Revisiting Old Foes: Updates on HSV

Herpes simplex viruses (HSV) cause chronic viral infections, and the seroprevalence ranges from 15% to 100%. The World Health Organization (WHO) reported that 3.7 billion people under the age of 50 years had HSV-1 infection, and genital herpes caused by HSV-2 affected an estimated 491 million people aged 15 to 49 years worldwide in 2016.¹

The seroprevalence of HSV-1 and HSV-2 were 47.8% and 11.9%, respectively, among individuals aged 14 to 49 years in the United States.² Substantial racial and ethnic disparities in HSV-2 infection exist. The cumulative lifetime incidence of HSV-2 reaches 25% in White women, 20% in White men, 80% in Black women, and 60% in Black men.³

PATHOPHYSIOLOGY AND TRANSMISSION

Herpes viruses possess an internal core containing double-stranded DNA surrounded by tegument and a lipid envelope. Both HSV-1 and HSV-2 are shed on mucosal surfaces or in oral or genital secretions and transmitted through inoculation of the virus onto mucosal surfaces or abraded skin.³

The primary HSV infection tends to be more prolonged and severe than recurrent infections. Following the primary infection, the virus enters sensory neurons, from which it is then transported to neuronal cell bodies where latency can be established. Subsequent reactivation causes recurrent less severe mucocutaneous infections of the oral cavity or genitalia. HSV-2 can be asymptomatically shed in the genital mucosa.⁴

PRESENTATIONS

Susceptible persons who are seronegative develop primary infection after their first exposure to HSV. Initial infection occurs when a person who is seropositive for either HSV-1 or HSV-2 is infected with the other virus for the first time.⁴ Manifestations of the primary infection can be asymptomatic, mild, or severe. The most common sites of infection are the skin and the mucous membranes regardless of virus type.

HSV-1 infection typically presents first as pain and paresthesia in the orolabial area followed by 3 to 5 vesicles that heal after several days. The primary infection may be accompanied by fever, systemic symptoms, and intraoral lesions. Intraoral ulcerative lesions indicate primary infection, whereas lip lesions suggest recurrent infection.

Primary infection lasts around 2 to 3 weeks whereas recurrences tend to be shorter, around 8 to 10 days. Although both HSV-1 and HSV-2 can cause devastating encephalitis, HSV-1 is by far the most common agent; furthermore, HSV-1 encephalitis is the most common fatal encephalitis in the US. Other manifestations of HSV-1 infection include herpetic whitlow, herpes gladiatorum seen in wrestlers, eczema perpeticum in patients with atopic dermatitis, and erythema multiforme.

Genital herpes typically starts as papules followed by vesicles, pustules, and finally ulcers. HSV-2 perianal and proctitis are most common in men who have sex with men. The condition can cause urinary retention in women. Localized inguinal adenopathy may also be present with fever and systemic symptoms during primary infection. Viral meningitis is much more common with HSV-2.

Benign recurrent lymphocytic meningitis (Mollaret meningitis) is characterized by recurrent self-liming meningitis without neurologic sequelae.^3,4 Other, more infrequent manifestations of HSV are acute lumbosacral radiculitis featuring cauda equina syndrome with myelitis, referred to as Elsberg syndrome,⁵ and disseminated HSV infection. Disseminated infection involves the skin, esophagus, liver, lungs, and central nervous system, and nearly all cases occur in immunocompromised hosts.³ HSV reactivations are common in critically ill patients with acute respiratory distress syndrome (ARDS).

