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APPENDIX 9
Herpes Simplex Virus
The herpes simplex virus exists as two biologically distinct serotypes, HSV-1 and HSV-2, which differ mainly by their mode of transmission. Initially, the infection caused by either type is a mucocutaneous infection which is followed later by a latent infection of neuronal cells in the dorsal root ganglia.
The spread of HSV- 1 generally occurs by direct contact, usually involving saliva. This strain of herpes typically presents itself in an infection known as herpes gingivostomatitis. Recurrences of this orolabial infection are commonly called fever blisters or cold sores. Other infections associated with HSV-1 include conjunctivitis, keratitis, and herpetic whitlow. A more serious infection, sporadic encephalitis, appears primarily in older children and adults. In some individuals with chronic skin diseases such as eczema, a severe primary HSV-1 infection known as Kaposi’s varicelliform eruption may be encountered.
Acquisition of HSV-2 usually occurs by sexual contact or from a maternal genital infection to a newborn. The most common infection identified with HSV-2 is known as herpes genitalis. HSV-2 is responsible for approximately 85% of symptomatic primary genital HSV infections, most of which are recurrent infections. Some complications associated with genital herpetic infections include aseptic meningitis, extragenital lesions, and neonatal herpes (in the case of maternal transmission).
HSV infection can occur in patients who develop malignancy, an immunodeficiency (i.e., AIDS), or any disease which demands immunosuppressive therapy. The infection may become severe, causing extensive mucocuta-
See Appendix 28 for more information.
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neous necrosis, viremia with dissemination to various organs causing meningoencephalitis, pneumonitis, hepatitis, and coagulopathy.
DISEASE BURDEN
Epidemiology
For the purposes of the calculations in this report, the committee estimated that there are 500,000 new oral infections with HSV each year in the United States. These infections occur in people between 1 and 44 years of age. There are approximately 20,000 new ocular infections with HSV each year. These occur in people between 1 and 84 years of age. There are approximately 1,500 cases of central nervous system infection with HSV each year. The incidence was assumed to be highest in children between 5 and 14 years of age. It was also assumed that there are 300,000 new cases of genital HSV infections occurring primarily in people between 15 and 34 years of age. There are also 1,500 new cases of neonatal HSV infections each year. See Table A9–1.
Disease Scenarios
Oral Infections
For the purposes of the calculation in this report, the committee assumed that the vast majority of symptomatic primary oral infections with HSV last 1 week and are associated with an HUI of .9. 2% of the infections are associated with an HUI of .62. It is assumed that 30% of infections are associated with 10 years of minor recurrences (HUI of .9) lasting 1 week and 5% of infections are associated with 5 years of similar recurrences of a longer period per year.
Ocular Infections
For the purposes of the calculations in this report, it was assumed that all ocular infections are associated with 2 weeks of an acute conjunctivitis, keratitis, or blepharitis (HUI of .9). It is assumed that 30% of infections become chronic and result in an HUI of .9 for two weeks per year for 10 years.
