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Herpes Simplex Virus

Herpes Simplex Virus. Reproductive Infectious Disease Seminars November 9, 2004 Natali Aziz, MD, MS Reproductive Infectious Disease and Maternal-Fetal Medicine Fellow Department of Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco. Microbiology

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Herpes Simplex Virus

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  1. Herpes Simplex Virus Reproductive Infectious Disease Seminars November 9, 2004 Natali Aziz, MD, MS Reproductive Infectious Disease and Maternal-Fetal Medicine Fellow Department of Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco

  2. Microbiology Pathogenesis Virulence Epidemiology Clinical Manifestations Diagnosis Treatment/Prophylaxis Pregnancy Considerations Suppression Serologic Testing Delivery Route: C/S vs. VD Prevention of Transmission Condoms ARV’s HIV-1 Association Vaccines/Immune Modulation Overview

  3. Microbiology • Double-stranded linear DNA enveloped virus • Member of Herpesviridae family • Alpha-herpesvirus subfamily • HSV-1 and 2,VZV • Beta-herpesvirus subfamily • CMV, HHV6, HHV7 • Gamma-herpesvirus subfamily • EBV, HHV8 (KS) http://biology.kenyon.edu

  4. Microbiology • Herpesvirus • Icosahedral capsid containing dS DNA viral structure • Capsids: 162 capsomers • Additional layer of surrounding protein (tegument) • Outer membrane envelope with spike-like glycoproteins http://access.ncsa..uiuc.edu JC Brown, Un Virginia

  5. Microbiology • HSV-1 and HSV-2 • Reproduce in epithelial cells • Alpha-herpesvirus: rapid cycle/code immediate early proteins • Neurotropic: infect sensory nerve fibers • Lyse epithelial cells • Enter body through break in mucous membrane integrity • Latent in neural tissue at site of regional ganglions

  6. Pathogenesis • Inoculation of virus onto mucosal surface • Focal necrosis and ballooning degeneration of cells  multi-nucleated giant cells and eosinophilic intranuclear inclusions • HSV ascends periphery sensory nerves • Enters nerve root ganglia  latency • Intermittent reactivation • Emotional stress, trauma, cold, sunlight, fatigue, fever, and menstrual cycle • HSV-1 15-20% reactivation • HSV-2 variable reactivation http://tray.dermatology.uiowa.edu

  7. HSV-1 HSV-2 Pathogenesis Trigeminal Nerve Sacral Nerves ***HSV-1 reactivates from latency less frequently in sacral ganglia than HSV-2. (Griffiths, RMV 2000; Lafferty, NEJM 1987)

  8. Virulence • Us3 and gJ proteins • Anti-apoptotic properties and cytotoxic T-lymphocytes (CTL) resistance • Blocks loading of peptide onto MHC I to blunt CTL effect • Virion host shutoff (VHS) protein • Interferes with alpha/beta-interferon mediated antiviral response • UL33 protein • Ocular infection • ICP34.5 protein • Allows replication in neurons http://www.universitario.com.br

  9. Epidemiology- US • Most prevalent viral STI • One of 3 most prevalent STI’s • Estimated 45 M adults with genital herpes • Estimated 50 M with oral herpes • 500,000- 1M new cases of HSV-2 diagnosed annually • HSV-2: 30% increase since 1970’s • HSV-1 seroprevalence: 60-95% (80%) • HSV-2 seroprevalence: 20-25% Diagnology, 2001 Fleming 1997; ASHA, 1997; Cunningham and Mikloska, 2001; Whitley 2001.

  10. Epidemiology- HSV-2Worldwide *Estimated that 80% of adult population infected with HSV-1 or HSV-2. (Ballard, 2001)

  11. Age Female gender (6X) Ethnicity (Af. Am. 4x, Hispanic) Serologic status Condom use (50% reduction) Number of sexual partners Frequency of sexual contacts (3-5 yrs, 18X) Duration of HSV-2 in source partner HIV infection Prior STI (3X) Epidemiology- Risk Factors http://www-micro.msb.le.ac.uk

  12. HSV-2 Prevalence by Sexual Partners, United States, NHANES III, 1988-1994 Fleming et al, NEJM, 1997

  13. Epidemiology of Perinatal HSV • Risk of Vertical Transmission • If woman HSV-2 IgG positive  <1% transmission • 1º infection in pregnancy  44% transmission • Timing of Infection • 5% intrauterine; 95% intrapartum Prober 1987; Chuang 1988; Baldwin 1989; Brown 1997

