5-7 Antivirals Flashcards by Simon Amar

Which are the targets of antiviral agents?

DNA/RNA synthesis inhibition
- Nucleoside/nucleotide analogs:
  - Need activation (2 or 3 phosphorylations) – triphosphate derivatives block DNA/RNA polymerase and/or cause chain termination after incorporation
- Non-competitive inhibitors (NNRTI, foscarnet, HCV)
Entry inhibitors (maraviroc, enfuvirtid)
Uncoating inhibitor (amantadine)
Other viral enzyme inhibitors
- Kinase inhibitor (CMV)
- Terminase inhibitor (CMV)
- Protease inhibitors (HIV, HCV)
- Integrase inhibitors (HIV)
- Neuraminidase inhibitor (Influenza)
Immunological agents
- Interferon α
- Imiquimod
- Palivizumab

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What are the 3 important factors for the resistance in antiviral agents?

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.
3 important factors for the resistance:
- “Viral fitness”:
  - Mutant viruses mainly can replicate slower then wild type
  - The agent selects the mutant type
  - A 2^nd 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

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Acyclovir, HSV-1, 2 and VZV antiviral!

Mechanism of action:

It is a guanosine analog ==> chain termination
It requires triple phosphorylation:
- Monophosphorylated by viral thymidine kinase (TK), then further bioactivated by host-cell kinases to the triphosphate
Acyclovir-triphosphate is both a substrate for and inhibitor of viral DNA polymerase
When incorporated into the DNA molecule, acts as a chain terminator because it lacks the equivalent of a ribosyl 3′ hydroxyl group

Pharmacokinetics:

Oral availability of 15%
It penetrates into secretions and into the CNS
Kidney elimination
Half-life: 2.5-3h
Administration:
- IV, oral and local

Clinical use:

HSV and VZV infections in immunosuppressed patients
- Nucleosides analogs only work on replicating viruses.
  - HSV and VZV don’t continuously replicate as they can be dormant in dorsal root ganglia for years and be reactivated by stress, thus these drugs will NEVER kill dormant forms of the viruses.
Herpes encephalitis
Neonatal herpes (IV)
Disseminated and ophthalmic zoster
Severe primer genital herpes
Recurrent genital herpes (oral)
Labial herpes (local)

Resistance:

1% prevalence in normal immunological state
3.5 – 10% in immune compromised patients (up to 25% for allogenic bone marrow transplantation)
Mutant viruses can present latent in sensory ganglia
Resistance possibly due to changes in DNA polymerase or to decreased activity of TK
> 50% of HSV strains resistant to acyclovir completely lack thymidine kinase (TK – strains)
Mostly total cross-resistance with penciclovir (in the case of altered kinase or DNA polymerase it can be active)
DNA polymerase mutants can also be resistant to foscarnet
No known cross-resistance with cidofovir

Adverse effects:

Minor with oral use, more obvious with IV
- Sometimes headache, nausea, vomiting
Crystalluria (maintain full hydration) and neurotoxicity (agitation, headache, confusion—seizures in OD)
Is not hematotoxic (ø BM suppression)!
Not teratogenic: it is given in case of active herpes to prevent vertical transmission

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Valcyclovir, HSV-1, 2 and VZV antiviral drug!

Mechanism of action:

It is a guanosine analog ==> chain termination
It is a valyl-ester prodrug
It requires triple phosphorylation

Pharmacokinetics:

Oral bioavailability of 15%
Administration:
- Oral

Clinical use:

During immune suppression prophylaxis indicated in case of HSV or VZV immune positivity
High dose for CMV prophylaxis

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Penciclovir, HSV-1, 2 and VZV antiviral drug!

Mechanism of action:

It is an ACV analog, but doesn’t cause chain termination
- Guanosine analog

Administration:

Local

Clinical use:

Similar to local acyclovir

Adverse effects:

Headache
Diarrhea
Nausea

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Famciclovir, HSV-1, 2 and VZV antiviral drug!

