Antivirals PDF

Anti-viral Drugs Anthony B. Pascasio, RMT, MD Antiviral Chemotherapy Antiviral Chemotherapy Antiviral drugs primarily target replication stages Must be able to target viral functions with minimal host damage These drugs are commonly used to reduce morbidity and mortality Drug resistan...

Anti-viral Drugs Anthony B. Pascasio, RMT, MD Antiviral Chemotherapy Antiviral Chemotherapy Antiviral drugs primarily target replication stages Must be able to target viral functions with minimal host damage These drugs are commonly used to reduce morbidity and mortality Drug resistance is relatively common compared to antibacterials and antiprotozoals Antiviral Resistance DRUG RESISTANCE - Changes in viral structures enable resistance CLINICAL RESISTANCE - Resistance due to other factors other than changes in the virus (e.g. immunity, pharmacokinetics of the drug, drug interactions) Antiviral Susceptibility Testing Antiviral Susceptibility Testing To evaluate new antivirals, cross-resistance, cross-reactivity, and frequency of drug-resistance mutations 2 Types: phenotypic or genotypic testing Phenotypic Assays Plaque Reduction Assay Inhibition of viral plaque formation in the presence of an antiviral agent The concentration of antiviral drug that inhibits plaque formation by 50% is the IC50; that is, the 50% inhibitory concentration and 50% effective concentration For susceptibility testing of HSV Dye Uptake Assay Only cells that are alive and viable take up a vital dye called neutral red Infected cells do not take up the dye drug concentration that inhibits viral lytic activity by 50% is the IC50. Used for susceptibility testing of HSV, CMV and VZV DNA Hybridization Measures the effect of antiviral agents of viral DNA synthesis Measures how much viral DNA is produced in the presence of antivirals Used for testing of HSV, VZV and CMV Enzyme Immunoassay spectrophotometric analysis to quantitatively measure the amount of viral activity concentration of antiviral agent that reduces the amount of absorbance by 50% compared with the absorbance values of a viral control is the IC50 Used for testing of influenza A, HSV and VZV Flow Cytometry distinguishes drug-resistant isolates from drug-susceptible isolates uses a fluorochrome-labeled monoclonal antibody to a CMV early antigen Flow cytometry is used to quantitate the number of virus-infected cells Compares the amount of antigen positive cells between the control (no drug) with a sample with antivirals Neuraminidase Inhibition Assay used to detect NA inhibition resistance when the drugs oseltamivir and zanamivir are used to treat influenza A and influenza B infection incubate cultured influenza isolates containing NA with varying concentrations of the drugs fluorogenic substrate is then added, allowing the fluorescence to be quantitated by a fluorimeter The IC50 is calculated by comparing the activity of viral NA to a control reaction that does not use any NA inhibitors. Recombinant Virus Assays monitors the phenotypic behavior of specific genes in the virus genome in the presence of the antiviral drug. One of the first RVA assays measured HIV-1 resistance to protease and revers transcriptase inhibitors An artificial genetic construct that includes a vector nucleic acid molecule with a reporter which emits light, as well as the patient’s gene of interest, is recombined into a chimeric molecule. This is then cotransfected into a susceptible cell line. The chimeric structure, or pseudovirus, can then be tested in vitro in the presence of antiviral drugs If the virus is susceptible to the antiviral, the light emission will decrease Genotypic Susceptibility Assays Genotypic Susceptibility Assays Use PCR to detect genes responsible for resistance response to an antiviral agent is also measured by quantitative monitoring of the viral load by means of the nucleic acid concentration in patient samples Pyrosequencing sequence-based detection method that allows rapid, accurate quantification of sequence variation In a sequence of enzymatic reactions, a polymerase enzyme catalyzes the addition of nucleotides into a nucleic acid chain. As a result of this addition, a PPi molecule is released and converted to adenosine triphosphate (ATP) by the ATP enzyme sulfurylase. Visible light is produced when a luciferin molecule is oxidized during the luciferase reaction 2 types: Solid-phase Liquid-phase Drugs for Treatment of Viral Disease susceptible to the antiviral, the light emission will decrease, Agents to treat HSV and Varicella-Zoste r Acyclovir Acyclovir triphosphate inhibits viral DNA synthesis by 2 mechanisms: 1. Competition w/ deoxyGTP for the viral polymerase → binding to the DNA template as an irreversible complex 2. Chain termination following incorporation in the viral DNA Guanosine analogue vs. HSV-1, HSV-2, and, VZV Acyclovir Mechanism of Resistance Changes in viral thymidine kinase or DNA polymerase Many resistant strains lack thymidine kinase which is the enzyme in the initial viral-specific phosphorylation → cross-resistance to Famciclovir, Ganciclovir, and Valacyclovir Acyclovir Pharmacokinetics Topical, oral, IV Oral BA is low (15-20%), unaffected by food T ½: 2.5-3 hours; 20 hours in anuric patients Diffuses readily into most tissues and body fluids CSF: 25-50% of serum values Cleared by glomerular filtration and tubular secretion Acyclovir Clinical Uses Reduce viral shedding, alleviate symptoms, decrease severity and duration of illness Decrease mortality in herpes encephalitis Suppression therapy in genital herpes Given for acute cases of varicella and shingles Hairy leukoplakia