Central Nervous System Infections
For the purposes of the calculations in this report, it was assumed that all CNS HSV infections are associated with a flu-like illness, and that chronic neurologic sequelae of HSV infection occurs in 20% of teenagers and 15% of
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Table A9–1 Incidence and Mortality of HSV Infections
Age Groups
Populations
Incidence Rates (per 100,000)
% Distribution of Cases
Cases
INCIDENCE OF ORAL HSV INFECTIONS
<1
3,963,000
0.00
0.0000
0
1–4
16,219,000
1,541.40
0.5000
250,000
5–14
38,056,000
394.16
0.3000
150,000
15–24
36,263,000
137.88
0.1000
50,000
25–34
41,670,000
60.00
0.0500
25,000
35–44
42,149,000
59.31
0.0500
25,000
45–54
30,224,000
0.00
0.0000
55–64
21,241,000
0.00
0.0000
65–74
18,964,000
0.00
0.0000
75–84
11,088,000
0.00
0.0000
85+
3,598,000
0.00
0.0000
Total
263,435,000
189.80
1.0000
500,000
INCIDENCE OF OCULAR HSV INFECTIONS
<1
3,963,000
0.00
0.0000
0
1–4
16,219,000
6.17
0.0500
1,000
5–14
38,056,000
7.88
0.1500
3,000
15–24
36,263,000
8.27
0.1500
3,000
25–34
41,670,000
7.20
0.1500
3,000
35–44
42,149,000
4.75
0.1000
2,000
45–54
30,224,000
6.62
0.1000
2,000
55–64
21,241,000
9.42
0.1000
2,000
65–74
18,964,000
10.55
0.1000
2,000
75–84
11,088,000
18.04
0.1000
2,000
85+
3,598,000
0.00
0.0000
0
Total
263,435,000
7.59
1.0000
20,000
INCIDENCEE OF HSV CNS INFECTION
<1
3,963,000
0.00
0.0000
1–4
16,219,000
0.00
0.0000
5–14
38,056,000
1.97
0.5000
750
15–24
36,263,000
0.00
0.0000
25–34
41,670,000
0.00
0.0000
35–44
42,149,000
0.00
0.0000
45–54
30,224,000
0.62
0.1250
188
55–64
21,241,000
0.88
0.1250
188
65–74
18,964,000
0.99
0.1250
188
75–84
11,088,000
1.69
0.1250
188
85+
3,598,000
0.00
0.0000
Total
263,435,000
0.57
1.0000
1,500
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Age Groups
Populations
Incidence Rates (per 100,000)
% Distribution of Cases
Cases
MORTALITY ASSOCIATED WITH HSV CNS INFECTION
<1
3,963,000
0.00
0.0000
1–4
16,219,000
0.00
0.0000
5–14
38,056,000
0.39
0.2222
150
15–24
36,263,000
0.00
0.0000
25–34
41,670,000
0.00
0.0000
35–44
42,149,000
0.00
0.0000
45–54
30,224,000
0.43
0.1944
131
55–64
21,241,000
0.62
0.1944
131
65–74
18,964,000
0.69
0.1944
131
75–84
11,088,000
1.18
0.1944
131
85+
3,598,000
0.00
0.0000
Total
263,435,000
0.26
1.0000
675
INCIDENCE OF GENITAL HSV INFECTION
<1
3,963,000
0.00
0.0000
1–4
16,219,000
0.00
0.0000
5–14
38,056,000
0.00
0.0000
15–24
36,263,000
275.76
0.3333
100,000
25–34
41,670,000
479.96
0.6667
200,000
35–44
42,149,000
0.00
0.0000
45–54
30,224,000
0.00
0.0000
55–64
21,241,000
0.00
0.0000
65–74
18,964,000
0.00
0.0000
75–84
11,088,000
0.00
0.0000
85+
3,598,000
0.00
0.0000
Total
263,435,000
113.88
1.0000
300,000
adults who experience the acute CNS disease. This chronic condition is assumed to be associated with an HUI of .19 for the duration of the person’s life.
Genital Infections
For the purposes of the calculations in this report, it was assumed that 100% of genital HSV infections are associated with a 2-week period at an HUI of .81 (genital lesions, fever, pain). It is assumed that 90% of infections lead to 10 years of minor recurrences; 10% of infections are associated with 5 years of more severe recurrences.
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Neonatal Infections
For the purposes of the calculations in this report, it was assumed that 33% of neonatal HSV infections result in acute encephalitis and the other 67% result in serious non-CNS disease. It is assumed that 200 cases of neonatal HSV infection are associated with very severe, chronic neurologic sequelae (an HUI of .19 for approximately 20 years until premature death). See Tables A9–1 and A9–2.
COST INCURRED BY DISEASE
Table A9–3 summarizes the health care costs incurred by HSV infections.
Oral and Ocular Infections
For the purposes of the calculation in this report, it was assumed that oral and ocular infections with HSV are associated with costs for medication (over-the-counter and more expensive prescription medications, depending on severity), and physician visits (general or specialists, depending on the severity). A very few cases of severe infections are associated with brief hospitalization.
