Agents to treat Herpes simplex (HSV), varicella-zoster (VZV) virus, cytomegalovirus (CMV) and respiratory syncytial virus (RSV) infection. Anti-influenza agents (5) Flashcards
treatment modalities for viruses
- preventive measures
- vaccines
- tonics
- hygiene
- specific treatment
- pharmacological
- natural products
• symptomatic, adjuvant treatment • hydration, volume supplementation • anti-inflammatories • pain management • GI: probiotics • respiratory support • prevention of secondary infection
• management of secondary
diseases
Targets of antiviral agents
- Entry inhibitors (maraviroc, enfuvirtid; HIV)
- Uncoating inhibitor (amantadin)
- DNA/RNA synthesis inhibition:
- Nucleoside/nucleotideanalogs
- Non-competitive inhibitors (NNRTI, foscarnet; HCV)
- Other viral enzyme inhibitors:
- Kinase(DNAsynthesis;CMV)
- Terminase (DNA maturation; CMV)
- Protease (protein processing; HIV, HCV)
- Integrase (HIV)
- Neuraminidase (release; influenza)
- Endonuclease(influenza)
- Immunological agents :
- Interferonα
- Imiquimod
- Palivizumab
- Bamlanivimab
- …
Resistance to antiviral agents
• Mutations are frequent
- „Viral fitness”
- Most mutant viruses can replicate slower then wild type
- The agent can select the mutant
- Another mutation can restore fitness
- „Antiviral Potency”
- Low potency agent: minimal pressure, no resistance
- High potency agent: blocks multiplication, no mutations, resistance
- Modest potency: problematic
Viruses can mutate rapidly. RNA viruses mainly faster. Mutations
can be present in the population (before treatment) and the
antiviral drug can select out them.
Three important factors for the resistance:
„Viral fitness”:
Mutant viruses mainly can replicate slower then wild type
The agent selects the mutant type
A 2nd mutation restores viral fitness
„Antiviral Potency”: how rapidly it can suppress viral replication
Low potent agent exerts minimal pressure upon the viral population (no
resistance)
High potent agent blocks multiplication rapidly (no mutations and
resistance)
Modest potency is most problematic for resistance
„Genetic barrier”: how many mutations are needed for
resistance development
• „Genetic barrier”: how many mutations needed for resistance
Agents against herpes viruses I.
Herpes simplex 1, 2, Varicella zoster viruses
• Aciclovir (iv., po., topical), Valaciclovir (po.)
(• Penciclovir (topical), Famciclovir (po.))
Many antiviral drugs are antimetabolites that resemble the structure of naturally occurring purine and pyrimidine bases or their nucleoside forms.
- Antimetabolites are usually prodrugs requiring metabolic activation by host-cell or viral enzymes. Commonly, such bioactivation involves phosphorylation reactions catalysed by kinases.
Aciclovir and Valaciclovir
Aciclovir (iv., po., topical), Valaciclovir (po.)
• Guanosine analogs, valacyclovir: valyl-ester prodrug
Antimetabolites are usually prodrugs requiring metabolic activation by host-cell or viral enzymes. Commonly, such bioactivation involves phosphorylation reactions catalysed by kinases.
Monophosphorylated by viral thymidine kinase (TK), then further bioactivated by host-cell kinases to the triphosphate form
- Need triple-phosphorylation
- Viral thymidine kinase – activated only in infected cells
Acyclovir-triphosphate is both a substrate and direct inhibitor of viral DNA polymerase
When incorporated into the DNA molecule, it acts as a chain terminator (lacks the equivalent of a 3′ -OH group)
• Indications:
Acyclovir:
- HSV-1, HSV-2
- VZV
- IV formulation to treat HSV encephalitis and neonatal infection
- Prophylaxis for immunocompromised patients
• HSV and VZV infection in immunosuppressed patient,
• herpes encephalitis, neonatal herpes (iv.),
• genital herpes,
• disseminated and ophtalmic zoster,
• prophylaxis during immune suppression: val(ACV)
(• penciclovir: labial HSV, VZV, only topical)
Valacyclovir:
- VZV (including shingles)
- May have activity against
strains resistant to acyclovir, but not TK– strains
• ACV does not eradicate latent viral colonization
- Kinetics:
- Penetration into secretum, CNS
- Eliminated via urine (filtration and secretion)
Acyclovir: • T1/2 2,5-3h - Topical, IV, oral (bioavailability 15%) - Short T1/2 - Renal elimination (dose adjustment in renal dysfunction)
Valacyclovir:
- Improved oral bioavailability (70%)
- Longer T1/2
• Adverse effects:
oral (minor side effects):
- GI distress
- Headache
IV formulation (more toxic)
- CNS effects (delirium, seizures, tremor)
- Nephrotoxicity
- Crystalluria
- Hypotension
- well-tolerated
- hydration important to prevent crystalluria
- non-teratogenic: recommended to prevent vertical transmission
• Aciclovir resistance:
• viral TK or DNA polymerase mutations
- Resistance involves changes of viral DNA polymerase, or decreased activity of thymidine kinase
- > 50% of HSV strains resistant to acyclovir lack thymidine kinase (TK–)
• 1% prevalence in normal state,
• 3.5-10% in immunocompromised patients, up to 25% in bone
marrow transplanted
- Latent, mutated viruses can be present in sensory ganglia • Mostly total cross-resistance with penciclovir
- DNApol-mutants can also be resistant to foscarnet
- No known cross-resistance with cidofovir
• Penciclovir and Famciclovir
not on the list
- Penciclovir (topical), Famciclovir (po.)
