Anti-Virals

viruses are obligate intracellular parasites, their replication depends on synthetic process of host cells.

Antivirals:

• -Block viral entry into or viral exit from the host cells
• -Inhibit viral replication inside the host cell.

• 1. Adsorption to and penetration into susceptible host cells
• 2. Uncoating of viral nucleic acid
• 3. Synthesis of early regulatory proteins
• 4. Synthesis of RNA or DNA
• 5. Synthesis of late, stuctural proteins
• 6. Assembly (maturation) of viral particles
• 7. Release from the cell

• Acyclovir
• Valacyclovir
• Famciclovir
• Penciclovir
• Trifluridine
• Docosanol

• Ganciclovir
• Valganciclovir
• Cidofovir
• Foscarnet

• Lamivudine
• Adefovir
• Interferon Alfa
• Pegylated Interferon Alfa
• Ribavirin
• Entecacir
• Telbivudine
• Tenofivir
• Emtricitabine

• Admantanes
• -Amantadine, Rimantadine
• Neuraminidase Inhibitors
• -Zanamivir, Oseltamivir

• Classes:
• 1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
• 2. Nucleoside Researve Transcriptase Inhibitors
• 3. NonNucleoside Reserve Transcriptase Inhibitors (NNRTIs)
• 4. Protease Inhibitors
• 5. Fusion Inhibitors
• 6. CCR5 Antagonits
• 7. Integrase Strand Transfer Inhibitors (InSTIs)

-Anti-HSV and anti-VZV drug, only one avaliable for IV use

-acyclic guanosine derivative- competes with guanosine to bind at catalytic site, leads to DNA chain termination

Requires THREE phosphorylation steps for activation.

FIRST converted into monophosphate by VIRAL THYMIDINE KINASE

then, di- and triphosphate in host further phosphorylates to active form

VIRAL KINASE is required for initial phosphorylation, acyclovir selectively activated and accumulates only in infected cells.

• Acyclovir TRIphosphate inhibits viral DNA synthesis by:
• 1. Competitive inhibition with deoxyGTP for viral DNA polymerase- binding to DNA template as trreversible complex
• 2. Chain Termination following incorporation into viral DNA

-Through ALTERATIONS (mutations) in Viral Thymidine Kinase or DNA Polymerase

foscarnet, cidofivir, trifluridine

nausea, diarrhea, headache

Ganciclovir, Cidofivir, Foscarnet

• -Anti-CMV
• - acyclic guanosine analog

-Requires triphosphorylation for activation

-Initial phophorylation by viral protein kinase phosphotransferase UL97 in CMV-infected cells

-Ganciclovir triphosphate competitively inhibits DNA ploymerase and causes termination of viral DNA elongation.

-Mutations in UL97- decreased levels of active Ganciclovir triphosphate (these mutations are NOT cross-resistant to cidofivir and foscarnet)

-Mutations in UL54- results in mutant DNA polymerase

Myelosuppression, neutropenia (more IV, than oral)

Retinal detachment (CMV retinitis)

-cytosine nucleotide analog

-phosphorylation to active diphosphate is INDEPENDENT of viral enzymes

• -INHIBITOR and ALTERNATE substrate for viral DNA polymerase
• -competitively inhibiting DNA synthesis and becomes incorporated into viral DNA chain

• Toxicities: dose-dependent nephrotoxicity
• -decreased intraocular pressure

-inorganic pyrophosphate analog

-inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase DIRECTLY, without activation by phophorylation

• -Resistance in HSV and CMV- point mutation in DNA polymerase gene (prolonged or repeated exposure to drug)
• -Also Mutations in HIV-1 reverse transcriptase gene

Toxicities: nephrotoxicity, ANemia, CNS Toxicity (headache, hallucinations, seizures)

• -Monotherapy should be AVOIDED
• -Need Maximal Potency to inhibit viral replication and AVOID premature development of resistance
• -Combination of drugs (HAART)- highly active antiretroviral therapy--effectivly reduced plasma HIV RNA levels and increase CD4 cells

