Herpes Simplex Virus in Immunocompromised Patients

Target Audience

The educational design of this activity addresses the needs of specialists in infectious disease, hematology/oncology, critical care, obstetrics/gynecology, dermatology, urology, microbiology, and transplant surgery; primary care providers; hospital/health-system/specialty pharmacists; nurse practitioners; and physician assistants involved in the treatment of patients with herpes simplex virus (HSV).

Statement of Need

In immunocompromised patients, reactivation of HSV is frequently prolonged, atypical, and resistant to standard antiviral therapy. The only FDA-approved salvage agents require intravenous administration and carry substantial toxicity burdens that often limit their use. Clinicians face knowledge gaps in recognizing atypical presentations, applying current diagnostic definitions, and selecting appropriate salvage therapy. A novel oral helicase–primase inhibitor is under FDA Priority Review, underscoring the need for timely education on emerging treatment options for this vulnerable population.

Goal

The goal of this activity is to educate clinicians about HSV infections in immunocompromised patients, including clinical presentation, use of diagnostic tests and clinical definitions, effective treatment strategies, the importance of considering resistance, the potential for atypical clinical presentations, and a new class of agents under regulatory review that may offer clinical advantages over existing salvage therapies.

Learning Objectives

After completing this activity, the participant should be better able to:

1. Discuss the risk factors and resistance mechanisms that may occur in immunocompromised patients with HSV.
2. Describe the presentation of HSV lesions in immunocompromised patients, highlighting variations in atypical cases.
3. Identify HSV reactivation in immunocompromised patients, using appropriate clinical definitions and recognizing the need for diagnostic testing.
4. Develop strategies to treat refractory HSV in immunocompromised patients, focusing on maximizing effectiveness, improving administration schedules, and minimizing toxicities.

Faculty

Physician Accreditation Statement

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation

Global designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Accreditation Statement

Global is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education with Commendation.

Pharmacist Credit Designation

Global designates this continuing education activity for 1.0 contact hour (0.01 CEUs) of the ACPE (Universal Activity Number - 0530-9999-26-027-H01-P).

This is a knowledge-based activity.

Global Contact Information

For information about the accreditation of this program, please contact Global at (303) 395-1782 or cme@globaleducationgroup.com.

Instructions to Receive Credit

In order to receive credit for this activity, participants must participate in the activity and complete and pass the post-test with a minimum score of 70%. In addition, participants must complete the evaluation. CME certificates will be sent via email to those who complete the activity successfully.

System Requirements

PC: 1.0 GHz or faster 64-bit processors (2+ cores), 4 GB RAM, 64 GB storage, UEFI secure boot, and TPM 2.0. For better performance, 8 GB+ RAM and SSD storage are recommended

MAC: Mac with an Apple silicon processor (M1 or newer) or Intel 64-bit processor, 4 GB RAM minimum, and 64 GB available storage. For optimal performance, 8 GB or more RAM and SSD storage are recommended

Browser: latest version of Chrome, Safari, Edge, or Firefox with cookies and JavaScript enabled

Internet connection: broadband internet connection with a minimum speed of 5 Mbps recommended for smooth streaming and interactive features

Fee Information and Refund/Cancellation Policy

There is no fee for this educational activity.

Disclosures of Relevant Financial Relationships

Global adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the ACCME and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scientifically rigorous. All persons in a position to control the content of an accredited continuing education program provided by Global are required to disclose all financial relationships with any ineligible company within the past 24 months to Global. All financial relationships reported are identified as relevant and mitigated by Global in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by Global to assure objectivity and that the activity is free of commercial bias.

All relevant financial relationships have been mitigated.

