Herpesvirus Infections

Herpes simplex virus (HSV-1 and HSV-2) and varicella-zoster virus (VZV) are related human herpesviruses that share a defining biological feature: after the initial infection, each establishes lifelong latency in sensory nerve ganglia and can reactivate periodically to cause recurrent disease. HSV causes orolabial disease (cold sores, most often HSV-1) and anogenital disease (genital herpes, most often HSV-2, though either type can cause either site through oro-genital contact); VZV causes chickenpox on primary infection and, on reactivation from the dorsal root or cranial nerve ganglia, herpes zoster (shingles) — a painful, dermatomal vesicular rash. Knowledge of HSV type does not change antiviral drug selection, since HSV-1 and HSV-2 are similarly susceptible to all three available agents — drug choice is driven by disease site, severity, and dosing convenience instead.^[1] This chapter covers the three antiviral nucleoside analogues (acyclovir, valacyclovir, famciclovir) that treat all of these presentations, the distinct dosing and duration each disease requires, the narrow treatment window that determines how effective zoster therapy will be, and the situations — ophthalmic zoster, disseminated disease in immunocompromised hosts, and pregnancy — that change management. Primary varicella (chickenpox) and routine varicella/zoster immunization schedules are outside this chapter's scope, which focuses on treating established HSV and herpes zoster disease.

HSV (orolabial and genital)

• Direct mucocutaneous or secretional contact with an infected partner, including during asymptomatic viral shedding — most transmission occurs when no lesion is visible.
• New or multiple sexual partners, for genital HSV specifically.
• Sun exposure, physical or emotional stress, febrile illness, local trauma, and menstruation are common recurrence triggers for orolabial and, less consistently, genital HSV.
• Immunosuppression (HIV, transplant, chemotherapy, high-dose corticosteroids, biologic therapy) — associated with more frequent, more severe, and longer-lasting recurrences, and a higher risk of antiviral-resistant disease.
• Orogenital contact, which can transmit HSV-1 to the genitals or HSV-2 to the mouth.

Herpes zoster

• Age 50 and older — risk and severity, including postherpetic neuralgia risk, rise steadily with age.
• Any cause of reduced cell-mediated immunity — HIV infection, hematologic or solid organ malignancy, transplant, chemotherapy, high-dose or prolonged corticosteroid use, and other immunosuppressive therapy.
• Physical or emotional stress and other causes of transient immune waning.
• A history of primary varicella (chickenpox) infection at any point in the past — required for zoster to occur at all, since it is caused by reactivation of latent VZV.

History

• For orolabial disease: ask about prodrome timing, sun/stress/illness triggers, and recurrence frequency over the past year.
• For genital disease: characterize the lesion (single vs. multiple, painful vs. painless, vesicular vs. ulcerative), ask about prodrome and exposure history, and screen for other STIs and HIV risk at the same visit.
• For a dermatomal rash: confirm it is unilateral and does not cross the midline, ask about preceding pain, and assess for herpes zoster risk factors (age, immunosuppression).
• For any of the three presentations, ask specifically about immunosuppression (HIV, transplant, chemotherapy, high-dose corticosteroids, biologic therapy) and pregnancy status, since both change management.

Examination and testing

Viral culture remains an acceptable alternative where NAAT is unavailable, though its sensitivity declines as lesions heal. Type-specific serology (glycoprotein G-based assays distinguishing HSV-1 from HSV-2) has a narrow role — confirming infection in a patient with a compatible history but negative virologic testing, or evaluating a partner in a discordant couple — but should not be used as a general screening test given its low positive predictive value in a low-prevalence population; a positive serology result alone, without a corresponding clinical picture, is not by itself an indication to start treatment.^[1]

Herpes zoster is usually diagnosed clinically from the characteristic dermatomal vesicular rash; testing (PCR of vesicular fluid, or a Tzanck smear showing multinucleated giant cells, which does not distinguish HSV from VZV) is reserved for atypical presentations, immunocompromised patients, or disseminated disease. Consider zoster even without a visible rash ("zoster sine herpete") in an older patient with new, severe, unilateral dermatomal pain.

Genital herpes ulcers are typically multiple, small, painful, and vesiculoulcerative, in contrast to the classically single, large, painless chancre of primary syphilis — but there is real overlap in presentation, as the Sexually Transmitted Infections chapter's Syphilis section notes when differentiating the two. Do not rule out syphilis on the basis of an atypical-looking ulcer, and consider concurrent syphilis serology, HIV testing, and screening for other STIs at the same visit as a new genital HSV diagnosis.

Do not delay empiric antiviral treatment while awaiting confirmatory results in a patient with a classic presentation — start therapy based on the clinical picture, since delaying treatment reduces its effectiveness for every condition covered in this chapter.

