MICROBIOLOGY

• Herpes simplex virus 1 and 2 (HSV-1, HSV-2): members of the Herpes DNA virus family, Herpesviridae, aka Human Herpes Virus 1 and 2 (HHV-1 and HHV-2).
• After primary infection, the virus establishes latency in neurons, with potential for reactivation--usually near the site of initial acquisition.
• Viral culture: obtain fresh cells or fluid from ulcer, blister or implicated tissue or source and inoculate using a Dacron swab into viral transport media on wet ice (4°C), which then is set for viral culture.
  • Tissue culture using Vero cell culture line or similar with tube or shell vial technique. Growth is often quick within 1-2d, with a cytopathic effect—confirmation of virus by immunologic staining.
  • Blood viral culture: use whole blood in a heparinized tube to obtain a buffy coat, an insensitive method.

CLINICAL

• Most infections are asymptomatic.
  
  • HSV-1: 50-80% of adults seropositive (U.S. data)
  • HSV-2: 20-40% of adults seropositive
• HSV-1: herpes labialis is the most common form of recurrent HSV-1, but 30% of genital HSV is nowadays HSV-1.
• Primary infection
  • Asymptomatic in two-thirds of both HSV-1 and 2. Most HSV is acquired from an infected but asymptomatic person.
  • Clinical presentations: vesicular presentation is often diagnosed clinically but can confirm with viral culture or PCR of ulcer/vesicle or use serology (e.g., Herpselect Ab I/II, type-specific).
    
    • Primary gingivostomatitis: fever, sore throat, cervical lymphadenopathy, oral cavity vesicular enanthem that may involve the lips, tongue and mucosal surfaces [Fig 1].
    • Mononucleosis syndrome: pharyngitis, fever, cervical lymphadenopathy; not uncommon primary infection of adolescents.
    • Genital infection: see the section below.
    • Neonatal infection: risk ~40% if primary genital HSV infection occurs in the mother during the third trimester.
  • Diagnostics: note that serotype-specific serology helps confirm seroconversion in primary infection; the role in non-primary infection diagnosis is poorly defined.
• Genital herpes
  • Presentation: classically presents as a small number of painful, clustered vesicles with an erythematous base; increased pain noted upon rupture, leaving shallow ulcers that heal spontaneously without treatment over 4-10 days.
    • Women: infection is often asymptomatic, but when clinically active, may include sores or vesicles around the vaginal region, including the vulva and cervix, perianal, buttocks or thighs [Fig 2]. Dysuria or difficulty voiding may accompany.
    • Men: often asymptomatic, less commonly with ulcers or vesicles on the penis, including glans and shaft [Fig 3], perianal or on buttocks/thighs.
    • Primary infection may be associated with constitutional symptoms, often with urinary retention (in women), with or without aseptic meningitis (30% women; 10% men) and takes longer to resolve than recurrent disease.
  • HSV-2 accounts for 70-80% of cases; HSV-1 for 20-30% of cases.
  • HSV-2 is more likely to have clinical recurrences.
  • Genital ulcer disease, including that caused by genital HSV, increases the risk of acquiring and transmitting HIV infection.
  • Clinical dx HSV is insensitive and nonspecific; lab dx needed to confirm.
    • Viral cx was the historical gold standard, but sensitivity is low (50%), especially for recurrent lesions or lesions that have begun to heal.
      