The faculty have the following relevant financial relationships with ineligible companies:

• Yeon Joo Lee: Contracted research (principal investigators must provide information, even if received by the institution): AiCuris, Eurofins-Viracor, Merck Sharp & Dohme; other: AiCuris (travel support)
• Jonathan Hand, MD: Consulting fees (eg, advisory board): AstraZeneca, Innoviva, Pfizer; contracted research (principal investigators must provide information, even if received by the institution): AstraZeneca, Janssen, Karius, Pfizer, Scynexis

The planners and managers have the following relevant financial relationships with ineligible companies: The planners and managers at Global and ACE have no relevant financial relationships to disclose.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global and ACE do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

This activity is jointly provided by
Global Education Group and Applied Clinical Education.

This activity is supported by an educational grant from AiCuris.

This activity is distributed by Infectious Disease Special Edition, CMEZone, and Pharmacy Practice News.

1. Before/after participating in this activity, how confident are you in identifying herpes simplex virus (HSV) reactivation in immunocompromised patients, using appropriate clinical definitions and recognizing the need for diagnostic testing?
   1. Very confident
   2. Somewhat confident
   3. Not very confident
   4. Not at all confident
   Polling question; no correct answer
2. In immunocompromised patients, approximately what proportion of acyclovir-resistant HSV strains result from thymidine-kinase (TK) deficiency or alteration?
   1. Approximately 30%
   2. Approximately 50%
   3. Approximately 75%
   4. Approximately 95%
   Correct answer: D

   Rationale: TK-deficient or TK-altered mutants account for approximately 95% of acyclovir-resistant strains in clinical practice and are typically cross-resistant to valacyclovir and famciclovir.
3. Which of the following patients is at highest risk for developing acyclovir-resistant HSV?
   1. A 45-year-old solid organ transplantation (SOT) recipient on stable maintenance immunosuppression with no prior HSV reactivations
   2. A 38-year-old with HIV on effective antiretroviral therapy and a CD4 count of 450 cells/mm³
   3. A 52-year-old allogeneic hematopoietic stem cell transplantation (HSCT) recipient with active graft-vs-host disease (GVHD) on corticosteroids and T-cell–depleting agents
   4. A 60-year-old receiving rituximab monotherapy for indolent lymphoma
   Correct answer: C

   Rationale: HSCT recipients with active GVHD requiring T-cell–depleting agents and corticosteroids represent the highest-risk profile, with acyclovir resistance documented in up to 14% of HSCT recipients.
4. A 63-year-old man with chronic lymphocytic leukemia presents with a rapidly enlarging, partially necrotic exophytic lesion on the nasal ala that has not responded to antibiotics. Which of the following is the most appropriate next step?
   1. Repeat bacterial cultures and broaden antibiotic coverage
   2. Empiric antifungal therapy
   3. Biopsy and polymerase chain reaction (PCR) testing of the lesion for HSV
   4. Surgical debridement without further diagnostic workup
   Correct answer: C

   Rationale: Atypical necrotizing or exophytic lesions in immunocompromised patients that fail to respond to antibiotics should prompt evaluation for HSV, including biopsy and PCR. HSV can mimic bacterial necrotizing infections, malignancy, and other ulcerative dermatoses in this population.
5. Which of the following visceral manifestations of HSV may occur in the absence of mucocutaneous lesions in profoundly immunocompromised patients?
   1. Pericarditis and myocarditis
   2. Hepatitis, pneumonitis, or encephalitis
   3. Colitis and small bowel ulceration
   4. Orchitis and epididymitis
   Correct answer: B

   Rationale: HSV can involve the liver, lungs, adrenal glands, and central nervous system in immunocompromised patients, presenting as hepatitis, pneumonitis, adrenalitis, or encephalitis, sometimes without any mucocutaneous findings, which can significantly delay diagnosis.
6. According to the HSV Resistance Working Group of the Transplantation Associated Virus Infections (TAVI) Forum, which of the following best defines refractory mucocutaneous HSV infection?
   1. Recurrence of HSV lesions within 30 days of completing a treatment course
   2. Detection of a TK mutation on genotypic resistance testing
   3. Lack of clinical improvement in HSV-positive lesions after at least 7 days of appropriately dosed directed antiviral therapy, in the absence of other plausible causes
   4. Failure to achieve complete lesion healing within 72 hours of initiating antiviral therapy
   Correct answer: C