Mechanism of action:

It is a diacethyl prodrug of penciclovir
- Guanosine analog

Pharmacokinetics:

Oral availability 70%
Administration:
- Oral

Clinical use:

Similar to oral valcyclovir

Adverse effects:

Headache
Diarrhea
Nausea

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Not -ciclovir, HSV-1, 2 and VZV antivirals!

Vidarabine, Trifluoruridine, Idoxuridine:

Old, not really selective agents
Used mainly locally
- Eye drops
- External solution

Brivudin:

Pyrimidine analog
Developed in DDR (East Germany)
Active only against HSV-1 and VZV

Docosanol:

22 C atom, alcohol derivative
Inhibitits the membrane penetration of HSV
Used as 10% cream for labial herpes

Trifuridine:

Guanosine analog
Local

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Ganciclovir and Valganciclovir, CMV antiviral drugs!

Mechanism of action:

Similar to that of acyclovir, guanosine analog
1^st phosphorylation step is viral-specific
- Involves thymidine kinase in HSV and a phosphotransferase (UL97) in CMV
Triphosphate form inhibits viral DNA polymerase and causes chain termination

Pharmacokinetics:

Good tissue penetration in tissues, including CSF
Renal elimination
Administration:
- IV (Ganciclovir)
- Oral (Valganciclovir)
Resistance mechanisms similar to acyclovir
- 5-15% after transplantation
- Up to 20% in HIV patients

Clinical use:

Not specific, but broader spectrum
- CMV (100x more potent than ACV), EBV, HHV-6, HHV-8
CMV retinitis (treatment and prophylaxis)
CMV pneumonia, esophagitis, colitis treatments (combined with anti-CMV hyperimmune serum)
Can’t be used for mononucleosis treatment

Adverse effects:

Dose-limiting hematotoxicity (leukopenia, thrombocytopenia), mucositis, fever, rash, and crystalluria (maintain hydration)
Seizures in overdose

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Cidofovir, CMV antiviral drug!

Mechanism of action:

It is a dCMP (cytosine) analog
Its phosphorylation doesn’t depend on viral or cellular enzymes
It inhibits viral DNA synthesis

Pharmacokinetics:

Weak penetration into CNS
Renal excretion (tubular secretion)
Administration:
- IV

Spectrum

Broad spectrum:
- Besides herpes virus, it is active against adeno-, polioma-, pox-, and papilloma viruses
ACV and GCV-resistant mutants (thymidine kinase deficiency)
DNA polymerase deficient mutants can be less sensitive

Clinical use:

CMV retinitis of HIV patients
Resistant HSV or CMV infections (3^rd choice)

Adverse effects:

Nephrotoxic
Neutropenia
Teratogenic

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Foscarnet, CMV antiviral drug!

Mechanism of action:

Pyrophosphate derivative
Non-competitive reversible inhibitor of DNA and RNA polymerase enzymes ==> interfering with viral DNA and RNA synthesis
- It blocks the cleavage of diphosphates during incorporation

Pharmacokinetics:

CNS entry
Accumulates in bones
Renal excretion (tubular secretion and filtration)
Administration:
- IV

Spectrum:

Mostly HSV (acyclovir-resistant), VZV and CMV
A bit against HIV and HBV
Synergistic with ganciclovir

Clinical use:

CMV retinitis in HIV patients
Acyclovir-resistant HSV infections
Ganciclovir resistance or intolerance (CMV) (2^nd choice)

Adverse effects:

Nephrotoxicity
- Interferes with Ca²⁺ and phosphate metabolism
Anemia: reduced Hb level (neutropenia is not typical)
Bone alteration

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Brivudin, Maribavir and Letermovir, CMV antiviral drugs!

Brivudin:

Pyrimidine analog
Developed in DDR (East Germany)
Active only against HSV-1 and VZV

Maribavir (Investigational)__:

Selective inhibitor of the nucleoside kinase
Low toxicity (tasting disturbances are reported)
After successful phase I and II trial phase III trial was unsuccessful (low dose for prophylaxis was tested)
Higher doses were used for the therapy against multiresistant CMV

Letermovir (under registration)__:

Blocks the terminase complex of CMV (this cleaves multiple DNA chain after duplication)
CMV-specific
Atoxic
No cross-resistance

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Which are the respiratory syncytial virus (RSV) infection antiviral drugs?