• Shorten the duration and severity of the acute episode for orolabial HSV, genital HSV, and herpes zoster alike, which requires starting antiviral therapy as early as possible in each.
• Reduce the frequency and burden of recurrent orolabial or genital HSV outbreaks with suppressive therapy when the recurrence pattern or patient burden warrants it.
• Reduce — though not eliminate — HSV viral shedding and the risk of transmission to sexual partners.
• Reduce the risk of postherpetic neuralgia by starting herpes zoster antiviral therapy within 72 hours of rash onset, or later if specific extension criteria apply.
• Prevent vision-threatening complications of herpes zoster ophthalmicus through same-day ophthalmology referral, in addition to systemic antiviral therapy.
• Prevent disseminated VZV or HSV disease and its complications (pneumonitis, hepatitis, encephalitis) in immunocompromised patients.
• Prevent neonatal HSV transmission at delivery and limit the impact of maternal VZV exposure or infection in pregnancy.

• Avoid touching, scratching, or picking at active lesions of any of the three conditions to reduce autoinoculation (e.g., spreading HSV to the eye or fingers) and secondary bacterial infection.
• Keep the rash/lesions clean and dry; loose, non-restrictive clothing over a zoster rash reduces discomfort.
• Orolabial HSV: avoid sharing lip balm, razors, cups, or utensils during an active outbreak; for sun-triggered recurrences, use a sunscreen lip balm and consider short-course antiviral prophylaxis before planned sun exposure (see Drug Tables).
• Genital HSV: avoid sexual contact from the first sign of prodrome until lesions have fully healed; barrier protection (condoms) reduces but does not eliminate transmission risk between outbreaks and during suppressive therapy, and should be continued.
• Disclose a genital HSV diagnosis to sexual partners and offer them information/testing — this is a counselling point, not a mandatory-notification requirement the way it is for classic bacterial STIs.
• Cool compresses, loose clothing, and non-adhesive dressings for herpes zoster; avoid topical antibiotics and adhesive dressings, which can irritate the rash and delay healing.
• Vaccine prevention (brief note): the recombinant zoster vaccine (Shingrix) is routinely recommended for immunocompetent adults 50 years of age and older, given as 2 intramuscular doses 2-6 months apart, and can be given starting at least 1 year after an acute zoster episode. NACI now also strongly recommends 2 doses for adults 18 years of age and older who are or will be immunocompromised, using the same interval. The vaccine treats nothing acutely — it is prevention only, for a future episode, and is a distinct topic from the antiviral treatment covered in the rest of this chapter.^[8]

Pregnancy — genital and orolabial HSV

Pregnancy — VZV exposure

Pediatrics

Primary HSV gingivostomatitis is more common in children than adults. In a child able to swallow, oral acyclovir suspension 15 mg/kg PO 5 times daily for 7 days accelerates resolution of oral lesions and fever and shortens viral shedding when started early in the illness; supportive care (analgesia, hydration) remains essential regardless.^[11] If the child cannot tolerate oral intake, hospitalize for IV acyclovir and IV fluids. Primary varicella (chickenpox) treatment and routine varicella/zoster immunization schedules are outside this chapter's scope.

Immunocompromised patients, including HIV

Recurrent genital HSV episodes in HIV-positive patients are treated with the same three agents at somewhat higher-intensity dosing and longer duration than in HIV-negative patients (see Drug Tables) — involve infectious diseases for guidance and ensure antiretroviral therapy is optimized, since ongoing immune suppression increases the risk of prolonged, refractory disease and antiviral-resistant HSV.^[1] Severely immunocompromised patients (hematopoietic stem-cell transplant, high-dose immunosuppression, advanced HIV) are at the highest risk of VZV dissemination and visceral organ involvement, and of acyclovir-resistant HSV/VZV requiring IV foscarnet.^[2]

Renal impairment

Acyclovir, valacyclovir, and famciclovir are all renally eliminated and require dose or interval adjustment as renal function declines. With IV acyclovir specifically, ensure adequate hydration and infuse over at least 60 minutes to reduce the risk of crystalline nephropathy from acyclovir precipitation in the renal tubules.

• Reassess healing and symptom resolution within the expected timeframe for the condition treated — days for a treated HSV outbreak, 2-4 weeks for herpes zoster — and reassess sooner if symptoms are worsening rather than improving.
• For patients on HSV suppressive therapy, periodically reassess adherence, breakthrough recurrences, and whether ongoing suppression is still needed, rather than continuing indefinitely by default — recurrence frequency for many patients decreases over time.^[1]
• Reassess renal function periodically in patients on long-term or high-dose antiviral therapy, and adjust doses as needed.
• Track pain trajectory after herpes zoster; screen for postherpetic neuralgia if pain persists beyond acute rash resolution, and manage per the Neuropathic Pain chapter's approach if it does.
• Confirm that a new genital HSV diagnosis included counselling on disclosure, safer sex practices, and the psychosocial impact of the diagnosis — this is a substantial part of management, not an afterthought.
• At a follow-up visit after an acute zoster episode, confirm the patient is aware of their eligibility for the recombinant zoster vaccine (Shingrix) once at least 1 year has passed, if not already vaccinated.^[8]
• Confirm ophthalmology follow-through for any patient referred for ocular involvement.