      • Obtain scraping of cells or fluid by unroofing intact blister with a sterile needle.
    • HSV DNA PCR from lesions 98-100% sensitive.
    • Viral shedding is intermittent, so negative PCR does not exclude the diagnosis. Specificity is 97%.
    • Type-specific HSV serology might be helpful for:
      • 1) Recurrent genital or atypical symptoms with negative HSV PCR or culture.
      • 2) Clinical diagnosis of genital herpes without laboratory confirmation.
      • 3) A patient whose partner has genital herpes.
    • See the Genital Ulcer Disease module for additional details.
  • The psychological impact of genital HSV cannot be overstated; 60% report being "devastated" when first told of their dx.
  • Recurrent genital herpes (>9 episodes/yr) in non-immunosuppressed may be due to persistently lower levels of IgG1, IgG3, and complement compared with infected persons without recurrent disease[15].
  • Condom use and valacyclovir reduce transmission of genital herpes in serodiscordant couples[22] (this observation was not replicated in HIV/HSV-2 discordant couples[10]).
• Recurrences: reactivation may be brought on by stress (illness, sun exposure)—usually one or few lesions.
  • Shedding may occur without clinically evident lesions.
• CNS HSV infections
  • Encephalitis: HSV-1 leading cause of sporadic encephalitis in U.S. adults with early onset of seizures and characteristically localizing signs suggesting temporal >> frontal lobe involvement.
    • Diagnosis: herpesvirus PCR on CSF sample preferred (Se 98%, Sp 94%; PPV 95%, NPV 98%). In patients with compatible HSV encephalitis and a negative HSV PCR, consider repeating LP in 3- 7 days.
      • CSF viral culture is insensitive.
      • Rarely CSF PCR negative, yet virus identified on brain biopsy/autopsy.
    • MRI may be normal early in the process, but later characteristic changes indicating necrosis in the temporal region is classic.
      • The prognosis is poor if the brain MRI shows edema with a shift.
    • Mortality is 70% without therapy.
  • Benign recurrent lymphocytic meningitis (BRLM, Mollaret’s meningitis)[19]:
    • Definition: >2 recurrences of fever and meningismus lasting 2-5 d with spontaneous recovery.
    • Usually due to HSV-2, but the history of clinical genital herpes is not common.
      • If presentation follows genital HSV recurrence, onset typically 5-7 days later.
      • Other viruses (EBV, VZV, echoviruses) have been implicated.
    • M:F is 1:2 with mean age = 35 years.
    • Recurrences are usually less frequent over time.
    • Syndrome: fever, headache (can be severe), photophobia, meningismus; symptoms reach maximum intensity in a few hours.
    • 50% have transient neurologic signs/symptoms, including cranial nerve palsies, diplopia, hallucinations, seizures, and altered consciousness. Thus, BRLM must be a dx of exclusion.
    • CSF findings: lymphocytic pleocytosis (may begin with polymorphonuclear pleocytosis), mild protein elevation, normal glucose.
      
      • Hallmark is large granular plasma cells (Mollaret cells) seen by Papanicolaou stain.
    • CSF PCR is the gold standard for diagnosis; 85% sensitivity; viral culture is usually negative.
      • Patients are completely well between episodes with CSF normalizing and spontaneous clinical resolution.
      • A study showed no benefit in risk reduction of meningitis recurrence at 2 years with suppressive valacyclovir (500mg twice daily )[12].
• Ocular herpes: infections are potentially sight-threatening and should be referred to an ophthalmologist for initial management.
  
