Current & Advanced Treatments for Sexually Transmitted Viral Infections Flashcards
what do warts most commonly originate from
human papilloma virus (HPV)
what does wart treatment focus on
removal of wart as opposed to removal of virus
what are the first line treatments of warts
imiquimod
podophyllotoxin
how does imiquimod work
immunoenhancing drug
cytokines secreted by cells of immune system and have effect on other cells (aka interferons, interleukins, TNF-a)
imiquimod switches on cytokines aka innate immune system to clear wart
imiquimod mechanism of action
binds to and activates toll-like receptors (TLR) 7 and 8
activates intracellular signalling pathways through NF-kB
NF-kB translocates to nucleus where it activates gene transcription
causes production of pro-inflammatory cytokines (e.g. TNF-alpha)
pro inflammatory proteins secreted from cell, then switch on immune cells e.g T cells
triggers immune response, wart cells removed
how is podophyllotoxin for warts administered
topically
podophyllotoxin mechanism of action
internalises into wart cells
binds to microtubules, preventing mitotic division
inhibits topoisomerase 2
cells cannot undergo cell division, triggers apoptosis, wart regresses
other than warts, what does HPV cause
cancers
what are the high risk HPVs (2)
HPV 16
HPV 18
what are the main types of cancer associated with HPV infection
Cervical cancer is the main cancer associated with HPV infection, but can also cause vaginal, vulval, penile, anal, mouth and throat cancers
what % of all cervical cancers are attributed to HPV 16
50
what % of all cervical cancers are attributed to HPV 18
20
what occurs when the body fails to clear the infection - causing precancerous lesions to develop
virus replicates in epithelial cells
can damage DNA
precancerous lesions can develop
what do the precancerous lesions undergo
many regress alone
but may undergo further transformation and become a cancerous tumour if infection persists
what vaccine is used by the NHS to protect against HPV 6, 11, 16, 18
gardasil (newer gardasil 9 protects against additional 5 HPV strains) - broader scope
mechanism of action of gardasil
contains purified L1 protein ( major capsid protein ) from each HPV strain
L1 proteins self assemble into HPV virus like particles (VLPs) which produce antibodies
reduces risk of viral infection developing into cancers
preventative/ inert vaccination
what is the L1 protein
the major capsid protein, come together to form capsomere and then a pentamere
when was the HPV vaccine introduced
2008
initially for 16-21 aged females which have seen reduction in HPV by 86%
then in 2019, administering to males and females aged 12 and above
4 examples of the 9 herpes virus types
herpes simplex virus 1 - HSV-1
herpes simplex virus 2 - HSV-2
varicella-zoster virus
epstein-barr virus (mononucleosis virus)
what does herpes simplex-1 HSV-1 tend to cause
cold sores
what does herpes simplex-1 HSV-1 and HSV-2 tend to cause
genital herpes
what are the symptoms of herpes (4)
small blisters that burst to leave red open sores around gential, anus, thighs, buttocks
tingling, burning, itching around genitals
pain during urination
vaginal discharge
first like treatment of herpes
aciclovir (prodrug)
mechanism of action of aciclovir
ACV converted to ACV-monophosphate (ACV-MP)
via HSV-1 thymidine kinase
HSV-1 TK enzyme only expressed in infected cells aka virus cells - rate dependent step, relies on this virus
grants specificity to drug and reduces off-target side effects
ACV-MP undergoes further phosphorylation to ACV-disphosphate (ACV-DP)
via cellular guanylate kinase aka humans take over
ACV-DP converted to ACV-triphosphate (ACV-TP)
via disphosphate kinase
enzymes expressed by cells, not dependent on viral enzymes
ACV-TP misincorporated into viral DNA aka means to target guanine residue but oopsies
ACV-TP misrecognised by DNA polymerase as deoxyguanosine triphosphate (dGTP) - guanine precursor
ACV-TP lacks 3’ hydroxyl group of dGTP so prevents attachment of additional nucleosides into DNA chain
terminates growing viral DNA chain
what does varicella-zoster virus cause
(chickenpox/ shingles)
what does epstein-barr virus cause
(mononucleosis virus)
when is oral aciclovir administered
shingles for systemic effect
aciclovir mechanisms of resistance (3)
reduced or absent HSV-1 thymidine kinase (no monophosphorylation)
altered thymidine kinase activity resulting in decreased aciclovir phosphorylation
altered viral DNA polymerase with dec affinity for aciclovir triphosphate (no more misincorporation)
how does the human immunodeficiency virus (HIV) destroy human immune system gradually
Attacks a subtype of white blood cell called CD4 cells which protect the body from infection
mechanism of HIV
uses cell machinery of CD4 to make copies of itself and spread throughout body
HIV life cycle - what are the 7 stages
1 - binding (HIV attaches to surface of CD4 cell)
