Antivirals for the treatment of influenza, herpes, hepatitis and HIV infection Flashcards
Describe the structure of viruses
- Nucleic acid core (DNA or RNA)
- Protein coat - structural (capsid)
- Enzymes within virus (non structural proteins)
- Some also have a lipid envelope
What type of viruses do acute infections tend to be caused by?
RNA viruses
e.g. Influenza, measles, mumps, hepatitis A virus
What type of viruses do chronic infections tend to be caused by?
Generally DNA viruses
- Latent with (or without) recurrences
- Persistent
What are examples of latent with (or without) recurrences viral infections?
Herpes simplex, Cytomegalovirus
What are examples of persistent viral infections?
HIV, HTLV, Hepatitis B virus, Hepatitis C virus
What is a viral syndrome?
Viral syndrome is a term used for symptoms of an infection caused by a virus.
What are examples of viral syndromes?
Rashes, respiratory infections, gastroenteritis, neurological disease
What are 2 types of rashes caused by viruses?
- Non-vesicular rashes
2. Vesicular rashes
What is a vesicular rash?
When a rash appears in the same place as multiple vesicles, it’s known as a vesicular rash
What viral infections cause a vesicular rash?
- Chickenpox (HHV3)
- Herpes simples (HHV1/2)
- Enterovirus
What viral infections cause a non vesicular rash?
Measles Rubella Parvovirus Adenovirus HHV6
Describe a vesicular rash
Fluid filled
Which viral infections can cause respiratory infections?
Influenza A/B Respiratory Syncytial Virus Parainfluenza virus Human Metapneumovirus Rhinovirus Coronavirus (including SARS)
What viral infections can cause gastroenteritis?
Rotavirus Norovirus Astrovirus Sapovirus Adenovirus (group F)
What viral infections can cause neurological disease?
Encephalitis/Meningitis caused by: HSV Enteroviruses Rabies Japanese encephalitis virus Nipah Virus
What viruses are blood-borne?
Hepatitis viruses:
HBV
HCV
Retroviruses:
HIV 1,2
HTLV 1,2
What is encephalitis?
Inflammation of the brain. There are several causes, but the most common is a viral infection.
e.g. Herpes simplex encephalitis (HSE)
What is a disseminated infection?
One in which a localised infection spreads (disseminates) from one area of the body to other organ systems.
When should antivirals be used?
- Acute infections in general population (where high risk of complications)
- Chronic infections eg. HIV, HBV, HCV
- Infections in immunocompromised
What are the most effective medications available for people infected with HSV?
Antiviral medications, such as acyclovir, famciclovir, and valacyclovir
N.B. These can help to reduce the severity and frequency of symptoms, but cannot cure the infection.
What invasive diseases can HSV lead to?
- Encephalitis
2. Disseminated HSV
What should be used to treat Herpes simplex encephalitis (HSE)?
Acyclovir
Who is disseminated HSV seen in?
immunocompromised and neonates (who have acquired it from mother)
What is used to treat frequent reactivations of HSV?
Acyclovir prophylaxis
What drug is used in treatment of chickenpox and shingles (VZV)?
Aciclovir
What virus causes chickenpox and shingles?
Varicella Zoster Virus
When should patients with chickenpox be treated with aciclovir?
> 13 as can get very severe
When should patients with shingles be treated?
- > 60 –> to reduce incidence of post-herpetic neuralgia
- If shingles involves the eye (any age)
- In the immunocompromised
What is post-herpetic neuralgia?
Lasting nerve pain in an area previously affected by shingles.
More likely to occur the older you are when you get shingles
What are the treatments for influenza?
Neuraminidase inhibitors oseltamivir (oral) and zanamavir (inhaled)
These only tend to work if given within 48 hours of onset of symptoms - after this the immune system tends to deal with it
Which patients with influenza should be treated?
Chronic neurological, hepatic, renal, pulmonary and chronic cardiac disease
Diabetes mellitus
Severe immunosuppression
Age over 65 years
Pregnancy (including up to two weeks post partum)
Children under six months of age
Morbid obesity (BMI ≥40)
What are the problems with treatment of chronic virus infections?