  • Approximately 50,000 new and recurrent ocular HSV/yr in the U.S., a leading cause of corneal opacification and infection-related visual loss.
  • Atopy increases the risk of ocular herpes[9].
  • The spectrum of ocular effects includes dendritic keratitis, uveitis, blepharoconjunctivitis, necrotizing keratitis and retinal necrosis.
    • Recurrent disease can damage the cornea and uvea with scarring and vision loss.
      • The recurrence rate is 20% by two years, 40% by five years, and 67% by seven years.
      • Herpetic Eye Disease Study Group has shown that oral acyclovir suppression following initial ocular herpes decreases recurrence by 45% in the first year; the most significant suppressive effect may be seen in those with concomitant history of atopy. This approach, however, may increase the risk of refractory disease due to the emergence of acyclovir resistance[11].
  • Acute follicular conjunctivitis and kerato-conjunctivitis: foreign body sensation, lacrimation, photophobia, conjunctival hyperemia followed by vesicular blepharitis, ulceration, blurring of vision secondary to keratitis, and ultimate healing without scarring.
  • Dendritic keratitis (herpes keratitis):
    • It begins with foreign body sensation, lacrimation, photophobia and decreased vision that is slow to heal; repeated recurrences can lead to scarring. It can also be sight-threatening.
    • Caused by viral reactivation, previously dormant in trigeminal ganglia.
    • Patients with atopy may have unusually severe keratitis due to impaired cell-mediated immunity.
    • Response to topical antivirals poor; use oral agents.
  • Herpes retinitis: rarer than VZV-related retinal necrosis, can lead to acute retinal necrosis secondary to occlusive vasculitis, sight-threatening.
• Infections in special populations
  • HIV-infected persons: 60-70% in the U.S. are infected with HSV-2; disseminated infection with visceral involvement can be seen when CD4 count < 200 cells/mL and is potentially life-threatening.
  • Pregnant women: may develop a disseminated infection if primary infection occurs during pregnancy.
    • Acyclovir is the most studied and is the preferred drug to use.
    • HSV outbreak in pregnancy, recommend treating for 7-10 days.
    • Pregnant women w/ HSV or a history of genital HSV are recommended to take oral antiviral suppression at 36 weeks.
  • Acute immunosuppression: may reactivate HSV within 2 wks of immunosuppression onset.
  • HSV esophagitis: seen in immunocompromised patients and must be differentiated from other causes of esophagitis, including CMV and Candida.
• Thymidine kinase (TK) deficient (acyclovir-resistant) strains:
  • Usually seen in those with significant anti-HSV medication exposure and immunosuppression.
  • The resistant virus occurs in approximately 5% of isolates from HIV-infected persons and 10-12% from bone marrow transplant recipients.
    • Acyclovir resistance is primarily due to TK-deficient strains.
• Severe, recurrent ano-genital herpes: commonly seen in patients with AIDS with low CD4 counts (< 200 cells/mL) and high viral loads. HIV-infected, especially w/ AIDS, need more prolonged treatment and/or higher doses for episodic cutaneous HSV.
• HSV tracheobronchitis: rare but most commonly seen in immunosuppressed or elderly intubated patients.
• Dermatological herpes:
  • Herpes dermatitis: seen in athletes (herpes gladiatorum), health care workers (herpetic whitlow) and patients with eczema who become superinfected with HSV (Kaposi’s varicelliform eruption).
  • Orolabial HSV (cold sores):
    • Usually due to HSV-1, but HSV-2 has increasingly been identified.
    • Recurrences:
      • It may reactivate after exposure to sunlight, wind, cold, emotional stressors or the late stage of the menstrual cycle.
      • Erythema multiforme: a condition in ~5% following recurrent or symptomatic HSV.
      • Mean duration of recurrence (vesicles to the healing of lesions): 7-8 d.
      • Mean duration of viral shedding: approximately 60h (measured by PCR) with a peak viral load during the vesicle/ulcer stage.
      • Data suggest that lesion size, progression to ulcers and duration are improved with topical acyclovir 5%/hydrocortisone 1% combination compared to topical acyclovir 5% alone.
• Neonatal herpes, including prevention
  • Occurs in 1:3,000-20,000 live births, 50% of cases are due to HSV type 1 and 50% to type 2.
  • Vertical transmission most likely occurs during passage through the birth canal among women with active lesions.
    • The vertical transmission risk to the neonate is 40-80% if primary transmission occurs at the delivery time.
    • Congenital herpes occurs by the transfer of infection in utero and is extremely rare.
    • Cesarean section if active disease at the time of labor.
  • Primary infection in mothers during the third trimester is associated with 10x increased transmission risk.
    • Symptoms may include fever, lethargy, poor feeding, seizures, bulging fontanelle and focal neurological findings.
      • Cutaneous/ocular/oral: lesions may be seen.
      • CNS: encephalitis may occur without mucocutaneous findings.
      • Disseminated infection: multiple organs involved, including the above and hepatitis, pneumonitis, and DIC.
  • Recurrent genital herpes is associated with a very low risk of neonatal herpes (0-3% for vaginal delivery).
  • 70% of neonatal herpes cases have CNS involvement, while 30% of neonatal cases have localized skin/eye or mouth infections.
    • Most neonates with CNS infection will not have skin/eye or mouth manifestations.
  • Neonates with CNS herpes may have better neurological development if continued on suppressive acyclovir after initial treatment[13].
  • Elective Cesarean section and suppressive therapy with acyclovir (400mg TID) at or beyond 36 weeks of gestation are recommended for women with first-episode genital lesions during the third trimester.
  • Vaginal delivery and suppressive acyclovir therapy are recommended for recurrent genital lesions during the third trimester.
  • Type-specific HSV serology might help distinguish primary from recurrent infection.
    • Note that ~15% of women with "primary" genital herpes present with recurrent infections.
  • Necessary for women to present at 36 weeks if active HSV or history of genital HSV within 6 weeks of expected delivery as it might change management. The presence of antibodies of the same type as the HSV isolated from a genital swab would confirm recurrent infection.
    • ACOG 2020 recommendations in pregnancy:
      • Re-testing is not needed for prior confirmed history.
      • Use type-specific HSV testing.
        • Active lesions: obtain a specimen for culture, antigen or molecular testing.
        • History of ulcers, no active lesions: obtain type-specific serology.
      • Insufficient data to recommend routine screening of all pregnant women for HSV.
    • Oral antiviral suppression is recommended at 36 weeks for those with genital HSV history.

