Herpes Simplex Virus

Valeria Fabre, M.D.

MICROBIOLOGY

Herpes simplex virus 1 and 2 (HSV-1, HSV-2): members of Herpes DNA virus family, Herpesviridae, aka Human Herpes Virus 1 and 2 (HHV-1 and HHV-2).
After primary infection, virus establishes latency in neurons; potential for reactivation--usually near site of initial acquisition.
Viral culture: obtain fresh cells or fluid from ulcer, blister or implicated tissue or source and inoculate using 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 often quick within 1-2d, with cytopathic effect. Confirmation of virus by immunologic staining.
- Blood viral culture: use whole blood obtain in heparinized tube to obtain buffy coat, 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 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 often diagnosed clinically, but can confirm with viral culture or PCR of ulcer/vesicle or use serology (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 section below.
  - Neonatal infection: risk ~40% if primary genital HSV infection in mother during third trimester.
- Diagnostics: note that serotype specific serology is useful to confirm seroconversion in primary infection; role in non-primary infection diagnosis is poorly defined.
Genital herpes
- Presentation: classically presents as 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 often asymptomatic, but when clinically active may include sores or vesicles around vaginal region including 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 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 acquisition and transmission of HIV infection.
- Clinical dx HSV is insensitive and nonspecific; lab dx needed to confirm.
  - Viral cx gold standard but sensitivity is low (50%), especially for recurrent lesions or lesions that begun to heal.
    - Obtain scraping of cells, or fluid by unroofing intact blister with sterile needle.
  - HSV DNA PCR from lesions 98-100% sensitive. Viral shedding is intermittent so negative PCR does not exclude diagnosis. Specificity is 97%.
  - Type-specific HSV serology might be useful in:
    - 1) recurrent genital symptoms 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 Genital Ulcer Disease module for additional details.
- 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[13].
- Both condom use and valacyclovir reduce transmission of genital herpes in serodiscordant couples[20] (this observation was not replicated in HIV/HSV-2 discordant couples[7]).
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 96%-98%, Sp 95%-99%). In patients with compatible HSV encephalitis and a negative HSV PCR, consider repeating LP in 3- 7 days.
    - Viral culture insensitive.
    - Rarely, CSF PCR negative yet virus identified on brain biopsy/autopsy.
  - MRI may be normal early in process, but later characteristic changes indicating necrosis in temporal region is classic.
- Benign recurrent lymphocytic meningitis (BRLM, Mollaret’s meningitis)[17]:
  - Definition: >2 recurrences of fever and meningismus lasting 2-5 d with spontaneous recovery.
  - Usually due to HSV-2, but 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 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, 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 completely well between episodes with CSF normalizing, and spontaneous clinical resolution.
    - Recent study showed no benefit in risk reduction of meningitis recurrence at 2 years with suppressive valacyclovir (500mg twice daily )[10].
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].
- Spectrum of ocular effects includes: dendritic keratitis, uveitis, blepharoconjunctivitis, necrotizing keratitis and retinal necrosis.
  - Recurrent disease can result in damage to the cornea and uvea with scarring and vision loss.
    - Recurrence rate is 20% by 2 years; 40% by 5 yrs; 67% by 7 yrs.
    - Herpetic Eye Disease Study Group has shown that oral acyclovir suppression following initial ocular herpes decreases recurrence by 45% in the first year; the greatest suppressive effect may be seen in those with concomitant history of atopy. This approach however may increase the risk of refractory disease due to emergence of acyclovir resistance[6].
- 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):
  - Begins with foreign body sensation, lacrimation, photophobia and decreased vision that is slow to heal; repeated recurrences can lead to scarring. 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 immunocompromised persons
- HIV-infected persons: 60-70% in 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 disseminated infection if primary infection occurs during pregnancy.
- 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.
  - Resistant virus occurs in approximately 5% of isolates from HIV-infected persons and 10-12% from bone marrow transplant recipients. Acyclovir resistance mostly 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 longer treatment and/or higher dose 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 in patients with eczema who become superinfected with HSV (Kaposi’s varicelliform eruption).
- Orolabial HSV (cold sores):
  - Usually due to HSV-1, but HSV-2 increasingly identified.
  - Recurrences:
    - May reactivate after exposure to sunlight, wind, cold, emotional stressors or late stage of menstrual cycle.
    - Erythema multiforme: condition in ~5% following recurrent or symptomatic HSV.
    - Mean duration of recurrence (vesicles to 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.
    - Recent data suggests that lesion size, progression to ulcers and duration are improved with topical acyclovir 5%/hydrocortisone 1% combination compared to topical acyclovir 5% alone[8].
Neonatal herpes
- 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 to occur during passage through the birth canal among women with active lesions.
  - Congenital herpes occurs by transfer of infection in utero and is extremely rare.
- Primary infection in mother during third trimester 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, DIC.
- Recurrent genital herpes is associated with 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 infection. 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[11].
- 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 third trimester.
- Vaginal delivery along with acyclovir suppressive therapy is recommended for recurrent genital lesions during third trimester
- Type-specific HSV serology might help distinguish primary from recurrent infection. Note that ~15% of women with "primary" genital herpes actually present with recurrent infection.
- Important for women presenting within 6 weeks of expected delivery as it might change management. Presence of antibodies of the same type as the HSV isolated from genital swab would confirm recurrent infection.

