Antiviral pharmacotherapy

double-stranded DNA viruses

Herpes Simplex Virus (HSV-1, HSV-2), Varicella-Zoster Virus (VZV), and Cytomegalovirus (CMV) are

Acyclovir

MOA: Competitive inhibition of viral DNA polymerase & strand termination

Activation Requirement: Triphosphorylated: 1st step by viral Thymidine Kinase (TK); 2nd & 3rd by host kinases.

Key Indications: HSV-1, HSV-2, VZV, HSV Encephalitis (IV).

Valacyclovir

MOA: Prodrug of Acyclovir (L-valyl ester); converted in liver/gut.

Activation Requirement: Same as acyclovir (higher oral bioavailability ~55%).

Key Indications: Genital herpes, Herpes zoster (shingles).

Famciclovir

MOA: Diacetyl ester prodrug of Penciclovir.

Activation Requirement: Viral TK → intracellular Penciclovir triphosphate.

Key Indications: Herpes zoster, recurrent genital herpes.

Ganciclovir / Valganciclovir

MOA: Competitive inhibition of viral DNA polymerase.

Activation Requirement: Activated by viral UL97 kinase (in CMV) or viral TK.

Key Indications: CMV Retinitis, CMV prophylaxis in transplant patients.

Foscarnet

MOA: Inorganic pyrophosphate analog; directly inhibits DNA/RNA polymerase & HIV RT.

Activation Requirement: No phosphorylation required (bypasses TK/UL97 mutants).

Key Indications: Acyclovir-resistant HSV/VZV, Ganciclovir-resistant CMV.

Cidofovir

MOA: Cytosine nucleotide analog; inhibits viral DNA polymerase.

Activation Requirement: Uses host cellular kinases only (bypasses viral enzymes).

Key Indications: CMV retinitis in HIV patients

Docosanol

MOA: Prevents viral entry by inhibiting fusion between viral envelope and host plasma membrane.

Activation Requirement: None (topical $10\%$ cream).

Key Indications: Cold sores (Orolabial HSV-1).

Acyclovir: Board-Testable Toxicities & Counseling

Crystalline Nephropathy (hydrate; infuse slowly over 1 hr), Neurotoxicity.

Valacyclovir: Board-Testable Toxicities & Counseling

High doses in immunocompromised cause TTP/HUS.

Famciclovir: Board-Testable Toxicities & Counseling

Headache, GI upset; lower frequency of dosing than acyclovir.

Ganciclovir / Valganciclovir: Board-Testable Toxicities & Counseling

Black Box Warning: Severe Myelosuppression (Neutropenia, Anemia, Thrombocytopenia).

Foscarnet: Board-Testable Toxicities & Counseling

Severe Nephrotoxicity, severe electrolyte imbalances (Hypocalcemia, Hypomagnesemia) → Seizures.

Cidofovir: Board-Testable Toxicities & Counseling

Severe Nephrotoxicity; MUST co-administer with oral Probenecid and IV Normal Saline.

Docosanol: Board-Testable Toxicities & Counseling

Apply at first sign of prodrome (5 times/day).

Anti-Influenza & Respiratory Antivirals

_{^{Influenza treatments are most effective when initiated within 48 hours of symptom onset.}}

Neuraminidase Inhibitors

Cap-Dependent Endonuclease Inhibitor

M2 Ion Channel Blockers

Guanosine Analog

Neuraminidase Inhibitors

_{^{Oseltamivir (Oral), Zanamivir (Inhaled), Peramivir (IV)}}

Inhibits viral neuraminidase; blocks cleavage of sialic acid residues, preventing release of new virions from host cells.

Clinical Application & Route: Influenza A and B treatment and post-exposure prophylaxis.

Cap-Dependent Endonuclease Inhibitor

Baloxavir marboxil

Inhibits cap-dependent endonuclease (PA subunit); blocks viral mRNA synthesis ("cap-snatching").

Clinical Application & Route: Influenza A and B (single oral dose).

M2 Ion Channel Blockers

Amantadine, Rimantadine

Blocks M2 proton channel; inhibits viral uncoating inside host endosomes.

Clinical Application & Route: Influenza A ONLY (not active against Influenza B).

Guanosine Analog

Ribavirin

Inhibits IMP dehydrogenase → depletes GTPPools; inhibits viral RNA polymerase.

Clinical Application & Route: Inhaled: Severe RSV in pediatrics.

Oral: Chronic Hepatitis C (with DAAs).

Oseltamivir

Delirium/neuropsychiatric events in pediatrics.

Zanamivir

Contraindicated in Asthma/COPD (causes bronchospasm).

Baloxavir marboxil

Polyvalent cations (antacids) chelate the drug and decrease absorption.

Amantadine, Rimantadine

Obsolete for flu due to high resistance. Amantadine increases dopamine release (used in Parkinson's disease).

Ribavirin

Black Box Warning: Hemolytic Anemia and Teratogenicity (Pregnancy Category X). Requires 2 forms of birth control during and for 6 months post-treatment.

