Antiviral Agents 2024.pdf

ANTIVIRAL DRUGS (NON-RETROVIRAL) Marie Nguyen, PhD Microbiology and Immunology Dept. Objectives 1. Describe the relationship between HSV thymidine kinase, HSV DNA polymerase, and acyclovir. Indicate the most common mechanism for the development of antiviral resistance to acyclovir. 2. Compare and co...

ANTIVIRAL DRUGS (NON-RETROVIRAL) Marie Nguyen, PhD Microbiology and Immunology Dept. Objectives 1. Describe the relationship between HSV thymidine kinase, HSV DNA polymerase, and acyclovir. Indicate the most common mechanism for the development of antiviral resistance to acyclovir. 2. Compare and contrast the mechanism of action, administration route, and major therapeutic indications for acyclovir, valacyclovir, trifluridine, ganciclovir, and foscarnet. 3. Identify the drug targets for letermovir and maribavir. 4. Discuss the steps in the virus life cycle and viral enzymes inhibited by oseltamivir, zanamivir, peramivir, baloxavir marboxil, amantadine, and rimantadine. 5. Compare and contrast the administration route and current therapeutic indications for oseltamivir, zanamivir, baloxavir marboxil, amantadine, peramivir, and rimantadine. 6. Discuss the general features of therapy with direct acting antivirals for chronic hepatitis C infections and be able to identify the mechanism of action for each of the anti-HCV drugs. 7. Describe the simplified HCV treatment regimens and patient populations for which they are indicated. 8. Become familiar with the treatments available for chronic HBV infections. 9. Describe the mechanism of action, administration routes, and therapeutic indications for ribavirin. 10. Determine the mechanism of action and administration route for each of the SARSCoV-2 antivirals discussed in lecture. Identify which drug is administered together with a “metabolic booster.” Review of Virus Life Cycle 1. Attachment 2. Entry 5. 6. Virion EgressAssembly 3. mRNA Production 4. Protein and Genome Synthesis Herpesviruses ◦ DNA viruses that encode their own polymerase = Target for most antivirals. ◦ Lytic (productive) and Latent (clinically silent) stages. Only the Lytic Stage is suppressed by antivirals. ◦ Treatment goals are to speed time to healing and increase time between outbreaks. ◦ Antiviral treatments are only indicated for infections with certain members of the herpesvirus family: VZV, HSV-1, HSV-2, and CMV. Herpesvirus Disease Review ◦ Herpes simplex virus 1 and 2 ◦ Oral herpes lesions aka cold sores ◦ Genital Herpes ◦ Neonatal Herpes ◦ Disseminated Herpes Infections * ◦ Herpes Encephalitis ◦ Ocular Herpes Infections ◦ Varicella Zoster Virus (VZV) ◦ Varicella aka chicken pox ◦ Zoster aka shingles ◦ Cytomegalovirus (CMV) * ◦ Pneumonitis ◦ Gastroenteritis ◦ Retinitis *Almost exclusively seen in immunocompromised individuals Acyclovir Herpesvirus Antivirals ◦ Drug Characteristics ◦ Nucleoside Analogue ◦ Mechanism of Action ◦ Requires initial phosphorylation by the viral thymidine kinase enzyme. ◦ Competitive inhibitor of the viral DNA polymerase ◦ Chain termination upon incorporation into the viral DNA. ◦ Pharmacokinetics ◦ 15 -20% oral bioavailability ◦ Antiviral Resistance ◦ Mutation of the thymidine kinase gene ◦ Cross-resistance with other antivirals with similar mechanism. Herpesvirus Antivirals Acyclovir Activation Acyclovir resistant mutants usually possess a mutation in HSV thymidine kinase that renders TK unable to phosphorylate ACV. Herpesvirus Antivirals Acyclovir ◦ Therapeutic Indications ◦ Oral Administration ◦ Genital herpes ◦ Varicella zoster ◦ Intravenous Administration ◦ Severe or disseminated mucocutaneous disease ◦ Neonate infections ◦ HSV encephalitis ◦ VZV in immunocompromised patients ◦ Adverse Effects ◦ Nausea, headache, diarrhea ◦ Reversible crystalline nephrotoxicity and neurological effects (higher risk with dehydration). ◦ Caution used when administered concurrently with nephrotoxic agents. Herpesvirus Antivirals Valacyclovir ◦ Prodrug of acyclovir. Acyclovir