9. Antiviral Drugs

HOAD ANTIVIRAL DRUGS Wandikayi C. Matowe, PhD Office: Room 125 Building #1 Email: wmatowe@aucmed.edu Wandikayi C. Matowe, PhD https://basicmedicalkey.com/wp-content/uploads/2016/06/image02755.jpeg 1 Readings and Practice Questions Practice questions at the end of the chapter AUC Library: Electronic copy Chapter 49: Antiviral Agents https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/book.aspx?bookid=3461#285552254 Reserved for captions Learning Objectives After this lecture the student should know and be able to: • Describe the different steps and molecular processes involved in the process of viral infection • Describe host cell targets of antiviral drug action • Identify first line and alternative agents used for treating Herpes group, Influenza A & B and Hepatitis B and C virus infections • Discuss the antiviral spectra of drugs discussed for each infection • Explain the mechanisms of action and modes of resistance to the main drugs used for each type of viral infection and describe their indications and adverse effects Reserved for captions Antiviral & Anti-retroviral Drugs HIV Drugs Reserved for captions Drugs for Herpes Simplex Virus Infections Docosanol: Aliphatic alcohol; inhibits fusion between host cell plasma membrane and HSV envelope;Topical agent for HSV-1 Idoxuridine & Trifluridine: • Thymidine analogs for topical (ophthalmic) use in HSV retinitis  poor systemic absorption • • • • • • Acyclovir Valacyclovir CLOVIRS Famciclovir Penciclovir Purine mimetics active against HSV-1 & HSV-2 Triphosphorylated to active metabolite Reserved for captions Clovirs: Mechanism of Action 1 2 3 Drugs for Herpes Simplex Virus Infections Herpes simplex (HSV) viruses and Varicella zoster (VZV) • • • • Acyclovir/Valacyclovir HSV Famciclovir/Penciclovir Ganciclovir/Valganciclovir CMV Foscarnet Useful for Acyclovir• Adefovir resistant strains • Cidofovir ▪ Also effective for adenoviruses Herpes labialis (HSV-1) Indications: treatment & prophylaxis • HSV-1, HSV-2 & Varicella (VZV) Chicken pox & Shingles Reserved for captions Shingles (Varicella zoster) Activation of Nucleoside / Nucleotide Analogues Mechanism of Action: • Administered agent is a pro-drug, nucleoside analog (NA),  activated by (viral) & host kinases via phosphorylation to active metabolite • Metabolite inhibits virus DNA polymerase Active metabolite NA – nucleoside analog Reserved for captions Clovirs: Adverse Reactions • Renal dysfunction • Pancytopenia • IV administration: ▪ Reversible kidney dysfunction due to crystalline nephropathy ▪ Infusion site phlebitis/inflammation (or extravasation) Resistance: • In HSV or VZV (Varicella-zoster virus): ▪  mutation or deletion of viral thymidine kinase • ▪  cross resistance with all other clovirs DNA polymerase mutation Reserved for captions FOSCARNET • Tri-sodium salt of phosphonoformate (Inorganic pyrophosphate) Pyrophosphate Foscarnet Mechanism of Action: • Specifically inhibits viral DNA polymerase, RNA polymerase & HIV reverse transcriptase by competing for the PP binding site • Resistance  mutations in CMV UL54 gene which encodes the DNA polymerase Indications: • Drug of choice for acyclovir-resistant HSV or VZV infections • Immunocompromised patients with CMV retinitis & mucocutaneous acyclovirresistant HSV infections Side Effects: • Renal impairment  hypokalemia, hypocalcemia & hypomagnesemia Reserved for captions Drugs for Cytomegalovirus (CMV) Infection Ganciclovir & Valganciclovir (nucleoside analogs): • activated via phosphorylation in CMV-infected cells; initial phosphorylation is by virus-specific kinase (UL97)), then (2x) by host kinase • Activated triphosphate inhibits viral DNA polymerase & terminates viral DNA elongation • Broad spectrum in vitro activity against CMV, HSV, VZV, EBV, HHV-6, and HHV-8 Indications: • Valganciclovir – oral drug of choice CMV retinitis treatment and CMV prophylaxis for solid organ transplant patients • Ganciclovir – IV for CMV retinitis treatment, oral for CMV prophylaxis • Foscarnet and cidofovir treatment of resistant CMC retinitis Reserved for captions Drugs for Influenza Amantadine and Rimantadine (Influenza A) • Prophylaxis & early treatment of ‘Influenza A’ not used much due to resistance Mechanism of Action: Bind to M-2 protein ion channel & prevent uncoating of Influenza A virus Resistance: Common, secondary to mutations of the M-2 protein Oseltamivir & Zanamivir - treatment and prophylaxis of both Influenza A & B Mechanism of Action: • Selectively inhibit viral neuraminidases of Influenza A and B, including (H1N1 & H5N1)  prevent release of virions Resistance • Viral neuraminidase mutations (~1% of