1. Confirm the diagnosis, the correct dose, and correct timing (started within the recommended window) before concluding the drug itself has failed.
2. For a genital ulcer not responding to appropriate HSV therapy, reconsider syphilis or another cause and retest, rather than repeating or escalating HSV therapy empirically.
3. In an immunocompromised patient whose lesions fail to improve or progress despite an adequate antiviral course, consider acyclovir-resistant HSV or VZV — obtain viral culture with resistance testing and switch to IV foscarnet under infectious diseases direction.^[2]
4. For breakthrough recurrences on suppressive therapy, confirm adherence first; if genuinely adherent, consider switching agent or increasing the dose (for example, valacyclovir 500 mg to 1 g once daily for 10 or more recurrences per year) before concluding suppression has failed.^[1]
5. For pain persisting beyond the acute zoster phase (postherpetic neuralgia), manage per the Neuropathic Pain chapter's approach — topical lidocaine, gabapentinoids, and tricyclic antidepressants are first- and second-line there — and refer to a pain specialist if refractory.
6. For vision changes, worsening eye pain, or new visual symptoms during or after treatment for zoster ophthalmicus, arrange urgent same-day ophthalmology reassessment rather than managing further by telephone.

• Declining to start herpes zoster antiviral therapy solely because more than 72 hours have passed, without checking for the specific situations (new vesicles still forming, ophthalmic involvement, immunocompromise, severe pain) that still justify starting it.^[2]
• Treating herpes zoster ophthalmicus, or any vesicles on the tip or side of the nose, with oral antiviral therapy alone and skipping the same-day ophthalmology referral.^[3]
• Relying on topical acyclovir cream as adequate therapy for genital HSV, extensive orolabial disease, or herpes zoster — none of these respond adequately to a topical agent alone.
• Assuming a single "textbook" painless genital ulcer excludes herpes, or a "textbook" cluster of painful vesicles excludes syphilis — real-world presentations overlap significantly.
• Telling a patient on HSV suppressive therapy that barrier protection is no longer needed because transmission risk is eliminated — it is reduced, not eliminated.^[1]
• Missing renal dose adjustment for antivirals in older adults or anyone with reduced renal function, especially with IV acyclovir.
• Withholding antiviral therapy for a pregnant patient with genital HSV or a VZV exposure/infection out of unfounded teratogenicity concern, when reassuring safety data exist for every trimester.^[9]
• Forgetting to counsel a patient recovering from an acute zoster episode about future recombinant zoster vaccine eligibility.^[8]
• Adding a corticosteroid to zoster therapy expecting it to reduce postherpetic neuralgia risk — it does not; use it for quality-of-life reasons only, in carefully selected healthy patients with significant acute pain.^[7]
• Missing the opportunity to offer VariZIG, or postexposure oral antiviral prophylaxis if VariZIG is unavailable or out of its window, to a non-immune pregnant patient with a significant VZV exposure.^[10]

How to use this table: Doses are adult doses unless otherwise labeled, and require patient-specific confirmation, including renal adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Nucleoside analogues — orolabial HSV

Acyclovir, valacyclovir, and famciclovir are equally acceptable; drug choice is driven by dosing convenience and patient preference rather than a meaningful efficacy difference.

Nucleoside analogues — genital HSV

Start therapy on clinical suspicion; do not delay for NAAT/PCR confirmation. Extend the first-episode course if healing is incomplete at 10 days.

Nucleoside analogues — herpes zoster (shingles)

Most effective within 72 hours of rash onset; still reasonable beyond 72 hours if new vesicles are still forming, the ophthalmic dermatome is involved, or the patient is immunocompromised.

Combination topical product

A topical option for patients who prefer it; oral therapy remains preferred given the modest effect size of topical agents overall.

Antiviral resistance — alternative agent

Reserve for confirmed or strongly suspected acyclovir-resistant HSV/VZV in an immunocompromised patient.

Passive immunoprophylaxis — VZV post-exposure

For a significant VZV exposure in a non-immune high-risk patient; does not treat established disease. See Special Populations for the full pregnancy exposure pathway.

Prevention — vaccine (not a treatment for active disease)

Brief cross-reference only — see Non-Pharmacologic Treatment for the full eligibility discussion.

Evidence note: drug inventory, dosing, adverse effects, and comments reflect standard Canadian practice, cross-checked against current CDC STI treatment guidance^[1], IDSA herpes zoster management guidance^[2], and Cochrane systematic review evidence on orolabial HSV prevention and postherpetic neuralgia^[5][6].