  14. HSV Sero-Incidence in Pregnancy • Seattle-Tacoma, 1989-93 • Serologic testing: initial visit, 16-24w & labor • 1.3% (94/7046) HSV seroconversion during pregnancy • HSV-1/2 neg 3.7% conversion for either • 13% conversion if HSV-2+ male partner • HSV-1 pos 1.7% conversion for HSV-2 • HSV-2 pos 0% conversion for HSV-1 • Conversions: • 30% in 1st 30% in 2nd 40% in 3rd • 36% of converters with symptoms Brown 1997

  15. Neonatal HSV in California • Review of discharge and death data • State of CA, 1985-1995 • ICD-9 diagnoses of HSV • Babies < 42 days Gutierrez, JID 1999

  16. Neonatal HSV in California 1985 19901995 Live births 470,816 611,666 551,226 # Neonatal HSV 55 69 63 NHSV/100,000 11.7 11.3 11.4 NHSV per live births = 1 / 8700 Gutierrez, JID 1999

  17. Neonatal HSV in Cincinnati • Jan. 1992 – December 1996 • Retrospective, population-based study • Hamilton County, Ohio • All cases of neonatal HSV in live infants 1992199419961992-1996 Cases/100,000 28 70 121 346 Stanberry, 1998

  18. Neonatal herpes Seattle, 1984-1989 • Prospective cohort • 15,923 asymptomatic women in labor • Results: • 56 (0.35%) HSV culture positive • 4 lost to follow-up Primary HSVRecurrent HSVHSV(-) 18 34 15,867 Neonatal HSV 6 (33%) 1 (3%) 3 (.02%) ** 10 NHSV cases/ 15,923 women = 1 / 1592 births ** Brown 1991

  19. Perinatal HSV EpidemiologySeattle group, JAMA 1/8/03 • Prospective cohort 1/82-12/99 • Specimen collection @ delivery • Vulvar/perineal viral cx • Upper vagina/cervical viral cx • Cx of lesion, if present • Maternal serology for HSV-1/2 Brown 2003

  20. Perinatal HSV Epidemiology • Neonatal HSV: 18/58,362 (0.03%) = 3/10,000 • NHSV by maternal shedding @ delivery • 10/18 (56%) with pos maternal cx • 6/18 (33%) with neg maternal cx • Type of HSV acquired • 8/18 (44%) HSV-1 • 4/8 (50%) maternal primary HSV-1* • 4/8 (50%) maternal recurrent HSV-1 • 10/18 (56%) HSV-2 • 7/10 (70%) 1° or non- prim 1st episode* • 3/10 (30%) recurrent HSV-2 * Numbers differ in different parts of text. Brown 2003

  21. Transmission by maternal status at time of delivery • Primary infection @ delivery: 9/58,362 = 1.5/10,000 • HSV-1: 3/9 (33%) vs. HSV-2: 6/9 (67%) • Non-1°/1st HSV-2: 16/58,362 = 2.7/10,000 • Recurrent infection @ delivery: 151/58,362 = 25.9/10,000 • HSV-1: 11/151 (7.3%) vs. HSV-2: 140/151 (92.7%) Brown 2003

  22. Summary Incidence Neonatal HSV per live births California, 1985-1995 1/8700 Cincinnati, 1992-1996 1/1445 Seattle, 1982-1999 1/3333

  23. Oral lesions Herpes labialis, gingivostomatitis, esophogitis Genital infections Vulvar/penile ulcers, cervicitis, urethritis, proctitis Clinical Manifestations

  24. Meningitis Encephalitis Urinary bladder retention Cutaneous lesions Autonomic NS dysfunction Pneumonitis Ocular lesions Hepatitis, EM, Myelitis Neonatal infections Clinical Manifestations www.medinfo.ufl.edu http://eyemicrobiology.upmc.com

  25. Clinical Course • Natural History • Primary • Non-primary, first episode • Secondary • Neonatal herpes syndrome

  26. Natural History • Primary Infection • Untreated lesions present for 19.7 days • Viral shedding for 11.8 days • IgM Ab’s appear 3-4 wks after 1º infxn • 1st episode/Non-Primary Infection • Lesions for 15.5 days • Shedding for 6.8 days • Recurrent Infection • Lesions for 9.3 days • Shedding for 3.9 day

  27. Neonatal Manifestations • Neonatal risks • Disseminated HSV infection • 60% mortality • Localized encephalitis • 14% mortality • Dermatologic, Ocular, and Oral infections • 0% mortality • 18.3% neonatal death • 15.4% severe neurologic impairment • 10.1% moderate neurologic impairment • 56.2% normal neonates

