were achieved by examination of retinal photographs, the primary cost analysis was based on these cli­nical outcome data. Mean daily costs per patient of intravenous and oral ganciclovir including home care and associated administration over the treat­ment period were calculated to be US$41.07 and US$28.07, respectively. In contrast, mean costs per patient of intravenous induction therapy (place­ment of a central venous catheter for the intrave­nous group versus less costly peripheral line place­ment for the oral group), treatment of adverse events, nursing administration service, home care service and outpatient monitoring costs were higher for intravenous treatment than for oral treat­ment (fig. I), offsetting the higher acquisition cost of oral ganciclovir.

Pharmacoeconomics 1997 Aug; 12 (2 Pt 1)

Ganciclovir: A Pharmacoeconomic Review

Based on photographically determined times to progression of 62 days for intravenous and 57 days for oral treatment (plus 21 days of intravenous induction therapy for both groups), the mean cost per patient was $US8587 for intravenous treat­ment, compared with $US4938 for oral treatment (p <0.0001) [table III]. However, because the time to disease progression was shorter with oral than with intravenous maintenance therapy, the exclu­sion of reinduction costs from the primary analysis may have resulted in a bias in favour of oral treat­ment.

Simulations of lifetime treatment costs (inclu­ding reinduction costs) of medical care related to cytomegalovirus retinitis resulted in values that were 25.2% lower for oral therapy than for intra­venous treatment ($US33 453 vs $US25 007 - a saving of $US8446 per patient receiving oral treat­ment). The 5 additional disease-free days con­ferred by intravenous therapy, compared with oral treatment, amounted to an incremental total cost of $US3649, or approximately $US730 per disease­free day.

Sensitivity analysis showed that the photogra­phically based cost data were robust to substitution with funduscopy data (table III), with oral mainte­nance therapy representing a mean cost saving of $US5161 per patient (p < 0.0001). Expected lifetime medical costs in this scenario were $US31 918 for intravenous and $US25 932 for oral treatment. Sensitivity analyses with respect to specific inde­pendent variables were not performed.

In the German cost analysis, the main source of efficacy and tolerability data was the European and Australian Cooperative Study (table II).[25] Differ­ent scenarios (table IV) were developed in this model to assess the cost impact of alternative treat­ment approaches and the costs of intravenous and oral ganciclovir therapy were compared. Scenario 1 was assumed to most accurately reflect actual clinical practice in Germany, but results of scena­rios 2 and 5 have been included in table III to be consistent with the practice patterns used in the US and UK studies.

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221

Table IV. Ganciclovir treatment scenarios in the German phar­macoeconomic model1281

Treatment IV reinduction scenario therapy details

IV scenarios 1 Hospital

2 Hospital

3 PhYSician's office (using a port)

4 Physician's office (using a port)

Oral scenarios

Maintenance therapy details

IV in physician's office (no port fitting)

IV at home (no port fitting)

IV in physician's office (no port fitting)

IV at home (no port fitting)

5 Hospital Oral

6 Physician's office Oral (using a port)

Abbreviation: IV = intravenous.

Because the clinical trial on which this model was based was 140 days in duration, a 140-day model was used in the primary analysis. Based on retinal photographic assessments of mean times to progression of cytomegalovirus retinitis of 51 days on oral therapy and 62 days on intravenous therapy (plus 21 days of reinduction therapy for patients with disease progression), costs of intra­venous maintenance therapy in the physician's office (scenario 1) or at home (scenario 2) and reinduction therapy in the hospital setting (sce­narios 1 and 2) were DM 17 448 and DM20 284, respectively (1993 Deutschmarks) [fig. 2].

These were lower (DM10941 to DM1417l) when the analyses were based on funduscopy data. Ranges of costs for scenarios 3 and 4 (intravenous reinduction in the physician's office) were lower than for scenarios 1 and 2 [DM9340 and DM 12 176 (based on retinal photography); DM 7941 and DMII 171 (based on funduscopy»).

Further breakdown of these costs indicated that daily costs of maintenance therapy with intrave­nous ganciclovir depended on the type of injection device and on whether the infusion was adminis­tered in the physician's office or at home. Costs per day of intravenous maintenance therapy admini­stered in the physician's office were DM55 (in­cluding intravenous port fitting in the physician's

Pharmacoeconomlcs 1997 Aug: 12 (2 PI 1)

222

Scenario 1 (IV) 25 o Scenario 2 (IV)

"' 0 o Scenario 3 (IV)

8 20 ':i

a M Ol Ol :::.