Antiretroviral Therapy (ART) for HIV

_{^{First-line HIV regimens typically consist of 2 NRTIs + 1 INSTI. Memorize class mechanisms, prototype drugs, and landmark toxicities.}}

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Protease Inhibitors (PIs) (Suffix: -navir)

Integrase Strand Transfer Inhibitors (INSTIs) (Suffix: -tegravir)

Entry & Fusion Inhibitors

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

• Mechanism: Competitive inhibition of HIV Reverse Transcriptase and incorporation into viral DNA causing chain termination (lacks 3-OH group). Must be intracellularly phosphorylated.

• Class Side Effect: Mitochondrial toxicity leading to Lactic Acidosis with Hepatic Steatosis.

Efavirenz (EFV)

CNS toxicities (vivid dreams, dizziness, psychosis); take on an empty stomach at bedtime to minimize CNS effects. Historically associated with neural tube defects

Nevirapine (NVP)

High risk of severe hepatotoxicity and fulminant skin reactions

Rilpivirine (RPV)

• Requires an acidic gastric environment (contraindicated with PPIs) and must be taken with a meal ( ≥390\ kcal).

Protease Inhibitors (PIs) (Suffix: -navir)

• Mechanism: Inhibits HIV protease (pol gene product); prevents cleavage of viral Gag-Pol polyprotein, resulting in immature, non-infectious virions.

• Class Side Effects: Metabolic abnormalities (Hyperglycemia/Insulin resistance, Dyslipidemia, Lipodystrophy/buffalo hump), GI distress.

Atazanavir (ATV)

Causes indirect hyperbilirubinemia ("bananavir" / jaundice) and kidney stones. Requires gastric acid for absorption.

Darunavir (DRV)

Contains a sulfonamide moiety (use caution in sulfa allergy).

Pharmacokinetic Boosters

PIs are co-administered with Ritonavir (RTV) or Cobicistat (COBI)—potent CYP3A4 inhibitors used to boost PI serum levels.

Integrase Strand Transfer Inhibitors (INSTIs) (Suffix: -tegravir)

• Mechanism: Inhibits HIV Integrase; prevents integration of proviral DNA into host cell chromosome.

• Key Agents: Dolutegravir (DTG), Bictegravir (BIC), Raltegravir (RAL).

• _{^{PHLE High-Yield Note: Polyvalent cations bind and chelate INSTIs, reducing bioavailability. Separate administration by at least 2 hours before or 6 hours after cation-containing products.}}

Enfuvirtide (T-20)

Binds to viral gp41 subunit; prevents conformational changes needed for viral fusion with host membrane. Given SubQ; causes injection site reactions.

Maraviroc (MVC)

Binds host CCR5 co-receptor; blocks viral gp120 attachment. Trofile assay (tropism test) MUST be performed before initiation (effective ONLY against CCR5-tropic HIV).

Hepatitis B Virus (HBV - DNA Virus)

• First-Line Nucleos(t)ide Analogs: Entecavir (guanosine analog) and Tenofovir (TDF / TAF). They competitively inhibit HBV DNA polymerase.

• Pegylated Interferon alfa-2a: Subcutaneous cytokine therapy. Causes severe flu-like symptoms, bone marrow suppression, and depression/suicidal ideation.

Hepatitis C Virus (HCV - RNA Virus)

NS3/4A Protease Inhibitors

NS5A Replication Complex Inhibitors

NS5B Polymerase Inhibitors

NS3/4A Protease Inhibitors (-previr)

Glecaprevir, Grazoprevir, Voxilaprevir

• Inhibits viral NS3/4A protease; stops cleavage of HCV polyprotein.

NS5A Replication Complex Inhibitors (-asvir)

Pibrentasvir, Ledipasvir, Velpatasvir

• Inhibits NS5A protein involved in viral RNA replication and assembly.

NS5B Polymerase Inhibitors (-buvir)

Sofosbuvir (Nucleoside), Dasabuvir (Non-nucleoside)

• Inhibits NS5B RNA-dependent RNA polymerase; causes RNA chain termination

Critical DAA Safety Warnings:

• HBV Reactivation: Screen all patients for current or prior HBV infection before starting DAAs.

• Sofosbuvir + Amiodarone: Risk of severe, life-threatening bradycardia; co-administration is contraindicated.

Nirmatrelvir / Ritonavir (Paxlovid)

Nirmatrelvir inhibits SARS-CoV-2 main protease (3CL^pro / M^pro); Ritonavir acts as a CYP3A4 pharmacokinetic booster. Subject to extensive drug-drug interactions.

Remdesivir (Veklury)

IV prodrug adenosine nucleotide analog; inhibits viral RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2.

Imiquimod (Aldara)

Topical immune response modifier (TLR-7 agonist) that stimulates local interferon production. Used for External Anogenital Warts (HPV), actinic keratosis, and superficial basal cell carcinoma.