- Penciclovir: ACV analogue, but does not cause DNA termination • Famciclovir: diacethyl-prodrug of penciclovir
• penciclovir: labial HSV, VZV, only topical
Vidarabin
not on the list
• isolated from sponge Tectitethya crypta
• adenosine stereoisomer
• higher IC50 than for ACV, lower selectivity
• local application (ointment, eye drop)
• HSV-1 and HSV-2, keratoconjunctivitis, to alleviate Herpes zooster lesions
in HIV infection
• USA
Docosanol
not on the list
- 22 carbon atom alcohol derivative
* Inhibits the membrane penetration of HSV • 10% cream for labial herpes
Agents against herpes viruse: CMV
Ganciclovir (iv.), Valganciclovir (po.
Cidofovir
Foscarnet
(Letermovir)
Passive immunization: Hyperimmune globulin (HIG) products: prophylaxis in pregnancy
Ganciclovir and Valganciclovir
Ganciclovir (iv.), Valganciclovir (po.)
• deoxy-guanosine analogs
- Mechanism similar to that of acyclovir (antimetabolite)
- First phosphorylation step is
catalysed by viral-encoded kinase (UL97 gene) in CMV
• not as specific as ACV, broader spectrum: 100× specificity to CMV, +EBV, HHV6, HHV8
• Indications
• CMV retinitis, CMV pneumonia, oesophagitis,
colitis in immunocompromised patients
- CMV 1st-line agent (treatment and prophylaxis) *Prophylaxis is indicated in patients undergoing solid- organ and bone-marrow transplantation
- HSV-1, HSV-2, VZV (to lesser extent)
Valganciclovir is a prodrug of ganciclovir with improved oral bioavailability; commonly used as prophylaxis agent.
• higher toxicity than ACV
• Same resistance methods as ACV
- Resistance involves mutation of UL97 gene
• prevalence: 5-12% after transplantation, HIV patients up to 20%
• Adverse effects: neutropenia, teratogenic.
