Intravitreal ganciclovir maintenance injection for cytomegalovirus retinitis: efficacy of a low-volume, intermediate-dose regimen.

OBJECTIVE: To report the clinical outcomes of highly active antiretroviral therapy (HAART)-naïve, human immunodeficiency virus (HIV)-positive patients with newly diagnosed cytomegalovirus (CMV) retinitis receiving intravitreal injections of a low-volume intermediate maintenance dose (1.0 mg/0.02 ml) of ganciclovir. DESIGN: Nonrandomized, retrospective, interventional series. PARTICIPANTS: A consecutive cohort of 34 eyes from 24 HAART-naïve patients with AIDS and diagnosed with CMV retinitis by retinal specialists at the Singapore Communicable Disease Centre. INTERVENTION: Patients received a maintenance dose of 1.0 mg/0.02 ml of intravitreal ganciclovir once weekly after standard induction therapy with 2.0 mg/0.04 ml of twice weekly intravitreal ganciclovir. MAIN OUTCOME MEASURES: Time to progression, visual acuity, and complications. Progression was observed using photographic documentation. RESULTS: The median time to progression was 152 days (mean, 380.1 days, 95% confidence interval, 240.8-519.4). The median follow-up was 95 days (mean, 207.9 days). Three eyes developed rhegmatogenous detachments, but there was no endophthalmitis after 1858 injections. Contralateral involvement of CMV retinitis occurred in 17.6% of the patients. The cost estimate for intravitreal injections over a 6-month period was 11.7% that of sustained-release implants for unilateral treatment and 11.1% that of daily continuous intravenous infusions and oral valganciclovir compared with bilateral treatments. CONCLUSIONS: Weekly low-volume, intermediate-dose (1.0 mg/0.02 ml) ganciclovir is an efficacious option in developing countries where newer options of sustained-release implants and oral valganciclovir are unavailable or prohibitively expensive. The regimen maintains a long time to progression, preserving vision while minimizing retinal toxicity complications.

Economic evaluation of treatment administration strategies of ganciclovir for cytomegalovirus retinitis in HIV/AIDS patients in Thailand: a simulation study.

BACKGROUND: There are many effective interventions, via various routes (intravenous [IV], oral [OR], intravitreal injection [IVT] and intraocular implantation [IMP]), for treating cytomegalovirus retinitis (CMVR) that have become available. There are large variations in treating CMVR in clinical practice in Thailand. OBJECTIVE: To evaluate the incremental cost-effectiveness ratio (ICER) of providing (i) IVT, (ii) IV/OR and (iii) IMP ganciclovir to patients with HIV/AIDS and CMVR versus providing no treatment. DESIGN: A simulation study for which the input parameters were derived from a systematic review of the literature, a hospital-based survey and patient interviews. SETTING: The analysis assumed a Thai healthcare system perspective. However, the model was run using both societal and healthcare provider perspectives. RESULTS: Our results suggest that IVT ganciclovir was cost effective and the best option for treating patients with CMVR irrespective of whether patients received antiretroviral treatment (ART). In patients receiving ART, moving from IVT to IV/OR ganciclovir was also likely to be a cost-effective option. Offering IMP ganciclovir was not likely to be cost effective. Providing treatments for patients with bilateral CMVR was more cost effective than providing treatments for those with unilateral CMVR, and offering treatments for patients receiving ART was better value for money than treating patients without ART. CONCLUSIONS: Our models suggest that IV/OR ganciclovir should be recommended for the treatment of unilateral and bilateral CMVR for patients receiving ART in the Thai healthcare system. IVT ganciclovir may also have a role in the treatment of CMVR patients not receiving ART.

The epidemiology, treatment patterns, and costs of cytomegalovirus retinitis in the post-haart era among a national managed-care population.