adults and 4% of children) Reserved for captions Drugs For Hepatitis B: Interferons & Peginterferon • Broad spectrum anti-viral cytokines released by cells infected by virus • Alpha, beta, gamma (glycoproteins produced naturally by different cells in immune system after exposure to viruses •  activity of Janus kinases (JAKS), enzymes that phosphorylate signal transducers and activate transcription & upregulate antiviral proteins Reserved for captions Drugs For Hepatitis B: INTERFERONS Indications: • HBeAg+ve carriers with chronic active hepatitis (Response rate is 30 to 40%) • may be considered for chronic active hepatitis C (Response rate is ~50% but 50% of responders will relapse upon withdrawal of treatment) Administration: parenteral routes only : • IM, SQ & Topical (nasal spray) Adverse Effects: • Flu-like symptoms (headache, fatigue or asthenia, myalgia, arthralgia, fever, chills) • Neuropsychiatric: ▪ Depression, emotional lability, insomnia • Alopecia • Thyroiditis:  can unmask or exacerbate; IFN-induced disease may not be reversible after stopping treatment Reserved for captions RIBAVIRIN • Guanosine analog phosphorylated by host cell enzymes to active drug • Used in combination with interferon- (Hepatitis B) or sofosbuvir, lepidasvir etc (Hepatitis C) Mechanism of Action: • Inhibits viral RNA-dependent DNA polymerase & capping of viral mRNA • Inhibits replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, RSV, paramyxoviruses, HCV, and HIV-1 Adverse Effect: drug-induced hemolytic anemia Reserved for captions Treatment of Viral Hepatitis C Primary goal: viral eradication in patients with chronic HCV • i.e. attain sustained virologic response (SVR)  undetectable RNA level 12 weeks after completing therapy Indications for treatment: • All patients with virologic evidence of chronic HCV infection (ie, detectable HCV viral level over a sixmonth period) Treatment of Viral Hepatitis C Sofosbuvir • Nucleotide inhibitor of  HCV RNA NS5B polymerase ( very high cure rates) Indications: • Chronic hepatitis C in patients infected with HCV genotypes 1, 2, 3, or 4 • Used with peginterferon alfa & ribavirin) • Contraindicated in women who are or may become pregnant & in men with pregnant female partners Adverse Effects: • Pancytopenia, suicidal ideation, diarrhea, anemia, headache, insomnia , fatigue Reserved for captions Treatment of Viral Hepatitis C Ledipasvir • Hyperphosphorylate NS5A, a viral polymerase required for viral assembly and interferes with proper liver metabolism  inhibits proper viral assembly by re-positioning NS5A's sub-cellular localization Sofosbuvir: • alone or in combination with interferon or ribavirin achieves very high cure rates (90–95%) Protease inhibitors, Boceprevir, Simeprevir, Telaprevir • Grazoprevir - potent, pan-genotypic protease inhibitor, reversibly binding to HCV NS3/4A protease • Always co-administered with ribavirin • Use in pregnant women and in men with pregnant partners is contraindicated Reserved for captions Drugs Used to Treat Viral Hepatitis C Pegylated interferon alfa-2a & alfa-2b + ribavirin Interferon alfa-2b + ribavirin Chronic hepatitis C Acute hepatitis C 2 nd l i n e t r e a t m e n t f o r H e p a t i t i s C Reserved for captions SAR-CoV-2 infection (Covid) Nirmaltrevir • FDA-approved oral prescription medication to treat adults who: ▪ have mild-to-moderate COVID-19, and ▪ have had symptoms for 5 days or fewer, and ▪ have a high-risk factor for progression to severe COVID-19nucleoside Remdesivir ▪ ▪ analog used to inhibit the action of RNA polymerase indicated for the treatment of non-hospitalized patients with mild-tomoderate COVID-19, who are at high risk for progression to severe COVID-19 Reserved for captions Summary Reserved for captions Antivirals Drugs Summary Virus Drug HSV/VZV Acyclovir Mechanism Activated by viral TK; inhibits DNA polymerase Resistance Major Toxicity TK mutation Nephrotoxicity Polymerase mutation Nephrotoxicity, electrolyte abnormalities UL97 mutation Myelosuppression HSV/VZV resistant Foscarnet Direct DNA polymerase inhibitor CMV Ganciclovir UL97 activation; inhibits DNA polymerase CMV resistant Cidofovir Nucleotide analog Influenza A/B Oseltamivir Neuraminidase inhibitor Influenza A Amantadine M2 channel blocker DNA polymerase mutation Neuraminidase mutation M2 mutation HBV Tenofovir Nucleotide RT inhibitor Polymerase mutation Renal toxicity HCV Sofosbuvir NS5B polymerase inhibitor NS5B mutation Usually well tolerated HCV Glecaprevir NS3/4A protease inhibitor Protease mutations Drug interactions Reserved for captions Nephrotoxicity GI upset CNS toxicity Questions Reserved for captions Question