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, aseptic meningitis, benign recurrent lymphocytic meningitis (Mollaret’s meningitis)
Esophagus: esophagitis
Respiratory system: pneumonia, tracheobronchitis
Liver: hepatitis
Rectum: proctitis
Multiple organs: disseminated infection

TREATMENT

Mucocutaneous Infections

Genital HSV and proctitis:
- Normal host, mild-moderate infection: medications may shorten duration of symptoms.
  - First clinical episode: if opting for treatment, duration 5-10d.
    - Acyclovir 400 mg PO three times daily
    - Acyclovir 200 mg PO five times daily
    - Famciclovir 250 mg PO three times daily
    - Valacyclovir 1g PO twice daily
  - Episodic rx for recurrences:
    - Acyclovir 400 mg PO three times daily x 5d
    - Acyclovir 800 mg PO twice daily x 5d
    - Acyclovir 800 mg PO three times daily x 5d
    - Valacyclovir 500mg PO twice daily x 3d
    - Famciclovir 125 mg PO three times daily x 5d
      - Famciclovir 1000mg PO twice daily x 1 day alternative short-course regimen
  - HIV positive, episodic treatment for recurrences:
    - Acyclovir 400 mg PO three times daily x 5-10d
    - Famciclovir 500 mg PO twice daily x 5-10d
    - Valacyclovir 1g PO twice daily x 5-10d
- Suppressive daily therapy for recurrent disease (HIV negative): The frequency of recurrence at which it is worth starting suppressive therapy is subjective and needs to balance frequency of reciurrence, impact of disease on the individual and cost and inconvenience of treatment.
  - Acyclovir 400 mg PO twice daily
  - Famciclovir 250 mg PO twice daily
  - Valacyclovir 500 mg PO daily
  - Valacyclovir 1g PO daily (recommended for persons with >10 recurrences/year)
- Suppressive daily therapy for recurrent disease (HIV positive):
  - Acyclovir 400-800 mg PO 2-3 times daily
  - Famciclovir 500 mg PO twice daily
  - Valacyclovir 500 mg PO twice a day.
- Severe infection: CNS, ocular, disseminated disease
  - Acyclovir 5-10 mg/kg IV q8h X 5-7d or until clinical resolution.
    - Encephalitis: duration of treatment x 21d typically advocated to minimize relapse. Neonatal CNS infection usually maintained on acyclovir suppression.
  - May convert to oral regimen upon sufficient clinical response.
- Pregnancy:
  - Use oral acyclovir per above regimen with initial HSV infection or if highly symptomatic recurrent HSV.
  - Parenteral acyclovir needed for life-threatening infection.
Stomatitis:
- Acyclovir 400 mg PO three times a day x 7-10d
- Acyclovir 200 mg PO five times a day x 7-10d
- Famciclovir 250 mg PO q8h X 7-10d
- Valacyclovir 1g PO twice daily x 7-10d
Herpes labialis prophylaxis:
- Acyclovir 400 mg PO twice daily
- Famciclovir 250 mg PO twice daily
- Valacyclovir 250 mg PO twice daily
- Valacyclovir 500 mg PO once daily
- Valacyclovir 1000 mg PO once daily
Esophagitis: duration typically 7-10d
- Acyclovir 400-800 mg PO five times daily
- Valacyclovir 1g PO twice daily
- Famciclovir 500mg PO twice or thrice daily
- Acyclovir 5 mg/kg IV q8h

