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APPENDIX 4
Cytomegalovirus

DISEASE BURDEN

Epidemiology

For the purposes of the calculations in this report, the committee estimated cases of Cytomegalovirus infection in infants born to infected mothers and in organ-transplant patients in the United States. The committee estimated that there are 40,000 infants born every year with CMV infection and that 2,800 transplant patients acquire CMV infection. The committee assumed 400 deaths annually from the congenitally acquired CMV infection, and 160 deaths from CMV infection in organ transplant patients.

The treatment of HIV infection and AIDS and the effect of those changes in the health status and costs of care experienced by those with HIV has changed rapidly in recent years and is expected to continue to do so. Therefore, the committee has chosen not to include a scenario specific to infection in those with HIV/AIDS. Consideration of this population would result in differences in the calculations achieved with this model, but the uncertainties associated with doing so were thought to be quite extreme.

Disease Scenarios

For the purposes of the calculations in this report, the committee estimated that 90% of congenitally acquired CMV infections are asymptomatic at birth. Of these 36,000 new cases per year, 5,400 infants develop neurologic sequelae, such as deafness. These sequelae are estimated to lead to a health utility index (HUI) of .89 and persist for the duration of that infant’s life. The committee



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Vaccines for the 21st Century: A Tool for Decisionmaking APPENDIX 4 Cytomegalovirus DISEASE BURDEN Epidemiology For the purposes of the calculations in this report, the committee estimated cases of Cytomegalovirus infection in infants born to infected mothers and in organ-transplant patients in the United States. The committee estimated that there are 40,000 infants born every year with CMV infection and that 2,800 transplant patients acquire CMV infection. The committee assumed 400 deaths annually from the congenitally acquired CMV infection, and 160 deaths from CMV infection in organ transplant patients. The treatment of HIV infection and AIDS and the effect of those changes in the health status and costs of care experienced by those with HIV has changed rapidly in recent years and is expected to continue to do so. Therefore, the committee has chosen not to include a scenario specific to infection in those with HIV/AIDS. Consideration of this population would result in differences in the calculations achieved with this model, but the uncertainties associated with doing so were thought to be quite extreme. Disease Scenarios For the purposes of the calculations in this report, the committee estimated that 90% of congenitally acquired CMV infections are asymptomatic at birth. Of these 36,000 new cases per year, 5,400 infants develop neurologic sequelae, such as deafness. These sequelae are estimated to lead to a health utility index (HUI) of .89 and persist for the duration of that infant’s life. The committee

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Vaccines for the 21st Century: A Tool for Decisionmaking estimated that 10% of the 4,000 congenitally acquired cases of CMV that are symptomatic at birth (400 cases annually) lead to death after a brief hospitalization following birth. Of those 3,600 infants who live beyond the initial phase described above, the committee estimated that 90%, or 3,240 infants, experience severe sequelae, and 10%, or 360 infants, experience mild sequelae. These sequelae are life-long. The HUI associated with the mild and severe sequelae were estimated to be .89 and .48, respectively. Those experiencing severe sequelae were estimated to have a reduced lifespan to only 20 years. Table A4–1 illustrates the estimated number of cases in each health state, the duration of time that state is experienced, and the health utility index (HUI) associated with each state. For the purposes of the calculations in this report, the committee estimated that there are 1,200 cases of moderate CMV disease (e.g., pneumonia and gastrointestinal disease) lasting 1 month, and 1,600 cases of severe CMV disease lasting 2 months in organ-transplant recipients each year. The HUI associated with moderate and severe CMV disease was estimated at .91 and .68 (further adjusted to reflect an altered baseline HUI for organ transplant patients compared to the general population). Further, the committee estimated that 10% of organ transplant patients with severe CMV disease die. COST INCURRED BY DISEASE Table A4–2 summarizes the health care costs incurred by cytomegalovirus infections. For the purposes of the calculations used in the report, it was assumed that costs for neurologic sequelae of CMV infection in newborns (whether symptomatic at birth or not) includes regular visits to a specialist for the lifetime of all infected individuals, and special schooling expenses. A small percentage of more severely affected newborns incur costs for hospitalization and long-term care. For infants who are symptomatic at birth, costs for hospitalization, diagnostics, and specialists are included in the calculations. Outpatient follow-up for these patients include several physician visits. For those infants who experience severe sequelae of the CMV infection, costs for 20 years of long-term care are included. The other group of patients with CMV infections assessed in this report are organ transplant recipients. Patients who develop CMV infections incur costs associated with hospitalization, diagnostics, and multiple physician visits.

