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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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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Vaccines for the 21st Century: A Tool for Decisionmaking   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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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Vaccines for the 21st Century: A Tool for Decisionmaking   % 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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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Vaccines for the 21st Century: A Tool for Decisionmaking 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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