Immunocompromised patients include those who are15
- Undergoing cancer therapy
- Transplant recipients (hematopoietic stem cell transplant [HSCT]/solid organ transplant [SOT])
- Receiving immunosuppressive treatment for autoimmune diseases
- Living with HIV
For immunocompromised patients, refractory and/or resistant herpes simplex virus (HSV) infections can be a significant burden.1-3
Refractory HSV infections are when a patient shows no improvement on appropriate antiviral therapy, mainly with nucleoside analogues.3,4
For immunocompromised patients, HSV infections can be more severe and persistent
Typical HSV course
Lesion characteristics
Acyclovir resistance
Immunocompetent Patients
- Typically localized and self-limiting lesions5,6
- Resolves spontaneously or with treatment5,6
- Superficial ulcerations5,7
- Cause pain, burning, or tingling at the site of infection5,7
Rare (prevalence of <1%)5
Immunocompromised Patients
- Severe, atypical, and often persistent3,5,6
- More likely to be refractory3
- Associated with antiviral resistance3,5,6
- Increased risk of systemic disease3,5,6
- May have large, deep, and necrotic ulcerations5,6,8
- May have atypical features5,6
- Recur frequently and last longer, often becoming chronic5,6
More common (prevalence of up to 16%)2,5,9
HSV is reported in nearly two-thirds of US adults and is a growing concern in immunocompromised patients5,9,13-16
>20
MILLION
PEOPLE
PEOPLE
6.6%
OF THE US
POPULATION
POPULATION
Immunocompromised individuals represent a large and growing population at increased risk for common and opportunistic infections, which can lead to morbidity and mortality.15
Recent estimates indicate that more than 20 million people are immunocompromised, representing as much as 6.6% of the general population in the United States.15
Immunosuppressive condition prevalence in the United States, %
Adapted from Hill JA et al. JAMA Network Open. 2025;8(8):e2528383.15
Between 2013 and 2021, the population of immunocompromised patients in the United States increased by approximately 2.5-fold from
2.7% to 6.6%.15,17-19
Immunocompromised patients are at risk for opportunistic viral infections, including HSV, cytomegalovirus, and varicella-zoster virus. These infections can lead to complications, including poor outcomes.20-22
Immunocompromised patients are at risk for opportunistic viral infections, including HSV, cytomegalovirus, and varicella-zoster virus. These infections can lead to complications, including poor outcomes.20-22
Refractory and/or resistant HSV infections could pose a significant threat in an already vulnerable immunocompromised patient population3,5
Refractory and/or resistant HSV infections could pose a significant threat in an already vulnerable immunocompromised patient population3,5
Up to
1 in 7
HSCT recipients may experience refractory and resistant HSV infections.4
What is HSV treatment failure?
Refractory HSV
HSV is refractory when a patient shows no improvement on appropriate antiviral therapy, mainly with nucleoside analogues.3,4
HSV resistance
Although genotypic and phenotypic testing can confirm resistance to nucleoside analogues such as acyclovir and valacyclovir, limited availability and prolonged turnaround times may delay results.3
What is HSV treatment failure?
Refractory HSV
HSV is refractory when a patient shows no improvement on appropriate antiviral therapy, mainly with nucleoside analogues.3,4
HSV resistance
Although genotypic and phenotypic testing can confirm resistance to nucleoside analogues such as acyclovir and valacyclovir, limited availability and prolonged turnaround times may delay results.3
Clinical diagnosis of refractory HSV infections should not await laboratory confirmation of resistance, especially when timely treatment is crucial.3,4,6,10,20,23
Although rare in immunocompetent hosts, HSV resistance to nucleoside analogues is more common in immunocompromised patients5
UP TO 16%
of immunocompromised patients may harbor acyclovir-resistant HSV2,9
Impacted patient populations may include
- HSCT recipients9
- Patients with blood cancers16
- SOT recipients2
- Patients with HIV2
- Patients on certain immunosuppressive therapies5,15
95%
Thymidine kinase (TK) mutations account for 95% of acyclovir-resistant HSV isolates.24
Because TK is required for activation of nucleoside analogues, TK mutations likely confer cross-resistance to all nucleoside analogues.3,25
Not a real doctor or patient.
Are your immunocompromised patients presenting with refractory and/or resistant HSV infections?
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Are your immunocompromised patients presenting with refractory and/or resistant HSV infections?
Select all that apply to patients you see in your practice.
