Chapter 191: Antiviral Drugs – High-Yield Board Notes
HERPES SIMPLEX VIRUS (HSV) ANTIVIRALS
First-Line Oral Agents
Valacyclovir, famciclovir, and acyclovir are the three FDA-approved first-line oral antivirals for HSV, with valacyclovir and famciclovir preferred due to superior dosing convenience. 1
Herpes Labialis (Cold Sores)
- Valacyclovir 2g PO twice daily for 1 day – reduces episode duration by 1.0 day 1
- Famciclovir 1500mg PO single dose – equally effective, convenient single-day dosing 1
- Critical timing: Initiate at earliest prodrome or within 24 hours of symptom onset – peak viral titers occur in first 24 hours 1
Genital Herpes – First Episode
- Acyclovir 400mg PO three times daily for 7-10 days 1
- Valacyclovir 1g PO twice daily for 10 days (alternative) 1
- Extend treatment if healing incomplete after 10 days 2
Orofacial Herpes – First Episode or Severe
- Valacyclovir 1g PO twice daily for 7-10 days 2
- Higher doses for oral/pharyngeal involvement: Acyclovir 400mg PO five times daily 2
Ocular HSV (Keratitis/Conjunctivitis with Corneal Involvement)
- Acyclovir 200-400mg PO five times daily PLUS topical antiviral 1
- Valacyclovir 500mg PO 2-3 times daily (alternative) 1
- Never use topical antivirals alone – substantially less effective than systemic therapy 2
Intravenous Acyclovir
Indications
- Severe HSV infections
- Immunocompromised patients with severe disease
- HSV encephalitis
Dosing
- Standard: 5mg/kg IV every 8 hours
- Immunocompromised: Acyclovir 400mg PO 3-5 times daily or 5mg/kg IV every 8 hours 2
Critical Administration Details
- Infuse over >10 minutes – rapid infusion (<10 minutes) causes transient elevations in serum creatinine/BUN in 5-10% of patients 3
- Inflammation/phlebitis at injection site occurs in ~9% 3
Adverse Effects
- Most common: Nausea/vomiting (7%), inflammation at injection site (9%) 3
- Renal toxicity: Elevated creatinine/BUN (5-10%), renal failure (rare) 3
- Neurologic: Encephalopathy, seizures, confusion, hallucinations, tremor – particularly in elderly 3
- Hematologic: Anemia, neutropenia, thrombocytopenia (<1%) 3
- Severe: Stevens-Johnson syndrome, toxic epidermal necrolysis, tissue necrosis with extravasation 3
Acyclovir-Resistant HSV
If lesions persist despite 7-10 days of appropriate valacyclovir therapy, suspect HSV resistance – all acyclovir-resistant strains are also resistant to valacyclovir. 2
Resistance Rates
Treatment of Resistant HSV
Safety Profile
- All oral antivirals (acyclovir, valacyclovir, famciclovir) are generally well-tolerated with minimal adverse events 1
- Common side effects: Headache (<10%), nausea (<4%), diarrhea (mild-moderate) 1
VARICELLA-ZOSTER VIRUS (VZV) ANTIVIRALS
Approved Drug Classes
- Acyclic guanosine analogues (acyclovir, valacyclovir, famciclovir)
- Nucleoside analogues
- 5-substituted 2'-deoxyuridine analogues
- Antibodies 4
CYTOMEGALOVIRUS (CMV) ANTIVIRALS
First-Line Agents
- Acyclic guanosine analogues (ganciclovir, valganciclovir)
- Acyclic nucleoside phosphonate analogues (cidofovir)
- Pyrophosphate analogues (foscarnet)
- Oligonucleotides 4
Valganciclovir (Oral Prodrug of Ganciclovir)
Critical Drug Interactions
- Zidovudine: Causes neutropenia and anemia – monitor CBC with differential and hemoglobin frequently 5
- Probenecid: Increases ganciclovir levels – monitor for ganciclovir toxicity 5
- Mycophenolate mofetil (MMF): Increases ganciclovir and MMF metabolite concentrations in renal impairment – monitor for toxicity of both drugs 5