NM, a 32-yo woman reported to the clinic complaining of pain & burning in the genital area for the past 2 days. The symptoms were worse during urination and were accompanied by fever and malaise. Physical examination revealed multiple blisters and ulcerative lesions in the vaginal area. A presumptive diagnosis of Herpes genitalis was made. She was prescribed an oral drug. Which of the following steps of the viral growth cycle was most likely inhibited by the drug? a. b. c. d. e. Entry Uncoating Transcription Translation Proteolytic cleavage and Viral assembly Reserved for captions Question A 32-yo male with HIV is suffering from recurrent HSV-2 infections. The virus is found to be acyclovir-resistant. Which of the following drugs is an approved treatment for the management of acyclovir-resistant HSV infections? a. Amantadine b. Docosanol c. Foscarnet d. Sofosbuvir e. Valacyclovir Reserved for captions Quick questions Several antiviral drug analogs are tested for therapeutic effectiveness against Influenza B virus. A drug similar to which of the following is most likely to be effective? a. Amantadine b. Docosanol c. Foscarnet d. Sofosbuvir e. Zanamivir Reserved for captions Quick questions A 27-year-old immunocompromised patient developed a herpes simplex infection due to HSV 2. Which of the following drugs would be least suitable for treating this infection? Acyclovir Cidofovir Foscarnet Trifluridine Ribavirin Reserved for captions Practice Questions A 24-year-old woman presents with recurrent painful vesicular lesions on her lips. She reports having had similar episodes several times per year since adolescence. During the current episode she is prescribed a medication that requires phosphorylation by a virus-encoded enzyme before becoming active. Once activated, the drug selectively inhibits viral DNA synthesis by acting as a guanosine analog and causing chain termination. Which of the following drugs was most likely prescribed? A. Acyclovir B. Foscarnet C. Ganciclovir D. Ribavirin E. Zidovudine Explanation: Acyclovir is activated by viral thymidine kinase and then inhibits viral DNA polymerase, causing DNA chain termination. It is first-line therapy for HSV and VZV infections. Correct Answer: A. Acyclovir • Foscarnet does not require activation. • Ganciclovir is primarily used for CMV. • Ribavirin treats selected RNA viral infections. • Zidovudine is an antiretroviral drug. Reserved for captions Practice Questions A 72-year-old woman develops a painful unilateral vesicular rash involving the T5 dermatome. She is diagnosed with herpes zoster and started on valacyclovir. Which adverse effect would most likely occur if excessive doses were administered in a patient with renal insufficiency? A. Cardiomyopathy B. Nephrotoxicity and neurotoxicity C. Optic neuritis D. Pulmonary fibrosis E. Severe hypoglycemia Explanation: Acyclovir and valacyclovir may precipitate in renal tubules causing nephrotoxicity. CNS toxicity may occur, especially in elderly patients and those with renal impairment. Correct Answer: B. Nephrotoxicity and neurotoxicity Reserved for captions Practice Questions A renal transplant recipient develops acyclovir-resistant VZV infection. He is treated with a pyrophosphate analog that directly inhibits viral DNA polymerase. Several weeks later he develops hypocalcemia and nephrotoxicity. Which drug caused these adverse effects? A. Acyclovir B. Cidofovir C. Foscarnet D. Ganciclovir E. Oseltamivir Correct Answer: C. Foscarnet Reserved for captions Explanation: Foscarnet commonly causes nephrotoxicity and electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia. Practice Questions A patient with CMV retinitis initially responds to ganciclovir but later relapses. Genetic testing identifies a mutation in the UL97 kinase gene. Which mechanism best explains resistance? A. Decreased neuraminidase activity B. Failure of drug phosphorylation C. Increased CYP450 metabolism D. Increased reverse transcriptase activity E. Loss of viral envelope proteins Correct Answer: B. Failure of drug phosphorylation Explanation: UL97 mutations impair activation of ganciclovir, producing resistance. Reserved for captions Practice Questions A patient with CMV retinitis is treated with a pyrophosphate analog. Shortly thereafter he develops muscle spasms and a prolonged QT interval secondary to electrolyte disturbances. Which drug is most likely responsible? A. Acyclovir B. Foscarnet C. Lamivudine D. Ribavirin E. Sofosbuvir Correct Answer: B. Foscarnet Reserved for captions Explanation: Foscarnet frequently causes electrolyte abnormalities and nephrotoxicity. Practice Questions A strain of