To examine the epidemiology, treatment patterns, and costs of cytomegalovirus (CMV) retinitis treatment in the post-HAART (highly active antiretroviral therapy) era, a retrospective cohort study was performed using data from US managed-care plans from 1997-2002. Cases with CMV retinitis were defined by requiring diagnosis codes for HIV (or AIDS), CMV, and retinitis and claims for anti-CMV treatment. Costs of oral, intravenous, and intraocular treatment periods were examined. The incidence of enrolled HIV or AIDS cases increased from 7 per million members in 1997 to 150 per million members in 2001. The incidence of CMV retinitis decreased from 23 per 10,000 HIV or AIDS cases in 1997 to 8 per 10,000 HIV or AIDS cases in 2001. The average duration of a CMV episode was 192 days and the average cost was 19,576 US dollars. In a multiple linear regression model adjusting for age, gender, insurance type, geographic region, HAART use, and co-existing AIDS-defining illnesses, intraocular and oral treatment periods saved 7135 and US dollars and 6866 US dollars, respectively, per treatment period compared with intravenous treatment (P < 0.05). The incidence of CMV retinitis decreased in this managed-care population during the post-HAART era. Use of oral or intraocular treatment saves costs compared with intravenous treatment in a managed-care environment.

Valganciclovir: A new oral alternative for cytomegalovirus retinitis in human immunodeficiency virus-seropositive individuals.

Oral valganciclovir recently was approved by the Food and Drug Administration for treatment of cytomegalovirus (CMV) retinitis. We performed MEDLINE (June 1998-May 2002) and AIDSLINE (June 1998-December 2000) searches of available information on valganciclovir, and the drug's prescribing information was used to identify relevant articles. Additional studies, case reports, reviews, and abstracts were identified from references in the reviewed literature. Most of the information was obtained from abstracts or product labeling, since few trials have been published in the medical literature. Valganciclovir is a prodrug of ganciclovir and has been shown to have significantly higher oral absorption than ganciclovir capsules. One short-term study found valganciclovir to be as effective as intravenous ganciclovir in treating CMV retinitis. Recommended dosages for patients with normal renal function are valganciclovir 900 mg twice/day for induction and 900 mg once/day for maintenance. Side effects are similar to those of intravenous ganciclovir and require periodic monitoring of complete blood count and renal function. Given the need for lifelong therapy for CMV retinitis in some human immunodeficiency virus-positive patients, valganciclovir is a welcome alternative to long-term administration of intravenous antivirals.

Economic evaluation of systemic treatments for cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To determine the cost of using systemic therapy to treat newly diagnosed cytomegalovirus (CMV) retinitis in persons with AIDS. DESIGN: Incidence-based simulation model of CMV treatment from a government payer perspective. SETTING: Swiss healthcare system. PATIENTS AND PARTICIPANTS: Patients with AIDS and newly diagnosed CMV retinitis. INTERVENTIONS: Patients were assigned to 1 of 4 treatment regimens for induction and maintenance therapy: (i) intravenous (IV) cidofovir induction and maintenance (cidofovir IV/IV); (ii) IV foscarnet induction and maintenance (foscarnet IV/IV); (iii) IV ganciclovir induction and maintenance (ganciclovir IV/IV); and (iv) IV ganciclovir induction and oral (PO) ganciclovir maintenance (ganciclovir IV/PO). Following a second relapse, patients were assigned to one of the other regimens. MAIN OUTCOME MEASURES: Time to first and subsequent progression, duration of maintenance treatment and direct medical expenditures [1998 Swiss francs (SwF)] . RESULTS: The median time to first progression was longest for cidofovir IV/IV, followed by foscarnet IV/IV, ganciclovir IV/IV and ganciclovir IV/PO. Mean survival was 13 months and mean costs for this period in the base case were lowest in those initially treated with cidofovir (SwF146,742), followed by initial treatment with foscarnet IV/IV (SwF194,809), ganciclovir IV/PO (SwF195,190) and ganciclovir IV/IV (SwF243,964). Costs were most sensitive to changes in efficacy estimates. CONCLUSIONS: Of the regimens studied, initiation of treatment with systemic cidofovir appears least costly over a 13-month period.

Proportional means regression for censored medical costs.