- Didanosine: Increases didanosine concentrations – monitor for didanosine toxicity 5
Ganciclovir
- Milestone drug for systemic and organ-specific CMV disease 6
- Nucleoside analogue targeting viral DNA polymerase 6
Foscarnet
Cidofovir
Letermovir (Newest Agent)
- Targets viral terminase complex (different mechanism than DNA polymerase inhibitors) 6
- Approved for CMV prophylaxis in hematopoietic stem cell transplant recipients 6
- Avoids cross-resistance with DNA polymerase inhibitors 6
Resistance Considerations
- All first-line agents (ganciclovir, foscarnet, cidofovir) target viral DNA polymerase – cross-resistance possible 6
- Letermovir offers alternative mechanism for resistant cases 6
HEPATITIS B VIRUS (HBV) ANTIVIRALS
Approved Drug Classes
- Lamivudine
- Interferons
- Nucleoside analogues
- Acyclic nucleoside phosphonate analogues 4
Treatment Initiation Criteria
HBeAg-Positive Chronic Hepatitis B
- Serum HBV DNA >20,000 IU/mL AND ALT >2× normal 7
- Consider treatment if ALT remains elevated >6 months 7
- Initial options: Interferon-α or lamivudine 7
HBeAg-Negative Chronic Hepatitis B
- Serum HBV DNA >20,000 IU/mL AND ALT >2× normal 7
- For lower HBV DNA (2,000-20,000 IU/mL) with borderline/minimally elevated ALT: Consider liver biopsy – treat if moderate/severe inflammation or significant fibrosis 7
- Preferred agents: Pegylated interferon-α, adefovir, or entecavir (due to need for long-term treatment) 7
Lamivudine Resistance Management
If adefovir is added:
- Continue lamivudine indefinitely – decreases hepatitis flares during transition and reduces adefovir resistance risk 7
If switching to entecavir:
- Stop lamivudine – continued lamivudine-resistant mutations increase entecavir resistance risk 7
Adefovir Resistance Management
In patients with no prior nucleoside analogue exposure:
- Add lamivudine or entecavir 7
In patients with prior lamivudine resistance:
- Add lamivudine – but durability unknown, re-emergence of lamivudine-resistant mutations reported 7
Entecavir Resistance Management
- Add or switch to adefovir or tenofovir 7
Telbivudine Resistance Management
- Add adefovir or tenofovir 7
- Switch to Truvada (emtricitabine 200mg + tenofovir 300mg combination) 7
- Switch to entecavir (but pre-existing telbivudine-resistant mutations predispose to entecavir resistance) 7
Monitoring During Treatment
- Serum HBV DNA (PCR assay) every 3-6 months 7
- Check medication compliance with virologic breakthrough 7
- Confirm antiviral resistance with genotypic testing 7
Prevention of Resistance
- Avoid unnecessary treatment 7
- Initiate with potent antiviral with low resistance rate or combination therapy 7
- Switch to alternative therapy in primary non-responders 7
Retreatment After Interferon Failure
- Patients who failed prior interferon-α (standard or pegylated) may be retreated with nucleoside analogues if they meet treatment criteria 7
Primary Non-Response
- <2 log decrease in serum HBV DNA after ≥6 months of nucleoside analogue therapy – switch to alternative treatment 7
HEPATITIS C VIRUS (HCV) ANTIVIRALS
Approved Drug Classes
- Ribavirin
- Interferons
- NS3/4A protease inhibitors
- NS5A inhibitors
- NS5B polymerase inhibitors 4
Combination Therapy
- Ribavirin + interferon-α superior to interferon-α alone for chronic hepatitis C 8
INFLUENZA ANTIVIRALS
Approved Drug Classes
- Ribavirin
- Matrix 2 (M2) protein inhibitors (amantadine)
- RNA polymerase inhibitors
- Neuraminidase inhibitors (zanamivir, oseltamivir) 4
Neuraminidase Inhibitors vs. Amantadine