Central Nervous System Infection

Encephalitis: acyclovir 10 mg/kg IV q8h X 14-21d.
- Duration of treatment x 21d advocated by some to minimize relapse.
- Neonatal CNS infection usually maintained on acyclovir suppression.
Acute meningitis: acyclovir 10 mg/kg IV q8h X 7-10d.
- HSV meningitis often with hemorrhagic features in CSF fluid.
- Treatment is controversial to some and may not be required if no concerning neurological signs or evidence for encephalitis.
Benign recurrent lymphocytic meningitis: acyclovir 10 mg/kg IV q8h X 7-10d.
- Antiviral treatment not necessary to use as condition usually self-limiting.
- Recent study showed no benefit of suppressive valacyclovir in prevention of recurrence of meningitis[10].

Ocular Infection

Requires ophthalmological consultation.
Follicular conjunctivitis: trifluridine, acyclovir and/or corticosteroids.
Keratitis: trifluridine, acyclovir and/or corticosteroids.

Prophylaxis for Immunosuppressed Patients

Acutely immunosuppressed, e.g., organ or bone marrow transplant patients, HSV seropositive:
- Initiation: acyclovir 5 mg/kg IV q8h X 7d.
- Maintenance: acyclovir 200-400 mg PO 3-5x daily x 1-3 mos.
HIV-infected:
- Acyclovir 400-800 mg PO twice or thrice daily
- Valacyclovir 500 mg daily
- Famciclovir 500 mg twice daily
Burn pts: acyclovir 5 mg/kg IV q8h x 7d then 200 mg PO 5x/d x 7-14d.

Acyclovir-Resistant Strains

Acyclovir resistance should be suspected in unresponsive cases .

Foscarnet 40-80mg/kg IV q8h until clinical resolution.
Topical cidofovir gel 1% for genital or perirectal lesions daily X 5 d may be tried (local pharmacy must compound).
Parenteral cidofovir: rarely used option due to toxicities, but may be considered for resistant systemic HSV infection, at 5mg/kg once weekly.

Selected Drug Comments

Drug	Recommendation
Acyclovir	Greatest experience in HSV treatment with this agent and only antiviral available in IV form. Data supports continuous use for suppression for up to 6 years without adverse effects or great risk of developing resistance (in normal hosts).
Cidofovir	Topical gel, 1% may be used if resistant genital HSV identified. One application per day x 5 days should be sufficient to permit lesion healing, decrease symptoms and viral shedding. The preparation must be made by a compounding pharmacy as it is not commercially available. Injectable use usually only considered for refractory acyclovir-resistant cases not responsive to foscarnet.
Famciclovir	Equivalent results to acyclovir when treating genital HSV. No data on adverse effects of long term suppression. Therefore, at 1 yr suppression should give pt a drug holiday and determine if sx recur.
Foscarnet	Effective against thymidine kinase (TK)-deficient, drug-resistant HSV. Close monitoring of renal function and serum level of K⁺, Ca⁺⁺, PO4^-, and Mg⁺⁺ required. Variable CNS penetration.
Valacyclovir	Prodrug of acyclovir. Advantage is less frequent dosing required. Equivalent results to acyclovir when treating genital HSV.

FOLLOW UP

Acyclovir resistance: uncommon, disease progression limited to almost exclusively to compromised hosts. If no clinical response and lab-confirmation of HSV infection obtained, change treatment (see acyclovir-resistant recommendations above).
- Resistance testing not routinely recommended unless clear clinical failure.
Recurrent HSV: in patients on long-term suppression, consider stopping after 12 months on therapy to observe if patient is still experiencing frequent relapses.
- Note that suppression therapy does not obviate recurrences but merely reduces frequency and severity. Relapse on therapy is not solved by escalating dose.