• Scenario 4 (IV) -D Scenario 5 (oral)

r-• Scenario 6 (oral)

'" 15 iii 0

r- -<J

C ., E 10 ... ~

r-

l-I-

-~ ., > 0 c:

5

'" ., ::::;:

0 ~I '----- L-

Funduscopy Photography

Fig. 2. Mean overall estimated treatment costs (1993 Deutsch· marks) of several intravenous and oral ganciclovir maintenance treatment scenarios for patients with AIDS·related cytomegalo­virus retinitis (see table IV) in a German cost analysis)281 Abbre­viation: IV = intravenous.

office), DM59 (with the port fitting in the hospital) and DM44 without a port fitting. Daily treatment costs were higher when maintenance intravenous therapy was administered by a nurse in the home [DM68 (no port fitting); DM79 (port fitting in a physician's office); DM83 (port fitting in a hos­pita!)]. In contrast, the cost per day of mainte­nance treatment with oral ganciclovir was lower (DM8 per day) than that of intravenous maintenance therapy because of the avoidance of costs associ­ated with intravenous administration, such as port fitting and port lavage. For daily costs of oral treat­ment, it was assumed that patients would receive 3 medical examinations during maintenance therapy (rather than the 2 examinations assumed for intra­venous maintenance therapy), since oral treatment was less effective than intravenous therapy in clini­cal trials. Costs per day of intravenous ganciclovir reinduction therapy, in the physician's office, ad­ministered by use of either a butterfly administra­tion device or an injection port, were DM64 and DM121, respectively. Although the material costs

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Perry & Davis

of butterflies are higher than those of ports, overall port administration costs are higher, as they also include the costs of port fitting, lavage and infu­sion. Reinduction therapy in the hospital was more expensive (DM403 per day) than in the physician's office.[28]

For scenario 5 (oral maintenance therapy plus intravenous reinduction in the hospital), costs were DM14438 for photographic and DM8609 for funduscopy evaluations (table III). Intravenous reinduction therapy in the physician's office plus oral maintenance therapy (scenario 6) resulted in lower costs in this scenario; these were DM5472 and DM3797 based on photographic and fundus­copy assessments, respectively (fig. 2).

Sensitivity analyses showed that the results of the primary cost analysis were robust to different probabilities for adverse effects, switching from oral to intravenous therapy after reinduction and different mean times to disease progression for oral ganciclovir (95% confidence interval values for the difference in means of time to progression).

As in the cost analysis reported by von den Schulenberg et al.,[28] the UK economic model was based on clinical outcome and adverse event data reported by the Oral Ganciclovir European and Australian Cooperative Study Group.[25] To esti­mate healthcare resource utilisation and costs, structured clinician interviews were conducted at 3 UK medical centres for the treatment of patients with AIDS. The questionnaire was designed to ac­quire information regarding routine clinical man­agement of patients with AIDS-related cytomega­lovirus retinitis, including anticipated treatment patterns for ganciclovir-related adverse events.[26] Estimated costs were updated to 1993/94 levels by use of a health service inflation index.

Expected costs per patient were 9% lower for oral than for intravenous maintenance therapy with ganciclovir, with mean total expected costs cal­culated as £7414 and £8147 per patient, respec­tively (table III). This difference was largely the result of the higher costs of drug administration and adverse events for the intravenous regimen. Al­though the primary cost analysis was based on

Pharmacoeconomics 1997 Aug; 12 (2 Pt 1)

Ganciclovir: A Pharmacoeconomic Review

funduscopy results, application of the analysis to photographic data indicated that the expected cost of the oral formulation would be £ 1430 less than the intravenous formulation. Administration costs of intravenous induction therapy were higher for the intravenous maintenance treatment group as it was assumed that central line placement would be necessary in this group, whereas the oral mainte­nance treatment group would require less costly peripheral line placement for induction therapy.

Results of the analyses of direct costs of oral and intravenous ganciclovir from the overall perspec­tive of the National Health Service (NHS) and from the perspectives of the hospital management and the hospital pharmacy are shown in figure 3; aver­age net cost savings of oral ganciclovir maintenance therapy were £732.94, £505.00 and £323.67, res­pectively.

Calculations of costs to the hospital pharmacy were based on costs of intravenous induction ther­apy and concomitant drug treatment, and on intra­venous administration delivery systems, whereas costs to hospital management excluded costs in­curred in the community settingY6]

Sensitivity analyses demonstrated that these re­sults were insensitive to variations in clinical out­comes, exclusion of costs of neutropenia and intra­venous catheter-related infections, substitution of funduscopic with photographic data, and high and low cost units (for example, costs of equipment and staff time) resulting from differences in treatment practices in the centres reviewed.