The semiparametric proportional means model specifies that the mean function for the cumulative medical cost over time conditional on a set of covariates is equal to an arbitrary baseline mean function multiplied by an exponential regression function. We demonstrate how to estimate the vector-valued regression parameter using possibly censored lifetime costs. The estimator is consistent and asymptotically normal with an easily estimable covariance matrix. Simulation studies show that the proposed methodology is appropriate for practical use. An application to AIDS is provided.

Incremental cost-effectiveness analysis of intravenous ganciclovir versus oral ganciclovir in the maintenance treatment of newly diagnosed cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To evaluate the cost effectiveness of a new product, oral ganciclovir, in comparison to a current therapy, intravenous (i.v.) ganciclovir, in the maintenance treatment of newly diagnosed cytomegalovirus (CMV) retinitis in patients with AIDS. DESIGN: This was a retrospective economic study of a prospective non-blinded randomised clinical trial. The model included i.v. ganciclovir induction, i.v. or oral ganciclovir maintenance and i.v. ganciclovir reinduction for patients whose CMV retinitis progressed. Safety and efficacy data were derived from the trial. A panel of Canadian infectious disease physicians and family physicians estimated the following in relation to i.v. ganciclovir treatment for CMV retinitis and related adverse events: healthcare resource utilisation, clinical practice patterns, patient out-of-pocket expenses and time loss from work. The incremental cost-effectiveness analysis is reported from a societal and a Ministry of Health perspective. SETTING: The trial was conducted in Canada (2 centres) and the US (13 centres) between March 1991 and November 1992. The model assumed that patients received either inpatient or outpatient care, or both. The model provided an analysis in a Canadian setting. PATIENTS AND PARTICIPANTS: Participants were patients with AIDS and newly diagnosed CMV retinitis. INTERVENTIONS: All patients received induction therapy with i.v. ganciclovir 5 mg/kg, twice daily for 14 days then once daily for 7 days. Patients whose CMV retinitis stabilised were randomised to maintenance therapy with either i.v. ganciclovir (5 mg/kg/day; n = 57) or oral ganciclovir (3000 mg/day; n = 60) and were followed for up to 140 days after the start of maintenance therapy. MAIN OUTCOME MEASURES AND RESULTS: The trial demonstrated that the mean time to progression of CMV retinitis was 57 days for oral ganciclovir compared with 62 days for i.v. ganciclovir maintenance therapy, as measured by masked fundus photography, and 96 days with i.v. ganciclovir compared with 68 days with oral ganciclovir according to the funduscopy results. There were more adverse events in the i.v. ganciclovir group compared with the oral ganciclovir group. The cost-effectiveness results provide the dollar amount expended in order to continue to provide additional benefit using i.v. ganciclovir compared with oral ganciclovir. The incremental cost-effectiveness (C/E) ratio was 482 Canadian dollars ($Can: 1993 to 1995 values) per progression-free day gained with i.v. ganciclovir. Sensitivity analysis using funduscopy, rather than fundus photography, to document progression of CMV retinitis resulted in a C/E ratio of $Can42. CONCLUSIONS: This analysis found that i.v. ganciclovir provided additional days free of progression of CMV retinitis when compared with oral ganciclovir, but the costs were higher.

Pharmacoeconomic analysis of 3 treatment strategies for cytomegalovirus retinitis in patients with AIDS.