SITES OF INFECTION

• Oro-facial: primary gingivostomatitis; recurrent stomatitis; herpes labialis
• Genital: genital ulcer disease
• Eye: follicular conjunctivitis, keratitis, acute retinal necrosis syndrome, endophthalmitis
• Other skin areas: eczema herpeticum, herpetic whitlow, herpes gladiatorum
• Central nervous system: sporadic encephalitis, meningoencephalitis, aseptic meningitis; sacral radiculopathy, benign recurrent lymphocytic meningitis (Mollaret’s meningitis)
• Esophagus: esophagitis
• Respiratory system: pneumonia, tracheobronchitis
• Liver: hepatitis
• Rectum: proctitis
• Multiple organs: disseminated infection

TREATMENT

FOLLOW UP

• Acyclovir resistance: uncommon, disease progression limited to almost exclusively to compromised hosts. If no clinical response and lab confirmation of HSV infection is obtained, change treatment (see acyclovir-resistant recommendations above).
  • Resistance testing is not routinely recommended unless there is an apparent clinical failure.
• Recurrent HSV: in patients on long-term suppression, consider stopping after 12 months of therapy to observe if the patient is still experiencing frequent relapses.
  
  • Suppression therapy does not obviate recurrences but reduces frequency and severity. Relapse if on suppressive therapy is not solved by escalating the dose.
• Encephalitis:
  • Outcomes of survivors, sequelae, regardless of age
    • Severe 30%
    • Moderate 40%
    • Mild or normal 30%
  • Predictors of a good outcome:
    • < 30 years of age
    • < 4 days of symptoms
    • Glasgow coma scale (GCS) score > 6
  • If GCS < 6 and > 30 years, only 35% with normal or mild impairments if they survive.
  • Neonatal HSV-2 infection is worse than HSV-1.

OTHER INFORMATION

• HSV suppressive therapy does NOT decrease the risk of HIV acquisition among HSV-infected, HIV-uninfected women.
• Breastfeeding is not contraindicated in women with active herpes simplex virus unless there is a lesion in the breast. Given that postnatally-acquired herpes can be as lethal as that acquired during delivery special consideration of handwashing should be taken by mothers and family members with active lesions in any part of the body.
• HSV serologic testing should be considered for persons presenting for an STD evaluation (especially for those persons with multiple sex partners), persons with HIV infection, and MSM at increased risk for HIV acquisition. Screening for HSV-1 and HSV-2 in the general population is not indicated.
• Management of partners:
  • Abstinence during the presence of symptoms or signs is not an effective strategy to reduce the risk of transmission since asymptomatic shedding plays a significant role in HSV transmission.
  • Transmission can be reduced with either suppressive therapy or condom use.

