HERPES SIMPLEX


See also "Herpes Simplex in Infants"

I. General issues

  1. HSV is a dsDNS enveloped icosohedral virus
  2. Two strains, HSV-1 and HSV-2; antibodies formed against either can to some degree inhibit the other
  3. HSV-1 is commonly acquired in childhood and tends to cause nongenital manifestations, e.g. orolabial (see below) though can cause genital herpes; only 10% of primary infections are overt
  4. HSV-2 is commonly acquired in adulthood and tends to case genital herpes (see below) though can cause nongenital manifestations; seroprevalence is much greater than prevalence of clinical genital herpes
  5. Primary infection is often followed by periodic recurrences ("outbreaks")
  6. Diagnosis
    1. Culture--less sensitive in recurrent than in primary disease
    2. Direct fluorescent Ab on ulcer material

II. Genital Herpes Simplex

  1. Clinical features
    1. Vesicles that rupture and subsequently appear as shallow ulcers, on vulva, vagina, and/or cervix
    2. Inguinal lymphadenopathy is common
    3. Systemic sx (malaise, myalgia, fever) may occur in primary infection
  1. Transmission
    1. Requires direct genital-to-genital contact or contact of genital tract with an area infected with HSV, e.g. oral-genital contact
    2. Risk of acquiring genital HSV-2 is less if already seropositive for HSV-1.
    3. Subclinical cervical and vulvar shedding occurs in 2.3% of women with HSV-2 and 0.65% in women with HSV-1
    4. In a study of 53 HSV-2-seropositive adults w/o any known h/o genital herpes outbreaks, who did self-collection of genital and perianal samples, 36 of them had positive HSV viral culture (w/o any genital lesions) on at least one day; rate was similar to a comparison cohort of 90 pts with positive HSV-2 serology and a history of genital herpes outbreaks ( (NEJM 342:844, 2000--AFP)
    5. Most of the transmission occurs when there are no active lesions
    6. 1484 pts with genital HSV-2 in monogamous heterosexual relationships with a seronegative partner randomized to Valacyclovir 500mg QD vs. placebo; over 8mos, acquisition of HSV-2 infection (by serology) by the partners was seen in 3.6% of placebo group and 1.9% of valacyclovir group (NEJM 350:11, 2004--JW)
  1. Primary genital HSV (no Ab to either HSV-1 or HSV-2 at time of infection)--may be asymptomatic; if symptomatic, tends to be more severe than recurrent and may be accompanied by systemic sx--see above--but otherwise hard to distinguish
    1. Treatment--7-14d of either:
      1. Valacyclovir 1g BID
      2. Acyclovir 200mg 5x/d or 400mg TID
      3. Famcyclovir 250mg TID
  1. Nonprimary first-episode genital HSV (Ab are present but not to the strain of HSV causing the episode)--clinically indistinct from recurrent
  1. Recurrent genital HSV (Ab are present to the strain of HSV causing the episode)
    1. Natural Hx
      1. May follow asymptomatic primary HSV (NEJM 341:1432, 1999--JW)
      2. 75% of one cohort of pts with genital HSV had gradual decrease in recurrence rate over a 5y f/u period (Ann. Int. Med. 131:14, 1999--JW)
    2. Treatment
      1. 1200 pts w/HSV outbreaks randomized to acyclovir 200mg 5x/d vs. Valacyclovir 1g BID vs. placebo. No sig. diff. between the 2 regimens in clinical response though both were better than placebo at decreasing the duration of visible lesions, pain, and viral shedding (Arch. Derm. 134:185, 1998--AFP)]
      2. Other common regimens--5d of Acyclovir 400mg TID; Valacyclovir 500mg BID; Famcyclovir 125 BID
      3. Shorter courses may be equally effective
        1. Acyclovir 800mg TID x 2d in a randomized trial in 84 adults with frequent recurrences of genital HSV was sig. more effective than placebo (Clin. Inf. Dis. 34:944, 2002--JW)
        2. Shortened courses of antivirals (Valacyclovir 500mg BID x 3d vs. 5d) werw ass'd with no sig. diff. in # of aborted episodes, duration of pain, or time to lesion healing in a randomized trial of 800 pts with recurrent genital HSV (Clin. Inf. Dis. 34:958, 2002--JW)
    3. Suppression
  1. Acyclovir 400mg BID is most commonly used
  2. Famcyclovir 250 BID is probably best famcyclovir regimen for prevention of recurrences of genital HSV (Arch. Int. Med 157:343, 1997-JW; f/u was 3mos)
  3. Valacyclovir 250mg BID or 1g QD had efficacy at reducing risk of recurrences similar to Acyclovir 400mg BID in a 1y randomized trial of 1,479 pts.; Valacyclovir 250mg QD or 500mg QD had slightly lower efficacies (J. Inf. Dis. 178:603, 1998--JW)