Usually has to be given lifelong
- antiviral toxicity can be a problem
- maintaining good adherence can be challenging
- need to avoid emergence of resistance
How is HCV an exception?
Is an RNA virus - 70% will get a chronic infection but 30% can eradicate virus
N.B. can be cured
What does a chronic HCV infection lead to?
Cirrhosis
Virus replication cycle
- Virus attachment to cell (via receptor)
- Cell Entry
- Virus Uncoating
- Early proteins produced – viral enzymes
- Replication
- Late transcription/translation – viral structural proteins
- Virus assembly
- Virus release and maturation
What are the targets of antivirals?
All viruses encode unique proteins many of which are vital for virus replication and infectivity
These unique proteins are targets for molecular inhibition
What are viral DNA and RNA polymerases?
Enzymes which are responsible for copying the genetic materials of viruses –> required for the replication of viruses
Viral polymerases are therefore an extremely favourable target for the development of antiviral therapy.
What are the different type of viral polymerases?
- DNA to DNA (produce DNA from DNA)
- Eukaryotes
- DNA viruses - DNA to RNA (produce mRNA from DNA)
- Eukaryotes
- DNA viruses - RNA to RNA
- RNA viruses - RNA to DNA
- Retroviruses (HIV)
- Hep B virus
What is a nucleotide composed of?
- Base
- Ribose sugar
- Triphosphate
What are Nucleoside reverse transcriptase inhibitors (NRTIs)? Mechanism?
Analogues of DNA nucleotides which prevent REVERSE TRANSCRIPTION of the HIV genome, thereby inhibiting the action of HIV-1 RT and viral replication
What is the first NRTI approved for the therapy of HIV-1?
Azidothymidine (AZT)
What are purine nucleotide analogue NRTIs?
Used to treat?
Examples?
Structural analogues of adenosine or guanosine
HIV NRTIs
- Abacavir
- Tenofovir
What are pyrimidine nucleotide analogue NRTIs?
Used to treat?
Examples?
Thymidine and cytosine analogues
HIV NRTIs
- Ziovudine (thymidine analogue)
- Lamivudine (cytosine analogue)
Which NRTIs are active against HBV as well as HIV?
- Lamividine
- Tenofovir
As well as retroviruses, what other virus have a virally-encoded DNA polymerase (P) called reverse transcriptase for copying RNA to DNA?
Hep B virus
What does Acyclovir target?
Acts as a specific inhibitor of herpesvirus DNA polymerase.
Why is Aciclovir chosen of Ganciclovir in treatment of HSV and VZV?
Less toxic
What is Ganciclovir used to treat?
CMV, HHV6 (as well as HSV and VZV)
What is the key enzyme involved in HCV?
a RNA-dependent RNA polymerase
What drugs are therefore used to treat HCV?
HCV RNA polymerase nucleotide inhibitor
e.g. Sofosbuvir
Mechanism of Sofosbuvir?
Sofosbuvir inhibits the hepatitis C NS5B protein.
Sofosbuvir is a prodrug –> activated by metabolism
How do antimetabolites work?
Antimetabolites act by mimicking purines and pyrimidines that are required for DNA synthesis
NRTIs vs NNRTIs
NNRTIs are chemically distinct from nucleosides and, unlike the NRTIs, do not require intracellular metabolism for activity.
NRTIs are like another zip giving the zipper another track to follow. NNRTIs work by sitting in a binding site in the virus structure and this is a bit like having an object that blocks the teeth of the zipper, so the zipper cannot get past the block.
What are protease inhibitors?
A class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis C.
Mechanism of protease inhibitor antivirals?
Protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.
What are 3 examples of HIV antiretroviral inhibitors — class stem?
Class stem –navir
- Atazanavir
- Darunavir
- Ritonavir
What are 2 examples of Hepatitis C virus NS3/4A protease inhibitors?
Class stem –previr
- Paritaprevir
- Grazoprevir
How can the risk of the development of drug-resistant mutated viruses be reduced?
To reduce this risk it is common to use several different drugs together that are each aimed at different targets.
What are the 6 main classes of antiretroviral drugs?