Intravenous costs may have been underesti­mated in this analysis for the following reasons: (i) the model used clinical outcome data assessed by funduscopy, which increased the relative pro­portion of oral ganciclovir recipients receiving in­travenous reinduction therapy; (ii) underestimates of intravenous administration costs in the outpa­tient setting were included; and (iii) underesti­mates of intravenous drug home delivery system costs were used.

Drug acquisition cost data available after com­pletion of this analysis were subsequently applied to the model. Based on the assumption that patients

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223

would receive oral or intravenous ganciclovir at dosages recommended by the manufacturer, the daily costs of maintenance therapy were calculated to be £37.92 and £25.41, respectively. Application of these costs to the primary analysis resulted in a cost saving for oral ganciclovir maintenance ther­apy when high unit costs of resources (cost saving £3680 per patient for 140 days' maintenance ther­apy) or when higher costs of home intravenous in­fusion pumps (cost saving £3620 per patient for 140 days' maintenance therapy) were included in the model. However, application of drug acquisi­tion cost data to all other scenarios resulted in higher costs that ranged from £126 to £1350 per patient for 140 days' oral ganciclovir maintenance therapy.

Two unpublished pharmacoeconomic model­ling studies have also compared oral with intra­venous ganciclovir in patients with AIDS-related cytomegalovirus retinitis in France and in The Netherlands.l44,451 Both studies were conducted from the perspective of the health insurer and excluded acquisition costs of oral and intravenous ganciclovir. The models integrated resource utilisation data from local expert interviews, costs

10

C .!!! 6 ~ ~ 4 0;

8 ~ 2 Q)

:2

o UKNHS

• Oral o Intravenous

Hospital management

Hospital pharmacy

Fig. 3. Average costs of oral or intravenous ganciclovir treatment for patients with AIDS-related Cy1omegalovirus retinitis. Bars show costs (£ thousands) from the perspectives of the UK Na­tional Health Service (NHS). hospital management. and hospi­tal pharmacy,!26]

Pharmacoeconomics 1997 Aug; 12 (2 Pt 1)

224

associated with induction and maintenance treat­ment of cytomegalovirus retinitis and adverse events. Efficacy and tolerability data from the Eu­ropean clinical trial were used in the 2 models. Re­sults of the evaluations showed that the introduc­tion of oral ganciclovir to France and to The Netherlands would result in potential changes in patient treatment patterns and cost savings. In the French study,[44] oral maintenance treatment costs were 47 to 50% lower than intravenous mainte­nance treatment costs, based on funduscopy data. Replacement of funduscopy data with photo­graphic data resulted in total oral treatment costs that were 39 to 40% lower than those of intrave­nous treatment. Reduced administration costs rep­resented the largest savings for oral compared with intravenous maintenance therapy. Similarly, the evaluation based on data from The Netherlands[451

showed that substantial savings could be achieved with oral ganciclovir maintenance therapy, with to­tal oral treatment costs 24 to 50% and 21 to 44% lower than total intravenous treatment costs based on funduscopy or photographic data, respectively.

4.2 Health State Utility Analysis

In recent years, improving quality of life has been an important goal of therapy in patients with HIV disease. Health state utility (or preference) as­sessment is a method used to measure quality of life in individuals with HIV infection, utility being a quantitative value indicating the preference peo­ple assign to different health states.l43] A health state utility assessment has recently been applied to intravenous versus oral ganciclovir maintenance treatment. l431 The setting for this study was a com­munity-based private clinic for HIV-infected pa­tients in Sydney, Australia. 80 HIV-infected pa­tients, none of whom had developed AIDS or cytomegalovirus retinitis, were recruited into the study. On the basis of data derived from a clinical trial and from expert clinician opinion, a cross­sectional, interviewer-administered time trade-off survey was devised. The time trade-off method, which requires patients to state a preference be­tween 2 health states and associated life expectan-

© Adis International Limited. All rights reserved .

1.0

0.8

~ 0.6 <.> (f)

.~ 5 0.4

0.2

o

Perry & Davis

Current health CMV retinitis CMV retinitis receiving receiving

oral ganciciovir IV ganciclovir

Fig. 4. Median and mean utility scores assigned to 3 different health states by HIV-infected individuals who had not developed cytomegalovirus retinitis.[43] Abbreviations and symbols: CMV = cytomegalovirus; IV = intravenous; 'p <0.005, "p <0.00005 vs IV ganciclovir.

cies,[46] was used to determine patient utility for current health state and hypothetical maintenance treatment with oral or intravenous ganciclovir. Cy­tomegalovirus retinitis health states were described by several different health attributes, such as treat­ment efficacy, visual function prognosis and treat­ment-related adverse events (based on tolerability data reported by Drew et al.[lS]). Life expectancy was held constant at 20 months, regardless of treat­ment in the health state description.