OTHER INFORMATION

HSV suppressive therapy does NOT decrease the risk of HIV acquisition among HSV-infected, HIV-uninfected woman.
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 risk of transmission since asymptomatic shedding plays a major role in HSV transmission.
- Transmission can be reduced with either suppressive therapy or condom use.

Basis for recommendation

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 management of anogenital herpes, including management of genital herpes during pregnancy.
Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137. [PMID:26042815]
Comment: 2015 update of the 2010 CDC recommendations for treatment of sexually transmitted diseases.
Widener RW, Whitley RJ. Herpes simplex virus. Handb Clin Neurol. 2014;123:251-63. [PMID:25015489]
Comment: Clinically useful overview with focus on neurological disease ranging from pregnancy/neonatal to adults.
ACOG Committee on Practice Bulletins. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82 June 2007. Management of herpes in pregnancy. Obstet Gynecol. 2007;109(6):1489-98. [PMID:17569194]
Comment: Clear description and rationale for the recommendation for HSV management in pregnancy.

References

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. [PMID:29784511]
Comment: Review of 1028 infants who had HSV PCR peformed in blood and CSF speciments. Of the 21 who had positive CSF PCR, 76% also had positive HSV PCR in blood. The important conclusion is that a blood PCR in this population cannot be used to exclude CNS HSV infection.
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
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 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 risk of HSV-2 transmission to susceptible partners.
Rating: Important
Hull CM, Levin MJ, Tyring SK, et al. Combination Antiviral--Anti-Inflammatory Treatment for Recurrent Herpes Simplex Labialis: Rationale and Efficacy Demonstrated with a Novel Composite Efficacy Measure. Antimicrob Agents Chemother. 2013. [PMID:24342632]
Borkar DS, Gonzales JA, Tham VM, et al. Association Between Atopy and Herpetic Eye Disease: Results From the Pacific Ocular Inflammation Study. JAMA Ophthalmol. 2013. [PMID:24370901]
Comment: This was a retrospective, population-based case-control study of 114 patients with HSV ocular disease and 137 patients with herpes-zoster ocular disease (HZO) in Hawaii. Authors found that patients who had 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
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 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
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 then 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 when they received suppressive therapy with oral acyclovir for 6 months.

Rating: Important
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 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
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 was a prospective case-control study to examine immunogenetic risk factors for recurrent genital herpes. the study population included 52 eligible consecutive 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 levels of 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 infection.
Rating: Important
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 ration = 3.91; 95% confidence interval [CI] =1.23-12.44) and younger age (p<0.03). Significant risk factor for HSV-2 acquisition was anal sex with casual partners.
Rating: Important
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 a 1-gram dose of 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 day period each participant reported daily on presence or absence of genital lesions and collected daily genital and ano-rectal samples. VAC significantly decreased total days of viral shedding amongst both clinical and subclinical cases as well as 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
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 was a 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 simples virus type 2 (HSV-2, ) evaluate the role of prevalent and incident HSV-2 infection in HIV infection acquisition, and to 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, 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. Intense behavioral intervention did not increase the risk of HSV-2 infection.
Rating: Important
Shalabi M, Whitley RJ. Recurrent benign lymphocytic meningitis. Clin Infect Dis. 2006;43(9):1194-7. [PMID:17029141]
Comment: Excellent review on RBLM.
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, 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
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 number 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
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 carried out 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 60% even in the absence of antiviral suppression. Acquisition of infection by the seronegative partner and recurrence and shedding by the positive partner was significantly reduced when valacyclovir was used.
Rating: Important
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, erythema were seen. Women were more likely to have extragenital lesions than were men.
Rating: Important
Grant DM. Acyclovir (Zovirax) ophthalmic ointment: a review of clinical tolerance. Curr Eye Res. 1987;6(1):231-5. [PMID:3549163]
Comment: 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 application of 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

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