Antiviral Chemotherapy, Excluding Antiretroviral Drugs¶
Chapter 196 | Part 5 – Infectious Diseases: Viral (incl. HIV) · Part 5 – Infectious Diseases: Viral (incl. HIV) · Chapter 196
Key Clinical Points¶
- Antiviral drugs target specific viral processes (e.g., DNA/RNA polymerases, proteases, entry) to maximize safety since viruses utilize host cell machinery.
- Acyclovir and Valacyclovir require phosphorylation by viral thymidine kinase; resistance occurs via mutations in thymidine kinase or DNA polymerase.
- Ganciclovir and Valganciclovir require phosphorylation by UL97 protein kinase; resistance is associated with UL97 or UL54 mutations.
- Foscarnet is a pyrophosphate analogue that directly inhibits viral DNA polymerase without requiring phosphorylation; it carries a high risk of nephrotoxicity.
- Cidofovir is a deoxycytidine monophosphate analogue; nephrotoxicity is managed with probenecid and saline hydration.
- Oseltamivir is the preferred treatment for complicated influenza; zanamivir is contraindicated in patients with asthma or COPD.
- Ribavirin is used for RSV in hospitalized infants and as part of combination therapy for hepatitis C.
- Nirmatrelvir/ritonavir reduces hospitalization risk by 50% in mild-to-moderate COVID-19; molnupiravir is a second-line option.
- Letermovir inhibits the CMV terminase complex (UL51, UL59) and is used for prophylaxis in stem cell or kidney transplant recipients.
- Maribavir inhibits the CMV UL97 protein kinase and is used for refractory posttransplant CMV disease.
DEFINITION & CLASSIFICATION¶
• Antiviral Therapeutics: Definition (Harrison's 22e): "drugs that usually do not eradicate latent viral infections but instead inhibit viral replication; thus, when treatment is stopped, the virus can reactivate and replicate again." • Mechanism of Action: Drugs target specific viral processes: 1. Viral entry 2. Viral RNA transcription 3. Protease cleavage of proteins 4. Virus uncoating after infection 5. Virus release from cells 6. DNA or RNA replication (e.g., inhibition of DNA polymerase)
ETIOLOGY & PATHOPHYSIOLOGY¶
• Viral Replication: Viruses are obligate intracellular parasites; injury to host cells during entry/replication leads to tissue and organ damage. • Drug Resistance: Resistance occurs due to mutations in viral proteins. Mutation rates: RNA viruses (higher mutation rate) > DNA viruses. • Combination Therapy: More than one antiviral agent with different mechanisms → more effective than monotherapy, especially for RNA viruses.
DIAGNOSTIC APPROACH¶
• Detection of Virus-Specific Antibodies: Antibody tests provide evidence of prior infection or exposure to antigens. 1. ELISA (Enzyme-Linked Immunosorbent Assay): High-throughput screening; measures bound antibody via color production from an enzyme coupled to human IgG. 2. Western Blot (Immunoblot): Confirmatory test; resolves viral proteins in a polyacrylamide gel and transfers them to a membrane. Note: More specific than ELISA because it detects antigens of a specific size. 3. Hemagglutination Inhibition Assay: Detects antibodies specific for viral surface proteins by their ability to block hemagglutination.