-Monitor Viral Load, CD4 cell counts, Drug Resistance Testing

Nucleoside Reverse Transcriptase Inhibitors

-binds to DNA polymerase catalytic site of reverse transcriptase enzyme

• -competitively inhibits DNA polymerase activity
• -can also be incorporated into viral DNA chain and cause termination
• -requires activation by phosphorylation to triphosphate (uses human cell kinases)

• -Resistance by viral mutations
• -Cross resistance exist amont NRTIs

-Major Toxicities: Lactic Acidosis, hepatomegaly

Reverse Transcriptase enzyme has two active, catalytic sites

• -RNase H (RNA cleaving) actice site
• -DNA polymerase (DNA synthesizing) active site

BOTH sites needed to reverse-transcribe HIV's RNA based genomic material into DNA

• NRTI
• -deoxythymidine analog (first antiretroviral)

• -decrease rate of clinical disease progression, prolong HIV infected survival
• -When administered during pregancy, during labor, AND to neonate, REDUCED rate of VERTICAL (mom to baby) transmission of HIV

• -Resistance may limit clinical efficacy
• -high resistance due to three or more mutations

Toxicities: Myelosuppression (anemia neutropenia)

Example: Tenofovir

-acyclic nucleoside phosphonate (nucleotide) analog of adenosine

-Req. activation by phosphorylation to triphosphate (catalyzed by human kinases)

-Tenofovir competitively inhibits DNA polymerase activity of the HIV reverse transcriptase enzyme, causes chain TERMINATION (once incorporated into viral DNA)

Toxicities: GI upset, lactic acidosis, hepatomegaly

Yes, b/c they share a similar binding site

a Nucleotide Reverse Transcriptase Inhibitor

• NonNucleoside Reverse Transcriptase Inhibitors
• -Bind directly to HIV-1 reverse transcriptase
• -Inhibition of RNA and DNA dependent DNA polymerase activities

Binding sites for NNRTIs are NEAR but DIFFERENT from binding sites of NRTIs.

Binding of the NNRTIs blocks the DNA Polymerase activity by disrupting the DNA polymerase catalytic site of the enzyme

Unlike NRTIs, NNRTIs DO NOT compete with nucleoside triphosphates and DO NOT req. phosphorylation to be active

NO cross resistance between NNRTIs and NRTIs or the protease inhibitors

Resistance to NNRTI is rapid with monotherapy and associated with viral mutations

• Nevirapine is an NNRTI
• -used in combination with other antiretroviral regimens
• -Severe/life threatening skin rashes, toxic epidermal necrolysis have occured, discontinue
• -hepatitis may occur within first 6 weeks of initial therapy, monitor liver function tests

• -Metabolized by CYP3A4 in liver (substrate)
• -ALSO is an INDUCER of CYP3A4 metabolism (drug interactions)

In later stages of HIV growth cycle, the Gag and Gag-Pol genes are translated into poluproteins, then become immature budding particles.

Proteases are responsible for cleaving these precursor molecules to produce final sturctural proteins of MATURE virion core.

-prevents clevage of Gag-Pol polyprotein by inhibiting the protease enzyme.

Results in production of IMMATURE noninfectious viral particles.

Specific genotypic mutations confer viral resistance-common

Monotherapy is contraindicated

Cross resistance exists, requires minimum of FOUR subsctitutions in gene.

• -Syndrome of redistribution and accumulation of body fat, Lipodystrophy
• -increases in triglycerides, LDL levels, glucose intolerance and insulin resistance
• -abnormalities appear to associate with use of protease inhibitos, cause yet not known

Tesmorelin, a growth hormone-releasing factor, once daily injection

All protease inhibitors are SUBSTRATES (metabolized by CYP3A4) and INHIBITORS (cause dec. clearance and increased plasma levels of other substraes drugs)

-SHOULD NOT be administered with other agents that are metabolized by CYP3A4.

• Ritonavir is a Protease Inhibitor.
• -inhibitor of HIV-1 and HIV-2 proteases.

-Ritonavir is an inhibitor of CYP3A4

-results in INC plasma levels of these agents (enhanced activity of other protease inhibitor-CYP3A4)

-Pharmacokinetic interactions, exploited to permit more convenient dosing (patient compliance), improve tolerability, and enhance efficacy.