Ribavirin:

Mechanisms:

It is a synthetic guanosine analog
It inhibits the replication of viral RNA and DNA

Spectrum:

Effective against a wide range of RNA and DNA viruses
- E.g. HSV, VZV, influenza A and B, RSV, HCV, hemorrhagic fever viruses (Lassa fever)

Pharmacokinetics:

Increased absorption if taken with a fatty meal
Renal elimination
Administration:
- Oral
- Inhalation
- IV

Clinical uses:

Adjunct to a-interferons in hepatitis C
Immunosuppressed infants and young children with severe RSV
Lassa fever
Hantavirus

Side effects:

Hematotoxicity:
- Hemolytic anemia
- Bone marrow suppression (in high dose)
Upper airway irritation
Teratogenic and carcinogenic
Skin problems
CNS:
- Fatigue, insomnia, asthenia
Contraindications:
- Anemia
- Kidney failure
- Ischemic vascular disease
- Pregnancy

Palivisumab (miscellaneous antiviral agent)__:

Prophylactic agent
Monoclonal antibody against RSV
Given IM for compromised children (premature, BPD, heart disease) in the RSV season (November-March)

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Neuraminidase inhibitors for anitiinfluenza agents!

Zanamivir, Oseltamivir (Peramivir, Laninamivir):

Mechanisms of action:

Inhibit neuraminidases of influenza A and B
- The role of neuraminidase is to cleave a sialic acid bridge and release the ready virion from the cell ==> prevent clumping of virions, so that more particles are available for infecting host cells
- So, these drugs agents inhibit the virus to infect new cells
Reduced likelihood that the virus will penetrate uninfected cells

Pharmacokinetics:

Eliminated unchanged in the urine
Administration:
- Zanamivir: Inhalation
- Oseltamivir: oral (prodrug hydrolyzed by the liver into active form)
- Peramivir: IV
- Laninamivir: parenteral (long-acting)
Resistance:
- Mutations of neuraminidase enzymes

Clinical uses:

Influenza A and B
Prophylaxis mainly, but may ↓ duration of flu symptoms by 2–3 days

Adverse effects:

Zanamivir:
- Irritation of respiratory tract (use with caution in COPD and asthmatic patients)
Oseltamivir:
- GI discomfort and nausea

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Amantadine, anti-influenza agent!

Mechanism of action:

They bind M2 protein on the viral membrane and block the uncoating, attachment and penetration of influenza A
Effective only against influenza A

Pharmacokinetics:

Good oral absorption and distribution
- CNS entry
Excreted unchanged in urine

Clinical uses:

Prophylaxis, may decrease duration of flu symptoms by 1-2 days

Side effects:

CNS:
- Insomnia, dizziness, ataxia
- Hallucinations, seizures
Causes atropine-like peripheral effects and livedo reticularis

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What is the HAART regime and its indications?

A combination of drugs is used to suppress the replication of HIV and restore CD4+ cell count
- This is the “HAART” regime = Highly Active Antiviral Therapy
There are 5 classes of antiviral therapy, each targeting one of the 4 viral processes
- Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- Protease inhibitors (PIs)
- Entry inhibitors
- Integrase inhibitors

Indications of starting the HAART therapy:

Start combination: 2NRTI + 1 NNRTI or PI or Integrase inhibitor or maraviroc
Important to hold application protocol
Life-long treatment is needed
HAART has often resulted in ↓ viral RNA.
- Synergy of these drugs increases the life expectancy of these patients, but increases the prevalence of the disease (since people live longer) and it improves the CD4+ count and can delay opportunistic infections
Indications:
- Presentation of HIV symptoms (opportunistic infections) or in the case of HBV coinfection
- CD4+ cell count < 200/µl (but if lower than 350/µl treatment is also recommended)
- Viral load (HIV RNA count) > 5000 – 10’000/ml
- During pregnancy
- Post exposition prophylaxis for medical staff (4 weeks)
- For children, more aggressive treatment (faster progression)

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Which are the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) for anti-HIV therapy?

