Antiviral Agents

• Most antiviral agents are antimetabolites
  • Structurally resemble natural purines, pyrimidines, or their nucleoside forms
  • Typically administered as prodrugs requiring intracellular activation
• Bioactivation pathways
  • Phosphorylation by host-cell or viral kinases
  • Sequential phosphorylation yields active triphosphate metabolites
• Major sites of antiviral action
  • Viral penetration or uncoating
  • DNA or RNA polymerase inhibition
  • Reverse transcriptase blockade
  • Protease, integrase, or neuraminidase inhibition

Acyclovir

• Mechanism
  • Monophosphorylated by viral thymidine kinase (TK) — HSV and VZV have TK
  • Further phosphorylation by host kinases yields the triphosphate
  • Triphosphate form inhibits viral DNA polymerase via competitive inhibition
  • Incorporation into viral DNA causes chain termination (lacks 3′ hydroxyl group)
• Resistance
  • Most commonly due to deficient thymidine kinase activity (TK− strains)
  • Altered DNA polymerase can also confer resistance
  • >50% of resistant HSV isolates are TK−
• Clinical uses
  • Active against HSV and VZV
  • Available as topical, oral, and IV formulations
  • Reduces viral shedding in genital herpes
  • Decreases acute neuritis in shingles but does not prevent postherpetic neuralgia
  • Effective for early chickenpox; used prophylactically in immunocompromised patients
• Adverse effects
  • Oral: generally well-tolerated with mild GI upset
  • IV: crystalluria (requires adequate hydration), neurotoxicity (agitation, headache, confusion, seizures with overdose)
  • Not hematotoxic — bone marrow sparing

Famciclovir & Valacyclovir

• Mechanistically similar to acyclovir
• Approved for HSV infections
• May retain activity against some acyclovir-resistant strains — but not TK− strains
• Longer plasma half-life compared with acyclovir

Ganciclovir

• Mechanism parallels acyclovir
  • Initial phosphorylation by viral kinases: TK (HSV) or UL97 phosphotransferase (CMV)
  • Triphosphate inhibits DNA polymerase and causes chain termination
• Resistance mechanisms analogous to acyclovir
• Clinical uses
  • Active against HSV, VZV, and CMV
  • Primary use: prophylaxis and treatment of CMV infections (retinitis, GI disease) in AIDS and transplant recipients
  • Relapses and retinal detachment are known complications
• Adverse effects
  • Dose-limiting hematotoxicity: leukopenia, thrombocytopenia
  • Mucositis, fever, rash
  • Crystalluria — hydration required
  • Seizures with overdose

Foscarnet

• Not an antimetabolite — directly inhibits viral DNA and RNA polymerases
• Clinical uses
  • Indications overlap with ganciclovir
  • Greater activity against acyclovir-resistant HSV strains
• Adverse effects
  • Dose-limiting nephrotoxicity: acute tubular necrosis
  • Electrolyte disturbances: hypocalcemia (tremors, seizures)
  • Avoid concurrent IV pentamidine — increases nephrotoxicity and hypocalcemia risk

• Highly active antiretroviral therapy (HAART)
  • Combination of 3–4 antiretroviral drugs
  • Suppresses viral RNA load
  • Reverses CD4+ T-cell decline
  • Reduces risk of opportunistic infections
• Drug classes used in HAART
  • Nucleoside reverse transcriptase inhibitors (NRTIs)
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  • Protease inhibitors (PIs)
  • Integrase strand transfer inhibitors (INSTIs)
  • Fusion / entry inhibitors

Nucleoside RTIs (NRTIs)

• Mechanism
  • Phosphorylated intracellularly to triphosphate form
  • Competitively inhibit reverse transcriptase
  • Incorporated into viral DNA → chain termination (lack 3′ OH)
• Backbone of most HAART regimens
• Tenofovir
  • NRTI with a single phosphate on the sugar residue
  • Requires further phosphorylation to the active triphosphate
  • Commonly coformulated with other NRTIs

Non-Nucleoside RTIs (NNRTIs)

• Efavirenz, nevirapine
• Mechanism
  • Bind to a distinct site on reverse transcriptase (not the NRTI-binding site)
  • Non-competitive inhibition
• Additive or synergistic when combined with NRTIs or PIs
• Adverse effects
  • Maculopapular rash
  • CNS effects: vivid dreams, dizziness, somnolence

Protease Inhibitors (PIs)

• Mechanism
  • Target HIV-1 aspartate protease (pol gene product)
  • Prevent cleavage of precursor polypeptides into mature viral core proteins
  • Result: immature, non-infectious viral particles
• Resistance
  • Point mutations in the pol gene
  • Cross-resistance is not complete among different PIs
• Common agents
  • Ritonavir, lopinavir, atazanavir, darunavir
  • Ritonavir is often used as a pharmacokinetic booster (inhibits CYP3A4)
• Adverse effects
  • Indinavir: crystalluria — maintain hydration
  • Ritonavir: potent CYP interactions — induces CYP1A2, inhibits CYP3A4 and CYP2D6
  • Class effects: metabolic syndrome — central adiposity, insulin resistance, dyslipidemia

Integrase Strand Transfer Inhibitors (INSTIs)

• Mechanism
  • Prevent integration of viral DNA into host genome
  • Block the strand transfer step of integration
• Raltegravir and other "-tegravir" agents
• Clinical use
  • Combined with 2 NRTIs as a complete treatment regimen
  • Used in post-exposure prophylaxis (PEP) regimens

Fusion / Entry Inhibitors

• Enfuvirtide
  • Binds to gp41 — prevents fusion of HIV-1 with CD4+ cells
• Maraviroc
  • Blocks gp120 binding to CCR5 co-receptor on macrophages
  • Prevents viral entry
• Both agents block HIV entry at different steps in the fusion process

Zanamivir & Oseltamivir

• Mechanism
  • Inhibit influenza neuraminidase (types A and B)
  • Neuraminidase prevents viral clumping — inhibition reduces release and spread
  • Decreases likelihood of viral penetration into uninfected cells
• Clinical uses
  • Primarily used for prophylaxis
  • Can reduce symptom duration by 2–3 days when started early

Ribavirin

• Mechanism
  • Inhibits inosine monophosphate (IMP) dehydrogenase → depletes guanine nucleotides
  • Also inhibits viral RNA polymerase
• Clinical uses
  • Combined with alpha-interferons for hepatitis C (historically)
  • Treatment of Lassa fever and Hantavirus infections
• Adverse effects
  • Hemolytic anemia — dose-dependent and reversible

• Sofosbuvir
  • Nucleotide analog that inhibits HCV RNA polymerase (NS5B)
  • Acts as a chain terminator
• Simeprevir
  • HCV NS3/4A protease inhibitor
  • Prevents viral polyprotein processing
• Ledipasvir
  • Inhibits HCV NS5A protein
  • Disrupts RNA replication and viral assembly