MANAGEMENT & TREATMENT¶
Herpesvirus Infections¶
• Acyclovir and Valacyclovir: Mechanism: Analogue of deoxyguanosine; phosphorylated by viral thymidine kinase → then by cellular kinases to active triphosphate form → inhibits viral DNA polymerase. Usage: Approved for initial/recurrent genital herpes, varicella, zoster, and herpes labialis. Advantage: Valacyclovir is a valine ester with much better oral absorption (4x higher plasma levels than acyclovir). Dosage (Table 196-1): - Orolabial herpes (primary): Acyclovir 400 mg tid x 7–10 d; Valacyclovir 1 g bid x 7–10 d. - Genital herpes (primary): Acyclovir 400 mg tid or 200 mg 5x daily x 7–10 d; Valacyclovir 1 g bid x 7–10 d. - Zoster: Acyclovir 800 mg 5x daily x 7 d; Valacyclovir 1 g tid x 7 d. - HSV Encephalitis: Acyclovir IV 10–15 mg/kg q8h x 14–21 d. • Ganciclovir and Valganciclovir: Mechanism: Deoxyguanosine analog; phosphorylated by UL97 protein kinase → inhibits viral DNA polymerase. Usage: Treatment/prevention of CMV disease in immunocompromised patients (retinitis, colitis, pneumonitis, encephalitis). Dosage (Table 196-1): - Ganciclovir IV: 5 mg/kg q12h x 14–21 d, then 5 mg/kg daily. - Valganciclovir Oral: 900 mg bid x 14–21 d, then 90 mg daily. • Foscarnet: Mechanism: Pyrophosphate analogue; directly inhibits viral DNA polymerase by blocking the pyrophosphate binding site (no phosphorylation required). Usage: CMV retinitis, mucocutaneous acyclovir-resistant HSV, and ganciclovir-resistant CMV. Safety: 1/3 of patients develop nephrotoxicity; manage with IV saline before/after dose. Dosage (Table 196-1): - Foscarnet IV: 60 mg/kg q8h x 14–21 d, then 90–120 mg daily. • Cidofovir: Mechanism: Deoxycytidine monophosphate analogue; phosphorylated to active diphosphate form. Usage: CMV retinitis in AIDS patients; ganciclovir-resistant CMV; HSV/VZV with thymidine kinase mutations. Safety: 1/5 of patients develop nephrotoxicity; manage with 1L saline before/after and probenecid (3h before, 2h after, 8h after dose). Dosage (Table 196-1): - Cidofovir IV: 5 mg/kg once weekly twice, then every other week. • Maribavir: Mechanism: Benzimidazole; inhibits CMV UL97 protein kinase and reduces viral egress from nucleus. Usage: Posttransplant CMV disease refractory to ganciclovir, cidofovir, or foscarnet. Dosage (Table 196-1): - Maribavir Oral: 400 mg bid. • Letermovir: Mechanism: Dihydroquinazolin; inhibits CMV DNA terminase complex (UL51, UL59). Usage: Prophylaxis of CMV in allogeneic hematopoietic stem cell or kidney transplant recipients. Dosage (Table 196-1): - Letermovir Oral/IV: 480 mg qd. • Other Agents: - Trifluridine & Vidarabine: Topical use only for HSV keratitis and mucosal infections. - Brincidofovir: Phospholipid conjugate of cidofovir; no nephrotoxicity; used for various herpesviruses.
Respiratory Virus Infections¶
• Influenza (A, B): 1. Oseltamivir: 75 mg bid x 5 d (treatment); 75 mg/d (prophylaxis). Choice for complicated influenza. 2. Zanamivir: 10 mg bid x 5 d (treatment); 10 mg/d (prophylaxis). Contraindicated in asthma/COPD. 3. Peramivir: 600 mg once (IV). 4. Baloxavir: 40 mg or 80 mg once (depending on weight >80 kg). • RSV: 1. Ribavirin: Inhaled aerosol 20 mg/mL for 12–18 h/d x 3–7 d; used in hospitalized infants. 2. Nirmatrelvir/ritonavir: 300 mg/100 mg bid x 5 days. • SARS-CoV-2: 1. Remdesivir: IV 200 mg day 1, then 100 mg qd x 2 (outpatient) or x 4 (inpatient). 2. Molnupiravir: Oral 800 mg q12h x 5 days.
Hepatitis Infections¶
• Hepatitis B (Table 196-3): 1. Interferons: - Pegylated α2a: 180 μg/week for 48 weeks. - Pegylated α2b: 1.5 μg/kg per week for 48 weeks. 2. Nucleoside Analogues: - Adefovir: 10 mg daily. - Entecavir: 0.5–1 mg daily (0.5 mg for treatment-naïve; 1 mg for experienced). - Tenofovir alafenamide: 25 mg daily. • Hepatitis C (Table 196-4): 1. Sofosbuvir: 400 mg daily (must be combined with another DAA). 2. Sofosbuvir/ledipasvir: 400 mg/90 mg daily. 3. Sofosbuvir/velpatasvir: 400 mg/100 mg daily. 4. Sofosbuvir/velpatasvir/voxilaprevir: 400 mg/100 mg/100 mg once daily.
COMPLICATIONS & PROGNOSIS¶
• Foscarnet Toxicity: Nephrotoxicity (common), hypomagnesemia, hypocalcemia, and electrolyte abnormalities. • Cidofovir Toxicity: Nephrotoxicity (1/5 patients), metabolic acidosis, and grossuria. • Ganciclovir Toxicity: Neutropenia and thrombocytopenia (common after 1 week).