Basis for recommendation

1. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187.  [PMID:34292926]

   Comment: Updated CDC STI Treatment Guidelines used in this module.
   

2. Management of Genital Herpes in Pregnancy: ACOG Practice Bulletinacog Practice Bulletin, Number 220. Obstet Gynecol. 2020;135(5):e193-e202.  [PMID:32332414]

   Comment: Recommendations for diagnosis and management in pregnancy are used in this module.
   

3. Valerio GS, Lin CC. Ocular manifestations of herpes simplex virus. Curr Opin Ophthalmol. 2019;30(6):525-531.  [PMID:31567695]

   Comment: The spectrum of disease and dosing recommendations, also photos.
   

4. Patel R, Green J, Clarke E, et al. 2014 UK national guideline for the management of anogenital herpes. Int J STD AIDS. 2015;26(11):763-76.  [PMID:25861804]

   Comment: 2014 update of the 2007 guidelines on the management of anogenital herpes.
   

5. Widener RW, Whitley RJ. Herpes simplex virus. Handb Clin Neurol. 2014;123:251-63.  [PMID:25015489]

   Comment: Clinically useful overview focusing on neurological disease ranging from pregnancy/neonatal to adults.d
   

References

6. Jakobsen A, Skov MT, Larsen L, et al. Herpes Simplex Virus 2 Meningitis in Adults: A Prospective, Nationwide, Population-Based Cohort Study. Clin Infect Dis. 2022;75(5):753-760.  [PMID:34979025]

   Comment: Database analysis from Denmark looked at 205 patients and found less favorable outcomes in 31%, evaluated at discharge. More concerning was 11% after 6 months, unrelated to any clinical or lab-based factors. Almost all received antiviral therapy (96%, majority oral ), so unclear whether it helped.
   

7. Luyt CE, Forel JM, Hajage D, et al. Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation: A Randomized Clinical Trial. JAMA Intern Med. 2020;180(2):263-272.  [PMID:31841577]

   Comment: Negative trial to see if patients with prolonged ventilation and (+) HSV secretions benefited from antiviral suppression.
   

8. Lyons TW, Cruz AT, Freedman SB, et al. Accuracy of Herpes Simplex Virus Polymerase Chain Reaction Testing of the Blood for Central Nervous System Herpes Simplex Virus Infections in Infants. J Pediatr. 2018;200:274-276.e1.  [PMID:29784511]

   Comment: Review of 1028 infants with HSV PCR performed in blood and CSF specimens. Of the 21 who had positive CSF PCR, 76% also had positive HSV PCR in their blood. The important conclusion is that a blood PCR in this population cannot be used to exclude CNS HSV infection.
   

9. Borkar DS, Gonzales JA, Tham VM, et al. Association between atopy and herpetic eye disease: results from the pacific ocular inflammation study. JAMA Ophthalmol. 2014;132(3):326-31.  [PMID:24370901]

   Comment: This was a retrospective, population-based case-control study of 114 patients with HSV ocular disease and 137 with herpes-zoster ocular disease (HZO) in Hawaii. Authors found that patients with atopy had a 2.6-fold (95% CI, 1.6-4.2) higher odds of having HSVocular disease and 1.8-fold (95% CI, 1.2-2.8) increased odds of having HZO compared to patients without atopy. Patients with 2 or more atopic conditions had an 8.9-fold (95% CI, 3.5-22.6) higher odds of having HSVocular disease and a 2.9-fold (95% CI, 1.1-7.7) higher odds of having HZO.
   Rating: Important
   

10. Mujugira A, Magaret AS, Celum C, et al. Daily acyclovir to decrease herpes simplex virus type 2 (HSV-2) transmission from HSV-2/HIV-1 coinfected persons: a randomized controlled trial. J Infect Dis. 2013;208(9):1366-74.  [PMID:23901094]