attached to a valine moiety. Metabolized into acyclovir in the liver and intestines. ◦ 3-5 X greater oral bioavailability than acyclovir. ◦ Therapeutic Indications ◦ Primary and recurrent genital herpes ◦ Varicella in older children and adults ◦ Zoster ◦ Orolabial herpes Herpesvirus Antivirals Foscarnet ◦ Drug Characteristics ◦ Phosphonoformic acid (PFA). Analogue of pyrophosphate. ◦ Occupies the site where pyrophosphate normally resides and blocks pyrophosphate release. This blocks the catalytic cycle. Foscarnet does not require prior phosphorylation by thymidine kinase in order to act. ◦ Pharmacokinetics ◦ Only intravenous administration ◦ Antiviral Resistance ◦ Rarely, mutations in DNA pol can cause resistance. ◦ Therapeutic Indications Acyclovir resistant mutants usually possess a mutation in HSV thymidine kinase that renders TK unable to phosphorylate ACV. ◦ HSV and VZV infections that are resistant to acyclovir. ◦ CMV retinitis, CMV colitis, CMV esophagitis ◦ Adverse Effects ◦ Renal impairment ◦ Blood chemistry – changes in Ca, Phosphate, potassium, or Mg levels. ◦ Avoid concurrent administration of drugs with nephrotoxic potential Ganciclovir Herpesvirus Antivirals ◦ Drug Characteristics ◦ Acyclic guanosine analogue ◦ Mechanism of Action ◦ Requires initial phosphorylation by the viral kinase enzyme. Ganciclovir is phosphorylated by CMV UL97 much more efficiently than acyclovir. Therefore, 100 times more active than acyclovir for CMV infections. ◦ Competitive inhibitor of the viral DNA polymerase ◦ Chain termination upon incorporation into the viral DNA. ◦ Pharmacokinetics ◦ Poor oral bioavailability. Approved for administration through IV, oral, or intraocular routes. ◦ Antiviral Resistance ◦ Mutation of the UL97 gene is most common ◦ Cross-resistance with other antivirals with similar mechanism. Herpesvirus Antivirals Ganciclovir ◦ Therapeutic Indications ◦ Intravenous Administration ◦ CMV retinitis (AIDS) ◦ CMV colitis, pneumonitis, and esophagitis ◦ IV followed by Oral Administration ◦ Reduce risk of CMV disease in transplant recipients ◦ Intraocular injection or implant ◦ CMV retinitis ◦ Adverse Effects ◦ Myelosuppression ◦ Bone marrow and CNS toxicity ◦ I.V. ganciclovir àphlebitis, anemia, rash, fever, liver enzyme abnormalities, nausea, vomiting, eosinophilia. Herpesvirus Antivirals Valganciclovir ◦ Prodrug of ganciclovir. L-valyl ester of ganciclovir. Metabolized into ganciclovir in the liver and intestines. ◦ Higher oral bioavailability than ganciclovir. Serum levels approach IV ganciclovir. ◦ Therapeutic Indications ◦ CMV retinitis (AIDS) ◦ Prevention of CMV disease in patients with heart, kidney, and kidney-pancreas transplants. Herpesvirus Antivirals Trifluridine ◦ Drug Characteristics ◦ Fluorinated nucleoside. ◦ Mechanism of Action ◦ Phosphorylated by cellular enzymes ◦ Competitive inhibitor of thymidine for incorporation into newly synthesized genomes. ◦ Therapeutic Indications ◦ Low selectivity does not allow for systemic administration. ◦ Ocular administration to treat keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 and HSV-2. Summary: Herpesvirus DNA polymerase Inhibitors Newly approved CMV antiviral : Letermovir ◦ Drug Target ◦ Inhibitor of the CMV DNA terminase (cleaves newly synthesized viral DNA into individual genomes). ◦ Administration ◦ Oral or intravenous infusion ◦ Therapeutic Indications ◦ Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMVseropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT). ◦ Adverse Effects ◦ Vomiting ◦ Edema ◦ Atrial fibrillation Newly approved CMV antiviral : Maribavir ◦ Drug target ◦ Inhibits the CMV UL97 kinase ◦ Administration ◦ Oral ◦ Individuals with post-transplantational cytomegalovirus (CMV) infections that do not respond to other available CMV treatments. ◦ Drug Interactions Interferes with activity of ganciclovir and similar nucleoside DNA polymerase inhibitors, so cannot be used together. ◦ Adverse Effects ◦ ◦ ◦ ◦ Taste Disturbances