Treatment of Herpes Infections

Core Antiviral Drugs

1. Acyclovir (prototypic agent)

• Mechanism: Guanosine analog - monophosphorylated by herpesvirus thymidine kinase (making it selectively active in infected cells), then converted to triphosphate by host cell kinases, which competitively inhibits viral DNA polymerase and causes chain termination.
• Spectrum: HSV-1, HSV-2, VZV, some EBV.
• Routes: IV, oral, topical (topical has questionable efficacy).
• Key uses: Genital herpes (first episode and suppression), HSV encephalitis (IV), prophylaxis in immunocompromised patients (bone marrow/heart transplant).
• Pharmacokinetics: Distributes well including into CSF; excreted renally (both glomerular filtration and tubular secretion); accumulates in renal failure - dose adjust.
• Adverse effects: Oral - headache, nausea, diarrhea. IV at high doses or in dehydrated patients - transient renal dysfunction. Topical - local irritation.
• Resistance: Altered or deficient thymidine kinase or DNA polymerase; most common in immunocompromised patients; cross-resistance with related drugs occurs.

2. Valacyclovir (prodrug of acyclovir)

• The valyl ester of acyclovir - rapidly hydrolyzed to acyclovir after oral absorption.
• Greater oral bioavailability than acyclovir; achieves plasma levels comparable to IV acyclovir.
• Preferred for most outpatient herpes management due to simpler dosing (twice daily vs. five times daily).

3. Famciclovir (prodrug of penciclovir)

• Oral prodrug metabolized to the active penciclovir.
• Penciclovir is an acyclic guanosine nucleoside derivative; monophosphorylated by viral thymidine kinase; penciclovir triphosphate has a longer intracellular half-life than acyclovir triphosphate.
• Approved for: acute herpes zoster, genital HSV, recurrent herpes labialis.
• Adverse effects: Headache, nausea.

4. Foscarnet (for resistant cases)

• A pyrophosphate analog that directly inhibits viral DNA polymerase without requiring activation by viral thymidine kinase - useful when acyclovir resistance is due to altered thymidine kinase.
• Used in acyclovir-resistant HSV or CMV in immunocompromised patients.
• Adverse effects: Nephrotoxicity, electrolyte disturbances (hypocalcemia, hypomagnesemia), anemia, CNS effects.

Treatment by Clinical Scenario

Genital Herpes (HSV-1 or HSV-2)

• Antivirals are most effective when started early (episodic therapy should be self-initiated at the first hint of symptoms).
• Suppressive therapy reduces transmission risk to sexual partners.
• All patients with a first episode should receive antiviral therapy due to potential for severe or prolonged symptoms.

HSV Encephalitis / Meningoencephalitis

• IV acyclovir is mandatory and should be started without delay.
• Treatment reduces mortality from >70% down to ~20%.
• Delay in diagnosis/treatment worsens neurologic outcomes (e.g., amnesia).
• (Frameworks for Internal Medicine, p. 412)

Herpes Zoster (Shingles - VZV)

• Start antivirals within 72 hours of rash onset (or if new vesicles are still forming at >72 hours).
• Treat immunocompromised patients regardless of time since rash onset.
• Benefits most pronounced in patients >50 years.
• Antivirals hasten lesion resolution, reduce new lesions, reduce viral shedding, and decrease acute pain - but do not prevent postherpetic neuralgia (PHN).

Herpes Labialis (Cold Sores - HSV-1)

• Topical penciclovir cream (applied every 2 hours while awake).
• Oral famciclovir (single-day regimen) for more significant episodes.

Special Populations

• Immunocompromised patients: Higher risk of disseminated or resistant disease. Use IV acyclovir for severe disease; foscarnet for acyclovir-resistant strains.
• Pregnancy (suppression to prevent neonatal HSV): Valacyclovir 500 mg PO twice daily OR Acyclovir 400 mg PO TID - typically started from 36 weeks until delivery to reduce neonatal transmission risk.
• Neonatal HSV: IV acyclovir (high-dose) - a medical emergency.
• Renal impairment: Dose-adjust acyclovir and valacyclovir; both accumulate in renal failure.

