Antivirals Flashcards
What is the composition of viruses like?
they consist of:
- nucleic acid (DNA or RNA)
- protein - protein coat (structural) and enzymes (non-structural)
- they may or may not have a lipid envelope
What type of parasites are viruses?
they are obligate intracellular parasites
this means that they need to be inside a host cell in order to replicate
What is the difference between structural and non-structural proteins within a virus?
structural proteins:
- these form part of the virion itself
- e.g. the protein coat
non-structural proteins:
- these are involved in replicating the virus and taking over cellular machinery
- this includes enzymes
What are the 2 different types of virus infections?
acute viruses:
- these are RNA viruses
- influenza, measles, mumps, hepatitis A virus
chronic viruses:
- these are generally DNA viruses
What are the 2 different types of chronic virus infections?
Latent:
- these may or may not be recurrent
- a lot of people will live with a latent virus and not have any reactivation
persistent:
- these can cause damage
- the host’s immune system may cause damage, opposed to the virus itself
What are examples of chronic latent viruses?
herpes simplex, cytomegalovirus
What are examples of chronic persistent virus infections?
HIV, HTLV, hepatitis B and hepatitis C
Why do chronic viruses tend to be DNA viruses?
viruses with bigger genomes are able to stay in their hosts for a long time
this is usually for the entire lifetime of the host
What are the 2 different types of rashes caused by virus syndromes?
non-vesicular rashes:
- measles, rubella, parvovirus, adenovirys, HHV6
vesicular rashes:
- these involve fluid-filled lesions
- chickenpox (HHV3)
- herpes simplex (HHV1/2)
- enterovirus
What are the typical viruses that cause respiratory infections?
- influenza a/b
- respiratory syncytial virus (mainly affects young children)
- parainfluenza virus
- human metapneumovirus
- rhinovirus
- coronovirus (including SARS)
What are the viruses that cause gastroenteritis?
these are mainly RNA viruses
- rotavirus
- norovirus
- astrovirus
- sapovirus
- adenovirus (group F)
what are the virus syndromes that cause neurological disease?
they cause encephalitis/meningitis
- herpes simplex virus
- enteroviruses
- rabies
- japanese encephalitis virus
- nipah virus
What are the 2 different types of blood-borne virus syndromes?
What are they caused by?
hepatitis viruses:
- hepatitis b virus
- hepatitis c virus
retroviruses:
- HIV 1, 2
- HTLV 1, 2 - this can be associated with neurological disease and lymphoma
In which 3 situations can antivirals be used?
most viruses are NOT treated with antivirals as they are self-limiting
- for acute infections in the general population
- in chronic infections
- infections in immunocompromised patients
When are antivirals used for acute infections in the general population?
they are used with patients who have a high risk of complications
e.g. diabetic patients, elderly, people with respiratory conditions in influenza
in what type of immunocompromised patients are antivirals used on?
- post transplant
- individuals receiving immunosuppressive therapies
- patients with primary immunodeficiencies
What drugs is used for the treatment of herpes simplex virus?
aciclovir
What types of conditions caused by HSV are treated with aciclovir?
invasive disease:
- encephalitis
- disseminated HSV in immunocompromised and neonates (this is when the infection spreads)
primary oral-labial or genital herpes
prophylaxis:
- this involves treatment with a lower dose of aciclovir in people with frequent reactivations
What is the treatment for chickenpox and shingles?
what are they caused by?
aciclovir
these are caused by varicella zoster virus
What types of patients with chickenpox should be given aciclovir?
ALL adults with chickenpox should be treated
young children do not require treatment as the infection is self-limiting
Which patients should be given treatment for shingles?
- >60 to reduce the incidence of post-herpetic neuralgia
- shingles involving the eyes
- immunocompromised patients
What is significant about the time when antivirals are given?
antivirals need to be given within the first day or two of infection in order for them to be effective
What 2 different drugs are used for the treatment of influenza?
neuraminidase inhibitors (oseltamivir) - these are oral
zanamavir - these are inhaled
Which patients should be given treatment for influenza?
high risk patients
- chronic neurological, hepatic, renal, pulmonary and chronic cardiac disease
- diabetes mellitus
- severe immunosuppression
- age over 65 years
- pregnancy and up to 2 weeks post partum
- children under 6 months of age
- morbid obesity (BMI > 40)
For how long should chronic virus infections be treated for?
What are the problems associated with this treatment?
treatment usually has to be given for the patient’s whole life
- antiviral toxicity can be a problem
- maintaining good adherence can be challenging
- need to avoud emergence of resistance
What is the exception of chronic virus infections that is treated differently?
hepatitis c - this is caused by an rna virus
this is treated with a course of drugs for 8-12 weeks
Why is it important to take medication every day when you have a chronic virus infection?
taking the drugs every day suppresses viral replication, meaning there are no symptoms
if the drug is not taken, viral replication will begin again
What are the stages involved in virus replication?
- virus attachment to cell (via receptor)
- cell entry
- virus uncoating
- early proteins are produced - viral enzymes
- replication
- late transcription/translation - viral structural proteins
- viral assembly
- virus release and maturation
What happens when the virus enters the host cell?
the viruses take over much of host intracellular machinery
what types of proteins do viruses encode for?
what are they targets for?
all viruses encode unique proteins - many of these are vital for virus replication and infectivity
these unique proteins are targets for molecular inhibition by antivirals
What are the 4 different types of polymerases and in which types of viruses/cells are they found?