Overall, the respondents indicated that they re­garded 16.7 months of remaining life in perfect health with the same magnitude of preference as 20 months with cytomegalovirus retinitis plus treat­ment with a maintenance regimen of oral gan­ciclovir. Participants rated 9.5 months of remaining life in perfect health with similar preference to 20 months of cytomegalovirus retinitis plus treatment with a maintenance regimen of intravenous gan­ciclovir. Oral ganciclovir was preferred to intrave­nous therapy by 60 (75%) of the participants. As shown in figure 4, mean and median utility values indicated a large and significant preference among

the participants for oral over intravenous therapy.

Pharmacoeconomics 1997 Aug; 12 (2 Pt 1)

Ganciclovir: A Pharmacoeconomic Review

Notwithstanding the positive features of this study, several limitations were discussed by the authors. In particular, patients were not asked to comment on their reasons for preferring one par­ticular treatment option. In addition, factors such as pain, general well-being, anxiety and worry re­lated to cytomegalovirus retinitis and/or AIDS were excluded from the health state attributes. It should also be mentioned that projections of the outcome of oral ganciclovir therapy may not be meaningful, given that the clinical trials of this for­mulation conducted to date have been short term only. Finally, the preferences in this study were expressed by HIY-infected patients at risk of de­veloping cytomegalovirus retinitis; however, it may be argued that the community at large may be a more appropriate audience for preference assess­ment.

4.3 Ganciclovir Resource Utilisation and Treatment Pattern Study

Efficacy and tolerability data from the Eu­ropean and Australian Cooperative Study were also used as the basis of a retrospective analysis, which was conducted to determine intravenous and oral ganciclovir treatment patterns and resource utilisation in the UK, France, Germany, The Nether­lands and Spain over a fixed period of 140 days,l32J Resource utilisation data regarding ganciclovir reinduction and maintenance therapy were estima­ted by interviewing 2 to 5 AIDS healthcare special­ists, including physicians, ophthalmologists and nursing staff in each of the participating countries. The questionnaire was also designed to acquire in­formation on the management of clinical events associated with intravenous ganciclovir therapy, such as neutropenia, catheter-related complica­tions and sepsis. Information requested in the ques­tionnaire included estimates of the number of full or part-time hospital days and/or days spent at home, physician consultations and nurse home vi­sits (to administer ganciclovir maintenance ther­apy). Data were also requested on diagnostic tests and procedures, equipment and drugs, such as an­tibacterial agent usage for the treatment of sepsis

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225

or intravenous catheter-related infections, or rG­CSF for the reversal of neutropenia.

Analyses of questionnaire responses indicated that ganciclovir intravenous induction protocols, and thus resource utilisation, varied widely among the different European countries included in the model. The author of the report suggested that this may have been the result of differences in reim­bursement schemes; for instance, in Germany at the time of the analysis, reimbursement costs were based on a cost per day in hospital, which may provide an incentive to hospitalise patients for as long as possible. It was concluded that the intro­duction of oral ganciclovir as maintenance therapy for cytomegalovirus retinitis would potentially re­duce healthcare resource use. Oral therapy was also expected to offer quality-of-life advantages over intravenous therapy.[32J

5. Pharmacoeconomic Positioning of Intravenous and Oral Ganciclovir

Cytomegalovirus retinitis in patients with AIDS is a devastating illness that requires expensive, lifelong drug treatment to delay disease progres­sion, to minimise loss of vision and to prevent pro­gression to cytomegalovirus encephalitis. Impor­tantly, individuals who receive drug treatment for this condition may be able to continue as active members of society, whereas untreated patients with deteriorating vision become increasingly de­pendent on their caregivers and/or society in gen­eraJ.l47J However, in the current economic climate of rising healthcare costs and limited resources, there is concern among healthcare policy makers regarding expenditure on new and costly drug ther­apies, particularly those that may provide only moderate health benefits. Thus, new drugs or new formulations of existing drugs, such as oral gan­ciclovir, require pharmacoeconomic evaluation to determine their effect on healthcare resource use and whether they provide acceptable value for money.

Over the last decade, intravenous ganciclovir has become recognised as a mainstay of treat­ment for AIDS-related cytomegalovirus retinitis. In

Pharmacoeconomics 1997 Aug; 12 (2 Pt 1)

226

clinical trials, it has been shown to delay retinal lesion enlargement and/or the development of new lesions (disease progression), and to preserve vi­sual acuity. More recently, an oral formulation of ganciclovir has also been shown to delay progres­sion of cytomegalovirus retinitis and to preserve vision in patients with the condition. Evidence from several comparative clinical trials has shown a trend towards a higher incidence of adverse events (notably, neutropenia and intravenous cathe­ter-related problems) in recipients of intravenous ganciclovir than in patients treated with the oral drug.