HSV-1 DNA has been isolated from the respiratory tract in patients with severe COVID-19 ARDS while they are mechanically ventilated, and it has also been isolated from blood. The proposed pathogenesis is a dysregulated and excessive immune response that also causes a deficiency of the necessary interferon activity for immune control of HSV-1. The therapy of dexamethasone and tocilizumab that is often used to treat severe COVID-19 infection can further induce immunosuppression and predispose individuals to HSV-1 infection. Cases of pneumonitis as well as 2 cases of fatal acute liver failure secondary to HSV-1 reactivation have been documented in the literature.⁶

DIAGNOSTICS

The infection is typically diagnosed clinically by characteristic painful vesicular lesions in the appropriate clinical setting. HSV infection is best confirmed by isolation of the virus by an HSV-1/2 polymerase chain reaction test or viral culture from the active mucocutaneous lesions or other affected sites. In general, the serological test has a limited role in diagnosing HSV infection, but it permits subtyping of the virus, which may have prognostic values for predicting the frequency of recurrence after the first episode. Acute- and convalescent-phase serum is useful in demonstrating seroconversion during HSV infection.

Should we test asymptomatic patients for HSV serology? The serology test for asymptomatic individuals is not recommended as many commercially available HSV serology tests are not sufficiently accurate, and false positive results can cause psychological harm among patients. Most people remain asymptomatic and never show any manifestation of the disease.^7,8

TREATMENT

The treatment of choice for most is the oral guanosine nucleoside analogues acyclovir, valacyclovir (prodrug of acyclovir), or famciclovir.⁴ These are appropriate treatment options for most immunocompetent individuals.⁴ Patients with disseminated and or visceral infection should receive intravenous acyclovir. Acyclovir-resistant strains of HSV are well described and mostly seen in immunocompromised patients such as recipients of solid organ transplant or hematopoietic stem cell transplants, individuals with hematologic malignancies or AIDS, those receiving antithymocyte biologic therapies, and those with congenital immunodeficiencies.

Recurrent disseminated or local infections can be common and associated with resistance to acyclovir and likely cross-resistance to other guanosine analogues.^9,10 The most common mechanism of resistance is absent, reduced, or altered viral thymidine kinase activity, which is essential for the phosphorylation of acyclovir, a nucleoside analogue, to be incorporated in the viral DNA.^4,10 Resistance and treatment failure should be suspected when active lesions persist without apparent reduction in size or development of satellite lesions 7 to 10 days after initiation of guanosine analogues.¹⁰

Molecular testing for acyclovir resistance is not available. A sample for viral culture is needed for phenotypic resistance testing. The initial step for suspected acyclovir-resistant HSV infection is to administer high-dose intravenous acyclovir at 10 mg/kg every 8 hours.¹¹ A higher dose of acyclovir clears the lesions in some patients, whereas in others the infection may persist. The therapy with foscarnet is often effective for acyclovir-resistant HSV; although, adverse reactions including electrolyte disturbances and renal insufficiency are common with foscarnet.^11,12 

Cidofovir can also be an option, as it is an deoxycytidine analogue, which does not require viral thymidine kinase; however, intravenous cidofovir is associated with severe toxicity, including neutropenia.^11,13 A new antiviral, pritelivir, with a novel mechanism of action, inhibits the helicase/ primase complex and does not require activation. Pritelivir is currently undergoing phase 3 clinical trials.^10,11,14

PREVENTION

Prevention is more often emphasized regarding HSV-2 than HSV-1, given the latter’s ubiquitous presence, although HSV-2 could become just as ubiquitous.¹⁵ Condoms and safer-sex practices can reduce the risk of acquiring HSV-2 infection from an asymptomatic infected partner by 30%.¹⁶ Abstinence during periods with active mucosal lesions is important.³ Chronic suppressive therapy with valacyclovir reduced transmission of genital herpes by 50%.¹⁷

Immunization is another potential avenue, as it could be cost-effective to prevent HSV-1 or HSV-2 and reduce their associated costs such as frequent outpatient visits, antiviral therapy, hospitalizations (intensive care unit stay for herpes encephalitis), and psychological burden. However, vaccine efforts have fallen short, possibly because HSV-1 and HSV-2 can reactivate even with intact cellular and humoral immunity.⁴ There is no promising vaccine under way.

