Session 9 Flashcards
Some differences between antibiotics (anti-bacterials, anti-fungals) and antivirals:
- Generally fewer viruses have specific antiviral drugs
- Antivirals are virostatic rather than virucidal, i.e. they do not ‘kill’ existing viruses, they just stop the replication of new viruses – the host immune response is required to clear existing virus
- Much less rarely given empirically – you normally confirm the presence of the virus before starting treatment - though now acyclovir (for treating HSV, VZV meningitis/encephalitis) and oseltamivir (for treating influenza) are being used more empirically, like antibiotics
• Much less broad-spectrum, i.e. antivirals are designed for a specific virus usually (exceptions, interferon, ribavirin), though some drugs can cover different viruses with the
same replication step/ virus family, e.g. tenofovir (HIV, HBV), acyclovir (HSV, VZV), ganciclovir (HSV, VZV, CMV, HHV6, HHV7, HHV8)
What are the ways Non-antiretroviral drugs work?
- Agents that directly inactivate viruses (virucides)
- Agents that inhibit viral replication
- Immunomodulators (of host response to viral infection)
- Immunoglobulins - Pooled human sera from blood donors, containing preformed antibodies (IM/ SC/ IV injection)
- Agents that directly inactivate viruses (virucides):
- Can they be systemically used?
- Mainly used for the?
- Non-organic (detergents, chlorine-based agents)
- Organic solvents (e.g. ether, alcohol,chloroform)
- Radiation (e.g. UV light, laser therapy for warts)
- Cryotherapy (e.g. for warts – removes lesions, may not inactivate virus itself)
- Non-organic (detergents, chlorine-based agents)
- However, these cannot be used systemically, and only in specific situations topically.
- cleansing of fomites
- Where are the targets for agents that inhibit viral replication:
- Disadvantages
- Give general examples of drugs which inhibit viral replication
- Attachment
- Uncoating
- RNA/DNA replication
- Protein synthesis
- Assembly
- Release
- Attachment
- Interference with host-cell metabolism can result in adverse effects
- Ineffective against non-replicating or latent viral infections.
- May exhibit rebound effects when drug is stopped
- Development of drug resistance is possible and common in some cases (e.g. HIV drugs)
- Non- or poorly standardised sensitivity/ resistance assays
- Interference with host-cell metabolism can result in adverse effects
Immunomodulators (of host response to viral infection):
- How do they work and which viruses do they target?
- Give examples of drugs which act as immunomodulators
- Replace deficient host immunity (e.g. immunoglobulins for HBV, VZV, HAV, rabies, vaccinia; HNIG/ IVIG; adaptive T cell immunotherapy)
- Enhance host immunity (e.g. interferons, Imiquimod)
What is this image showing?
Oral herpes (HSV 1) in a PWH ICU patient
What is this image showing?
Buttock herpes (HSV 2) in a PWH postnatal patient
How can we test for HSV
Detect virus in vesicle fluid
type specific serology
in the image -> Immunofluorescent (IF) confirmation of HSV1 or HSV 2 after positive CPE in viral culture
Anti-herpes virus drugs
- Give examples
- These drugs are mainly active against which viruses
- Resistance arises via?
- ADRs
- Aciclovir (oral, IV)/ valaciclovir (oral, prodrug);
Penciclovir (topical, IV)/ Famciclovir (oral, prodrug) - guanosine nucleoside analogues:
- Mainly active against HSV 1/2, VZV
Resistance arises via absent/ reduced TK enzyme, or altered TK substrate target, or
altered DNA polymerase
Well tolerated, but some nephrotoxicity. 1- 4% of patients may show
CNS symptoms:
lethargy, confusion, tremor, myclonus, hallucinations, delirium, seizures, extrapyramidal signs, autonomic symptoms, coma
Mechanism of Action of Acyclovir
- HSV-infected human cell
- acyclovir enters the cell and are converted to acyclovir monophosphate by the herpes simplex virus enzyme thymidine kinase (TK)
- Enzymes in the human cell add two more phosphates -> active drug acyclovir triphosphate
- The acyclovir triphosphate competes with 2 - deoxyguanosine triphosphate (dGTP) as a substrate for viral DNA polymerase as well as acting as a chain terminator.