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A4–1 Disease Scenarios for CMV Infection in Infants   No. of Cases % of Cases Committee HUI Values Duration (years) Asymptomatic at birth 36,000 90.0% 1.00   Asymptomatic at birth: neurologic sequelae 5,400 13.5%     neurologic sequelae (especially deafness) (15% of asymptomatic): for normal lifespan     0.89 26.854 (discounted quality adjusted life expectancy at 6 months) Symptomatic at birth 4,000 10.0%     initial infection (hospitalization)     0.50 0.0384 (14 days) death (10% of symptomatic)   1.0% 0.00   Symptomatic at birth: mild sequelae 360 0.9%     mild sequelae (deaf, blind, mild retardation) (10% of survivors): for normal lifespan     0.89 26.854 (discounted quality adjusted life expectancy at 6 months) Symptomatic at birth: severe sequelae 3,240 8.1%     severe sequelae (severe mental retardation) (90% of survivors): for 20-year period     0.48 20 death by age 20     0.00 23.955 (discounted quality adjusted life expectancy at age 20) VACCINE DEVELOPMENT The committee assumed that the development of a CMV vaccine is feasible and that licensure can occur within 7 years. The estimates for the model are that 360 million needs to be invested. Table 4–1 summarizes vaccine development assumptions for all vaccines considered in this report. VACCINE PROGRAM CONSIDERATIONS Target Population The committee’s model assumes that immunization with this vaccine will occur during puberty. As described in the body of the report, for these purposes that is 12 years of age. Both males and females would receive the immunization.

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A4–2 Health Care Costs for CMV Infection in Infants and Transplant Patients   Duration (years) % with Care Cost per Case Units per Case (or per year) Form of Treatment INFANTS Asymptomatic at birth (no treatment) Asymptomatic at birth: neurologic sequelae   Yearly costs 75.350 10% $225 365 Long-term care (per year) 90% $100 6 Physician B (per year) 10.000 90% $2,000 1 Schooling for moderately deaf ($ per year) Acute care 0.0384 10% $2,500 14 Neonatal intensive care Symptomatic at birth   Initial infection (hospitalization) 0.0384 10% $12,000 1 Hospitalization 90% $7,000 1 Hospitalization 100% $500 4 Diagnosis C 100% $150 14 Physician C Outpatient follow-up 90% $100 2 Physician B

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Vaccines for the 21st Century: A Tool for Decisionmaking Symptomatic at birth: mild sequelae   Mild sequelae (deaf, blind, mild retardation) (10% of survivors): for normal lifespan 75.350       Care for neurologic sequelae   75.350 100% $100 4 Physician B or other (per year) 10.000 10% $8,000 1 Schooling (per year) Symptomatic at birth: severe sequelae   Severe sequelae (severe mental retardation) (90% of survivors): for 20-year period 20.000 100% $225 365 Long-term care (per year) 10.000 10% $8,000 1 Schooling (per year) TRANSPLANT PATIENTS Severe CMV disease   (pneumonia, GI disease) 0.1667 100% $14,000 1 Additional hospitalization 0.1667 100% $500 1 Diagnostic C 0.1667 100% $150 60 Physician C Moderate CMV disease   (pneumonia, GI disease) 0.0833 100% $7,000 1 Additional hospitalization 0.0833 100% $500 1 Diagnostic C 0.0833 100% $150 30 Physician C