Central Nervous System Infections
For the purposes of the calculations in this report, it was assumed that all CNS infections are associated with hospitalization and multiple specialist examinations, plus diagnostic evaluation. Long-term-care costs are included for the few patients who experience lifelong, serious neurologic sequelae.
Genital Infections
For the purposes of the calculations in this report, it was assumed that genital HSV infections are associated with outpatient treatment consisting of physician visits, occasional diagnostic evaluation, and medication. The frequency of physician visits increases with the severity of the recurrences.
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Table A9–2 Disease Scenarios for HSV Infection
No. of Cases
% of Cases
Committee HUI Values
Duration (years)
ORAL
asymptomatic primary infection
80%
symptomatic primary infection
490,000
98.0%
gingivostomatitis, pharyngitis, fever
0.90
0.0192 (1 week)
severe primary infection
2.0%
gingivostomatitis, pharyngitis, fever
10,000
0.62
0.0192 (1 week)
minor recurrences
150,000
30.0%
0.90
0.0192 (1 week)
serious recurrences
25,000
5.0%
0.90
0.0384
OCULAR
Primary infection
20,000
100.0%
blepharitis, conjunctivitis, keratitis
0.90
0.0384 (2 weeks)
Recurrences
6,000
30.0%
0.90
0.0384 (2 weeks)
CNS (ENCEPHALITIS, MENINGITIS)
Acute infection
1,500
100.0%
flu-like symptoms, CNS disturbance
0.19
0.0833 (1 month)
Chronic neurologic sequelae—children/teenagers
300
20.0%
severe neurologic impairment for 20-year period
0.19
20.0000 (20 years)
death after 20 years impairment
0.00
2 1.7793 (discounted quality adjusted life expectancy at age 30)
Chronic neurologic sequelae—adults
225
15.0%
severe neurologic impairment for 10-year period
0.19
10.0000 (10 years)
death after 10 years impairment
0.00
8.5536 (discounted quality adjusted life expectancy at age 70)
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No. of Cases
% of Cases
Committee HUI Values
Duration (years)
GENITAL
Acute symptomatic infection
300,000
100.0%
genital lesions, pain, fever
0.81
0.0384 (2 weeks)
Minor recurrence
270,000
90.0%
0.95
0.0384 (2 weeks)
Serious recurrence
30,000
10.0%
NEONATAL HSV
Acute non-encephalitis
1,000
66.7%
0.24
0.0833 (1 month)
Acute encephalitis
500
33.3%
0.24
0.0833 (1 month)
Chronic neurologic sequelae
200
13.3%
severe neurologic impairment for 20-year period
0.19
20.0000 (20 years)
death after 20 years impairment
0.00
47.0252 (discounted quality adjusted life expectancy at age 20)
Neonatal Infections
For the purposes of the calculations in this report, it was assumed that all neonates infected with HSV require hospitalization. It was assumed that hospitalization costs for encephalitis are higher than for the non-encephalitic manifestations. Additional costs related to labor and delivery of the neonate are included. Long-term-care costs are included for the few patients who experience lifelong serious neurologic sequelae from neonatal infections.
VACCINE DEVELOPMENT
The committee assumed that it will take 7 years until licensure of a HSV vaccine and that $240 million needs to be invested. Table 4–1 summarizes vaccine development assumptions for all vaccines considered in this report.