HSV lesions persist despite first-line prophylaxis and treatment3,4
Manifestations of HSV last longer or become more severe3
Prolonged hospitalization12,26
Requires extended courses of antiviral therapy26
Treatment may need to be adjusted for underlying conditions due to active HSV3,20,27
HSV lesions persist despite first-line prophylaxis and treatment3,4
Manifestations of HSV last longer or become more severe3
Prolonged hospitalization12,26
Requires extended courses of antiviral therapy26
Treatment may need to be adjusted for underlying conditions due to active HSV3,20,27
SCROLL TO VIEW
FAQs
HSV infections should be considered refractory when a patient shows no improvement on appropriate antiviral therapy, mainly with nucleoside analogues. Persistent or new HSV-positive lesions should prompt consideration of refractory HSV.3,4,12 Importantly, refractory HSV is a clinical diagnosis and does not necessarily indicate antiviral resistance.3,12
An immunocompromised status is a major risk factor for refractory and/or resistant HSV. Although rare in immunocompetent individuals, acyclovir-resistant HSV is more likely in immunocompromised patients, including people living with HIV, recipients of HSCT or SOT, patients receiving treatment for cancer, and those receiving certain immunosuppressive therapies. Immunocompromised patients with refractory and/or resistant HSV are at risk of severe manifestations of disease, recurrent infections, prolonged antiviral therapy, and renal injury.3,5,15
Although nucleoside analogues remain the standard first-line treatment for most HSV infections, acyclovir resistance can occur, particularly in immunocompromised patients. Alternate therapies for refractory and/or resistant disease may require intravenous administration, inpatient care, or laboratory monitoring, or they may carry the potential for significant toxicities, creating additional treatment challenges.3,12
ACV-R, acyclovir-resistance; HSCT, hematopoietic stem cell transplant; HSV, herpes simplex virus; SOT, solid organ transplant; TK, thymidine kinase.
References: 1. Bussini L et al. Clin Microbiol Infect. 2025;31(7):1234-1236. doi:10.1016/j.cmi.2025.04.011 2. Schalkwijk HH et al. Biochem Pharmacol. 2022;206:115322. doi:10.1016/j.bcp.2022.115322 3. Chemaly RF et al. Clin Infect Dis. 2025;81(3):593-601. doi:10.1093/cid/ciae638 4. Shafat T et al. Clin Microbiol Infect. 2025;31(5):761-772. doi:10.1016/j.cmi.2025.01.033 5. Birkmann A, Saunders R. Antiviral Res. 2025;237:106152. doi:10.1016/j.antiviral.2025.106152 6. Piperi E et al. Oral Dis. 2024;30(3):877-894. doi:10.1111/odi.14635 7. World Health Organization. Updated May 30, 2025. Accessed July 17, 2026. https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus 8. National Institutes of Health. Updated May 27, 2026. Accessed July 17, 2026. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/whats-new 9. Sallée L, Boutolleau D. Rev Med Virol. 2024;34(5):e2574. doi:10.1002/rmv.2574 10. Dähne T et al. Clin Microbiol Infect. 2025;31(9):1484-1490. doi:10.1016/j.cmi.2025.04.046 11. Gupta R et al. Lancet. 2007;370(9605):2127-2137. doi:10.1016/S0140-6736(07)61908-4 12. Hammond SP et al. Open Forum Infect Dis. 2024;11(3):ofae046. doi:10.1093/ofid/ofae046 13. American Sexual Health Association. Updated April 22, 2026. Accessed July 17, 2026. https://www.ashasexualhealth.org/herpes/ 14. United States Census Bureau. Updated July 1, 2025. Accessed July 17, 2026. https://www.census.gov/quickfacts/fact/table/US/PST045225 15. Hill JA et al. JAMA Netw Open. 2025;8(8):e2528383. doi:10.1001/jamanetworkopen.2025.28383 16. Alsuliman T et al. Lancet Haematol. 2024;11(10):e792-e802. doi:10.1016/S2352-3026(24)00210-2 17. Harpaz R et al. JAMA. 2016;316(23):2547-2548. doi:10.1001/jama.2016.16477 18. Patel M et al. Emerg Infect Dis. 2020;26(8):1720-1730. doi:10.3201/eid2608.191493 19. Martinson ML, Lapham J. JAMA. 2024;331(10):880-882. doi:10.1001/jama.2023.28019 20. Lee DH et al. Clin Transplant. 2019;33(9):e13526. doi:10.1111/ctr.13526 21. Pergam SA et al. Clin Transplant. 2019;33(9):e13622. doi:10.1111/ctr.13622 22. Haidar G et al. J Infect Dis. 2020;221(suppl 1):S23-S31. doi:10.1093/infdis/jiz454 23. Papanicolaou GA et al. Open Forum Infect Dis. 2026;13(7):ofag377. doi:10.1093/ofid/ofag377 24. Shehadeh R et al. J Oral Pathol Med. 2026;55(2):244-248. doi:10.1111/jop.70078 25. Park JJ et al. J Hematol Oncol Pharm. 2021;11(4):210-215. 26. Berger JI et al. Cureus. 2026;18(6):e110131. doi:10.7759/cureus.110131 27. Eckardt K-U, Kasiske BL; Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Working Group. Am J Transplant. 2009;9(suppl 3):S1-155. doi:10.1111/j.1600-6143.2009.02834.x