Nausea Vomiting Diarrhea Influenza virus ◦ Segmented, RNA virus from the orthomyxovirus family. ◦ Three serotypes, Influenza A, B, C. ◦ Powerful tool for combating influenza disease are vaccines. (injectable, inactivated and inhaled, attenuated formulations available) ◦ High propensity for mutation and therefore, acquiring resistance to antivirals ◦ Antivirals must be given with first 48 hr to have an impact on disease progression. Influenza Disease ◦ Uncomplicated Seasonal Influenza ◦ Fever, myalgia, headache, shaking chills, and cough. Acute symptoms typically 1 – week. Cough, fatigue, and generalized weakness may last 2- 6 weeks. ◦ Complications ◦ Increased risk with very young, elderly, pregnant women and those in the postpartum period, and patients with certain pre-existing medical conditions. ◦ Most common is pneumonia (primary viral or secondary bacterial pneumonia). General -Influenza Antivirals ◦ Three classes of antivirals, based on mechanism of action ◦ Neuraminidase inhibitors ◦ Endonuclease inhibitor ◦ M2 inhibitors/adamantanes (not used due to resistance) ◦ For uncomplicated influenza, give within first 48 h of symptoms. ◦ Do not give with the attenuated influenza vaccine. Influenzavirus Antivirals Neuraminidase Inhibitors Neuraminidase Inhibitors: Mechanism of Action Progeny virions Infected cell Influenza virus: Neuraminidase Inhibitors Oseltamivir Zanamivir Peramivir Characteristics Sialic Acid analogue Sialic Acid analogue Cyclopentane analogue Mechanism of Action Bind to active site of neuraminidase of Influenza A and B viruses to inhibit its function. Inhibits spread of progeny virions through the respiratory tract. Administration Oral Inhalation Intravenous Therapeutic indications Influenza A & B virus infections 2 wks + Influenza A & B virus infections 7 yrs+ Influenza A & B virus infections 2 yrs+ Adverse Effects Contraindications GI effects Headache Fatigue Rash (rare) Mental status changes (rare) Cough Bronchospasm ↓ pulmonary function (temporary). Nasal and throat discomfort pre-existing pulmonary disease GI effects Rash Steven Johnson syndrome Hyperglycemia Hypertension Mental status changes (rare) Influenzavirus Antivirals Baloxavir marboxil Endonuclease Inhibitor ◦ Endonuclease inhibitor. Inhibits the Influenza cap-dependent endonuclease of Influenza A and Influenza B viruses. ◦ Pharmacokinetics. Administered through the oral route with a single dose. ◦ Therapeutic Indications. Approved for use in individuals 12 years of age and older, that are experiencing acute, uncomplicated influenza. ◦ Available data indicates adverse effects similar to placebo. Influenzavirus Antivirals M2 protein inhibitors Amantadine and Rimantadine ◦ Drug Characteristics ◦ Symmetric tricyclic amines ◦ Mechanism of Action ◦ Inhibits the activity of Influenza A M2 protein. This is an ion channel forming protein required for nucleocapsid release. ◦ Pharmacokinetics ◦ Readily absorbed with high bioavailability ◦ Development of Resistance ◦ Amino acid substitutions in M2 confer resistance to both drugs. Influenza viruses with high levels of resistance have been circulating since 2005. Therefore, they are of limited clinical usefulness. USE is NOT recommended by CDC at this time. Hepatitis C virus ◦ RNA virus from the flavivirus family ◦ Six genotypes (1-6) which differ in their sensitivity to antiviral treatment ◦ Genotype 1 less responsive to traditional treatment regimes than other genotypes. ◦ Transmitted through percutaneous exposure, contaminated blood exposure, sexual transmission. ◦ Causes hepatitis – inflammation of the liver. ◦ Jaundice, diarrhea, acholic stool, increase ALT and AST levels. ◦ Acute infections generally very mild ◦ 70% chronic infection (defined as HCV that has not cleared by 6 months post acquisition). ◦ Chronic hepatitis – high risk for cirrhosis of the liver and hepatocellular carcinoma. Hepatitis C Virus Treatment ◦Who? ◦ Treatment is recommended for all acute or chronic Hepatitis C Virus