Mechanism of action:

Prodrug: chain terminators (use non-specific kinases for activation)
- Ribosides analogs (nucleosides, -tides containing riboses)
  - They act as triphosphates both on HIV-1 and HIV-2

Drug types:

Thymidine analogs:
- Zidovudine (AZT)
- Stavudine (D4T)
Cytidine analogs:
- Lamivudine (3TC)
- Emtricitabine (FTC)
- Zalcitabine
Purine analogs:
- Didanosine (ddl)
- Abacavir (ABC)
- Tenofovir (TDF)
  - Used as a prodrug ==> reduced nephrotoxicity and bone toxicity

Pharmacokinetics:

They all penetrate the CNS except tenofovir
Renal excretion
Abacavir, zidovudine and didanosin are metabolized in higher amounts

Clinical use:

Part of most combination drug regimens used in HIV infection
Used together with a protease inhibitor (PI)
Lamivudin, emtricitabin and tenofovir are active against EBV
Resistance:
- For complete resistance, more mutations are needed (high genetic barrier)
- No cross-resistance among them

Adverse effects:

May toxicities are due to the inhibition of the mitochondrial DNA polymerase in certain tissues.
All drugs:
- GI disturbances (Nausea, vomiting, diarrhea)
- Headache, fatigue
- Lactic acidosis, hepatomegaly
- Hepatitis, increased liver enzymes
Zidovudine: Anemia, leukopenia
Stavudine and didanosine: Pancreatitis, Peripheral neuropathy
Abacavir: Hypersensitivity reactions
Tenofovir: Nephrotoxicity

Which are the non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-HIV therapy?

Mechanism of action:

Highly selective, non-competitive inhibitors of HIV-1 reverse transcriptase
- Inhibition of RNA-dependent DNA polymerization
Not prodrugs ==> ø myelosuppression

Drugs:

1^st generation:
- Nevirapin
- Efavirenz
- Delacirdin
2^nd generation:
- Etravirin
- Rilpivirin

Pharmacokinetics:

Catabolized in the liver by CYP enzymes
Nevirapin penetrates well into the CNS
- Efavirenz, etravirin and rilpivirin have low penetration, but enough for controlling HIV
Administration:
- Oral

Clinical use:

They are only effective against HIV-1 (but also there is a rare subtype “group 0”, which is resistant)
Resistance:
- A single point-mutation causes total cross resistance for 1^st generation agents.
  - Etravirin has higher genetic barrier

Adverse effects:

Liver and GI disorders
Skin reactions (rash), up to Stevens-Johnson syndrome
Efavirenz: CNS disturbances and it is highly teratogenic
- Etravirin and Rilpivirin are better tolerated
Nevirapin: CNS problems

Which are the portease inhibitors (PIs) for anti-HIV therapy?

Mechanisms of action:

HIV protease cleaves Gag and Gag-Pol polyproteins of HIV, that has a key role for maturation of HIV
HIV protease differs on structure (it is a dimer) and on function (cleaves before Pro) from all human protease/peptidase enzymes

Drugs (“RiTiLoDaAt”):

Ritonavir
Tipranavir
Lopinavir
Darunavir
Atazanavir
Indinavir
Nelfinavir
Squinavir
Fosamprenavir

Pharmacokinetics:

The oral availability and kinetics are variable.
- P-glycoproteins (MDR1) inhibitors increased oral availability, slow metabolism, and increased plasma levels of other PIs
They do not penetrate CNS
They are metabolized in the liver primary through CYP3A4 (exception: nelfinavir is primary CYP2C19 to also active metabolite)
In low dose ritonavir block CYP2C19 and P-glycoprotein
Half-life of PIs is variable

Clinical uses:

Ritonavir is the most commonly used protease inhibitor.
Resistance:
- Specific point mutations in the pol gene ==> no complete cross-resistance between different PIs

Side effects:

Insulin resistance
Hyperlipidemia (increased LDL, increased total cholesterol, increased TAG)
Abdominal fat uptake with peripheral lipodystrophy
- Less pronounced in Atazanavir
Increased transaminase
GI and neurological disorders
Allergic reactions

Which are the integrase inhibitors for anti-HIV therapy?