Several cost analyses of oral and intravenous ganciclovir treatment have been conducted from the perspective of the healthcare payer. Direct com­parison of results of these studies is confounded by differences in methods, clinical setting and country of the evaluation, clinical outcome and interven­tion assumptions, and proportional cost differences of healthcare resources integrated in the analyses. Nevertheless, all of these studies showed that oral ganciclovir was a less costly treatment than intra­venous ganciclovir, albeit based on restrictive as­sumptions in the UK and German studies which did not include drug acquisition costs in the main analyses. In the US study, the higher acquisition cost of oral ganciclovir compared with that of the intravenous formulation was more than offset by short term savings in some of the healthcare re­sources required for intravenous ganciclovir admi­nistration. These included costs of intravenous drug administration and costs of treating adverse events. Incorporation of costs relevant to a broader societal perspective may also have increased the economic advantage of oral therapy compared with intravenous therapy in these analyses.

Some caveats should be attached to the results of these cost analyses. Firstly, it may be questioned whether the treatment pattern assumptions in­cluded in the models reflected current treatment patterns in those countries. Indeed, intraocular ganciclovir is now prescribed for a substantial number of patients with cytomegalovirus retinitis and some patients experiencing their first relapse

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Perry & Davis

on oral ganciclovir may receive intravenous gan­ciclovir maintenance therapy thereafter. In addi­tion, none of the economic evaluations included the high surgical costs of repairing retinal detach­ments, a frequent complication of cytomegalovirus retinitis. Since the incidence of retinal detachment is directly related to the size of the lesion, inade­quate control of cytomegalovirus retinitis may well result in higher costs incurred by managing dis­ease-related complications. Moreover, the costs of blindness have not been included in any of the eco­nomic evaluations. If long term comparative clini­cal trials show that oral therapy is less effective than intravenous therapy in terms of preventing blindness, it would be appropriate to include the associated cost in future economic analyses. It is also noteworthy that there are no evaluable data for more than 2 to 3 months' oral ganciclovir adminis­tration in patients with AIDS-related cytomegalo­virus retinitis. Conceivably, clinical resistance to the drug may emerge during longer term therapy, and lead to substantial increases in treatment costs and to worsened quality of life for some patients.

Notwithstanding the cost savings associated with oral ganciclovir in the simple economic asses­sments conducted to date, this formulation can be recommended only for the treatment of selected patients because of the difference in efficacy be­tween the 2 formulations regarding disease pro­gression. Indeed, it has been suggested that oral gan­ciclovir treatment should be limited to patients who show no evidence of developing sight-threatening cytomegalovirus retinitis, balancing the risk of de­veloping retinitis against the benefits of avoiding daily intravenous infusions.[48] In patients with more central localisation of cytomegalovirus reti­nitis in whom visual loss is evident, intravenous ganciclovir maintenance therapy is preferred to oral treatment. Intravenous ganciclovir may also be preferred for the treatment of patients who experi­ence persistent diarrhoea, nausea and vomiting during oral treatment.

Formal cost-effectiveness evaluations of oral and intravenous ganciclovir, in which all relevant treatment costs are related to the health outcome

Pharmacoeconomics 1997 Aug; 12 (2 Pt 1)

Ganciclovir: A Pharmacoeconomic Review

(such as the number of disease-free days achieved), have not yet been published. Future economic analyses should focus on comparing intravenous ganciclovir, oral ganciclovir, intravitreal ganci­clovir, foscarnet and cidofovir.

In summary, 3 economic models, based on effi­cacy and tolerability data from large, randomised clinical trials and on non trial resource usage data, have shown that maintenance treatment with oral ganciclovir is generally less costly than intrave­nous maintenance therapy for patients with AIDS and stabilised cytomegalovirus retinitis. Further­more, in a health state utility analysis, most HIV­infected patients indicated a preference for oral over intravenous ganciclovir treatment. Thus, on the basis of limited pharmacoeconomic data, oral ganciclovir appears to be preferable to its intrave­nous counterpart for the maintenance therapy of carefully selected patients with stabilised AIDS­related cytomegalovirus retinitis.

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Correspondence: Caroline M. Perry, Adis International Lim­ited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand. e-mail: demail@adis.co.nz

Pharmacoeconomics 1997 Aug; 12 (2 PI 1)