EX: Saquinavire and Ritonavir, lopinavir/ritonavir, tipranavir/ritonavir

Saquinavir with low (subtherapeutic) dose of Ritonavir.

The sub therapeutic dose of ritonavir inhibits the CYP3A4-meadiated metabolism of saquinavir, results in increased exposure of saquinavir.

High saquinavir plasma levels maintain potent viral suppression, and provide pharmacologic barrier to resistance.

Enfuvirtide, peptide, subcutaneously, in combination for HIV-1 therapy

• -BLOCKS entry of virus into cell
• -binds to gp41 subunit of viral envelope glycoprotein, preventing conformational changes req. for fusion

-Resistance can occur- being investigated. NO cross resistance between enfuvirtide and other antiretrovirals

Toxicities: local injection site reations, hypersensitivity reactions

• Chemokine Receptor 5 (CCR5)- in early disease
• Chemokine Receptor 4 (CXCR4) - more advanced disease

• -new anti-HIV drug, CCR5 Antagonist
• -used in combination to treat CCR5-tropic HIV-1- detectable disease

• -targets host CD4 T cells
• -binds to and BLOCKS CCR5 on CD4 cells
• -BLOCKS the ENTRY of HIV into CD4 cells, prevents infection

• -ONLY effective in patients with CCR5-tropic disease
• -INeffective against HIV that uses both(dual/mixed) or CXCR4 for cell entry.

• -screening test to determine TROPISM of HIV infection.
• -TROFILE, may fail to detect presence of small CXCR4-tropic virus (thus maravoric would fail)

-Maraviroc treats CCR5-tropic HIV infection ONLY

• -hepatotoxicity (boxed warning),
• -systemic allergic reactions
• -cardiovascular events- myocardial ischemia/infacrtion, postural hypotension--caution in patients with inc. risk of cardiovascular disease
• -may INC risk of infections and malignancy

HIV-1 integrase strand transfer inhibitors (InSTIs)

-used in combination therapy for patients with multiple antiretroviral resistance

-inhibits integrase enzyme, preventing viral DNA from integrating with cellular DNA

-avtive against HIV strains that are resistant to other antiretroviral drugs

enzymes that catalyze important steps in the process of inserting viral DNA into the host cell genome.

(InSTIs)

Resistance occurs due to mutations in the integrase enzymes

Increase in serum creatine kinase, myopathy, and rhabdomyolysis- cause/effect not clear

no, anti-hepatitis therapy is suppressive, not curative.

-prevalence of HBV/HCV high worldwide.

• -treats HBV
• -suppress HBV replication and improve liver histology and fibrosis
• -HBV DNA appears after cessation of therapy

-nucleotide analog of adenosine monophosphate (similar to tenofovir)

-phosphorylated by cellular kinases to active diphosphate metabolite

-competitively inhibits HBV DNA polymerase, results in chain termination after incorporation into viral DNA

-dose dependent nephrotoxicity, INC risk in patients with preexisting renal dysfunction/those treated for longer duration

-Lactic acidosis, hepatomegaly (similar to NRTIs)

• -treats HBV and HCV
• -administered SC or IM

-interferon alphas are cytokines, endogenous protiens, that exert complex antiviral, immunodulatory, and antiproliferative activities invovling synthesis of RNA and proteins.

Pegylated interferon alpha has a linear/branched polyethylene gycol (PEG) attached by a covalent bond.

pegylated- have longer half-lives, slower clearance, steadier serum concentrations, less frequent dosing

Bind to specific membrance receptors on the cell surface

• initiates a series of intracellular events:
• -enzyme induction
• -suppression of cell proliferation
• -immunomodulatory activities
• -inhibition of viral replication

• -Activate JAK-STAT signal transduction pathway, leads to nuclear translocation of cell protein complex that binds to genes containing IFN-specific responses
• -Synthesis of over 24 antiviral proteins- works at different stages of viral penetration

-Modifies immune response to viral infections

Inhibition of viral protein synthesis for many viruses.

A given virus may be inhibitied at several steps, and the perincipal inhibitory effect differs among virus families

-Blocking production or Activity of selected IFN-inducible antiviral proteins

IFN-induced expression of MHC antigens, by enhancing the lytic effects of cytotoxic T-lymphocytes.