CONCLUSION

Genital herpes caused by HSV-2 affects an estimated 491 million (13%) individuals aged 15 to 49 years worldwide.¹ HSV is a lifelong infection; the prevalence increases with age, although the highest number of new infections is in adolescents. Both HSV-2 and HSV-1 are spread through contact with a herpetic lesion, mucosal surface, or genital or oral secretions of an infected person.

Consistent condom use is the mainstay of preventing HSV-2. Antiviral agents are effective in reducing the risk of transmission, preventing recurrent genital herpes, and treating the disease. The prevalence of acyclovir-resistant HSV is less than 1% in immunocompetent individuals.¹⁸ Highdose acyclovir and foscarnet are usually effective in treating acyclovir-resistant HSV infection. Despite the global health burden of HSV and several decades of research, there are no licensed prophylactic or therapeutic vaccines.

References

1. Herpes simplex virus. WHO. March 10, 2022. Accessed September 7, 2022. https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus

2. Prevalence of herpes simplex virus type 1 and type 2 in persons aged 14-29: United States, 2015-2016. National Center for Health Statistics. Updated February 7, 2018. Accessed September 12. 2022 https://www.cdc.gov/nchs/products/databriefs/db304.htm

3. Mandell, Douglas, and Bennett’s Principal and Practice of Infectious Diseases, 17th edition

4. Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet. 2001;357(9267):1513-1518. doi:10.1016/S0140-6736(00)04638-9

5. Savoldi F, Kaufmann TJ, Flanagan EP, Toledano M, Weinshenker BG. Elsberg syndrome: a rarely recognized cause of cauda equina syndrome and lower thoracic myelitis. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e355. doi:10.1212/NXI.0000000000000355

6. Giacobbe DR, Di Bella S, Lovecchio A, et al. Herpes simplex virus 1 (HSV-1) reactivation in critically ill COVID-19 patients: a brief narrative review. Infect Dis Ther. 2022;1:1-13. doi:10.1007/s40121-022-00674-0

7. Serologic screening for genital herpes infection: recommendation statement. Am Fam Physician. 2017;95(12):online.

8. Feltner C, Grodensky C, Ebel C, et al. Serologic screening for genital herpes: an updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2016;316(23):2531-2543. doi:10.1001/jama.2016.17138

9. Martin SI, Marty FM, Fiumara K, Treon SP, Gribben JG, Baden LR. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis. 2006;43(1):16-24. doi:10.1086/504811

10. Bacon TH, Levin MJ, Leary JJ, Sarisky RT, Sutton D. Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev. 2003;16(1):114-128. doi:10.1128/CMR.16.1.114-128.2003

11. Piret J, Boivin G. Antiviral resistance in herpes simplex virus and varicella-zoster virus infections: diagnosis and management. Curr Opin Infect Dis. 2016;29(6):654-662. doi:10.1097/QCO.0000000000000288

12. Garikapati S, Nguyen M. Foscarnet. [Updated 2022 Jan 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556108/

13. Gupta M, Shorman M. Cytomegalovirus. [Updated 2022 May 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459185/

14. Wald A, Timmler B, Magaret A, et al. Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences: a randomized clinical trial. JAMA. 2016;316(23):2495-2503. doi:10.1001/jama.2016.18189

15. Wald A, Corey L. Persistence in the population: epidemiology, transmission. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al, eds. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge University Press; 2007. Accessed September 12, 2022. https://www.ncbi.nlm.nih.gov/books/NBK47447/

16. Martin ET, Krantz E, Gottlieb SL, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med. 2009;169(13):1233-1240. Published correction appears in: Arch Intern Med. 2010;170(11):929.

17. Corey L, Wald A, Patel R, et al; Valacyclovir HSV Transmission Study Group. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350(1):11-20. doi:10.1056/NEJMoa035144

18. Christophers J, Clayton J, Craske J, et al. Survey of resistance of herpes simplex virus to acyclovir in northwest England. Antimicrob Agents Chemother. 1998;42(4):868.