DNA to DNA:
- found in eukaryotes and DNA viruses
DNA to RNA:
- found in eukaryotes and DNA viruses
RNA to RNA:
- found in RNA viruses only
RNA to DNA:
- found in retroviruses (HIV)
- hepatitis B
What is the role of polymerases?
most viruses have their own polymerases to replicate RNA or DNA genomes
sometimes they will also use host enzymes, depending on whether the enzyme is availble in the host cell
What is the structure of a nucleotide like?
How do nucleoside reverse transcriptase inhibitors work?
(NRTIs)
they mimic the nucleotide and inhibit the reverse transcriptase enzyme
HIV uses reverse transcriptase to convert its RNA into DNA
blocking this enzyme prevents HIV from replicating
What is the structure of AZT (azidothymidine) like?
What is it used to treat?
it was originally used as an anti-cancer drug but it was too toxic at the required concentration
it inhibits HIV replication at a lower concentration
it is a nucleoside reverse transcriptase inhibitor and is based on a thymidine molecule
What are the 2 different types of HIV NRTIs?
What are examples of these?
pyrimidine analogues:
- thymidine analogues - zidovudine
- cytosine analogues - lamivudine
purine analogues:
- these are adenoside and guanoside analogues
- abacavir
- tenofovir
What enzyme does hepatitis b virus have?
Which drugs are used to treat it?
hepatitis b contains the reverse transcriptase enzyme
some NRTIs used for HIV are also active against HBV
this includes lamividine and tenofovir
If there is a dual infection with hiv and hepatitis b virus, how should it be treated?
lamividine and tenofovir are used together
What are the two herpesvirus polymerase inhibitors?
What is their structure like?
aciclovir and gancicolvir
they are both analogues of guanosine
What is aciclovir used to treat?
infections caused by herpes simplex virus and varicella zoster virus
What is ganciclovir used to treat?
cytomegalovirus and HHV6
it is also used to treat herpes simplex virus and varicella zoster
What is the main difference between aciclovir and ganciclovir?
Which one is safer?
aciclovir is a chain terminator, whereas ganciclovir does not terminate the chain
it is incorporated into viral DNA and can cause oncogenetic and teratogenic effects
there is no extension of the chain with aciclovir so it is a very safe drug
What drug is used to treat hepatitis C infection?
How does it work?
Sofosbuvir
this is an RNA polymerase nucleotide inhibitor
it is an analogue of deoxycytodine
it is a pro-drug that turns into the active phosphorylated form within cells
What are the 2 main non-nucleotide reverse transcriptase inhibitors? (NNRTIs)
efavirenz and nevirapine
these do not resemble nucleotides
they bind to different parts of the reverse transcriptase enzyme and stop it from working properly
Why are protease inhibitors (PIs) effective in treating viral infections?
cutting up proteins is performed by host proteases
most viruses also create their own proteases
these are important for viral replication as the proteins cannot fold up properly and form enzymes and structural proteins
What protease inhibitors are used in HIV infection?
atazanavir and darunavir
ritonavir is used to boost the levels of other protease inhibitors
which protease inhibitors are used to treat hepatits c virus?
paritaprevir and grazoprevir
How do “entry inhibitor” drugs work in treating HIV?
viruses have to enter a cell in order to cause an infection - this can be prevented
HIV must also bind to the CD4 molecule and it ues the CCR-5 co-receptor
What are the 2 entry inhibitor drugs used to treat HIV?
enfuviritide:
- T20, given by IM injection
- this is a fusion inhibitor
maraviroc:
- this is a chemokine receptor antagonist
- it blocks co-receptor CCR-5
What are the 2 integrase inhibitors used in HIV treatment?
How do they work?
raltegravir and dolutegravir
integrase is an enzyme which integrates HIV into the host cell
What does HAART stand for?
How many drugs does it involve?
highly active antiretroviral therapy
it involves 2 NRTIs + NNRTI
or
2 NRTIs + boosted PI or integrase inhibitor
What is the purpose of HAART?
How long must a patient have treatment in this way?
fixed drug combinations are used (more than one drug in the pill)
this works to switch off virus replication
life long treatment is required
How many mutations are found within the HIV genome?
the HIV genome contains 9,000 nucleotides
every genome contains at least one mutation
Why does the HIV genome contain so many mutations?
mutations in HIV polymerase are deliberate
some amino acid mutations will change the virus, but most will be deleterious and the virus will not replicate
a strain will become predominant if it has a selection advantage over fellow progeny
What is the result of the M184V mutation in HIV?
it results in resistance to lamivudine
in the presence of lamivudine, the rare population strains with this mutation will soon predominate
Why does the HIV virus mutate?
What is the treatment response to this?
the virus can mutate in response to T cell immunity, antiviral therapy and depending on the host
a combination of 2 or 3 drugs are needed as the virus may have a mutation which makes it resistant to a particular drug
What is the treatment for hepatitis C virus?
How long does the treatment last for?
directly acting antivirals are used rather than combined with interferon
generally, combination therapy is used (2 or 3 agents) for 8-12 weeks
What are the cure rates for HCV treatment?
cure rates > 95%
different genotypes of HCV require different combinations although some antivirals work against all genotypes
What actually do antivirals work on and how do they work?
they work by blocking a particular stage of viral replication
they act on virally encoded proteins
What is the main problem with antiviral therapy?
viruses can rapidly mutate and become resistant to antivirals
RNA viruses mutate more rapidly than DNA viruses