influenza A develops resistance due to mutation of neuraminidase. Which antiviral drug would most likely lose effectiveness? A. Acyclovir B. Cidofovir C. Oseltamivir D. Sofosbuvir E. Tenofovir Correct Answer: C. Oseltamivir Reserved for captions Explanation: Neuraminidase mutations confer resistance to oseltamivir and zanamivir. Practice Questions An elderly nursing home resident receives amantadine for influenza A prophylaxis. He develops confusion, insomnia, and hallucinations. Which viral target is inhibited by this drug? A. M2 proton channel B. Neuraminidase C. Reverse transcriptase D. Viral protease E. Viral thymidine kinase Correct Answer: A. M2 proton channel Explanation: Amantadine blocks the influenza A M2 proton channel, preventing viral uncoating. Reserved for captions Practice Questions A 48-year-old man with chronic hepatitis B infection is started on tenofovir. Which mechanism best describes the antiviral action of this drug? A. DNA chain termination through nucleotide analog incorporation B. Inhibition of neuraminidase C. Inhibition of viral protease maturation D. Inhibition of viral uncoating E. Stimulation of interferon receptors only Correct Answer: A. DNA chain termination through nucleotide analog incorporation Explanation: Tenofovir is a nucleotide reverse transcriptase inhibitor that inhibits HBV DNA synthesis. Reserved for captions Practice Questions A patient with chronic hepatitis C receiving a direct-acting antiviral regimen begins taking a potent enzyme-inducing anticonvulsant. Several weeks later viral loads increase significantly. Which mechanism best explains this outcome? A. Accelerated metabolism reducing antiviral concentrations B. Increased thymidine kinase activity C. Increased viral neuraminidase activity D. Loss of interferon receptors E. Reduced renal excretion of antivirals Correct Answer: A. Accelerated metabolism reducing antiviral concentrations Explanation: Many direct-acting antivirals interact with CYP and transporter systems. Strong enzyme inducers such as carbamazepine, phenytoin, and rifampin can markedly reduce antiviral levels and cause treatment failure. Reserved for captions DRUG SUMMARY TABLE: ANTIVIRALS DRUG CLASS MECHANISM OF ACTION CLINICAL APPLICATIONS SIDE EFFECTS AND TOXICITIES Antiherpes drugs Acyclovir Valacyclovir (prodrug) Penciclovir Famciclovir (prodrug) Activated by viral thymidine kinase (TK) to forms that inhibit viral DNA polymerase Treatment and prophylaxis for HSV-I, HSV-2, and VZV Oral forms cause nausea, diarrhea, and headache • – None of these drugs is active against TK IV acyclovir may cause renal and CNS toxicity strains Drugs for cytomegalovirus Ganciclovir Valganciclovir Cidofovir Foscarnet Viral activation of ganciclovir to the form Treatment of CMV infections in immunoinhibiting DNA polymerase; suppression (eg, AIDS) and organ no viral bioactivation of transplantation cidofovir and foscarnet Ganciclovir: Bone marrow suppression, hepatic and neurologic dysfunction • Cidofovir and foscarnet: Nephrotoxicity • Foscarnet: CNS effects and electrolyte imbalance Antihepatitis B drugs Interferon-α (IFN-α) Adefovir dipivoxil Entecavir Lamivudine Ribavirin Sofosbuvir Reserved for captions Degrades viral RNA via activation of host cell RNAse (IFN-α) Inhibition of HBV polymerase (others) • multiple antiviral actions (ribavirin) Suppressive treatment of HBV (except ribavirin and sofosbuvir) • treatment of HCV (sofosbuvir, ribavirin +/– IFN-α) IFN-α: Alopecia, myalgia, depression, flu-like syndrome Adefovir: Lactic acidosis, renal and hepatic toxicity Ribavirin: Anemia, teratogen DRUG SUMMARY TABLE: ANTIVIRALS Drug Class Mechanism of Action Clinical Applications Toxicities Anti-Hepatitis C drugs • • • • • • • • Ledipasvir, Elbasvir Pibrentasvir, Velpatasvir NS5A inhibitors Dasabuvir Sofosbuvir NS5B RNA pol inhibitors Grazoprevir Voxilaprevir NS3/4A protease inhibitors Headache, fatigue HCV (part of combination regimen) HCV (part of combination regimen) Nausea, insomnia HCV (part of combination regimen) Headache, fatigue, nausea Sulfa-allergies for simeprevir Anti-influenza drugs • • • • • • • • Amantadine Rimantadine Oseltamivir Zanamivir Peramivir Baloxavir Reserved for captions Amantadine and rimantadine: block of M2 proton channels Oseltamivir & Peramivir: Gastrointestinal M2 blockers virtually obsolete • others effects Oseltamivir and zanamivir inhibit prophylaxis vs most current flu strains and Delirium in pts w active influenza neuraminidase shorten symptoms, low level of resistance Zanamivir: Bronchospasm in asthmatics Gastrointestinal disturbances Blocks viral endonuclease • Baloxavir: blocks virus replication