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Table A9–3 Health Care Costs Associated with HSV Infection
% of Cases
% with Care
Cost per Unit
Units per Case
Form of Treatment
ORAL
Symptomatic primary infection
98.0%
gingivostomatitis, pharyngitis, fever
100%
$10
1.0
medication a
10%
$50
1.0
physician a
Severe primary infection
2.0%
gingivostomatitis, pharyngitis, fever
10%
$3,000
1.0
hospitalization
100%
$100
1.0
physician b
100%
$50
1.0
medication b
100%
$50
1.0
diagnostic a
Minor recurrences
30.0%
100%
$50
1.0
physician a
100%
$50
1.0
medication b
Serious recurrences
5.0%
100%
$50
2.0
physician a
100%
$50
2.0
medication b
OCULAR
Primary infection
100.0%
blepharitis, conjunctivitis, keratitis
100%
$50
1.0
medication a
100%
$50
1.0
physician a
Recurrences
30.0%
30% of primary cases 1 per year for 10 years
100%
$50
1.0
medication a
25%
$50
1.0
physician a
CNS
Acute infection
100.0%
flu-like symptoms, CNS disturbance
100%
$6,000
1.0
hospitalization
100%
$1,500
15.0
physician c
100%
$500
2.0
diagnostics c
Chronic neurologic sequelae—children/teenagers
20.0%
severe neurologic impairment for 20 year period
100%
$225
365.0
Institutional care (per year)
Chronic neurologic sequelae—adults
15.0%
severe neurologic impairment for 10 year period
100%
$225
365.0
Institutional care (per year)
GENITAL
Acute symptomatic infection
100.0%
genital lesions, pain, fever
100%
50%
1.0
physician a
100%
$50
1.0
medication b
50%
$50
1.0
diagnostic a
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% of Cases
% with Care
Cost per Unit
Units per Case
Form of Treatment
Minor recurrence
90.0%
100%
$50
1.0
physician a (per year)
100%
$50
1.0
medication b (per year)
Serious recurrence
10.0%
100%
$50
4.0
physician a
100%
$50
4.0
medication b
NEONATAL HSV
Acute non-encephalitis
66.7%
100%
$7,000
1.0
hospitalization
100%
$150
28
physician b
100%
$500
4.0
diagnostic c
100%
$1,000
1
additional delivery costs
Acute encephalitis
33.3%
100%
$12,000
1.0
hospitalization
100%
150
28.0
physician c
100%
$500
4.0
diagnostic c
100%
$1,000
1.0
additional delivery costs
Chronic neurologic sequelae
13.3%
100%
$225
365.0
Institutional care (per year)
VACCINE PROGRAM CONSIDERATIONS
Target Population
For the purposes of the calculations in this report, it is assumed that the target population for this vaccine is all adolescents (age 12 years). It was assumed that 50% of the target population would utilize the vaccine.
Vaccine Schedule, Efficacy, and Costs
For the purposes of the calculations in this report, it was estimated that this vaccine would cost $50 per dose and that administration costs would be $10 per dose. Default assumptions of a 3-dose series and 75% efficacy were accepted. Table 4–1 summarizes vaccine program assumptions for all vaccines considered in this report.
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RESULTS
If a vaccine program for HSV 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 28,000. 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 7,500. Most of the disease burden is associated with genital and CNS infections due to the large number of genital infections and the serious, chronic sequelae associated with the relatively fewer cases of CNS HSV disease.
If a vaccine program for HSV 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 $850 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 health care costs saved would be $225 million.
If a vaccine program for HSV 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 $7.2 million for a HSV 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 -$6,000. 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 vaccine program is implemented, the annualized present value of the cost per QALY gained is $3,000.
See Chapters 4 and 5 for details on the methods and assumptions used by the committee for the results reported.
READING LIST
Hirsch MS. Herpes Simplex Virus. In: Principles and Practice of Infectious Diseases. GL Mandell, JE Bennett, Dolin R eds. New York, NY: Churchill Livingstone, 1995, pp. 1336–1345.
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Institute of Medicine. New Vaccines Development: Establishing Priorities, Volume 1. Diseases of Importance in the United States. Washington, DC: National Academy Press, 1985a.
Koelle DM, Benedetti J, Langenberg A, et al. Asymptomatic Reactivation of Herpes Simplex Virus in Women after the First Episode of Genital Herpes. Annals of Internal Medicine 1992; 116:433–437.
Kohl S. Postnatal Herpes Simplex Virus Infection. In: Textbook of Pediatric Infectious Diseases. RD Feigin and JD Cherry eds. Philadelphia, PA: WB Saunder Company, 1992, pp. 1558–1583.
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.
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