Mechanism of action:

Prevents integration of viral genome in host cell DNA

Administration:

Oral

Adverse effects:

GI disturbances: Nausea, diarrhea
Headache
Myopathy
Rhabdomyolysis

Which are the entry inhibitors for anti-HIV therapy?

Enfuvirtide:

Mechanism of action:
- Binds to pg41 and inhibits the fusion of HIV-1 to CD4+ cells
  - Gp41 is bound to gp120, which binds CD4+ receptor on T cells
  - Chemokine receptors CCR5 and CXCR4 bind gp41.
  - This drug binds very strongly gp41 and takes so much room that gp120 can’t bind CD4+ receptor
Polypeptide structure
Administration: subcutaneous
Adverse effects:
- Reaction at injection site
- Headache
- Nausea
- Bacterial pneumonia

Sifuvirtide:

Enfuvirtide analog
In early experiments, more potent.
Effect on some enfuvirtide-resistant mutants.

Ibalizumab:

Monoclonal antibody
Binds CD4⁺, but isn’t immunosuppressive
It doesn’t inhibit the binding of gp120 to CD4⁺, but blocks the interaction with the coreceptor.

Maraviroc:

Mechanism of action:
- It blocks the CCR5 coreceptor that works with gp41 to facilitate HIV entry through the membrane into the cell.
Clinical use:
- Prior to use, a test to determine viral tropism is required to distinguish whether the strain of HIV virus uses the CCR5 coreceptor, the CXCR4 coreceptors or is dual-tropic.
Administration: oral
Pharmacokinetics:
- Liver metabolism (CYP3A4)
Adverse effect:
- Headache, dizziness, orthostatic hypotension
- Airways infection, cough, pyrexia, abdominal pain
- Allergic liver disorder, increased prevalence of malignancies

Which is the maturation inhibitor for anti-HIV therapy?

Bevirimat:

Binds to gag protein of HIV
It can be mutated in 50% ==> ineffective

What are interferons? Which ones are used for hepatitis virus infections?

Interferon:

INF are a family of naturally occurring inducible glycoproteins that interfere with the ability of viruses to infect cells
They are synthetized by recombinant DNA technology
Types:
- alpha, beta and gamma

INF_a_2a, IFN_a_2b:

INF**a2b has been approved for hepatitis B and C treatment, as well as condylomata acuminate and cancers like hairy cell leukemia and Kaposi sarcoma.
- In the case of HBV, the effect could be faster and longer than the effect of nucleoside analogs, but the answer rate is lower and they are less tolerated
They have a complex antiviral activity (induces production of > 20 antiviral proteins)
They are peptides
Administration: subcutaneous
- Today, polyethyleneglycol bound (“pegylated”) derivatives are preferred, because of better kinetic properties (once a week possible).
Adverse effects:
- Flu-like symptoms (fever, fatigue, myalgias, …)
- Suppression of hematopoiesis
- GI disturbances
- Liver and kidney function disorders
- CNS disturbances

Which are is the treatment and the drugs used for HBV infection?

Lamivudine (, Emtricitabin)
- Most often used, but not a really good choice
- Cytosine analog (triphosphate active form)
- Inhibitor of HBV and HIV reverse transcriptase
  - Competitive inhibition of HBV RNA-dependent DNA polymerase
- High rate of resistance following long-term therapy
- Pharmacokinetics:
  - Well absorbed orally and widely distributed
  - Mainly excreted unchanged in the urine
- Adverse effects:
  - Well tolerated, but rarely there are headaches and dizziness
Adefovir (-dipivoxil)
- AMP analog –> termination of chain elongation ==> prevents HBV replication
- Pharmacokinetics:
  - Administered 1x/day
  - Renal excretion (glomerular filtration, tubular secretion)
  - No cross-resistance with lamivudine, but relative more primer resistance
- Adverse effects:
  - Nephrotoxic
  - Discontinuation ==> severe exacerbation of hepatitis
Entecavir
- Guanosine analog
  - Competitive inhibitor of viral reverse transcriptase.
- Pharmacokinetics:
  - Administered 1x/day
  - Unchanged renal excretion
  - Almost no primer resistance
- Clinical use:
  - Effective against lamivudine-resistant strains of HBV
- Adverse effects:
  - Well tolerated, but risk of nephrotoxicity
Tenofovir
- More potent than adefovir, no resistance has been observed yet
Telbivudine
- Thymidine analog –> termination of chain elongation ==> prevents HBV replication
- Pharmacokinetics:
  - Administered orally 1x/day
  - Renal excretion (glomerular filtration)
  - No cross-resistance with lamivudine, but fast primer resistance development
- Adverse effects:
  - Well tolerated, but
    - Fatigue, headache, diarrhea, increased liver enzymes, increased CK
Investigational:
- Clevudine (nucleoside)
- Tymosine a1 (immunomodulator)