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Vaccines for the 21st Century: A Tool for Decisionmaking It is estimated that only 50% of the target population will accept the immunization. Vaccine Schedule, Efficacy, and Costs The committee estimated that this would be a relatively low-cost vaccine, costing $50 per dose. Vaccine administration would cost an additional $10. The committee has accepted default assumptions for this vaccine that it will require a series of 3 doses and that efficacy will be 75%. Table 4–1 summarizes vaccine program assumptions for all vaccines considered in this report. RESULTS If a vaccine program for CMV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the QALYs gained would be 70,000. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the QALYs gained would be 18,000. The vast majority of these QALYs are attributable to the long-term sequelae experienced by infants who acquire congenital-CMV infections. If a vaccine program for CMV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the health care costs saved would be $4 billion. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the health care costs saved would be $1.1 billion. If a vaccine program for CMV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the program cost would be $680 million. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the program cost would be $240 million. Using committee assumptions of time and costs until licensure, the fixed cost of vaccine development has been amortized and is $10.8 million for a CMV vaccine. If a vaccine program were implemented today and the vaccine were 100% efficacious and utilized by 100% of the target population, the annualized present value of the cost per QALY gained is -$50,000. A negative value represents a saving in costs in addition to a saving in QALYs. Using committee assumptions of less-than-ideal utilization and including time and monetary costs until a vac

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Vaccines for the 21st Century: A Tool for Decisionmaking cine program is implemented, the annualized present value of the cost per QALY gained is -$45,000. See Chapters 4 and 5 for details on the methods and assumptions used by the committee for the results reported. READING LIST Demmler GJ. Acquired Cytomegalovirus Infections. In: Textbook of Pediatric Infectious Diseases. RD Feigin and JD Cherry eds. Philadelphia, PA: WB Saunder Company, 1992, pp. 1532–1547. Demmler GJ. Congenital Cytomegalovirus Infection. Seminars in Pediatric Neurology 1994; 1:36–42. Demmler GJ. Summary of a Workshop on Surveillance for Congenital Cytomegalovirus Disease. Reviews of Infectious Diseases 1991; 13:315–29. Demmler GJ. Vaccines for Cytomegalovirus. Seminars in Pediatric Infectious Diseases 1991; 2:186–190. Ho M. Cytomegalovirus. In: Principles and Practice of Infectious Diseases. GL Mandell, JE Bennett, Dolin R eds. New York, NY: Churchill Livingstone, 1995, pp. 1351– 1363. Institute of Medicine. New Vaccines Development: Establishing Priorities, Volume 1. Diseases of Importance in the United States. Washington, DC: National Academy Press, 1985a. Istas AS, Demmler GJ, Dobbins JG, et al. Surveillance for Congenital Cytomegalovirus Disease: A Report from the National Congenital Cytomegalovirus Disease Registry. Clinical Infectious Diseases 1995; 20:665–70. Pass RF. Immunization Strategy for Prevention of Congenital CMV Infection. Infectious Agents and Disease 1996; 5:240–4. Porath A, McNutt RA, Smiley LM, et al. Effectiveness and Cost Benefit of a Proposed Live Cytomegalovirus Vaccine in the Prevention of Congenital Disease. Reviews of Infectious Diseases 1990; 12:31–40. Starr SE. Cytomegalovirus Vaccines: Current Status. Infectious Agents and Disease 1992; 1:146–148. U.S. Bureau of the Census. Statistical Abstract of the U.S.: 1995 (115th edition). Washington, DC, 1995. Ventura SJ, Martin JA, Mathews TJ, et al. Advance Report of Final Natality statistics, 1994. Monthly Vital Statistics Report 1996; 44. Yow MD, Demmler GJ. Congenital Megalovirus Disease—20 Years is Long Enough. New England Journal of Medicine 1992; 326:702–703.

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