A decision-analytical simulation model was constructed to perform a pharmacoeconomic analysis of the following 3 treatment strategies for previously untreated cytomegalovirus (CMV) retinitis in patients with AIDS: (i) intravenous foscarnet (IVF) for induction and maintenance therapy; (ii) intravenous ganciclovir (IVG) for induction and maintenance therapy; and (iii) intravenous ganciclovir for induction therapy, followed by oral ganciclovir for maintenance therapy (IVG-ORG). Patients who experienced significant adverse effects during, or who failed, initial therapy were switched once to one of the other 2 treatments. The model was used to estimate the direct medical cost (from the perspective of a public payer), survival, and survival adjusted for disutility because of lost vision, for each strategy in the first year following treatment initiation. The expected first-year costs of treatment initiated with IVF, IVG and IVG-ORG were $US47,918, $US38,817 and $US32,036 (1994 values), respectively, while expected first-year survival was 41 weeks, 35 weeks and 35 weeks, respectively. The incremental cost per incremental year of survival using IVF was $US78,000 versus IVG and $US138,000 versus IVG-ORG before adjustment for lost vision, and $US93,000 versus IVG and $US166,000 versus IVG-ORG after adjustment for lost vision. About 23% of the cost of the IVG treatment strategy was attributable to treatment-related adverse events, compared with 14% of the cost of IVF and 16% of the cost of IVG-ORG. Because of the high failure rate with IVG-ORG, initial treatment with IVG-ORG frequently led to switching to another treatment. Only 27% of the costs associated with the IVG-ORG treatment strategy were in fact attributable to the cost of induction and maintenance therapy prior to a switch to alternative treatment. In this analysis, initial treatment with IVG-ORG was the least costly approach for treating CMV retinitis in patients with AIDS. Initial treatment with IVF resulted in slightly longer survival adjusted for vision-related quality of life. New treatments for AIDS may reduce the survival benefit of initial treatment with IVF.

Cost-utility analysis of prophylactic treatment with oral ganciclovir for cytomegalovirus retinitis.

OBJECTIVE: Cytomegalovirus (CMV) retinitis is a relatively common opportunistic infection in late-stage HIV disease, causing significant morbidity and mortality. Prophylactic use of oral ganciclovir has recently been shown to decrease the incidence of CMV retinitis but is relatively expensive and may not be very well tolerated by many patients. We performed a decision analysis to assess the cost-effectiveness of prophylactic oral ganciclovir therapy. METHODS: A decision analysis using a Markov approach compared absence of prophylaxis and prophylaxis with oral ganciclovir. Estimates of effectiveness of prophylaxis and costs of illness were obtained from published literature. Drug costs were based on national average wholesale prices. All health care costs were based on 1996 U.S. dollars. Sensitivity analyses were done over ranges of estimates of cost and effectiveness. RESULTS: Using our baseline estimates of cost and effectiveness, use of oral ganciclovir prophylaxis in patients with CD4 counts <50 cells/mm3 would be associated with average lifetime health care costs of $104,746, compared with $90,985 for no prophylaxis. Using oral ganciclovir, the average quality-adjusted life-years (QALYs) would be 2.05, and the CMV retinitis-free life-years would be 1.64, compared with 1.87 and 1.27, respectively, for no prophylaxis. The incremental cost-utility of oral ganciclovir is $76,676 per year of life saved and $37,542 per year of additional CMV retinitis-free life. Oral ganciclovir would become more cost-effective relative to no prophylaxis if the probability of CMV retinitis while taking oral ganciclovir declined. Oral ganciclovir would be less cost-effective if the cost of treating CMV retinitis declines, if our estimates of quality of life are low, or if the overall incidence of CMV retinitis declines. CONCLUSIONS: Oral ganciclovir is a less cost-effective approach than several other interventions used for HIV-disease prophylaxis. It would potentially become cost-effective if it is possible to target oral ganciclovir prophylaxis to patients who are most likely to benefit.

Ganciclovir. A pharmacoeconomic review of its use as intravenous or oral maintenance therapy in the management of cytomegalovirus retinitis in patients with AIDS.

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 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 developed for 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 cytomegalo-virus 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 individuals for oral over intravenous maintenance treatment. In conclusion, oral ganciclovir appears to be a cost-saving and patient-preferred 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.

A utility assessment of oral and intravenous ganciclovir for the maintenance treatment of AIDS-related cytomegalovirus retinitis.