- Bone marrow suppression
- Mucositis, gastroenteritis
- Hepatic dysfunction
- Seizures (in overdose)
- Crystalluria (nephrotoxic)
• Kinetics • Ganciclovir: poorly absorbed (3-7%) - Oral, IV, intraocular implant - Renal elimination (directly proportional to creatinine clearance) • Valganciclovir: absorbed well (60-70%) from GI • Good penetration in tissues and CNS • Renal elimination
Cidofovir
• dCMP analogue
- Antimetabolite; drug activation by host cell kinase
- Active diphosphate inhibits viral DNA polymerase
- broad spectrum:
- herpes viruses,
- adeno-, polioma-, pox- and papilloma viruses
- effective on ACV- and GCV-resistant mutants
• Indications: LECTURE: • CMV retinitis of HIV patients, • resistant HSV or CMV infections • a lipid-conjugated formulation was tested in Ebola, adenovirus infection
Notes: - HSV, CMV - Adenovirus, HPV -> Active against acyclovir- and ganciclovir-resistant strains (including TK– strains)
• Kinetics: •iv. • does not penetrate CNS well • excreted in urine - IV - Renal elimination (dose adjustment in proportion to creatinine clearance) - Maintain hydration during course of treatment
• Adverse effects: nephrotoxic (additive effect with amphotericin B and aminoglycosides), Toxic renal effects may be reduced by co- administration with probenecid
- neutropenia,
- teratogenic
- Resistance involves changes in DNA polymerase gene
Foscarnet
• Pyrophosphate analog
- Inhibits viral RNA- and DNA- polymerase (binds to pyrophosphate binding site)
- Not an antimetabolite
• non-competitive inhibitor of DNA polymerase enzymes
• Indications:
• CMV Retinitis
• Mucocutaneous Acyclovir Resistant HSV Infections, 2nd option
- CMV 2nd-line agent (treatment and prophylaxis)
- HSV (active against many acyclovir-resistant strains)
- Active against human herpes viruses; less efficient against HBV, HIV
- Synergistic with ganciclovir
• Kinetics: • i.v. • CNS penetration, • accumulates in bone, • excreted in urine - IV - Renal elimination (directly proportional to creatinine clearance)
• Adverse effects: nephrotoxicity (dose- limiting, additive effect)
- bone alterations,
- decreased hemoglobin level
- Electrolyte disorders (K+↓, Mg2+↓, Ca2+↓)
- Genitourinary ulceration
- CNS effects (headache, hallucination, seizures)
- Resistance involves changes in DNA polymerase gene
- Co-administration of Foscarnet with IV Pentamidine (against pneumocystis pneumonia in HIV patients) produces additive nephrotoxic effect, with potentially life-threatening hypocalcemia.
Letermovir
not on the list
• Inhibits CMV terminase complex (cleavage of DNA after replication) • indication: prophylaxis in bone marrow transplantees • CMV-specific • Well-tolerated; only headache, malaise, and mild cardiovascular side effects • No cross-resistance • Per os and i.v.
• FDA: fast track status, EMA: orphan drug
ribavirin
• Guanosine analog - Monophosphate form inhibits IMP dehydrogenase (prevent GMP synthesis) - Triphosphate form inhibits viral RNA polymerase and end-capping of viral RNA
Indication:
- Hepatitis C infection (acute and chronic);
in combination with IFN-α
- Respiratory syncytial virus (aerosol preparation)
- Other viral infections:
influenza A and B, paramyxovirus, HIV, parainfluenza virus
- Early IV administration is effective against viral hemorrhagic fever: Dengue-, Yellow-, Lassa- fever, Ebola, Bunya virus
• Broad spectrum – HCV and RSV. (Lassa, Hanta, Krim-Kongo fever)
kinetics:
- P.o.,
- i.v.;
- aerosol for RSV
Renal elimination (dose adjustment in renal dysfunction)
• Adverse effects: • malaise, insomnia, coughing, itching • anemia, bone marrow suppression - Drug-induced hemolytic anemia (IV) - Conjunctival, bronchial irritation (aerosol)
- possibly carcinogenic and teratogenic
- HCV: 12 to 48 week p.o. as adjunct therapy in patients with decompensated cirrhosis and in genotype 4
Antiviral therapy of influenza
Adamantins – Amantadin, (Rimantadin)
Neuraminidase inhibitors – Oseltamivir, (Zanamivir), (Peramivir,) (Lanimamivir)
(Baloxavir marboxil)-
• inhibits cap-dependent endonuclease: blocks synthesis of viral mRNA
• per os, for non-complicated influenza in >12years of age
• USA, JP, 2018
(Umifenovir) -
• China, Russia
• Inhibits membrane fusion?
• Investigated against COVID
Amantadin
• block uncoating by inhibiting M2 proton pumps
- Inhibit M2 protein (proton channel) – required at the onset of infection to permit acidification of the viral core, which in-turn activates viral RNA transcription
• prevention, early treatment
- Influenza A virus (prophylaxis mainly); may reduce duration of flu-symptoms by 1-2 days
• only against influenza A – resistance possible.