Regarding Recent Evidence

Current Treatment of Rabies

Part 1: Post-Exposure Prophylaxis (PEP)

Step 1 - Wound Care (most time-critical step)

• Immediately flush and wash all wounds and scratches with plenty of soap and water under running tap for at least 15 minutes.
• For puncture wounds, use a catheter to irrigate deeply.
• Follow with a virucidal agent: povidone-iodine solution, aqueous iodine (0.01%), or alcohol (400-700 ml/L).
• Do not suture immediately - bite wounds should not be closed right away as suturing drives virus deeper. If suturing is necessary, wait 24-48 hours and apply minimum stitches under rabies immunoglobulin cover.
• Give antibiotics and anti-tetanus measures as indicated.

Step 2 - Rabies Immunoglobulin (RIG) - Passive Immunization

• Given only once, at or as soon as possible after the first vaccine dose.
• Do NOT give after day 7 of vaccination (by then, active antibody response has developed).
• Infiltrate as much as anatomically feasible directly into and around the wound(s); remaining volume given IM at a distant site (never in same syringe or same anatomical site as the vaccine).
• Never administer in the gluteal area.

• HRIG is preferred; ERIG (after skin testing) is used where HRIG is unavailable and is significantly cheaper.
• Previously vaccinated individuals: do NOT give RIG.

Step 3 - Rabies Vaccine

WHO Exposure Categories and PEP Decisions

Vaccine Regimens (IM Route)

Intradermal (ID) Route - Cost-Saving Alternative

• 2-site ID regimen: 0.1 ml at 2 sites on days 0, 3, 7, and 28 (endorsed by national authorities in applicable countries - dose-sparing and cheaper).

Previously Vaccinated Individuals

• 2 doses only (days 0 and 3), IM or ID.
• No RIG needed.
• Applies to those with documented complete prior PEP or pre-exposure prophylaxis with confirmed neutralizing antibody titre ≥0.5 IU/ml.

Immunocompromised Patients (including HIV/AIDS)

• Full 5-dose IM regimen + complete wound care + HRIG (Category II and III).
• Check rabies-virus neutralizing antibody titre 2-4 weeks post-vaccination; give extra dose if insufficient response.

Can PEP Be Discontinued?

• Laboratory testing confirms the biting animal is rabies-free, OR
• For domestic dogs/cats/ferrets: the animal remains healthy throughout a 10-day observation period from the date of the bite.

Part 2: Clinical Rabies (Symptomatic Disease)

Standard of Care: Palliative Care

• Comfort-focused care: pain control, sedation, anxiolytics for hydrophobia/aerophobia spasms.
• ICU support in some centers.
• Counseling of family.

The Milwaukee Protocol (Experimental)

• Developed in 2004 after a rare survivor (Jeanna Giese) who received it.
• Components: Induced therapeutic coma (ketamine, midazolam) + antiviral cocktail (amantadine, ribavirin) + supportive care.
• Rationale: Suppress CNS activity to allow the immune system time to clear the virus.
• Outcome: Despite multiple attempts worldwide, the protocol has produced very few additional survivors and has largely fallen out of favor. A 2024 review (PMID 38275970) describes it as "from palliation to promise" - the standard remains palliation, with ongoing investigation of new antiviral compounds and immunotherapies.
• A 2024 case report (PMID 39456043) describes an adapted Milwaukee protocol attempt in a Brazilian child.

Emerging / Investigational Approaches

• Monoclonal antibodies targeting the rabies virus glycoprotein.
• Favipiravir and other RNA polymerase inhibitors (animal studies).
• Immune modulators and intrathecal interferon.
• None are yet standard-of-care.

Pre-Exposure Prophylaxis (PrEP) - For High-Risk Individuals

• 3 doses of CCEEV on days 0, 7, and 21 or 28 (IM or ID).
• Booster doses based on antibody titre monitoring.
• If later exposed: only 2 vaccine doses needed (days 0 and 3); no RIG.

Summary Table

Key point: Rabies is the only infection where post-exposure treatment can reliably prevent a fatal disease - but only if started before symptoms appear. Once neurological symptoms develop, survival is exceedingly rare regardless of treatment.