8.2 Antiviral Drugs
Antiviral drugs target viral replication processes while minimizing damage to host cells. Unlike antibiotics, antivirals face the challenge of targeting viruses that use host cellular machinery, making selective toxicity difficult to achieve.
Principles of Antiviral Therapy
Viral Replication Targets
- • Attachment & entry
- • Uncoating
- • DNA/RNA synthesis
- • Protein processing
- • Assembly & release
Drug Classes
- • Nucleoside/nucleotide analogs
- • Protease inhibitors
- • Integrase inhibitors
- • Entry/fusion inhibitors
- • Neuraminidase inhibitors
Resistance Mechanisms
- • Viral polymerase mutations
- • Protease mutations
- • Decreased drug activation
- • Enhanced viral replication
Anti-HIV Drugs
HIV Lifecycle & Drug Targets
Combination antiretroviral therapy (cART) uses ≥3 drugs from ≥2 classes to suppress viral load to undetectable levels, preserve CD4+ T cells, and prevent resistance.
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Competitive inhibitors of viral reverse transcriptase; chain terminators lacking 3'-OH group. Require intracellular phosphorylation to active triphosphate form.
Common Agents:
- • Zidovudine (AZT): First anti-HIV drug; bone marrow suppression
- • Lamivudine (3TC): Minimal toxicity; also for HBV
- • Emtricitabine (FTC): Similar to 3TC
- • Tenofovir (TDF/TAF): Nucleotide analog; renal toxicity
- • Abacavir (ABC): Hypersensitivity in HLA-B*5701+ patients
⚠️ Class Toxicity:
- • Mitochondrial toxicity: Inhibit mitochondrial DNA polymerase γ
- • Lactic acidosis, hepatic steatosis
- • Peripheral neuropathy
- • Lipoatrophy
- • Screen HLA-B*5701 before abacavir
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Bind allosterically to reverse transcriptase, causing conformational change. Do not require phosphorylation. Specific for HIV-1 (not HIV-2).
- • Efavirenz: CNS effects (vivid dreams, dizziness); teratogenic
- • Nevirapine: Hepatotoxicity, Stevens-Johnson syndrome risk
- • Rilpivirine: Fewer CNS effects than efavirenz
- • Doravirine: Newer agent, minimal drug interactions
Resistance:
Single mutation can confer high-level resistance. Often use in combination to prevent resistance.
Protease Inhibitors (PIs)
Inhibit HIV-1 protease, preventing cleavage of Gag-Pol polyprotein into functional viral proteins. Potent CYP3A4 inhibitors; "boosted" with ritonavir or cobicistat to increase levels.
- • Darunavir/ritonavir: High genetic barrier to resistance
- • Atazanavir: Once-daily; hyperbilirubinemia (indirect)
- • Lopinavir/ritonavir: Fixed-dose combination
Adverse Effects:
- • GI intolerance (diarrhea)
- • Lipodystrophy, hyperlipidemia
- • Insulin resistance
- • Drug-drug interactions (CYP3A4)
Integrase Strand Transfer Inhibitors (INSTIs)
Block integration of viral DNA into host genome by inhibiting HIV integrase enzyme. Preferred first-line agents due to efficacy, tolerability, and high genetic barrier.
- • Raltegravir: First INSTI approved; twice-daily dosing
- • Dolutegravir: Once-daily; minimal drug interactions; high barrier to resistance
- • Bictegravir: Coformulated with FTC/TAF; single-tablet regimen
- Adverse: Generally well-tolerated; weight gain, insomnia, neural tube defects (dolutegravir)
Entry & Fusion Inhibitors
Fusion Inhibitors:
- • Enfuvirtide (T-20): Binds gp41, prevents fusion
- Subcutaneous injection; injection site reactions; salvage therapy
CCR5 Antagonists:
- • Maraviroc: Blocks CCR5 co-receptor
- Only effective against CCR5-tropic HIV; requires tropism testing
Anti-Hepatitis Drugs
Hepatitis B (HBV)
- Nucleoside/nucleotide analogs:
- • Tenofovir (TDF/TAF): First-line; high barrier to resistance
- • Entecavir: Alternative first-line
- • Lamivudine: Resistance common; used for HIV co-infection
- Interferons:
- • Pegylated interferon-α: Finite therapy duration; flu-like symptoms
Hepatitis C (HCV)
- Direct-Acting Antivirals (DAAs):
- • NS5A inhibitors: Ledipasvir, velpatasvir, elbasvir
- • NS5B polymerase inhibitors: Sofosbuvir (nucleotide analog)
- • NS3/4A protease inhibitors: Glecaprevir, grazoprevir
- Combination regimens (e.g., sofosbuvir/velpatasvir) cure >95% with 8-12 weeks treatment
Anti-Herpes Drugs
Nucleoside Analogs
Require viral thymidine kinase for initial phosphorylation (selective toxicity). Inhibit viral DNA polymerase, causing chain termination.
- Acyclovir:
- • HSV-1/2, VZV (chickenpox, shingles)
- • Poor oral bioavailability (~20%)
- • Resistance: Mutated thymidine kinase or DNA polymerase
- Valacyclovir:
- • Prodrug of acyclovir; better bioavailability
- • Suppressive therapy for genital herpes
- Ganciclovir:
- • CMV retinitis, colitis (HIV/transplant)
- • Bone marrow suppression (neutropenia)
- • Valganciclovir: Oral prodrug
- Foscarnet:
- • Non-nucleoside DNA polymerase inhibitor
- • Resistant HSV, CMV
- • Nephrotoxicity, electrolyte disturbances
Anti-Influenza Drugs
Neuraminidase Inhibitors
Block viral neuraminidase, preventing release of new virions from infected cells. Effective against influenza A and B if started within 48 hours of symptom onset.
- • Oseltamivir (Tamiflu): Oral; 5 days; GI upset
- • Zanamivir: Inhaled; risk of bronchospasm in asthmatics
- • Peramivir: Single IV dose
M2 Ion Channel Inhibitors (Obsolete)
Block M2 protein, preventing viral uncoating. Influenza A only. No longer recommended due to widespread resistance.
- • Amantadine: Also used for Parkinson's disease
- • Rimantadine: Fewer CNS effects than amantadine
- ⚠️ >99% resistance in circulating strains
Antiviral Drug Interactions
| Drug Class | Interaction Mechanism | Clinical Significance |
|---|---|---|
| Protease Inhibitors | CYP3A4 inhibition | ↑ Statins, CCBs, immunosuppressants; avoid simvastatin/lovastatin |
| NNRTIs (efavirenz) | CYP3A4 induction | ↓ Contraceptives, warfarin, methadone |
| Tenofovir | Renal tubular transport | ↑ Levels of didanosine; avoid combination |
| Ribavirin | Antagonizes zidovudine | Avoid co-administration in HIV/HCV coinfection |