  28. Diagnosis • Herpes culture • High specificity • Range of sensitivity • Depending on age of lesion • Allows direct fluorescent antibody (DFA) typing-HSV-1 vs. HSV-2 • PCR • High sensitivity and specificity • Not clinically available • Serology • Type-specific assays for HSV-1 & HSV-2 IgG

  29. Serological Testing • U.W. HSV-1 and HSV-2 Western blot • Focus Technologies HSV-1/HSV-2 immunoblot • Focus Technologies HSV-1 and HSV-2 IgG EIA • 96-100% sensitive, 95-98% specific • Diagnology POCkit rapid HSV-2 test • 93-96% sensitive, 95-98% specific Ashley, STI 2001; Turner, STD 2002

  30. Treatment(Immunocompetent Non-pregnant Adults)

  31. Treatment in Pregnancy • Primary infection • Acyclovir 400mg tid x 7-10d • Valacyclovir 1 gm bid x 5-10 d • Better bioavailability than ACV • Limited studies in pregnancy • Avoid if HIV+ (possible risk of TTP ) • Not indicated if concerned about ACV-resistant HSV (thymidine kinase absent/deficient/altered) b/c same active metabolite • Recurrent infection • Acyclovir 400mg tid x 5-7d • Valacyclovir 500mg bid x 3-7d

  32. Antiviral Suppressive Therapy and Pregnancy • Effectiveness of acyclovir therapy in pregnant women starting at 36 weeks gestation with a 1st episode genital HSV during pregnancy • N=46 women ACV (n=21)Placebo (n=25) Herpes at delivery 0 9 (36%) C-section 0 9 (36%) NHSV 0 0 Scott, Ob Gyn 1996

  33. Acyclovir Suppression in Pregnancy • Acyclovir suppression in 3rd trimester • 400mg po tid (accounting for volume distribution, as ACV widely distributed to tissues/body fluids) •  clinical recurrences in 3rd trimester • OR 0.10 (0-0.86) • Systematic Review (Sheffield, et al, 2003): • Reduction in clinical recurrenceat delivery OR 0.25 (0.15-0.40) • Reduction in C/S for recurrent HSV OR 0.30 (0.13-0.67) • Reduction in total HSV detection at delivery OR 0.11 (0.04-0.31) • Reduction in asymptomatic HSV shedding at delivery OR 0.09 (0.02-0.39) • More cost-effective than c/s for recurrent lesion in labor Randolph 1996; Watts 2001; Scott 2002; Sheffield 2003

  34. Acyclovir Safety in Pregnancy • June 1984-April 1999, 1244 infants exposed to ACV during pregnancy in GSK database • 28/1244 (2.2%) birth defects • 19/756 (2.5%) 1st trimester • 2/197 (1.0%) 2nd trimester • 7/291 (2.4%) 3rd trimester • 2-3% in general population • In women, low risk of nephrotoxicity • Category B • safe in animals, no controlled studies in women

  35. Valacyclovir Suppression in Pregnancy • Phase I trial: PK of valacyclovir and acyclovir in late pregnancy • 20 gravid women with h/o recurrent genital HSV randomized at 36 weeks to oral valacyclovir 500 mg bid or acyclovir 400 mg tid. • ACV PK profiles at 36 (initial dose) and 38 (steady state) weeks • AF samples, cord blood, maternal serum at delivery • Kimberlin, Am J Ob Gyn 1998

  36. Valacyclovir Suppression in Pregnancy • *P<0.0001; **P<0.001; + P<0.001; ++P=0.009 • Kimberlin, Am J Ob Gyn 1998

  37. Serological Testing in Pregnant Women • Brown, Ashley, Corey et al, 1997—”Serologic testing for HSV in the latter half of pregnancy could identify women who are susceptible to HSV infection, so that serologic testing of their partners and appropriate counseling as to the risk of acquiring genital herpes could be undertaken” • ACOG, 1999—None • AMA, July 2001—”Routine screening of pregnant women with known infected partners may be considered to identify women who are at high risk for acquiring genital herpes during pregnancy”

  38. Serologic HSV Testing in Pregnancy • Elements of cost-effective strategy • Neonatal HSV needs to be sufficiently morbid and prevalent • HSV-susceptibility needs to be sufficiently prevalent • Testing needs to be sensitive, specific, cheap, and feasible for pt and partner • HSV-2 vs. HSV-1/2 testing? • Need an effective intervention • No oral-genital or genital-genital contact • Throughout pregnancy? Near term? If sxs? • Use condoms • ACV for HSV+ partner?

