Pharmacology of Antiviral Agents Tufts University School of Medicine December 2016 Linden Hu, MD

TREATABLE VIRAL INFECTIONS Influenza Herpes viruses Herpes simplex Cytomegalovirus Varicella zoster virus HIV Hepatitis C Hepatitis B

Mechanism of Action of Antiviral Agents Inhibit one or more of the following: Viral nucleic acid synthesis Viral uncoating Binding of viral particle to host cell Antiviral drugs must distinguish virus from host!

Influenza Hemagglutinin Neuraminidase Site by which virus binds to host cell receptor Neuraminidase Degrades host cell receptor, allowing release of virus after replication has occurred

Approaches to Control of Influenza Vaccination at start of influenza season (immunoprophylaxis) Treatment with antiviral agents Greatest effect when rx begun w/in 24 hrs

Antiviral Agents for Influenza M2 Inhibitors (influenza A only) Amantadine Rimantadine Neuraminidase inhibitors Oseltamavir (Tamiflu) Zanamivir (Relenza) Peramivir (Rapivab)

Amantadine Inhibits M2 protein (only present on influenza A) M2 protein is a protein channel which enhances viral uncoating and thus inhibition of M2 protein inhibits viral replication Resistance conferred by a single amino acid mutation in the M2 protein

Amantadine Usual dose 100 mg po bid – rx is for 5 days Dosed reduced in persons >65 yrs and Cr Cl <50 Toxicity CNS side effects (insomnia, hallucinations, jitteriness, irritability, confusion, seizures) CNS side effects increase when drug given along with anticholinergics or antihistamines

Rimantadine Better tolerated than amantadine, likely due to lower blood levels Lower rate of CNS side effects compared to amantadine Resistance results from single point mutation of M2 protein Mutation confers cross resistance between amantadine and rimantadine

Neuraminidase Inhibitors Active against influenza A and B Blocks neuaminidase preventing release of viral particles Reduce median duration of sx by ONE DAY and reduce odds of developing influenza by 70-90%

Oseltamivir (Tamiflu) Given orally – rapidly absorbed from GI tract Excreted by kidney Standard dose is 75 mg po bid Can be given for treatment and prophylaxis Main side effect is GI upset Few reports of neurotoxicity in children During 2013-4 influenza season in US, >99% of influenza isolates were susceptible to oseltamivir Double dose has been suggested for severely ill, immunocompromised persons In Japan reports of delirium and self injury in children with use of oseltamivir

Peramivir (Rapivab) IV formulation of neuraminidase inhibitor Recently FDA approved for treatment of uncomplicated influenza Dosed as one time 600 mg dose IV Potential adverse events include rash, elevated creatinine, CNS side effects (delirium, halllucinations, abnormal behavior)

Zanamivir (Relenza) Inhaled - not orally bioavailable May precipitate bronchospasm Decreases sx of influenza by 1.5 days if given w/i 48 hrs of sx onset – also reduces severity of sx Not widely used due to lack of oral administration IV zanamivir is being evaluated in clinical trials and is available for compassionate use

Neuraminidase Inhibitors - Resistance Lower risk of resistance compared to amantadine compounds Active against strains of influenza A resistant to amantadine and rimantadine, given different mechanism of action

Indications for Antiviral Treatment for Suspected or Confirmed Influenza Severe illness requiring hospitalization Pregnancy Age <2 years or >65 years Chronic medical condition Avoid treating young otherwise healthy persons to minimize development of resistance to influenza compunds

Summary of Influenza Drugs Mechanism Virus type Side Effects Amantadine M2 inhibitor A CNS toxicity Rimantadine Few side effects Oseltamavir Neuraminidase inhibitor A & B GI distress Zanamivir Peramivir Bronchospasm Rash, increased creatinine

Herpes Viruses Herpes simplex virus, type 1 (HSV-1) Varicella zoster virus (VZV) Cytomegalovirus (CMV) Epstein Barr virus (EBV) Human herpesvirus 6 (HHV 6) Human herpesvirus 7 (HHV 7) Human herpesvirus 8 (HHV 8)

Acyclovir and Derivatives Acyclovir- topical, IV and PO Prodrugs (increase bioavailability; acyclovir ~25%) Valacyclovir (PO pro-drug of acyclovir; ~50% bioavailable) Famciclovir (PO prodrug of penciclovir; ~75% bioavailable)

Acyclovir and Derivatives Analog of 2’ deoxyguanosine Require phosphorylation to monophosphate form by virus-encoded thymidine kinase Drug concentrates in herpes virus-infected cells as little phosphorylation occurs in uninfected cells Monophosphate form is converted to a triphosphate form by host cell kinases Triphosphate form inhibits viral DNA polymerase

Acyclovir, valacyclovir, Famciclovir Ganciclovir CMV UL97 kinase Herpesvirus thymidine kinase Drug monophosphate Drug monophosphate Host cell kinases Host cell kinases Drug Triphosphate Drug Triphosphate Viral DNA Polymerase