- Neuraminidase inhibitors (zanamivir, oseltamivir) active against both influenza A and B 8
- Amantadine only active against influenza A 8
- Neuraminidase inhibitors are well-tolerated 8
RESPIRATORY SYNCYTIAL VIRUS (RSV) ANTIVIRALS
Approved Agents
- Ribavirin
- Antibodies 4
HUMAN PAPILLOMAVIRUS (HPV) – EXTERNAL ANOGENITAL WARTS
Imiquimod
Mechanism
- Immune response modifier 4
FDA-Approved Indications
- External anogenital warts (HPV)
- Actinic keratosis
- Superficial basal cell carcinoma 9
Actinic Keratosis Regimen
- Apply 2 times per week for 16 weeks to 25 cm² contiguous treatment area 9
- Apply to entire treatment area before sleep, leave on ~8 hours 9
- Complete clearance rate: 44-46% (vs. 3-4% vehicle) 9
- Partial clearance (≥75% lesions cleared): 58-60% (vs. 10-14% vehicle) 9
- 48% of patients experience increase in AK lesions during treatment (subclinical lesions become apparent) – similar response to those without increase 9
Superficial Basal Cell Carcinoma Regimen
- Apply 5 times per week for 6 weeks to target tumor + 1 cm margin 9
- Target tumor: 0.5-4.0 cm², maximum diameter 2.0 cm, biopsy-confirmed sBCC 9
- Apply before sleep, leave on ~8 hours 9
- Composite clearance (clinical + histological): 75% (vs. 2% vehicle) at 12 weeks post-treatment 9
- 6% of clinically clear patients had residual tumor on histological examination 9
Other HPV Treatments
- Sinecatechins
- Podofilox 4
HIV POST-EXPOSURE PROPHYLAXIS (PEP)
First-Line Regimen (2025 Guidelines)
Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) 50/200/25mg as single tablet once daily for 28 days is the preferred PEP regimen. 10
Critical Timing
- Initiate ideally within 24 hours, absolutely within 72 hours maximum – efficacy decreases significantly with delayed initiation 10
- Complete full 28-day course regardless of regimen 10
Advantages of TAF Over TDF
- Tenofovir alafenamide (TAF) preferred over tenofovir disoproxil fumarate (TDF) – superior renal and bone safety profiles 10
- Strongly preferred in patients with impaired renal function 10
Alternative Multi-Tablet Regimen
- Dolutegravir 50mg once daily PLUS emtricitabine/tenofovir alafenamide 200/25mg once daily for 28 days 10
Monitoring Requirements
- Baseline: Rapid or laboratory HIV antigen/antibody combination test 10
- 4-6 weeks: HIV Ag/Ab test + HIV NAT 10
- 12 weeks: Laboratory HIV Ag/Ab combination immunoassay + HIV NAT 10
Critical Pitfalls to Avoid
- Never prescribe only two NRTIs (e.g., tenofovir/emtricitabine alone) – inadequate protection, requires third drug (integrase inhibitor) 10
- Never delay initiation beyond 72 hours – effectiveness drops precipitously 10
Transition to PrEP After PEP
- For MSM with/at risk for kidney dysfunction, osteopenia, or osteoporosis: Daily tenofovir alafenamide/emtricitabine recommended 10
HIV POST-EXPOSURE PROPHYLAXIS (2001 Guidelines – Historical Context)
Basic Regimen
- Zidovudine (ZDV/AZT) 600mg/day in 2-3 divided doses + Lamivudine (3TC) 150mg twice daily (available as Combivir) 7
- Advantages: ZDV associated with decreased HIV transmission risk in CDC case-control study; serious toxicity rare for PEP; safe in pregnancy; single tablet twice daily 7
- Disadvantages: Common side effects (low adherence); potential resistance; unknown delayed toxicity 7
Alternate Basic Regimens
Lamivudine + Stavudine
- 3TC 150mg twice daily + d4T 40mg twice daily (30mg if <60kg) 7
- Well-tolerated, rare serious toxicity, twice-daily dosing 7
Didanosine + Stavudine
- ddI 400mg daily on empty stomach + d4T 40mg twice daily (adjust for <60kg) 7