What features are there to HBV treatment?

Development of resistance in HBV highly depends on initial viral count (as higher then faster)
Reduced count should be as fast as possible
Constant suppression is very important
The most often used lamivudine, is not really a good choice
For post-exposure prophylaxis: anti-HBV immunoglobulin

What is the treatment of HCV?

* Combination therapies depending on the genotype * It is possible to reach SVR * 12 weeks undetectable viral level (97-100% chance of eradication, often without relapse) ***_Ribavirin_****_:_* * Cf topic 5, under RSV * For HCV combined for 12 to 48 weeks orally. *_New targets and agents for HCV treatment:_* * ***STAT-C***: specifically-targeted antiviral treatment for hepatitis C *_NS3 protease inhibitors:_* * ***Drugs:*** * *Simeprevir* * *Boceprevir* * *Paritaprevir* * *Grazoprevir* * *Glecaprevir* * *Voxilaprevir* * ***Pharmacokinetics:*** * Metabolized by CYP3A (possible interactions) * Administration: oral * Relative fast resistance development * Only with RBV+INF combination * ***Clinical use:*** * Effective for genotype 1 and 4 * ***Adverse effects:*** * GI disturbance * Anemia (*Boceprevir*) * Skin reaction * Photosensitivity *_NS5B polymerase inhibitor – **Sofosbuvir**:_* * TMP analog --\> termination of chain elongation ==\> prevents HCV replication * Effective on genotypes 1-6 * Resistance still not registered * Low toxicity: * Headache, nausea, insomnia, fatigue *_Non-nucleoside NS5B polymerase inhibitor – **Dasabuvir:**_* * It is used as a part of a combination for Type 1 HCV with *Paritaprevir* and *Ombitasvir* (+ *ritonavir* as „booster”) * ***Side effects:*** * Fatigue, nausea, insomnia, itchiness *_NS5A transcription complex inhibitor:_* * ***Drugs:*** * *Daclatasvir* * *Ledipasvir* * *Ombitasvir* * *Elbasvir* * *Velpatasvir* * *Pibrentasvir* * NS5A have a role in viral replication and assembly, but the real method is unknown. * Therefore, the exact mechanism of action of the drugs is unknown as well. * The drugs are effective in all genotypes. * There genetic barrier is low. * Only *Daclatasvir* is available as simple pill, the others only as combination * ***Side effects:*** * Headache, nausea, fatigue (mild to middle) *_Treatment of hepatitis C based on genotype:_* * ***Best choice for all genotypes (naïve _and_ after treatment failure):*** * *Sofosbuvir* + *Velpatasvir* (12 weeks) * *Sofosbuvir* + *Daclatasvir* (12-16-24 weeks depending on genotype, cirrhosis, except genotype IV) * It can be extended with *ribavirin* and rarely with infection * ***For genotype I:*** * *Grazoprevir + elbasvir* * *Ombitasvir + Paritaprevir (+ritonavir) + dasabuvir* * *Sofosbuvir + Ledipasvir* * *Sofosbuvir + Simeprevir* * ***For genotype IV:*** * *Grazoprevir + elbasvir + ribavirin* * *Ombitasvir + paritaprevr (+ritonavir) + ribavirin* *Sofosbuvir + Ledipasvir*