    Comment: This randomized controlled trial evaluated the impact of acyclovir 400mg twice daily on the prevention of transmission of HSV-2 genital herpes in HIV-1/HSV-2 discordant couples in Africa. Key findings: Treatment of HSV-2/HIV-1-infected persons with daily suppressive acyclovir did not decrease the risk of HSV-2 transmission to susceptible partners.
    Rating: Important
    

11. van Velzen M, van de Vijver DA, van Loenen FB, et al. Acyclovir prophylaxis predisposes to antiviral-resistant recurrent herpetic keratitis. J Infect Dis. 2013;208(9):1359-65.  [PMID:23901090]

    Comment: This retrospective study analyzed 169 corneal swabs from 78 immunocompetent patients with recurrent herpetic keratitis for acyclovir resistance. Key findings: 1) 26% of the isolates were acyclovir-resistant, 2) acyclovir prophylaxis x ≥12 m and recurrence duration of ≥45 days were associated with acyclovir resistance and acyclovir refractory disease, 3) acyclovir-resistant isolates were a risk factor for acyclovir refractory disease (OR 2.28; 95% CI, 1.06–4.89).
    Rating: Important
    

12. Aurelius E, Franzen-Röhl E, Glimåker M, et al. Long-term valacyclovir suppressive treatment after herpes simplex virus type 2 meningitis: a double-blind, randomized controlled trial. Clin Infect Dis. 2012;54(9):1304-13.  [PMID:22460966]

    Comment: This Sweedish randomized, double-blind, placebo-controlled multicenter trial investigated the effect of valacyclovir on the prevention of recurrence of HSV meningitis. Patients received valacyclovir 500 mg twice daily (n=50) or placebo (n=51) for 1 year after primary or recurrent, confirmed or probable, HSV meningitis. Patients were followed for 2 years. Key finding: no difference between the 2 groups during the first year however, during the second year, the risk of recurrence was higher among patients exposed to valacyclovir (HR, 3.29 [95% confidence interval, 10.06–10.21]).
    Rating: Important
    

13. Kimberlin DW, Whitley RJ, Wan W, et al. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med. 2011;365(14):1284-92.  [PMID:21991950]

    Comment: A study of 74 infants with neonatal HSV: 45 with CNS involvement were enrolled in a study; 29 with skin, eye and mouth involvement (enrolled in a different study). All 45 neonates with CNS involvement received 14-21 d of parenteral acyclovir and were randomly assigned to receive acyclovir suppression TID x 6 mo vs. placebo. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. Infants surviving neonatal HSV disease with CNS involvement had significantly improved neurodevelopmental outcomes after receiving suppressive therapy with oral acyclovir for 6 months.
    
    
    
    Rating: Important
    

14. Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371(9630):2109-19.  [PMID:18572080]

    Comment: This randomized, double-blind, placebo-controlled multicenter, multinational phase III clinical trial among HIV-uninfected, HSV-2 seropositive heterosexual women (n=1358) and men who have sex with men (MSM; n=1814) examined the primary outcome of new HIV-1 acquisition and the secondary outcome of the incidence of genital ulcers amongst those receiving twice daily acyclovir (400 mg) and placebo. Amongst participants from all countries, no reduction in HIV-1 incidence was noted between the treatment and control groups. HSV-2 positive ulcers were reduced by 63% in the treatment group compared with the control group (Relative risk = 0.37, Confidence Interval 0.31-0.45). No serious drug effects were noted in the study.
    Rating: Important
    

15. Seppanen M, Meri S, Notkola IL, et al. Subtly impaired humoral immunity predisposes to frequently recurring genital herpes simplex virus type 2 infection and herpetic neuralgia. J Infect Dis. 2006;194(5):571-8.  [PMID:16897653]