The purpose of this study was to determine the magnitude of the difference in patient preference/utility for intravenous (i.v.) ganciclovir compared with oral ganciclovir for maintenance treatment of cytomegalovirus (CMV) retinitis. We used a cross-sectional, interviewer-administered time trade-off (TTO) exercise with hypothetical health state descriptions, based upon data from clinical trials and the published literature. The study was conducted in a private clinic in Sydney Australia, specialising in the care of people with HIV. A total of 80 individuals with HIV infection who had not developed AIDS were administered the TTO instrument. The main outcome measure was the difference between each respondent's utility score for oral and i.v. ganciclovir maintenance therapy. When the 80 HIV-positive patients were presented with information on drug efficacy, adverse effects and mode of administration, 60 (75%) preferred oral ganciclovir, 4 patients preferred i.v. ganciclovir, and 16 were indifferent. The median utilities were 0.837 (oral ganciclovir) and 0.475 (i.v. ganciclovir). The difference in rankings was statistically significant by Wilcoxon's signed-ranks test (Z = -6.69, p < 0.00005). The median utility scores suggest that, all other things being equal, individuals with HIV infection would prefer an oral formulation of ganciclovir to i.v. administration in the event of CMV retinitis infection.

An economic exploration of oral and intravenous ganciclovir in the induction and maintenance treatment of AIDS-related cytomegalovirus retinitis.

The objective of the study was to compare the impact of oral and i.v. ganciclovir on resource use and direct health care costs, from the perspective of the UK National Health Service (NHS). The analytical framework used was cost analysis. The sources of data were an open, randomized clinical trial, and additional research which collected resource use and cost data. From the perspective of the UK NHS, the expected cost of i.v. ganciclovir for initial induction and 140 days maintenance and reinduction therapy was pounds 730 higher than that of oral (pounds 8145 vs pounds 7415). Conservative estimates which did not favour oral ganciclovir were used wherever possible. Overall, the resource use and costs of maintenance therapy with oral ganciclovir calculated in the model used for this study were lower than those of i.v. ganciclovir, principally reflecting lower costs for the administration of therapy. In this model the drug cost of ganciclovir maintenance therapy was excluded.

German health economic cost evaluation on oral ganciclovir in treating cytomegalovirus retinitis.

The purpose of this study was to discuss the cost of oral ganciclovir in comparison with its intravenous formulation in treating CMV retinitis. A cost-cost evaluation was carried out to compare the costs of oral and intravenous treatment with ganciclovir. Costs were calculated by employing the usual prices charged to sickness funds (German social health insurers). The costs of induction and maintenance therapy depend on the period of time the therapy takes, the site of administration (e.g. hospital, physician's office, patient's home) and the charges for the services. Different treatment scenarios were created in order to calculate the costs of the treatment alternatives and in a sensitivity analysis the robustness of the results was tested. Different probabilities for adverse effects were used. The study results showed that total costs of treating CMV retinitis with oral ganciclovir were substantially lower than the costs of intravenous treatment.

An economic evaluation of oral compared with intravenous ganciclovir for maintenance treatment of newly diagnosed cytomegalovirus retinitis in AIDS patients.

This prospective, clinical economic study was done to determine the cost impact of oral compared with intravenous (i.v.) ganciclovir for the maintenance treatment of newly diagnosed cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). Efficacy and safety data were extracted from a trial of oral and i.v. ganciclovir. Medical care utilization and reimbursement data were obtained from the clinical trial, a survey of home care and nursing companies, an 11-member physician panel, and a Medicaid cost database. The primary outcome measures were time to first retinitis progression and associated direct medical care expenditures. Nonmedical costs and quality-of-life benefits were not considered. Based on masked evaluation of retinal photographs, the Kaplan-Meier mean time to first progression was 62 days for i.v. ganciclovir and 57 days for oral ganciclovir (a nonsignificant difference). he expected mean cost of treatment for i.v. ganciclovir was significantly different at $8587.00 compared with $4938.00 for oral treatment. Sensitivity analysis using funduscopically determined mean time to first progression showed similar cost savings. We concluded that oral ganciclovir is a cost-saving alternative to i.v. ganciclovir for the maintenance treatment of AIDS patients with newly diagnosed CMV retinitis. Cost differences are attributable to reduced home care expenditures and lower incidence and costs of treating major adverse events in the oral treatment group.