- Resistant is common
- Oral
• side effects:
- nightmare,
- seizure,
- palpitation,
- dizziness
- Atropine-like effects
- Livedo reticularis
- GI distress
• kidney, liver function checks, not with CNS treatments
CNS indication: Potential use in Parkinson disease
Oseltamivir
Neuraminidase inhibitors – Oseltamivir, (Zanamivir -> Inhalation), (Peramivir), (Lanimamivir)
Inhibit neuraminidase (cleave sialic acid residues from viral proteins and surface proteins of infected cells) – promote virion release, prevent clumping of newly released virions
• neuraminidase: release of virion from the cell
spectrum:
- Influenza A virus
- Influenza B virus
- Prophylaxis mainly;
may reduce duration of flu- symptoms by 2-3 days
• most effective in first days of the infection
• Oseltamivir: prodrug; p.o.
adverse effects: - GI distress (oseltamivir) - Flu-like symptoms (- Cough, bronchospasm in asthmatic patients (zanamivir))
• uncommon cross-resistance
- Resistance via mutation of viral neuraminidase (currently not common)
Antiviral agents with miscellaneous mode of action
(• Imiquimod)
• Palivizumab
(• Tecovirimat)
Imiquimod
not on the list
- Possibly induces INFα, TNFα production
- local injection
- for condyloma accuminatum (HPV) and for basal cell cc. Sometimes for acyclovir-resistant genital HSV.
Palivizumab
- Monoclonal antibody against RSV
- i.m., monthly
- for immuncompromised children in the RSV season, prevention
Tecovirimat
not on the list
- Variola
* Inhibits maturation and release by attacking the coat • Licensed by FDA without any human studies
Zaire ebola virus treatment
not on the list
atoltivimab, maftivimab, odesivimab-ebgn (Inmazeb)
• fixed combination of monoclonal antibodies
• Indication: Treatment of Ebola virus infection in adults and
children.
• FDA: Oct 14, 2020. Orphan drug, breakthrough designation
- i.v. infusion
- side effects: severe allergic reactions, life threatening
• supportive data:
• 1 major study (NCT03719586), open label, 322 patients, 4 arms with
active agents.
• 28-day mortality: 34% vs. 51% in the other treatment arms.
• a conclusion:
„Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response.
Therapeutic tools for COVID 19 with evidence
not on the list
- Remdesivir:
- RNA-dependent RNA polymerase inhibitor nucleotide
- Developed against Ebola; as orphan drug in EU
- I.v.
- for hospitalized medium-severity patients, where no cytokine storm has developed • with dexamethasone for patients require at least high-flow oxygen delivery
- In US: for hospitalized patients with high risk of progression
- Favipiravir
- RNA-dependent RNA polymerase inhibitor,
- developed in Japan, manufactured in China (Hungary) against influenza
- P.o.
- for not yet hospitalized low- to medium severity patients; in the US it is not recommended for non-hospitalized patients
- Bamlanivimab, Bamlanivimab-Etesevimab, Casirivimab-Imdevimab • Monoclonal antibodies against spike protein
- I.v.
- for hospitalized patients not yet on oxygen
- In US: for outpatients with high risk of progression
- Cytokine storm:
- steroids, e.g., dexamethasone
- baricitinib+remdesivir
Treatment approaches of COVID-19, with no evidence
not on the list
•hydroxychloroquine, chloroquine ±azithromycin
• malaria treatment: enrichment in lysosomes, blocks the heme detoxification of parasite, Zn-ionophore, blocks uptake
of thiamine
• severe side effects, e.g., aplastic anemia
• March 20, 2020: FDA: no effect on SARS-COV-2
- Ivermectin
- treatment for parasite infestation, e.g., roundworms, head lice
- neurotoxicity
- in-vitro antiviral effect, only at higher than safe concentrations
- March 2021, FDA, EMA: should not be used; no supporting data.
- Lopinavir/ ritonavir and darunavir/cobicistat
- HIV protease inhibitors; titer needed for effect not achievable
- RECOVERY and WHO Solidarity Trials: no efficacy
- merimepodib
- inhibits guanine synthesis. In combination with remdesivir.
- Oct. 2020: Phase 2 studies are terminated: unfavorable safety signs for severe cases
- convalescent plasma
- Mayo Clinic Expanded Access Program (EAP): >70,000 patients, but there was no control arm: efficacy is uncertain.
- Lower mortality in patients over 80 years of age, who received high-titer plasma than those received low-titer plasma (6.3% vs. 11.3%)
- immunmodulators
- IL-1 inhibitors (e.g., anakinra), interferon: no supportive data available
- anti-IL-6 receptor antibodies (e.g., sarilumab, tocilizumab); anti-IL-6 antibodies (e.g., siltuximab); tyrosine kinase inhibitors (e.g., zanubrutinib, baricitinib): use not recommended
• vitamin C, D, Zinc: no data available, 25 ongoing clinical studies.
Anti-RSV agentes
Palivizumab
Ribavirin