Acyclovir Adverse Effects GIT disturbances, headache, phlebitis, delirium, tremors, seizures, hypotension Reversible nephrotoxicity Crystalline nephropathy or interstitial nephritis Acyclovir Drug Interactions Concurrent use of other nephrotoxic drugs may enhance potential for nephrotoxicity Probenecid and Cimetidine decrease Acyclovir clearance and increase exposure Zidovudine - somnolence and lethargy Valcyclovir L-valyl ester of Acyclovir Rapidly converted to Acyclovir after oral administration via first-pass enzymatic hydrolysis in the liver and intestine Oral bioavailability: 50-70% of the serum Half-life: 2.5-3.3 hrs Valcyclovir Clinical Uses First or recurrent genital herpes Suppression of recurrent herpes Varicella zoster infection Orolabial herpes Preventing CMV disease after organ transplantation and suppressive therapy Prevents VZV reactivation after hematopoietic stem cell transplantation Valcyclovir Adverse Effects Rash, nausea & vomiting, headache, confusion, hallucination, seizure AIDS: GIT disturbance, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome Transplant patients: confusion and hallucinations Famciclovir MOA similar to Acyclovir except no chain termination Active vs. HSV-1 & 2, VZV, EBV, and HBV Rapidly deacetylated (oral) Oral bioavailability 70% Half-life 7-20 hrs Oxidized by first-pass metabolism to Penciclovir Penciclovir triphosphate has lower affinity for the viral DNA polymerase than Acyclovir but achieves higher intracellular concetrations Excreted in the urine Famciclovir Clinical Use First and recurrent genital herpes Suppressive therapy Herpes labialis, herpes zoster Famciclovir Adverse Effects Nausea, headache, diarrhea, testicular atrophy, mammary adenocarcinoma Penciclovir Guanosine analogue Active metabolite of Famciclovir Topical 1% cream Shortened the median duration of recurrent herpes labialis Adverse effects: Local reaction - 1% Docosanol Inhibits fusion between the host cell plasma membrane and the HSV envelope Preventing viral entry and replication Topical 10% cream Used for recurrent orolabial herpes Adverse effect: local reaction - 2% Trifluridine Fluorinated pyrimidine nucleoside Inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses Phosphorylated intracellularly by host cell enzymes - competes with thymidine-3-phosphate for incorporation by the viral DNA polymerase 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 and HSV-2 Cutaneous application alone or in combination with interferon-alpha has been used successfully in the treatment of Acyclovir-resistant HSV infections Valomaciclovir Investigational agent Clinical trial for the treatment of acute zoster and acute EBV infection (IM) Inhibitor of viral DNA polymerase Agents to treat CMV infections Agents used to treat CMV infections Advanced immunosuppression and reactivation of latent infection Disseminated infection: end-organ disease Retinitis, colitis, esophagitis, CNS and pneumonitis Clinical reactivation of CMV infection after organ transplantation is still prevalent Oral Valganciclovir has decreased the use of IV Ganciclovir, IV Foscarnet and IV Cidofovir for the prophylaxis and treatment of end-organ CMV disease Oral Valganciclovir has replaced oral Ganciclovir because of its lower pill burden Ganciclovir Mode of Action: Guanine derivative that is triphosphated to a nucleotide that inhibits DNA polymerase and causes chain termination viral DNA elongation Resistance: changes in DNA polymerase and mutations in the genes for activating viral phosphotransferase Ganciclovir Pharmacokinetics IV, poor oral bioavailability (90%), not food-dependent Highly lipophilic, CSF 40% Rilpivirine E138K substitution emerged most frequently during Rilpivirine treatment in combination with M1841 substitution Recommended only in treatment-naïve patients w/ HIV-1 RNA 98% protein bound; T ½: 3.5-5 hours Metabolized by CYP3A Excretion by feces Ritonavir Recommended for pregnant women ↑ risk of QT prolongation (Torsades de Pointes) and PR interval prolongation with Saquinavir Saquinavir Negligible CSF levels Perform liver test when given with Delavirdine or Rifampicin Reformulation for once daily dosing in combination with low-dose Ritonavir has improved efficacy and decreased GI adverse effects Tipranavir Induces P-glycoprotein transporter → alter the disposition of many other drugs Used in combination with Ritonavir to achieve effective serum levels Entry Inhibitors Enfurvitide Resistance: mutations in gp41 Lacks cross-resistance w/ other ARV MOA: binds to gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes In combination with other ARV in treatment-experienced patients with evidence of viral replication despite ongoing ARVT No drug-drug interactions Maraviroc Resistance: one or more mutations in the V3 loop of gp120 MOA: binds specifically and selectively to the host protein CCR5 In combination with other ARV in treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable who are resistant to other ARVs No cross-resistance w/ drugs from any other class, including Enfuviritide Integrase Strand Transfer Inhibitors Dolutegravir Current evidence suggests that Dolutegravir retains activity against some viruses resistant to both Raltegravir and Elvitegravir Elevations in serum aminotransferase and fat redistribution syndrome Taken with or without food Taken 2 hours before or 6 hours after taking cation-containing antacids, laxatives, Sucralfate, oral iron supplements, Calcium supplements, or buffered medications Elvitegravir Fixed dose combination Elvitegravir/Cobicistat/Tenofovir/Emtricitabine should not be initiated if calculated CrCl