77. Antiviral drugs against HIV and influenza viruses

Last updated on October 25, 2019 at 10:02

Antivirals against HIV
  • Nucleotide reverse transcriptase inhibitors (NRTIs)
    • Zidovudine
    • Lamivudine
    • Abacavir
  • Non-nucleotide reverse transcriptase inhibitors (NNRTIs)
    • Nevirapine
    • Efavirenz
  • Protease inhibitors (PIs)
    • Darunavir
    • Lopinavir
    • Ritonavir
  • Integrase strand transfer inhibitors (INSTIs)
    • Raltegravir
    • Dolutegravir
  • Entry inhibitors
    • Enfuvirtide
  • CCR5-antagonists
    • Maraviroc

Indications:

The standard regimen for antiretroviral therapy (ART) is called highly active antiretroviral therapy (HAART) or combined antiretroviral therapy (cART). This consists of (at least) three antiretroviral drugs. 2 of them should be NRTIs and the last can be a PI, INSTI or NNRTI. The exact antiretroviral to use should depend on the result of drug resistance testing but treatment should be started as soon as diagnosis is made (and before the result of the drug resistance testing is available). The treatment lasts indefinitely and so the ease of administration is important. Those antiretrovirals which are not taken orally should be reserved for resistant cases.

All types are given orally except the entry inhibitor. It must be given subcutaneously and is therefore reserved for treatment-resistant cases.

The protease inhibitor ritonavir is often combined with other protease inhibitors like darunavir or lopinavir, because ritonavir “boosts” their efficacy. We call the combination ritonavir-boosted darunavir, or boosted protease inhibitors.

Monotherapy should never be used as it increases the risk of resistance.

Mechanism of action:

Nucleotide reverse transcriptase inhibitors are nucleotide analogues. They’re phosphorylated inside the cell, which converts them into false substrates for reverse transcriptase. This yields competitive antagonism and chain termination.

Non-nucleotide reverse transcriptase inhibitors are non-competitive inhibitors of reverse transcriptase. They don’t require intracellular phosphorylation to be activated.

Protease inhibitors inhibit viral protease, which is necessary to cleave the viral polypeptides into mature viruses. When viral protease is inhibited will only immature, non-infectious virus particles be formed.

Integrase strand transfer inhibitors inhibit the enzyme integrase, which integrates the viral DNA into the host cell chromosome.

Entry inhibitors bind to the viral gp41 protein, which is necessary for the entry of HIV into the target cell.

CCR5 antagonists block the CCR5 coreceptor on the cell surface. Some genotypes of HIV use CCR5 to enter the cells (the rest use CXC4 instead or both). CCR5 antagonists are only effective against those genotypes which use only the CCR5 receptor to enter the cell.

Pharmacokinetics:

All NRTIs are orally absorbed except the entry inhibitor. Most of them are renally eliminated. The exceptions are abacavir and zidovudine, which are eliminated by the liver.

Many NNRTIs have interactions with CYP enzymes. Efavirenz inhibits CYP while nevirapine induces it.

All protease inhibitors, but especially ritonavir, are strong Pgp and CYP3A4 inhibitors. They’re also eliminated by CYP3A4, and so the combination of ritonavir with other protease inhibitors decreases their elimination. This is the mechanism of the ritonavir “boosting”.

INSTIs are eliminated by the liver, either by glucuronidation or by CYP enzymes.

Adverse effects:

NRTIs

  • Bone marrow suppression – especially zidovudine
  • Hypersensitivity – only for abacavir
    • Potentially life-threatening
    • Abacavir should only be used in HLA-B*5701 negative patients as they cannot develop hypersensitive reaction to abacavir
  • Mitochondrial toxicity – especially zidovudine
    • Because mitochondrial DNA polymerase is also affected
    • Myopathy
    • Neuropathy
    • Hepatic steatosis
    • Lactic acidosis

NNRTIs

  • Hepatotoxicity – only for nevirapine
  • CNS effects like mood disorders, psychosis – only for efavirenz
  • Hypersensitivity
    • Common
    • Can be anything from rash to Stevens-Johnson syndrome
  • GI symptoms

Protease inhibitors

  • Hyperglycaemia
    • As they inhibit GLUT4
  • Hyperlipidaemia
  • Lipodystrophy – abnormal distribution of fat
    • Cushingoid appearance
  • GI symptoms

INSTIs

  • GI symptoms
  • CNS symptoms

Entry inhibitors and CCR5 antagonists

  • Hepatotoxicity
  • Myopathy
Antivirals against influenza viruses
  • Antivirals against influenza A
    • Amantadine
    • Rimantadine
  • Antivirals against influenza A and B
    • Oseltamivir (Tamiflu)
    • Zanamivir
  • New antivirals against influenza viruses
    • Baloxavir marboxil (new since 2018)

Indications:

Amantadine and rimantadine are used for influenza prophylaxis for people who cannot get vaccinated and would develop complications if they developed influenza.

Oseltamivir, zanamivir and baloxavir marboxil are used to treat influenza, shortening the duration of the illness. Baloxavir marboxil improves symptoms already after 24 hours.

Mechanism of action:

Amantadine and rimantadine block a viral-encoded ion channel called M2. The influx through this ion channel is necessary for the viral replication. These drugs are also NMDA receptor antagonists, which gives them a small role in the treatment of Parkinson disease.

Oseltamivir and zanamivir inhibit neuraminidase (NA), the enzyme which is necessary for the virus to exit the cell.

The new drug baloxavir marboxil inhibits an enzyme called cap-dependent endonuclease, an enzyme the virus uses to hijack the host cell RNA synthesis to make viral RNA.

Pharmacokinetics:

Amantadine and rimantadine are orally absorbed and renally excreted.

Oseltamivir is orally absorbed. It’s an ester prodrug which is activated in the liver. Zanamivir is not orally absorbed and is instead inhaled.

Adverse effects:

  • Amantadine and rimantadine
    • Neurological symptoms
      • Due to the NMDA antagonism
      • Livedo reticularis
      • Anxiety
      • Dysphasia
    • GI symptoms
    • QT elongation – only amantadine
  • Oseltamivir
    • GI symptoms
    • Headache
  • Zanamivir
    • Cough, bronchospasm
    • Upper respiratory tract infections
Immunoglobulins as antivirals

Immunoglobulins against viruses can be used as post-exposure prophylaxis for infections like rabies, hepatitis A, hepatitis B and measles.

Hyperimmune gamma globulins are antibodies which are highly specific for a specific virus. Hyperimmune gamma globulins exist against many viruses like HBV, VZV, etc.

Palivizumab is a humanized monoclonal antibody against RSV. It’s used as prophylaxis against RSV in infants who are at high risk for RSB infection.


Previous page:
76. Antiviral drugs against herpes and hepatitis viruses

Next page:
79. Anthelminthic drugs

5 thoughts on “77. Antiviral drugs against HIV and influenza viruses”

  1. CCR5 agonists are only effective against those genotypes which use only the CCR5 receptor to enter the cell.
    Shouldn’t it be CCR5 “Antagonists” ?

  2. All NRTIs are orally absorbed except the entry inhibitor. Most of them are renally eliminated. The exceptions are abacavir and zidovudine, which are eliminated by the liver

    2/3, then most of them is eliminated by the liver?

    1. I understand the confusion. There are many more NRTIs than I have mentioned, and most of them are renally excreted. I always try to include just a few examples of drugs.

Leave a Reply

Only the "Comment" field must be filled in. It is not compulsory to fill out your name; you can remain anonymous. Do not fill out e-mail or website; if you do, your comment will not be published.