    Comment: This prospective case-control study examined immunogenetic risk factors for recurrent genital herpes. the study population included 52 consecutive eligible patients, without immunodeficiency, with culture-confirmed HSV-2 from an active lesion >12 months before enrollment and >9 recurrences per year and 80 HSV seropositive and 70 HSV seronegative controls. Anti-HSV-2 antibodies did not correlate with protection from recurrence. Risk factors for recurrence included lower IgG1 antibody -Confidence Interval (CI), 2.0-12.5; p< 0.001 and IgG3 antibody - CI 1.7-7,8, p< .001. Complement levels were lower in patients with recurrent symptomatic infections.
    Rating: Important
    

16. Jin F, Prestage GP, Mao L, et al. Transmission of herpes simplex virus types 1 and 2 in a prospective cohort of HIV-negative gay men: the health in men study. J Infect Dis. 2006;194(5):561-70.  [PMID:16897652]

    Comment: This Australian community-based cohort study of 1,427 HIV-negative gay men examined risk factors for herpes simplex virus type 1 (HSV-1) and HSV type 2 (HSV-2) over a median follow-up period of 2 years. At enrolment, the prevalence of HSV-1 was 75%, and HSV-2 was 23%, and both infections had a lower prevalence in those < 25 years. The incidence of HSV-1 infection was 5.58/100 person-years (PY) and 1.45/100 PY for HSV-2. Using multivariate analysis, significant independent risk factors for HSV-1 infection were insertive oral intercourse with casual sex partners (hazards ratio = 3.91; 95% confidence interval [CI] =1.23-12.44) and younger age (p< 0.03). A significant risk factor for HSV-2 acquisition was anal sex with casual partners.
    Rating: Important
    

17. Brown EL, Wald A, Hughes JP, et al. High risk of human immunodeficiency virus in men who have sex with men with herpes simplex virus type 2 in the EXPLORE study. Am J Epidemiol. 2006;164(8):733-41.  [PMID:16896053]

    Comment: This randomized, controlled Phase IIb trial of a 10-session behavioral intervention vs. brief counseling session (control group) to reduce HIV acquisition among 4295 high-risk HIV-uninfected men who have sex with men (MSM). Sera and behavioral data collected during this trial were subsequently examined to determine risk factors for herpes simplex virus type 2 (HSV-2, ) evaluate the role of prevalent and incident HSV-2 infection in HIV infection acquisition, and determine the impact of the behavioral intervention on HSV acquisition (already shown not to have a role in HIV acquisition). 91% of subjects had evaluable data; 20.3% were HSV-2 positive (by serology) at enrolment; 4.3% acquired infection over the 24-month study period, and 75.4% remained uninfected with HSV-2. Risk factors for seroconversion included unprotected anal receptive intercourse in the prior 6 months, having at least 1 HIV-infected partner in the past 6 months, and having >5 male sex partners in the last 6 months. HIV risk was increased among MSM with recent HSV-2 infection identified compared with HSV-2 uninfected MSM. The intense behavioral intervention did not increase the risk of HSV-2 infection.
    Rating: Important
    

18. Fife KH, Warren TJ, Ferrera RD, et al. Effect of valacyclovir on viral shedding in immunocompetent patients with recurrent herpes simplex virus 2 genital herpes: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc. 2006;81(10):1321-7.  [PMID:17036557]

    Comment: This is the report of a 27-site multicenter randomized, double-blinded parallel placebo control trial examining the efficacy of 1-gram valacyclovir (VAC) in reducing HSV-2 viral shedding in both clinical and asymptomatic infections among immunocompetent persons. 152 persons were randomized--43 placebo (40 completed) and 109 VAC (94 completed. Over 60 days, each participant reported daily on the presence or absence of genital lesions and collected daily genital and anorectal samples. VAC significantly decreased total days of viral shedding amongst clinical and subclinical cases and a viral load when shedding compared with the controls. In the intent-to-treat group, a 71% reduction in total shedding was noted (p< 0.001), a 58% reduction in subclinical shedding (p< 0.001), and a 64% reduction in clinical shedding (p< 0.01) was seen in the VAC group. There were no major adverse effects noted with VAC over the 60-day study period.
    Rating: Important
    

19. Shalabi M, Whitley RJ. Recurrent benign lymphocytic meningitis. Clin Infect Dis. 2006;43(9):1194-7.  [PMID:17029141]

    Comment: Excellent review on RBLM.
    