  39. ACOG Recommendations (Guidelines for Perinatal Care, 4th Edition, 1997; Practice Bulletin, October, 1999) • Question women about a hx of genital HSV • Perform a careful perineal exam in labor • Perform C/S if primary HSV lesions in labor • Expedite C/S if vaginal delivery not imminent • Avoid scalp monitors and sampling • Perform C/S if recurrent HSV lesions or prodromal sxs at delivery

  40. BMJ Clinical Evidence Recommendations • “Insufficient evidence for the effect of abdominal delivery on the risk of neonatal herpes. The procedure carries the risk of increased maternal morbidity and mortality.” Wald 2001

  41. Delivery Route and Transmission • “Perhaps the most clinically important observation from our study was the finding that cesarean delivery protects against neonatal transmission of HSV.” • Neonatal HSV by delivery route (n=202) • 1/85 (1.2%) if C/S • 9/117 (7.7%) if vaginal delivery • p-value=0.047 • Bivariate analysisaOR 0.14 (0.02-1.26) • No multivariate analysis b/c too few outcomes!! Brown 2003

  42. HSV and Delivery Route • Transmission and C-Section • 20-30% of infected neonates born by c/s • 8% infected neonates born by c/s with intact membranes • C/S for 1º HSV lesion in labor • 9-26 excess C/S per poor outcome averted • Save $38,758/case averted; $2,640/QALY gained • C/S for recurrent HSV in labor • 1580 excess C/S per poor outcome averted • $2.5 million/case averted; $203,000/QALY gained • 2.3 maternal deaths/poor neonatal outcome averted • If transmission 0.25%-20% Stone 1989; Randolph 1993

  43. Vaginal Delivery and Active Genital HSV • In the Netherlands, women with recurrent genital HSV at delivery have been delivered vaginally since 1987 • No increase of neonatal herpes • 1981-1986 26 cases • 1987-1991 19 cases Smith, BJOG1998

  44. Delivery Route Considerations • No trials demonstrating protective effect of C/S for primary or secondary! • Cost-effectiveness analyses suggest benefit outweighs harm if 1° infection • Cost-effectiveness analyses suggest harm outweighs benefit if recurrent infection

  45. Prevention with Condoms • 267 HSV-2 susceptible women in serodiscordant monogamous relationships • Followed for 18 months • 26 (9.7%) women seroconverted • Condom use protective • > 25% use HR 0.085 (0.011-0.67) Wald, JAMA 2001

  46. Valacyclovir in Discordant Couples • 1484 immunocompetent, heterosexual, monogamous couples discordant for HSV-2 • Partners with HSV-2 randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months • Susceptible partner evaluated monthly for clinical signs and symptoms of genital herpes Corey, NEJM 2004

  47. Valacyclovir in Discordant Couples *hazard ratio, 0.25; 95 % confidence interval, 0.08 to 0.75; P=0.008; # hazard ratio, 0.52; 95 % confidence interval, 0.27 to 0.99; P=0.04; + P<0.001 Corey, NEJM 2004

  48. HSV and HIV • HSV-2 Ab + • 75% HIV+ pregnant women • 32% HIV- controls • Recurrent HSV in labor • 8% HIV+ women • 2% HIV- women • Genital shedding of HIV with HSV lesion Hitti, 1997

  49. HSV and HIV • Clinical and subclinical HSV-2 reactivation 2-4x higher in HIV positive persons • Data suggesting biological interaction between two viruses may result in more efficient transmission of HIV-1 • High levels of HIV-1 virions shed through herpetic ulcerative lesions; HSV-2 individual more likely to transmit HIV-1 • Schacker, et al JAMA 1998 • Estimated risk of HSV-2 infection for HIV-1 acquisition 3.9 (95% CI, 3.1-5.1) • Wald, et al JID 2002

  50. Vaccines • Prophylactic and therapeutic goals • Chiron gB2/gD2: poor efficacy in clinical trial • Outcome: time to HSV-2 infection • GSK gD2 MPL: ?partial success in 2 clinical trials • Outcome: genital herpes • Prevented clinical genital herpes disease in HSV negative women • Not significant in preventing disease in men or HSV-1 seropositive women • Trend towards lower rate of infection in women (P=0.06, 0.07) Sacks, AVR 2004

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