KEY PEARLS & HIGH-YIELD POINTS¶
• Antiviral Logic: Drugs do not eliminate latent infections; they inhibit replication. • Resistance Rule: RNA viruses → higher mutation rates → more common resistance. • Foscarnet vs. Cidofovir: Foscarnet is used for DNA polymerase mutations; Cidofovir is used for thymidine kinase mutations (but requires probenecid/saline to protect kidneys). • Letermovir Advantage: Does not cause nephrotoxicity or myelosuppression, making it ideal for transplant prophylaxis.
Reference Tables¶
TABLE 196-1 Antiviral Drugs for Herpesvirus Treatment and Prophylaxis in Adults DISEASE Orolabial herpes, primary…¶
Harrison's 22e, p.1486
| DISEASE | DRUG | ROUTE | ADULT DOSE | COMMENTS |
|---|---|---|---|---|
| Orolabial herpes, primary episode |
Acyclovir Valacyclovir Famciclovir |
Oral Oral Oral |
400 mg tid × 7–10 d 1 g bid × 7–10 d 500 mg bid or 250 mg tid × 7–10 d |
Reduces duration of fever, lesions, and virus shedding |
| Acyclovir Valacyclovir Famciclovir |
Oral Oral Oral |
400 mg 5 times daily × 5 d 2 g bid × 1 d 1500 mg × 1 d |
||
| Orolabial herpes, suppression |
Acyclovir Valacyclovir Famciclovir |
Oral Oral Oral |
400 mg bid 500 mg or 1 g once daily 500 mg bid |
In patients with >6 recurrences per year, reduces number of recurrences by ~50% and increases time to first recurrence |
| Acyclovir Valacyclovir Famciclovir |
Oral Oral Oral |
400 mg tid or 200 mg 5 times daily × 7–10 d 1 g bid × 7–10 d 250 mg tid × 7–10 d |
||
| Genital herpes, recurrence |
Acyclovir Valacyclovir Famciclovir |
Oral Oral Oral |
800 mg tid × 2 d or 400 mg tid × 5 d 500 mg bid × 3 d or 1 g daily × 5 d 500 mg once, then 250 mg bid × 2 d |
Reduces duration of symptoms, genital lesions, and virus shedding by 1–2 d |
| Acyclovir Valacyclovir Famciclovir |
Oral Oral Oral |
400 mg bid 250 mg bid 500 mg to 1 g daily |
||
| HSV encephalitis | Acyclovir | IV | 10–15 mg/kg q8h × 14–21 d | Reduces mortality and sequelae |
| Acyclovir Trifluridine Vidarabine |
Topical Topical Topical |
3% ophthalmic ointment, 5 times daily 1% ophthalmic solution, 1 drop q2h when awake (9 drops daily max) 3% ointment, 0.5-inch ribbon 5 times daily |
||
| Mucocutaneous herpes in immunocompromised patient |
Acyclovir Valacyclovir Famciclovir |
IV Oral Oral |
5 mg/kg q8h × 7–14 d 500 mg to 1 g bid × 7–10 d 500 mg bid × 7–10 d |
IV acyclovir reduces time to healing, duration of pain, and duration of virus shedding |
| Acyclovir Valacyclovir |
Oral Oral |
20 mg/kg (800 mg max) 5 times daily × 5 d 20 mg/kg (1 g max) tid × 5 d |
||
| Zoster | Acyclovir Valacyclovir Famciclovir |
Oral Oral Oral |
800 mg 5 times daily × 7 d 1 g tid × 7 d 500 mg tid × 7 d |
Reduces time for last new lesion formation, virus shedding, and pain duration |
| Acyclovir | IV | 10 mg/kg q8h × 7 d | ||
| Cytomegalovirus disease | Ganciclovir Valganciclovir Foscarnet Cidofovir Maribavir |
IV Oral IV IV Oral |
5 mg/kg q12h × 14–21 d, then 5 mg/kg daily (maintenance dose) 900 mg bid × 14–21 d, then 90 mg daily (maintenance dose) 60 mg/kg q8h × 14–21 d, then 90–120 mg daily (maintenance dose) 5 mg/kg once weekly twice, then every other week 400 mg bid |
Neutropenia and thrombocytopenia common after 1 week Levels and side effects similar to ganciclovir Nephrotoxicity, electrolyte abnormalities; give with additional saline Nephrotoxicity; give with probenecid and saline Used for disease refractory to ganciclovir, foscarnet, or cidofovir Antagonizes activity of ganciclovir Numerous drug interactions |
| Letermovir | Oral IV |
480 mg qd 480 mg qd |
TABLE 196-2 Antiviral Drugs for Respiratory Virus Treatment and Prophylaxis in Adults DISEASE Influenza A, B Influenza…¶
Harrison's 22e, p.1488