20. Tran TH, Stanescu D, Caspers-Velu L, et al. Clinical characteristics of acute HSV-2 retinal necrosis. Am J Ophthalmol. 2004;137(5):872-9.  [PMID:15126152]

    Comment: The authors report the largest case series of 11 patients/12 eyes with HSV-2 acute retinal necrosis (ARN) and review the world’s literature. Although other infections are associated with ARN, the authors identify some HSV-2-specific features, including young age at DX, hx of HSV at birth, and a preexisting chorioretinal scar in the ARN eye, triggering events such as trauma or steroids. Also, the clinical syndrome described with HSV-2 is more aggressive and rapid. This is a sight-threatening condition and requires prompt consultative referral to an ophthalmologist.
    Rating: Important
    

21. Filén F, Strand A, Allard A, et al. Duplex real-time polymerase chain reaction assay for detection and quantification of herpes simplex virus type 1 and herpes simplex virus type 2 in genital and cutaneous lesions. Sex Transm Dis. 2004;31(6):331-6.  [PMID:15167640]

    Comment: The authors report the findings of a study among 89 pts with HSV-like lesions--81 with genital and 8 with cutaneous lesions. Specimens were collected for quantitative duplex PCR and culture; 64% were PCR positive, 51% were cx positive. PCR detected 30 of 34 primary and 24 of 29 recurrent infections. 2 HSV-1 samples were positive on cx only despite repeated PCR attempts. Symptomatic pts had significantly higher copy numbers on PCR. In this study, duplex qPCR for HSV-1 and HSV-2 was more sensitive than the gold standard cx for mucocutaneous HSV.
    Rating: Important
    

22. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350(1):11-20.  [PMID:14702423]

    Comment: The authors conducted a study among 528 mutually-monogamous heterosexual couples discordant for HSV-2 infection. Although the antiviral was the intervention under observation, data were also collected re: condom use. When condoms were used more than 70% of the time by the discordant pairs with a positive man and a negative woman, transmission risk was reduced by 60%, even in the absence of antiviral suppression. Acquisition of infection by the seronegative partner and recurrence and shedding by the positive partner were significantly reduced when valacyclovir was used.
    Rating: Important
    

23. Lautenschlager S, Eichmann A. The heterogeneous clinical spectrum of genital herpes. Dermatology. 2001;202(3):211-9.  [PMID:11385226]

    Comment: Report of a chart review of 170 patients seen on referral to a dermatology clinic found to have culture-confirmed HSV. This specialty practice was likely to see "outliers" in presentation as only 49% had "typical" cluster genital lesions. Single ulcers, erosion, crusts, fissures, edema, and erythema were seen. Women were more likely to have extragenital lesions than men.
    Rating: Important
    

24. Grant DM. Acyclovir (Zovirax) ophthalmic ointment: a review of clinical tolerance. Curr Eye Res. 1987;6(1):231-5.  [PMID:3549163]

    Comment: The author reviewed 29 published clinical trials. Notable that ACV ointment did cause superficial punctate keratitis in 9.8% of 998 pts and 4% noted burning of the eye with the application of the agent. Found to compare favorably with other topical antiherpetics available.
    Rating: Important
    

Media

Primary Herpes Simplex virus infection

Primary Herpes Simplex virus infection involving lips and tongue.

Source: CDC

Genital HSV female

Ulcers and vesicle from genital HSV are seen around vaginal introitus due to HSV-2.

Source: CDC

Genital HSV male

Vesicle seen on penile shaft due to HSV-2.

Source: CDC/Suan Lindsley