- In actual infection, the herpes simplex virus releases its naked capsid that delivers DNA to the human nucleus; the active drug acyclovir triphosphate exerts its action on the viral DNA located in the nucleus.
- What is this image showing?
- How do we treat this?
- State the route of administration for the treatment
- CMV retinitis
- Ganciclovir or foscarnet initially.
Cidofovir can be used for resistant cases
- Ganciclovir (IV, intravitreal)/ valganciclovir (oral, prodrug)
Anti-herpes virus drugs (2)
Ganciclovir (IV, intravitreal)/ valganciclovir (oral, prodrug) – guanosine nucleoside analogues:
- Mechanism of action?
- Resistance arises due to ?
- Adverse effects: ?
- Inhibits viral DNA polymerase, slowing and terminating viral DNA elongation
- UL97 gene mutations or DNA polymerase (UL54) gene mutations
- nephrotoxic, myelosuppressive, neurotoxic. 5-15% patients
may show CNS symptoms: headache, behavioural changes, confusion, psychosis,
convulsions, coma
Give an example of an anti-herpes drug which is a cytidine nucleotide analogue and how it is administered
Cidofovir (IV, topical)
Anti-herpes virus drugs (3)
Cidofovir (IV, topical) - cytidine nucleotide analogue:
- Mainly active against?
- Mechanism of action?
- Resistance arises only via ?
- Adverse effects:
- Active against dsDNA viruses including possibly all human herpes viruses (HHV 1-8),
polyomaviruses, poxviruses, adenoviruses. - Inhibits viral DNA polymerase and DNA chain elongation
- mutations in the viral DNA polymerase (e.g. mutations in the CMV UL54 gene)
- nephrotoxic, myelosuppressive. Neutropenia (~24%) may be show as: fever,
nausea, vomiting, diarrhoea, headache, rash, lethargy, iritis, uveitis
Give an example of a herpes drug which is a pyrophosphate analogue & route of administration
Foscarnet (IV, intravitreal)
Anti-herpes virus drugs (4)
Foscarnet (IV, intravitreal) - pyrophosphate analogue:
- Active against ?
- Resistance arises via
- ADRs and why
- ganciclovir (GCV)-resistant CMV, aciclovir (ACV)-resistant HSV, e.g. for CMV retinitis
- mutations in the viral DNA polymerase or RT, but these do not usually cause resistance to GCV or cidofovir
- Narrow therapeutic index, with mainly nephrotoxicity. CNS adverse effects: headache,
seizures, tremor, irritability, hallucinations, fever, rash, diarrhoea, nausea, vomiting, anxiety,
fatigue, genital, ulcerations
What is the information in the table telling us?
State the Anti-hepatitis drugs that can be used for Hepatitis B and their routes of administration
- Lamivudine (3TC, oral) - cytidine nucleoside analogue
- Adefovir (oral) - adenosine nucleotide analogue
- Emtricitabine – a 5’ fluorinated nucleoside analogue derivative of lamivudine
- Entecavir – a guanosine nucleoside analogue:
Tenofovir
Anti-hepatitis drugs: Hepatitis B
Lamivudine (3TC, oral) - cytidine nucleoside analogue:
- Mechanism of action
- Resistance arises by?
- ADRs?
- Acts as false substrate and chain terminator of reverse transcriptase (RT) enzyme in HIV and HBV replication
- point mutations: M550I/V+others in YMDD motif of HBV DNA polymerase-RT with: 14-32%, 38%, 53% and 67% after 1, 2, 3 and 4 years of treatment, respectively
- Usually well-tolerated, though a rise in liver enzymes is one of the most common adverse effects
Anti-hepatitis drugs: Hepatitis B
Adefovir (oral) - adenosine nucleotide analogue
- Mechanism of action?
- ADRs?
- Acts as competitive false substrate and chain terminator of reverse transcriptase (RT) enzyme in HIV and HBV replication (including HBV DNA polymerase)
- Usually well-tolerated at the lower doses used to treat HBV (occasional headache, abdominal discomfort, diarrhoea). The main problem when using higher doses initially for HIV treatment was nephrotoxicity, hence it is no longer used for HIV treatment.
