Herpes Simplex Viruses: Disease Burden. Richard Whitley The University of Alabama at Birmingham Herpes Virus Infection and Immunity June 18-20, 2012

Transcription

1 Herpes Simplex Viruses: Disease Burden Richard Whitley The University of Alabama at Birmingham Herpes Virus Infection and Immunity June 18-20, 2012

2 Mucocutaneous HSV Infections Life-Threatening HSV Diseases

3 Differences Between HSV-1 & HSV-2 Disease HSV-1 HSV-2 Genital Infection Primary 50% 50% Recurrent 10% 90% Nongenital 80-90% 10-20% Labialis Keratitis Whitlow ++ + Encephalitis + - Neonatal Infection -30% -70%

4 Netter FH by Icon Learning Systems. Viral Latency and Reactivation Virus Virus Reactivated Virus Latent Virus Spinal Cord Primary Infection Recurrent Infection

5 Primary Herpes Simplex Infection: Cutaneous Lesions

6 Herpes Simplex Labialis

7 Immunocompromised Host

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9 Spectrum of Clinical Presentation Classical recurrence First infection Atypical recurrence

10 Changes in Weighted Herpes Simplex Virus 2 Seroprevalance in Persons Aged 14 to 49 years between NHANES in and Sample Size NHANES HSV-2 Seroprevalence (95% CI) Sample Size HSV-2 Seroprevalence (95% CI) Change (95% CI) Overall , Age Group JAMA, August 23/30, 2006 Vol 296 No 8 pg 968

11 The Clinical Spectrum of HSV-2 Recognized Infection 10% HSV-2 Seroprevalence 90% Unrecognized and/or Asymptomatic Infection Mertz GJ. Infect Dis Clin North Am. 1993;7:

12 Genital Herpes: Transmission Men Women Transmission Symptomatic Recurrence Asymptomatic Recurrence 30% 70% Corey L. Sex Transm Dis. 1994;21(suppl):S38-S44. Mertz GJ, et al. Ann Intern Med. 1992;116:

13 HSV-1 and Genital Herpes HSV-1 HSV-2 Episodes cannot be distinguished clinically from HSV HSV-1 recurrence rate lower than HSV-2 (1 vs. 5 in the first year) Women Heterosexual men Manavi et al. STD 2004 MSM HSV-1 shedding less frequent than HSV-2

14 Genital Herpes: Viral Shedding Duration is longer in primary than in recurrent episodes Higher rates in People with frequent outbreaks First year after acquisition Primary: 12 days Recurrent: 2-3 days Oral antiviral suppressive therapy shortens the duration of, but does not eliminate, viral shedding Genital Herpes A Clinician s Guide to Diagnosis and Treatment. American Medical Association. 2001:1-20. Whitley RJ, et al. Clin Infect Dis. 1998;26:

15 Age-Adjusted Herpes Simplex Virus Type 2 Seroprevalence According to the Lifetime Number of Sex Partners by Race/Ethnicity and Sex on NHANES in JAMA, August 23/30, 2006 Vol 296 No 8 pg 967

16 Persons living with HIV, 2008 Persons infected with HSV-2, 2003 North America 1.4 million 30 million Caribbean and Latin America 2.24 million 54 million Western & Central Europe 850, million Middle East & North Africa 31, million Sub-Saharan Africa 22.4 million 124 million Eastern Europe & Central Asia 1.5 million 41 million East Asia 850, million South & South-East Asia 3.8 million 131 million Oceania 59, million HIV Total: 33.4 million HSV-2 Total: 536 million HIV: UNAIDS HSV-2: Looker et al., Bull. World Health Org. 86:805

17 Learnings Genital HSV Infections are very common Risk for acquisiton of HIV increases with HSV genital ulcerative infection Latency is not prevented with therapy of primary infection Daily PCR evaulations of genital secretions has taught us much about the nature of infection: recurrent versus chronic

18 Challenges Can person to person transmission be interrupted? Improved Drugs Vaccines Can latency/reactivation be prevented Can the frequency of genital ulcerative disease be decreased? Reduce the probability of HIV acquisition

19 Percentage with Overall acq/hsv-1 seroc. Time to Acquisition of HSV-1 or HSV-2 in Susceptible Partners Placebo (n=741) Valacyclovir (n=743) Time in days

20 Mucocutaneous HSV Infections Life-Threatening HSV Diseases

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22 Herpes Simplex Encephalitis Survival Comparison of survival in patients with biopsy-proved Herpes Simplex Encephalitis Treated with Vidarabine (ARA-A) or Acyclovir (ACV); P=0.008

23 Sensitivity and Specificity of PCR Biopsy Positive Biopsy Negative PCR Positive PCR Negative Sensitivity 98% Specificity 94% Positive Predictive Value 95% Negative Predictive Value 98%

24 Pathogenesis of Neonatal HSV Infection Maternal Genital Herpes Simplex Virus Infection Intrauterine Infection (5%) (transplacental or ascending) Intrapartum Infection (85%) Superficial Replication on Skin or Eye or in Mouth Postnatal Infection (10%) 45% VIREMIA = NEURONAL SPREAD = Disseminated Disease 30% Localized Encephalitis 25% SEM CNS Disseminated

25 Incidence of Neonatal HSV Infection Country Population Incidence USA Seattle, WA 1 in 1,800 USA Birmingham, AL 1 in 2,700 UK National voluntary reporting 1 in 60-70,000 Netherlands National 1 in 35,000 Norway National (CNS only) 1 in 25,000 Sweden Stockholm 1 in 15,000 Japan National 1 in 14-20,000 USA Birmingham, AL ( ) 1 in 1,000

26 Neonatal HSV Disease

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28 Mortality of Neonatal HSV Infections Central Nervous System: 5% Disseminated Disease: 50%

29 Percentage Neonatal Morbidity Among Survivors With Known Outcomes After 12 Months Severe Moderate Mild Normal SEM Disease mg/kg/day CNS Disease Disseminat ed Disease Pediatrics 2001;108:

30 Summary We can decrease morbitity and mortality from life-threatening HSV infections Morbidity remains significant Treatment of women with recurrent gential herpes during last four weeks of gestation did not prevent transmission PCR is the diagnostic of choice for CNS infections Spectrum of disease really does not change

31 Challenges Can we prevent transmission of HSV from mother to baby? Vaccine Delivery room diagnosis and baby prophylaxis Can we improve morbidity and mortality from life threatening HSV infections of the brain with better therapeutic approaches? The conomitant use of antiinflamatories Can we alter chronic CNS replication?

32 Neonatal HSV Encephalitis Bayley Mental Score at 1 Year Acyclovir (N=16) Median = 90.5 Mean= Placebo (N=12) Median = 66.5 Mean= P-value = % 6% 19% 69% 33% 33% >80 (normal development) (mild impairment) (moderate impairment) <59 (severe impairment) 25% 8%

33 Road to the Future Combination therapy with CMX 001 Suppressive therapy with valacyclovir for a longer time Can this disease be prevented Maternal vaccination At delivery PCR and prophylaxis of the newborn