Acyclovir Active against HSV-1, HSV-2, VZV Generally not useful for rx of CMV Phosphorylated sequentially by viral thymidine kinase followed by host cell kinases to active tri-phosphate form Competitively inhibits viral DNA polymerase Incorporated into viral DNA resulting in chain termination Available in oral, intravenous, and topical forms

Clinical Use of Acyclovir HSV infections Genital HSV (primary, recurrent, suppression) Oral-Labial HSV HSV Encephalitis Neonatal HSV Prophylaxis (prevent reactivation of HSV in immunocompromised hosts) VZV Varicella (chickenpox) Herpes zoster (shingles)

Acyclovir Preparations Oral bioavailability 20-30% Topical Oral (200, 800 mg) Intravenous Oral bioavailability 20-30% Penetrates well into CSF - CSF level 50% of serum level >60% excreted unchanged in the urine

Acyclovir Toxicity Nephrotoxicity (particularly after rapid intravenous infusion and inadequate hydration) CNS Agitation, lethargy, tremors Hallucinations Disorientation

Mechanisms of Resistance Thymidine kinase deficient mutant Thymidine kinase with altered substrate and unable to phosphorylate acyclovir Mutations in viral DNA polymerase *Almost all clinically significant acyclovir resistance seen in immunocompromised hosts *Commonly associated with cross resistance to famciclovir and valacyclovir

Herpes labialis and genitalis (HSV1 and HSV2) Can use oral agents for treatment with modest effect in shortening length of symptoms (not usually recommended) Topical agents can be used but needs to be applied very frequently to work Can be used in prevention for recurrent outbreaks. Does NOT reduce risk of transmission to uninfected partners

Chickenpox Treat with acyclovir (or derivatives) Treat immunocompromised hosts with varicella Treat pregnant women in 2nd and 3rd trimester given risk of disseminated disease Treat perinatal varicella Treat adults >18 yrs; reduces number of lesions and accelerates time to crusting

Herpes Zoster Treated with oral agents except in immunocompromised patients with evidence of dissemination Shortens course by one to two days May decrease incidence of post-herpetic neuralgia Fitzpatrick's Color Atlas & Synopsis of Clinical Dermatology Klaus Wolff, Richard Allen Johnson, Dick Suurmond Copyright 2005, 2001, 1997, 1993 by The McGraw-Hill Companies

Special Uses for Intravenous Acyclovir Neonatal Herpes HSV Encephalitis Immunocompromised host with chickenpox or herpes zoster

Ganciclovir Active against CMV, HSV-1, HSV-2 Not commonly used to rx HSV given that it is more toxic than acyclovir

Ganciclovir Guanosine derivative Ganciclovir triphosphate selectively inhibits CMV DNA polymerase Resistance common among persons treated for >3 months and is usually due to mutations in CMV UL97 gene Available in oral and intravenous forms

Acyclovir, valacyclovir, Famciclovir Ganciclovir Herpesvirus thymidine kinase CMV UL97 kinase Drug monophosphate Drug monophosphate Host cell kinases Host cell kinases Drug Triphosphate Drug Triphosphate Viral DNA Polymerase

Ganciclovir Toxicity Nephrotoxicity Bone marrow suppression (leukopenia)

Valganciclovir Orally bioavailable prodrug that is rapidly metabolized to ganciclovir in the intestine and liver 60% of oral valganciclovir dose is absorbed Used for prophylaxis of CMV disease in immunocompromised hosts and maintenance rx IV ganciclovir used to treat severe CMV disease

Cidofovir Nucleotide analogue that inhibits viral DNA polymerase Activity against CMV, smallpox, BK virus, acyclovir resistant HSV Long intracellular half-life that allows intermittent intravenous administration Nephrotoxic Nucleotide analog with broad spectrum antiviral activity

Foscarnet Inhibits DNA polymerase – does not require phosphorylation Effective against resistant CMV and HSV Less well tolerated than ganciclovir and associated with considerable toxicity Nephrotoxicity Hypomagnesemia, hypokalemia, hypocalcaemia

Antiviral Therapy for CMV Induction Dose Maintenance Dose Toxicity Ganciclovir (IV) 5mg/kg bid 5 mg/kg qd NephrotoxicityBone marrow suppression Foscarnet (IV) 90 mg/kg bid 90 mg/kg qd Renal toxicity, Electrolyte disturbance Cidofovir 5 mg/kg qwk 5 mg/kg q 2wks Nephrotoxicity Valganciclovir (PO) 900 mg bid 900 mg qd Bone marrow suppression

Antiviral Take Home Points Early initiation of therapy is a key Impact is often minimal in immunocompetent patients; you do not always need to treat for viral infections Toxicities can be limiting amantadine - neurotoxicity oseltamivir - GI toxicity ganciclovir - bone marrow suppression foscarnet - nephrotoxicity, electrolyte abnormalities