Anti-hepatitis drugs: Hepatitis B
Emtricitabine – a 5’ fluorinated nucleoside analogue derivative of lamivudine:
- Mechanism of action?
- Resistance develops within?
- ADRs
- Inhibitor of viral DNA polymerase, as per lamivudine
- 2 years of therapy against HBV
- Well-tolerated, with reports of nausea, headache, hyper-pigmentation of palms and soles. Other adverse effects difficult to distinguish from those of other drugs in HIV combination therapy
Anti-hepatitis drugs: Hepatitis B
Entecavir – a guanosine nucleoside analogue:
- Mechanism of action?
- Resistance?
- Adverse effects: ?
- Selectively inhibits hepadnaviruses (HBV), anything between 30-1000-fold more active
than lamivudine against HBV, in vitro - No reported viral resistance to this drug during these trials
- headache dizziness, lethargy, GI upset (abdominal discomfort, nausea, diarrhoea), photosensitivity
Give examples of Anti-hepatitis drugs for Hepatitis C & their route of administration
- Ribavirin (oral, IV, inhaled) - guanosine analogue
Anti-hepatitis drugs: Hepatitis C
Ribavirin (oral, IV, inhaled) - guanosine analogue:
- Mechanism of action?
- Resistance?
- Adverse effects:
- Inhibits both RNA/ DNA viruses, probably by different mechanisms in different viruses
- Reversibly alters cellular nucleotide stores, viral RNA/mRNA synthesis, lethal mutagenesis of some viral RNA genomes
- Inhibits both RNA/ DNA viruses, probably by different mechanisms in different viruses
- is rare, only documented in Sindbis virus and HCV (with the HCV RNA polymerase mutation F415Y) to date
- systemic dosing causes reversible anaemia (extravascular haemolysis) with bone-marrow suppression at higher doses. Other reported adverse effects include: pruritus, myalgia, rash, nausea, depression, anxiety, cough
Interferons are produced by?
Naturally produced by the body’s non-specific, innate immune response (IM injection):
Interferons (IFNs)
Naturally produced by the body’s non-specific, innate immune response (IM injection):
- Potent cytokines:
- Three major classes in clinical use:
- Used mainly in treating?
- Mechanism of action?
- Adverse effects?
- immunomodulating, antiproliferative
- IFN-a and IFN-b (30% aa similarity) produced by almost all cells: response to viral infection, ds RNA, bacteria, protozoa, mycoplasma, IL-1, IL-2, TNF
- IFN-g restricted to T-lymphocytes, NK cells in response to IL-2, antigens, mitogens
- IFN-a and IFN-b (30% aa similarity) produced by almost all cells: response to viral infection, ds RNA, bacteria, protozoa, mycoplasma, IL-1, IL-2, TNF
- HBV and HCV (PEG-IFNs – longer half-life)
- Not directly antiviral but stimulate proteins to enhance cellular resistance to viral infection
- In the first hours to days : flu-like illness, fever, chills, headache, malaise, myalgia, arthralgia, nausea, vomiting, diarrhoea
Give examples of protease inhibitors, NS5A inhibitors & polymerase inhibitors
Give an example of Anti-influenza drugs & route of administration
Neuraminidase inhibitors (NAIs) - oseltamivir (oral)/ zanamivir (inhaled)
Anti-influenza drugs
Neuraminidase inhibitors (NAIs) - oseltamivir (oral)/ zanamivir (inhaled):
- Mechanism of action?
- Effective against?
- Resistance arises due to?
- Adverse effects (oseltamivir): ?
- Adverse effects (zanamivir): ?