infections (with few exceptions). ◦What? ◦ Combination therapy with direct acting antivirals. Generally, at least two different drugs from two different classes. http://www.hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy Hepatitis C virus Direct Acting Antivirals (DAAs) HCV virion +ssRNA Genome Translation (host enzymes) Viral polyprotein Protease Inhibitors Proteolytic processing HCV NS3/4A Mature Viral proteins Genome Replication HCV NS5B (RdRp) HCV NS5A RNA Polymerase Inhibitors +ssRNA Genome 27 -ssRNA template HCV NS5A Inhibitors Virion Assembly HCV NS5A HCV Antiviral Naming Convention Drug Class HCV Protease Inhibitors HCV RdRp* Inhibitors HCV NS5A Inhibitors Drug name suffix “–previr” “–buvir” “-asvir” Drugs Paritaprevir Simprevir Grazoprevir Glecaprevir Voxilaprevir Sofosbuvir Dasabuvir Ledipasvir Omvitasvir Elbasvir Velpatasvir Daclatasvir Pribentasvir * RdRp = RNA-dependent-RNA polymerase Simplified HCV Treatment Regimens for chronic HCV https://www.hcvguidelines.org/treatment-naive/simplified-treatment Simplified HCV Treatment Regimens Glecaprevir/Pibrentasvir ◦ Mechanism of action ◦ Glecaprevir: Inhibits the NS3/4A protease of HCV ◦ Pibrentasvir: Inhibits the NS5A enzyme of HCV ◦ Pharmacokinetics. Oral administration. Taken with food. 8week treatment. ◦ Therapeutic Indications ◦ Chronic hepatitis C (HCV monoinfected or HCV/HIV co-infected patients) without cirrhosis. ◦ Frequently Reported Adverse Effects ◦ Headache ◦ Loss of strength and energy ◦ Nausea ◦ Diarrhea Simplified HCV Treatment Regimens Sofosbuvir/Velpatasvir ◦ Mechanism of action ◦ Sofosbuvir: uridine analogue that inhibits the RdRp of HCV ◦ Velpatasvir: Inhibits the NS5A enzyme of HCV ◦ Pharmacokinetics. ◦ Oral administration. -12 week treatment ◦ Velpatasvir requires acidic gastric pH. ◦ Not to be used with potent Pgp or CYP3A inducers ◦ Therapeutic Indications ◦ Approved for use in all HCV genotypes ◦ Administered as a fixed dose combination tablet for 12 weeks ◦ Frequently Reported Adverse Effects ◦ Fatigue and headache Simplified HCV Treatment Hepatitis B Virus (HBV) ◦ A DNA virus that uses reverse transcriptase. ◦ Half of infected adults are asymptomatic ◦ Acute hepatitis symptoms often milder ◦ Risk of chronic infection correlated with age at infection. ◦ Transmission route = body fluids ◦ Sexual transmission, percutaneous needle stick (6-30%), perinatal transmission at birth (70 – 90%). 100 90 80 Carrier risk (%) ◦ Causes hepatitis – inflammation of the liver. ◦ Jaundice, diarrhea, acholic stool, increase ALT and AST levels. 70 60 50 40 30 20 10 0 Birth 1-6 mo 7-12 mo Age of infection 1-4 yrs 5+ yr s How do you know if someone has a chronic HBV infection? HBV Status HBsAg anti-HBsAg anti-HBc Total Acutely Infected Chronic Infection Vaccinated Previous Infected Susceptible + + - + + - + + + - IgM + Note: Ag = antigen anti=antibody HBV Treatment ◦ Only approximately 10% of the patients achieve a “functional cure” ◦ Undetectable HBV DNA ◦ Development of anti-HBsAg ◦ Relapse can occur ◦ Treatments for Chronic HBV ◦ Pegylated interferon* ◦ Reverse Transcriptase Inhibitors ◦ Entecavir* ◦ Tenofovir* ◦ Lamivudine ◦ Telbivudine ◦ Adefovir * Included in preferred regimens HBV Antivirals Pegylated Interferon ◦ Pegylation ◦ attachment to an inert molecule (polyethylene glycol), ◦ slows absorption and clearance. ◦ weekly dosing via injection. ◦ Mechanism of Action ◦ Recombinant cytokine ◦ Signaling through binding to interferon receptors and Jak/Stat pathways to invoke an “antiviral state” in cells. ◦ Adverse Effects ◦ ◦ ◦ ◦ ◦ ◦ ◦ flu-like symptoms injection site inflammation depression autoimmune disorders myelosuppression neurotoxicity cardiovascular effects (rare) Entecavir HBV Antivirals Reverse Transcriptase Inhibitor ◦ Oral administration ◦ Nucleoside analogue Reverse Transcriptase inhibitor ◦ Adverse Effects ◦ Headache, fatigue, dizziness, drowsiness, insomnia, Hematuria, lactic acidosis (including fatal cases). ◦ Not used for HIV treatment