III. Orolabial Herpes Simplex

  1. Primary infection is often more severe than recurrences
  2. Recurrences usually last 5-6d
  3. Treatment of recurrent oral/labial herpes:
    1. Acyclovir (Zovirax) 5% ointment 5x/d x 5d
      1. Available in a combined formulation with hydrocortisone 1% (Xerese) for use in pts > 12yo
      2. Use associated with slight reductions in likelihood of developing ulcerated lesion, and in time to healing compared with placebo.
    2. Penciclovir 1% cream (a metabolite of famciclovir) starting at first sign/sx of outbreak and repeating Q2h while awake x 4d showed healing about 1 day sooner than users of placebo (e.g. 4 rather than 5d) in 2 randomized trials. No head-head trials vs. other antiherpetics (JAMA 277:1374, 1997-JW; Med. Letter 39:57, 1997)
    3. Docosanol 10% cream (Abreva) 5x/d for max 10d (reduced time to healing by about 0.5d c/w placebo in one randomized trial (J. Am. Acad. Derm. 45:222, 2001--JW)
    4. Tetracaine topical (Cepacol Viractin Cream) Q2h while awake up to max 12d ass'd with reduced time to healing of about 2d in a randomized trial (J. Am. Acad. Dermatol. 41:996, 1999--abst) 
    5. Oral antivirals plus topical steroids
      1. 49 pts with herpes labialis tx'd with Famciclovir 500mg PO TID x 5d and randomized to 0.05% fluocinonide gel TID x 5d vs. placebo; nonsig. quicker healing time in steroid group (5.3 vs. 8.9d) (J. Inf. Dis. 181:1906, 2000--JW)
    6. In a study in 701 immunocompetent adults with > 2 episodes of herpes labialis in the prior year randomized to self-initiated famciclovir 1500mg x 1 vs. placebo(to start within 1h of onset of prodromal sx), time to healing and time to resolution of pain were both sig. shorter (by 2d and 1d, respectively) in the active-tx group. (J. Am. Acad. Dermatol. 55:47, 2006--JW)

IV. Other nongenital manifestations

  1. Keratoconjunctivitis
  2. Herpetic whitlow

V. HSV in pregnancy

  1. Maternal-fetal transmission
    1. HSV doesn't cross the placenta; most infections of the infant occur perinatally from contact with infected maternal secretions
    2. Most neonatal HSV is acquired from asymptomatic mothers without identified lesions
    3. Transmission is more common with delivery at earlier gestational ages
    4. Transmission much more common with primary HSV than recurrent
      1. 33 vs. 3% in one sries of 15,923 women (NEJM 324:1247, 1991)
      2. In one series of 8,500 women followed through pregnancy, about 2% of all susceptibles (seronegative at first prenatal visit) seroconverted during pregnancy; 2/3 of these were asymptomatic, i.e. no outbreak. Neonatal infections occurred only in those women who had acquired HSV by the time of labor (as dx'd by lesions and/or cx of external genitalia and cx) and in none of the women who had seroconverted by the time they were in labor.
    5. In a cohort study of 58,632 pregnant women, 40,023 of whom had cervical/labial HSV cultures in labor, positive culture was ass'd with an OR of 346 (not a typo) for neonatal clinically evident HSV infection.  Cesarian delivery was ass'd with sig. lower risk (OR 0.14).  Delivery < 38wks, invasive monitoring, and first-known HSV infection at time of delivery were ass'd with sig. higher risks of neonatal HSV infection (JAMA 289:203, 2003--abst)
  2. Primary infection in 2nd or 3rd trimester increases risk for preterm delivery
  3. Congenital HSV infection, i.e. infection of the fetus during pregnancy, before labor, is extremely rare
  4. Management principles for women with HSV
    1. For first-ever genital herpes episode in pregnancy:
      1. Do serology to see if it's a primary infection
      2. Treat primary HSV infection w/antivirals (see above)
      3. Consider suppressive antivirals for duration of pregnancy
    2. For other genital herpes episode in pregnancy
      1. Acyclovir started at 36wks reduced c/s rate in a randomized trial in women with h/o HSV (didn't distinguish between primary and recurrent disease) (Obs. Gyn 87:69, 1996)
      2. Acyclovir started at 36wks was ass'd with a sig. reduction in clinical recurrences and a nonsig. reduction in c/s rate in women with recurrent genital HSV (JAMA 252:2058, 1989)
    3. For woman with h/o HSV but no outbreak at present
      1. In a meta-analysis of five randomized trials involving a total of 799 pregnant women with HSV, acyclovir starting at 36wks reduced incidence of herpes recurrences at delivery and need for cesarian (Obs. Gyn. 102:1396, 2003--FP News 4/15/06)
    4. Consider vag/cerv. culture for HSV in labor, so if baby gets sick, cx results could help guide tx.
    5. "Cesarian delivery is indicated in women with active genital lesions or sx of vulvar pain or burning, which may indicate an impending outbreak..cesarian delivery is not recommended for...women with recurrent HSV and non-genital lesions [e.g. thigh or buttock]...the lesions should be covered with an occlusive dressing" (ACOG 10/99). They go on to say that if membranes are ruptured, c/s should be done ASAP, regardless of the duration of ROM
    6. For preterm PROM with active lesions, ACOG 10/99 says consider expectant management (e.g. to give steroids time to work for baby) + antivirals
    7. Avoid transcervical invasive procedures, including fetal scalp electrode, in moms with HSV and active lesions
    8. A rapid (median results availability 2h)PCR assay for HSV is available and had high sensitivity and specificity (99.5% and 96.7%, respectively, compared with standard HSV PCR) on vaginal swabs in women in labor (Obs. Gyn. 115:1209, 2010-JW)

IV. Ophthalmic HSV

  1. 703 immunocompetent pts with at least one episode of ophthalmic HSV in the previous year randomized to acyclovir 400mg BID vs. placebo x 1y. Over 18mos f/u, recurrance of any ophthalmic HSV was sig. lower in acyclovir group (19% vs. 32%); during 6mos post-tx, no diff. in 2 groups (NEJM 339:300, 1998--JW)

(Sources include ACOG Practice Bulletin #8, 10/99)