- Reversible inhibitors of NA enzyme that cleaves the sialic-acid receptor-HA bond between host-cell and virus
- Inf A and B and amantadine/ rimantidine resistant strains
- mutations in NA gene (H274Y/ H275Y), producing a less fit virus. It is relatively infrequent, at present
- generally well-tolerated, some nausea, vomiting, abdominal discomfort (10-15% of patients), also rashes (rarely SJS), headaches
- again well-tolerated, though reported bronchospasm, pulmonary oedema, respiratory arrest (rarely), exacerbation of underlying airways disease in some patients
Antiretroviral (HIV) drugs
What is the life cycle of HIV showing stages for possible drug interventions
Give the categories for anti-retroviral (HIV) drugs
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
- Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
- Protease Inhibitors (PIs)
- Fusion Inhibitors (FIs)
- Integrase inhibitors (INIs)
- Receptor inhibitors (R5 inhibitors)
- Others (continually in development)
Give examples of drugs which fall under these categories
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
- Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
- Protease Inhibitors (PIs)
Drugs for treating HIV (antiretrovirals): trade and generic names, and abbreviations.
NRTIs
- Give examples of NRTIs
- Mechanism of action
- Active against?
- Specific adverse effects:
- Nucleoside RT inhibitors: zidovudine (AZT), didanosine (ddI), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine, tenofovir (a nucleo tide RTI), etc.
- Act by inhibiting the DNA polymerase function of the HIV RT enzyme. The NRTIs act as false substrates and lack the 3’-OH group for DNA elongation, so when incorporated, will terminate production of the HIV DNA provirus
- HIV-1 and HIV-2
- hyperlactataemia, lactic acidosis, hepatomegaly+steatosis (possibly fatal).
- Resistance is common, and arises readily with poor adherence, with many primary resistance mutations: M41L, E44D, K65R, D67N, K70R, L74V, V118I, M184V, L210W, T215Y, K219Q, Q151M – some may sensitise to NNRTIs
- hyperlactataemia, lactic acidosis, hepatomegaly+steatosis (possibly fatal).
NNRTIs
- Give example of NNRTIs
- Mechanism of action?
- Active against HIV-1 but NOT HIV-2
- Specific adverse effects:
- Non-nucleoside RT inhibitors: nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, etc.
- Non-competitive inhibitors of HIV RT by allosteric inhibition of enzyme function, binding at different sites from the NRTI sites – therefore synergism possible with combination therapy
- erythematous maculopapular rash, raised LFTs both of which can be serious, occasionally fatal (nevirapine);
- light-headedness, dizziness, sleep disturbance, headache, mania, psychosis, rash and raised LFTs and cholesterol (efavirenz)
- Resistance mutations arise readily, especially with poor adherence and monotherapy and can be long-lasting and class-specific, including: K103N, V106M, V108I, Y181C, Y188L, G190A/S
- erythematous maculopapular rash, raised LFTs both of which can be serious, occasionally fatal (nevirapine);
PIs
- Give examples of protease inhibitors:
- Mechanism of action?
- Active against both?
- Specific adverse effects:
- saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, tipranavir, darunavir, etc.
- Block the cleavage of viral polyproteins by HIV protease enzyme, preventing the production of viral proteins for the formation of final mature, complete virions
- HIV-1 and HIV-2
- may induce or inhibit cytP450 and alter the hepatic metabolism of other drugs
- chronic use increases cholesterol, TAGs; hyperglycaemia, hyperlipidaemia, new onset DM - resulting increased risk of MIs; may alter body fat distribution (lipodystrophy)
- Resistance tends to increase with the cumulative number of mutations present and tend to be drug-specific, including: D30N, L33I, M46L, I50V, V82A, I84V, L90M
- may induce or inhibit cytP450 and alter the hepatic metabolism of other drugs
FIs
- Give an example ofa fusion inhibitors:
- Mechanism of action
- Administration
- Active against ?
- Specific adverse effects:
- enfuvirtide (T-20)
- Interfere with attachment/ fusion process between HIV gp120/ gp41 and cellular CD4/ CCR5/ CXCR4 receptors
- The only HIV drug that must be given by injection (s/c) – as part of salvage combination Rx
- HIV-1 only, NOT HIV-2
- Injection site pain, induration, erythema, nodules, cysts, pruritis, ecchymoses
- Hypersensitivity reactions, rash, fever, nausea, vomiting, chills, hypotension, raised LFTs
- Resistance has been documented in vitro in the gp41 coding region of HIV (codons 36-45)
- Injection site pain, induration, erythema, nodules, cysts, pruritis, ecchymoses