- Effective against ZDV/3TC-resistant strains 7
- Major disadvantages: Difficult to administer, unpalatable; serious toxicity (neuropathy, pancreatitis, hepatitis); ddI interferes with quinolone antibiotics and indinavir absorption 7
- Monitor closely for pancreatitis, lactic acidosis, hepatitis 7
Expanded Regimen (Basic + One of Following)
Indinavir
- 800mg every 8 hours on empty stomach 7
- Serious toxicity: Nephrolithiasis (requires 8 glasses fluid/day); hyperbilirubinemia (avoid late pregnancy) 7
Nelfinavir
- 750mg three times daily OR 1250mg twice daily with meals/snack 7
- Potent HIV inhibitor, twice-daily dosing improves adherence 7
- Contraindicated with: Astemizole, terfenadine, ergot derivatives, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam, triazolam 7
- Accelerates clearance of oral contraceptives (use alternative contraception) 7
Efavirenz
- 600mg daily at bedtime 7
- Advantages: Does not require phosphorylation (may be active earlier); once-daily dosing 7
- Major disadvantages: Rash (can progress to Stevens-Johnson syndrome); CNS side effects (dizziness, somnolence, insomnia, abnormal dreaming, severe psychiatric symptoms); teratogenic – contraindicated in pregnancy 7
- Contraindicated with: Astemizole, cisapride, midazolam, triazolam, ergot derivatives, St. John's Wort 7
Abacavir
- 300mg twice daily (available as Trizivir with ZDV/3TC) 7
- Potent HIV inhibitor, well-tolerated 7
- Severe hypersensitivity reactions (usually within first 6 weeks) 7
Lopinavir/Ritonavir (Kaletra)
- 400/100mg twice daily 7
- Potent HIV inhibitor, well-tolerated 7
- Contraindicated with: Flecainide, propafenone, astemizole, terfenadine, ergot derivatives, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam, triazolam 7
- Accelerates clearance of oral contraceptives 7
Nevirapine
- 200mg daily for 2 weeks, then 200mg twice daily 7
- Major disadvantages: Severe hepatotoxicity (including liver failure requiring transplantation in PEP patient); rash progressing to Stevens-Johnson syndrome 7
Follow-Up Testing (2001 Guidelines)
HBV Exposures
- Anti-HBs testing 1-2 months after last vaccine dose 7
- Cannot assess vaccine response if HBIG received in previous 3-4 months 7
HCV Exposures
- Baseline and follow-up anti-HCV and ALT at 4-6 months 7
- HCV RNA at 4-6 weeks if earlier diagnosis desired 7
- Confirm repeatedly reactive anti-HCV EIAs with supplemental tests 7
- No PEP recommended for HCV 7
HIV Exposures
- HIV antibody testing for ≥6 months: Baseline, 6 weeks, 3 months, 6 months 7
- Test if acute retroviral syndrome symptoms occur 7
- Evaluate within 72 hours after exposure, monitor for drug toxicity ≥2 weeks 7
- Advise precautions to prevent secondary transmission during follow-up 7
GENERAL ANTIVIRAL PRINCIPLES
Mechanism of Action
- Antivirals inhibit viral replication by interacting with specific elements of the viral replication cycle 11
Therapeutic Window Challenges
- Acute infections (influenza, COVID-19) offer small therapeutic window due to pathophysiological dynamics 11
- Optimal timing: Immediately after virus exposure – frequently limits practical application 11
Persistent vs. Acute Viral Infections
- Persistent viruses (HIV, HBV, herpes viruses): Cannot be cured with current agents 11
- Acute infections: Complete viral elimination possible 11
Pre-Exposure and Post-Exposure Prophylaxis
Resistance Concerns
- Herpesvirus resistance to antivirals is of concern 8
- Validation of alternative treatments for documented resistance required 8