| DISEASE | DRUG | ROUTE | ADULT DOSE | COMMENTS |
|---|---|---|---|---|
| Influenza A, B | Oseltamivir | Oral | Treatment: 75 mg bid × 5 d Prophylaxis: 75 mg/d |
Shortens duration of symptoms by 1 d when given within 2 d of onset; reduces complications; considered drug of choice for patients with complications of influenza |
| Zanamivir | Inhaled | Treatment: 10 mg bid × 5 d Prophylaxis: 10 mg/d |
||
| Influenza A, B | Peramivir | IV | 600 mg once | Shortens duration of symptoms by 1–2 d when given within 2 d of onset |
| Baloxavir | Oral | Treatment or postexposure prophylaxis: 40 mg once; if >80 kg, 80 mg once |
||
| Influenza A | Amantadine | Oral | Treatment: 100 mg bid × 5 d Prophylaxis: 200 mg/d |
Most influenza virus strains are resistant; use only if virus is known to be sensitive. |
| Rimantadine | Oral | Treatment: 100 mg bid × 5 d Prophylaxis: 200 mg/d |
||
| Respiratory syncytial virus |
Ribavirin | Inhaled | Aerosol from reservoir containing 20 mg/mL for 12–18 h/d × 3–7 d |
Reduces severity of symptoms in hospitalized infants with lower respiratory tract disease; anecdotal reports of reduced progression to lower respiratory tract disease and mortality in stem cell transplant patients |
| Nirmatrelvir/ ritonavir |
Oral | 300 mg/100 mg bid × 5 days | ||
| SARS-CoV-2 | Remdesivir | IV | 200 mg on day 1, then 100 mg qd × 2 d for outpatients, × 4 days for inpatients |
Reduces duration of hospitalization in some studies. Duration of treatment extended up to 10 days if no improvement. |
| Molnupiravir | Oral | 800 mg q12h × 5 days |
TABLE 196-3 Antiviral Drugs for Chronic Hepatitis B Treatment in Adults DRUG Interferons Pegylated α 2a¶
Harrison's 22e, p.1490
| DRUG | ROUTE AND DOSE | DEVELOPMENT OF RESISTANCE |
COMMON SIDE EFFECTSa | TREATMENT MONITORING | COMMENTS |
|---|---|---|---|---|---|
| Interferons | |||||
| Pegylated α2a Pegylated α2b |
SC injection; 180 μg/week for 48 weeks SC injection; 1.5 μg/kg per week for 48 weeks |
Not described in long- term studies. |
Side effects are common and include fevers, chills, myalgia, fatigue, neurotoxicity, and leukopenia. Autoantibodies can develop, particularly antithyroid antibodies. |
Complete blood counts should be performed biweekly for the first month and then monthly, renal and liver function testing monthly, thyroid function testing every 3 months. |
Recommended as first-line therapy. Best treatment response seen among patients with HBV genotype A and B infections. Contraindicated in clinically significant portal hypertension and pregnancy. |
| Nucelos(t)ide Analogues | |||||
| Oral; 100 mg daily | 30% after 1 year; 70% after 5 years |
Malaise or fatigue, GI symptoms (nausea/ vomiting, abdominal pain, diarrhea), headache, upper respiratory tract infection |
Renal and liver function testing every 3–6 months Assessment of lactic acid level HBV DNA and serologic testing every 3–6 months |
||
| Adefovir | Oral; 10 mg daily | 20–29% after 5 years Adefovir is usually active against lamivudine-resistant HBV strains. |
Headache, asthenia, GI symptoms (abdominal pain, nausea) |
Renal and liver function testing every 6 months Assessment of lactic acid level HBV DNA and serologic testing every 3–6 months |
— |
| Oral; 600 mg daily | 11–25% after 2 years Cross-resistance is common between lamivudine- and telbivudine-resistant HBV strains. |
Headache, fatigue, GI symptoms (abdominal pain) |
Measurement of creatine kinase level if there is concern about myopathy Renal and liver function testing every 3–6 months Assessment of lactic acid level HBV DNA and serologic testing every 3–6 months |
||
| Entecavir | Oral; 0.5–1 mg daily | 1–2% after 5 years in nucleos(t)ide-naïve patients; 50% after 5 years in lamivudine-resistant patients |