   Rationale: The TAVI Forum consensus definition requires at least 7 days of appropriately dosed directed—not prophylactic or suppressive—antiviral therapy before a diagnosis of refractory infection can be made. Laboratory confirmation of resistance is required for the designation of resistant HSV but not for refractory HSV.
7. A clinician suspects acyclovir-resistant HSV in an immunocompromised patient and orders phenotypic resistance testing. Which of the following statements about this testing is accurate?
   1. FDA-cleared commercial assays are widely available and provide results within 48 hours.
   2. A negative phenotypic result reliably excludes resistance in immunocompromised patients.
   3. Phenotypic testing is less useful than serology for confirming active resistance.
   4. Results typically require 2 to 3 weeks and are available only at specialized centers.
   Correct answer: D

   Rationale: Phenotypic plaque reduction assays require viable virus and specialized laboratory infrastructure, with turnaround times that typically exceed 2 to 3 weeks. No FDA-cleared commercial HSV phenotypic resistance assay exists, and treatment decisions must often be made empirically while testing is pending.
8. In the PRIOH-1 phase 3 trial, what was the rate of complete lesion healing with pritelivir at the primary end point (day 28) compared with investigator’s choice therapy?
   1. 52.1% vs 34.0%
   2. 62.7% vs 34.0%
   3. 74.3% vs 41.2%
   4. 82.4% vs 42.0%
   Correct answer: B

   Rationale: Complete lesion healing at day 28 occurred in 62.7% of pritelivir-treated patients vs 34.0% of those receiving investigator’s choice therapy (treatment difference 28.4%, P=0.0047). The 82.4% vs 42% figures represent day 42 outcomes with extended treatment.
9. Which of the following most accurately describes what makes pritelivir mechanistically distinct from all currently available salvage therapies for resistant HSV?
   1. Pritelivir inhibits viral DNA polymerase and requires TK activation, providing higher potency than acyclovir
   2. Pritelivir is an oral helicase–primase inhibitor that does not require TK activation and retains activity against both TK-deficient and foscarnet-resistant HSV strains
   3. Pritelivir is an IV pyrophosphate analog that inhibits DNA polymerase without requiring TK activation
   4. Pritelivir acts as an immune response modifier that enhances local antiviral immunity without direct antiviral activity
   Correct answer: B

   Rationale: Pritelivir targets the viral helicase–primase complex (UL5, UL52, UL8), bypasses TK activation entirely, and retains activity against TK-deficient and foscarnet-resistant strains. It is oral and well tolerated—a combination of properties not shared by any currently approved salvage agent.
10. A 72-year-old man with advanced HIV (CD4 count 50 cells/mm³) presents with necrotizing perianal and anogenital HSV-2 lesions confirmed as acyclovir-resistant with preserved foscarnet susceptibility. His eGFR is 40 mL/min/1.73 m². He is initiated on renal dose-adjusted IV foscarnet; by day 7 his eGFR falls to 28 mL/min/1.73 m² and foscarnet is discontinued at day 17 due to progressive nephrotoxicity with residual ulcerations persisting. Cidofovir is contraindicated given his renal dysfunction. Which of the following represents the most appropriate next step?
    1. Reinitiate foscarnet at a further reduced dose and accept ongoing nephrotoxicity risk
    2. Initiate high-dose continuous IV acyclovir infusion as definitive salvage therapy
    3. Refer for evaluation for the pritelivir expanded access program, with topical compounded cidofovir as a temporizing measure
    4. Transition to oral valacyclovir suppressive therapy and monitor for spontaneous resolution
    Correct answer: C

    Rationale: This patient has failed the only FDA-approved salvage option and cannot receive cidofovir due to renal dysfunction—the scenario that defines the critical unmet need in this population. Pritelivir, available through expanded access protocol NCT05844436 for immunocompromised patients with refractory HSV who have no approved alternatives, is oral, TK-independent, and has a renal-sparing profile. Topical compounded cidofovir serves as a bridge while enrollment is pursued.