- NRTIs
- NNRTIs
- Integrase inhibitors
- Entry inhibitors
- Protease inhibitors
- Post-attachment inhibitors
Enfuviritide is an example of an entry inhibitor (given by IM injection). What is its mechanism?
Enfuvirtide binds to the viral envelope glycoprotein (by mimicking binding site) and prevents the conformational changes required for the fusion of viral and cellular membranes.
Maraviroc is another example of an entry inhibitor.
What is its mechanism?
Chemokine receptor antagonist:
Maraviroc selectively binds to the human chemokine receptor CCR5, which is present on the cell membrane. This binding prevents the interaction of HIV-1 gp 120 with CCR5-tropic HIV-1 and thereby inhibits the virus from entering the cell.
What is the mechanism of action of integrase inhibitors?
Integrase inhibitors are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell.
What are 2 examples of integrase inhibitors?
- Raltegravir
2. Dolutegravir
What is HAART?
Highly active antiretroviral therapy
A treatment regimen typically comprised of a combination of three or more antiretroviral drugs:
- 2 NRTIs + NNRTI
- 2 NRTIs + boosted PI or integrase inhibitor
Purpose of HAART?
- Decreased viral loads
- Increased counts of CD4 cells
- Helps prevent resistance to any single drug used due to drug combinations
Why can HIV undergo many mutations?
HIV genome contains ~9,000 nucleotides
Every genome will contain at least one mutation –> RNA polymerase has high error rate
Most of these mutations will be deleterious to the virus but sometimes will become predominant
Gives HIV ability to evade antivirals e.g. M184V mutation results in resistance to Lamivudine
How is HCV treated?
Now have directly acting antivirals rather than combined with interferon
Generally us combination therapy (2 or 3 agents) for 8-12 weeks
Cure rates >95%
N.B. Different genotypes of HCV require different combinations although some antivirals work against all genotypes.
Conclusion:
Antivirals work by blocking a particular stage of viral replication
These act on virally encoded proteins
Viruses can rapidly mutate and become resistant to antivirals (RNA»DNA viruses)
For acute infections antivirals only tend to work if given soon after symptoms develop
NRTIs Summary:
Work by targeting the action of an HIV protein called reverse transcriptase.
After the HIV virus releases its genetic material into a host cell, reverse transcriptase converts the viral RNA into DNA, a process known as ‘reverse transcription’.
NRTIs disrupt the construction of a new piece of proviral DNA, thereby stopping the reverse transcription process and halting HIV replication.
NNRTIs Summary:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) also target reverse transcriptase, but in a different way to NRTIs.
NNRTIs interfere with the reverse transcriptase enzyme by binding directly to it, blocking the reverse transcription process.
Integrase Inhibitors Summary:
Integrase inhibitors target a protein in HIV called integrase which is essential for viral replication.
Integrase is responsible for inserting viral genomic DNA into the host chromosome. The integrase enzyme binds to host cell DNA, prepares an area on the viral DNA for integration, and then transfers this processed strand into the host cell’s genome.
Integrase inhibitors stop the virus from inserting itself into the DNA of human cells.
What are the 2 types of entry inhibitors?
Entry inhibitors stop HIV from entering human cells. There are two types: CCR5 inhibitors and fusion inhibitors.
How do CCR5 inhibitors work?
In order to enter a host cell, HIV must bind to two separate receptors on the cell’s surface: the CD4 receptor and a co-receptor (CCR5 or CXCR4). Once HIV has attached to both, its envelope can fuse with the host cell membrane and release viral components into the cell. CCR5 inhibitors prevent HIV from using the CCR5 co-receptor by binding to it, blocking viral entry.
How do fusion inhibitors work?
A fusion inhibitor (enfuvirtide) is used only for people who have no other treatment options. It works by stopping the fusion of the HIV envelope protein with the CD4 cell.
Protease inhibitors summary:
Protease inhibitors (PIs) block the activity of the protease enzyme, which HIV uses to break up large polyproteins into the smaller pieces required for assembly of new viral particles. While HIV can still replicate in the presence of protease inhibitors, the resulting virions are immature and unable to infect new cells.