HBV Antivirals Tenofovir Reverse Transcriptase Inhibitor ◦ Nucleotide analogue of adenosine that targets the reverse transcriptase of HBV (and HIV). ◦ Pharmacokinetics ◦ Oral administration. Tenofovir itself is poorly soluble (25 -39% oral bioavailability. Tenofovir disoproxil is the water soluble prodrug of tenofovir. ◦ Adverse Effects ◦ ◦ ◦ ◦ GI discomfort (more common in lactose intolerant patients) Headache, asthenia Renal and bone toxicity, Fanconi syndrome (rare) Drug crosses placenta. Decreased bone density and fetal growth in primate models. ◦ Resistance ◦ Single codon change can lead to resistance. ◦ Therapeutic Indications ◦ Recommended for use in Chronic Hepatitis B infections. Also used in HIV treatment. Respiratory Syncytial Virus (RSV) ◦ Enveloped, RNA virus paramyxovirus family ◦ Disease ◦ Most common cause of bronchiolitis and pneumonia in children under 1 year. ◦ Severe respiratory infections can also be seen in the elderly and patients who are immunosuppressed. ◦ Common Cold in adults and older children. ◦ Treatment with Ribavirin indicated for severe LRT illness in: ◦ Premature Infants ◦ Immunocompromised individuals ◦ Patients with chronic lung or congenital heart disease. Antiviral for RSV Antiviral used for RSV Ribavirin ◦ Drug Characteristics ◦ Guanosine analogue 2023 ◦ Mechanism of Action ◦ PhosphorylatedNew by cellular adenosine kinase. Interferes with the Preventative Tools for RSV synthesis of guanosine triphosphate, inhibit viral mRNA capping, inhibits now available… RdRp of RSV. 1.Vaccines for older adults 2. Vaccines for pregnant persons ◦ Therapeutic Indications immunoprophylaxis for in certain ◦ Aerosolized for3.Passive severe respiratory illness due to RSV infants populations ◦ Adverse Effects ◦ Hemolytic anemia ◦ Depression, fatigue, rash, cough, insomnia, pruritus, nausea ◦ Contraindications ◦ Pregnancy, anemia, ischemic vascular disease, severe renal disease. RSV Passive Immunoprophylaxis ◦ Nirsevimab: recombinant antibody directed against the prefusion conformation of the RSV fusion (F) protein, which is required for cell entry. ◦ Protection lasts at least 5 months. ◦ A single dose is recommended for infants to protect them from their first RSV season. ◦ Exception = Most infants born to mothers who were vaccinated for RSV during pregnancy do not need Nirsevimab. ◦ Palivizumab: chimeric human-mouse monoclonal antiRSV antibody. ◦ Used in some high-risk infants with a history of premature birth. ◦ Protection lasts 1 month. (Infants may require up to five monthly injections to cover an RSV season.) NOTE: NOT effective in treatment. SARS-CoV-2 Antivirals Remdesivir (Veklury) Antiviral targeting the RNA-dependent-RNA polymerase of SARS-CoV-2 Administered through intravenous injection. FDA Approved for Approved for adults and pediatric patients 28 days of age and older with positive results of direct SARS-CoV-2 viral testing, who are: Hospitalized, or Not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. SARS-CoV-2 Antivirals Molnupiravir (Lagevrio) ◦ Ribonucleoside analogue. Induces hypermutation of SARS-CoV-2 ◦ EUA for use for mild to moderate COVID-19 disease in individuals 18 yrs or older who are at high risk for progressing to severe disease. ◦ Treatment started within 5 days of symptom onset ◦ Oral delivery. ◦ Not recommended for use during pregnancy or in hospitalized patients. SARS-CoV-2 Antivirals ◦ Ritonavir boosted nirmatrelvir (Paxlovid) ◦ SARS-CoV-2 Protease inhibitor (nirmatrelvir) + ritonavir ◦ Ritonavir is a potent inhibitor of cytochrome enzymes = “metabolic booster.” Increases stability in the body. Similar strategy used in HIV treatment. ◦ EUA for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients ◦ with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, ◦ who are at high risk for progression to severe COVID-19. ◦ Treatment started within 5 days of symptom onset. ◦ Oral delivery. ◦ Not for use in hospitalized patients References ◦ https://www.hcvguidelines.org/