Headache, fatigue, elevated alanine aminotransferase level |
Renal and liver function testing every 3–6 months Assessment of lactic acid level HBV DNA and serologic testing every 3–6 months |
Recommended as first-line therapy. Dose of 0.5 mg daily in treatment-naïve patients, 1 mg daily in treatment-experienced patients. Dose adjusted in renal dysfunction. |
| Oral; 300 mg daily | No resistance after up to 10 years of treatment |
Headache, fatigue, nasopharyngitis, upper respiratory tract infection, nausea |
Renal and liver function testing every 3–6 months Phosphorus assessment in patients with chronic kidney disease Assessment of lactic acid level HBV DNA and serologic testing every 3–6 months |
||
| Tenofovir alafenamide |
Oral; 25 mg daily | No resistance after up to 3 years of treatment |
Headache, fatigue, nasopharyngitis, upper respiratory tract infection |
Renal and liver function testing every 3–6 months Phosphorus assessment in patients with chronic kidney disease Assessment of lactic acid level HBV DNA and serologic testing every 3–6 months |
Recommended as first-line therapy. May be used during pregnancy; possible risk of low birth weight. |
| Oral; 200 mg daily | Not defined | Headache, GI symptoms (nausea, diarrhea, abdominal pain), fatigue, depression, insomnia, abnormal dreams, rash, asthenia, increased cough, rhinitis |
Renal and liver function testing every 3–6 months Assessment of lactic acid level HBV DNA and serologic testing every 3–6 months |
TABLE 196-4 Antiviral Drugs for Hepatitis C Treatment in Adults a¶
Harrison's 22e, p.1492
| DRUG FORMULATION | ROUTE, DOSE, DURATION | MECHANISM(S) OF ACTION |
SPECTRUM OF ACTIVITY |
COMMON SIDE EFFECTS |
COMMENTS |
|---|---|---|---|---|---|
| Sofosbuvir | Oral; 400 mg daily; duration varies (12–24 weeks) |
Nucleoside analogue | Genotypes 1–6 | Headache, fatigue | Should be combined with at least one other DAA from a different class. |
| Oral; 400 mg/90 mg daily; 8, 12, or 24 weeks |
Nucleoside analogue/ NS5A inhibitor |
Genotypes 1, 4, 5, and 6 |
Headache, fatigue | ||
| Sofosbuvir/velpatasvir | Oral; 400 mg/100 mg daily; 12 weeks |
Nucleoside analogue/ NS5A inhibitor |
Genotypes 1–6 | Headache, fatigue | Avoid coadministration with antacid medications. |
| Oral; 400 mg/100 mg/100 mg once daily; 12 weeks |
Nucleoside analogue/ NS5A inhibitor/protease inhibitor |
Genotypes 1–6 | Headache, fatigue, diarrhea, nausea |
||
| Elbasvir/grazoprevir | Oral; 50 mg/100 mg once daily; 12 or 16 weeks |
NS5A inhibitor/protease inhibitor |
Genotypes 1 and 4 |
Fatigue, anemia, headache, nausea |
Pretreatment testing for resistance- associated variants recommended in patients infected with genotype 1a. Monitor hepatic function panel at 8 weeks and again at 12 weeks if patient is receiving 16 weeks of treatment. |
| Oral; 3 100-mg tablets/40 mg once daily; 8, 12, or 16 weeks |
NS5A inhibitor/protease inhibitor |
Genotypes 1–6 | Headache, fatigue | ||
| Daclatasvir | Oral; 60-mg tablet once daily; 12 weeks Dose reduced to 30 mg once daily when taken with a strong CYP3A inhibitor Dose increased to 90 mg once daily when taken with moderate CYP3A inducers |
NS5A inhibitor | Genotypes 1 and 3 |
Headache, fatigue | Use recommended only along with sofosbuvir—with or without ribavirin—for genotype 1 or 3 infection; no longer considered a first- or second-line regimen. |
| Oral; 3–6 200-mg capsules once daily or in divided doses, based on weight, history of cardiovascular disease, and renal function |
Nucleoside analogue, also unknown mechanisms |
Unknown, used for all genotypes |
Anemia, nausea, teratogenic in pregnancy |