IFNs may mediate some of the systemic symptoms associated with viral infections and contribute totissue damage in certain viral diseases.

Side effects: flu like syndrome within 6 hrs after dosing, resolve upon cont. therapy

Thrombocytopenia, hypotension, neuropsychiatric side effects.

Contraindications: phychosis, severe depression, symptomatic heart disease, uncontrolled seizures.

Interferons are ABORTIFACIENT

combination with IFN alpha to treat HCV infections

• -guanosine analong, requires intracell. activation
• -phosphorylated by host enzymes into active triphosphate

-not fully understood

• 1. Interferes with synthesis of guanosine triphosphate
• 2. Inhibits capping of viral mRNA
• 3. Inhibits viral RNA-dependent RNA polumerase

dose dependent hemolytic anemia and depression

contraindicated during pregnancy (teratogenic and mutagenic)

Admantanes (amantadine, Rimantadine)

Neuraminidase Inhibitors (Zanamivir, Oseltamivir)

anti-influenza therapy

• Rimantadine is a derivative of Amantadine.
• -cyclic amines
• -rimantadine more active than amantadine

-Resistance of influenza A virus to both agents have INC in recent years

• -inhibit uncoating of viral RNA of influenza A, prevents replication
• (In some influenza A strains, also inhibit viral assmebly)

• -Primary target, M2 Protein on viral membrane (highly specific against influenza A)
• -binds and inhibits M2 Protein, inhibits acid-mediated dissociation of viral ribonucleoprotein complex early in viral replication (inhibits viral uncoating) and alter hemagglutinin processing later in replication- conformational changes- (inhibit viral assembly)

• Resistance due to mutations, rapidly develops, transmission of resistance virus to household contacts
• -Both drugs share cross-suscept and cross resistance

Cross resistance to Zanamivir and Oseltamivir DOES NOT occur.

CNS toxicity- less frequent with Rimantadine

Serious neurotoxic reactions- with high Amantadine plasma levels (1-5 ug/mL)

Amantadine is teratogenic

Neuraminidase (Zanamivir and Oseltamivir) are active against BOTH influenza A and B

Adamantanes- only influenza A

both neuraminidase inhibitors

• zanamivir- oral inhalation, IV
• Oseltamivir- oral (prodrug), IV

-both for prophylaxis or treatment of acute uncomplicated influenza infection

• --Administrator 36-48 hrs after onset of symptoms for 5 days, both agents shortens severity and duration of illness and MAY decrease incidence of respiratory complications
• (the earlier to start, the more effective in treating influenza)

-hospitalized patients- both agents reduce duration of hospitalization and risk of death. May also DEC viral shedding and risk of spread to contact (even after 48 hrs after onset)

• -both are 70-90% effectivie prophylaxis after exposure to influenza A or B
• -Give within 48 hrs after household exposure or close contact with infected person

Resistance reported in Influenza A and B strains

Antivirals may interfee with the efficacy of the live-attenuated intranasal flu vaccine (Flumist). stop 48 hours before, and atleast 2 weeks after FluMist administration.

Inactivated flu vaccines are NOT affected by viral neuraminidase inhibitors (Flu shot)

-inhibitors of vial neuraminidase enzymes, inhibis viral release/infection

[Neuraminidase is essential viral glycoprotein for viral release]

Resistance (oseltamivir) associated with mutation in viral neuraminidase

Zanamivir- cough, nasal/throat irritations, bronchospasm, NOT for patients with asthma or COPD

Oseltamivir- headache, nausea, vomiting, take with food to reduce GI effects

Neuropsychiatric events with Oseltamivir, cause not established

-FDA 'emergency use authorization' for neuraminidase inhibitor, Peramivir

-Peramivir, given IV- still investagational drug- inhibits viral neuraminidase

-FDA authroized use in hospitals for confirmed or suspected pandemic 2009 H1N1 influenza infection who cannot take or are not responding to treatment with Oseltamivir or Zanamivir

-Many isolates resistant to Oseltamivir, ALSO resistant to Peramivir

Susceptibility varies from one strain to another, from one flu season to another.

strains evolve rapidly, treatment recommendations change during flu seasons

www.cdc.gov/flu- provides updated info on viral resistance/susceptibility