2 - fusion (HIV can enter cells)
3 - reverse transcription (virus converts RNA to DNA (dsDNA) and degrades remaining viral RNA)
4 - integration (HIV DNA integrates with cells DNA and is referred to as proviral DNA)
5 -replication (virus uses cell machinery to make copies of HIV proteins and RNA)
6 - assembly (new HIV protein and RNA assemble into immature virus)
7 - budding (immature HIV pushes itself out of cell)
what are the two main methods of HIV prevention
Pre-exposure prophylaxis (PrEP)
Post-exposure prophylaxis (PEP)
what medicines are involved in Pre-exposure prophylaxis (PrEP)
Emtricitabine & Tenofovir
what medicines are involved in Post-exposure prophylaxis (PEP)
Emtricitabine, Tenofovir & Raltegravir
what is PrEP (Pre-exposure prophylaxis)
commonly given as the combination therapy emtrictabine and tenofovir to HIV-negative patients
how often is PrEP (Pre-exposure prophylaxis) administered
daily
how long for is PEP (Post-exposure prophylaxis) administered
28 day course after patient may have come into contact with HIV virus
what is Emtricitabine (FTC)
Reverse Transcriptase Inhibitor
works in a mechanism similar to aciclovir
does not have an effect on already infected cells
what does emitricitabine undergo phosphorylation to form
emtricitabine triphosphate (FTC-TP)
emtricitabine mechanism of action
phosphorylation forming emtricitabine triphosphate (FTC-TP)
FTC-TP misrecognised by reverse transcriptase enzyme (which converts viral RNA to DNA)
misincorporated into DNA instead of cytosine nucleotides
FTC-TP lacks a 3’ hydroxyl group and so this stops the attachment of additional nucleosides into the chain preventing viral replications
terminates chain
what is Tenofovir
also a reverse transcriptase inhibitor
similar to emticitabine but incorporated instead of adenine
does not have an effect on already infected cells
has a phosphate group so only requires disphosphorylation to become active aka 2 rounds
Raltegravir mechanism of action
when reverse transcriptase enzymes converts viral RNA to DNA, virus tries to integrate this with host genome
viral integrase enzymes cut host genome
integrase incorporates HIV DNA into host genome, allowing production of new viral proteins
Raltegravir simply acts to inhibit the viral Integrase enzymes
current phase 3 trials for HIV treatment
into long-acting antiretroviral therapies (LA-ART) with a single-dose every one to three months
One new LA-ART is cabotegravir, a highly potent integrase inhibitor, with a T1/2 of up to 54 days
what is cabotegravir
long-acting antiretroviral therapy (LA-ART)
highly potent integrase inhibitor
T1/2 of up to 54 days
given as a nanosuspension injection
what is a nanosuspension injection
A suspension of drugs within the nanoparticle size range which are normally poorly soluble in water
what is Cabotegravir being trialled in combination with nanosuspension with
rilpivirine, a long-acting reverse transcriptase inhibitor
what is rilpivirine
a long-acting reverse transcriptase inhibitor
what is abacavir
used in combination with other antiretroviral therapy for HIV infection
reverse transcriptase inhibitor and so similar to emtricitabine and tenofovir
hypersensitivity reactions have been observed in 5-8% of abacavir-treated patients
what are the symptoms of a hypersenstivity reaction (5)
Skin rash, fever, malaise, gastrointestinal symptoms and respiratory symptoms
in hypersensitivity reactions, what does severe skin rash result in (3)
systemic lupus erthematosus
stevens-johnson syndrome
toxic epidermal necrolysis
what is Human leukocyte antigen (HLA)-B*5701
an allele more common in those who are suspected to have a hypersensitivity reaction to abacavir compared to those who dont
what allele is more common in those who are suspected to have a hypersensitivity reaction to abacavir compared to those who dont
Human leukocyte antigen (HLA)-B*5701
what is HLA 3
gene complex encoding major histocompatibility complex (MHC) in humans
cell surface proteins
responsible for regulation of immune system
what is the MHC major histocompatibility compex
Depending on the specific MHC, it may present antigens to the immune system
allows immune cells e.g. CD4 to hunt for and destroy these antigens
how is HLA-B*5701 identified in patients
before treatment or if restarting treatment and HLA-B*5701 status not known
by taking a blood or saliva sample, PCR amplifying the gene and sequencing the HLA-B gene
what is EBT-101
CRISPR-based therapeutic candidate in development as a potential functional cure for chronic HIV
what is CRISPR (clustered regularly interspaced short palindromic repeats)
is based on a system from bacteria which is used to protect them from viral infection
EBT-101 mechanism of action
bacteria detects viral DNA
produces two short RNA strands called guide RNA
gRNA contains sequence that matches invading virus
two RNA strands then form complex with Cas9
nuclease, enzyme that cuts DNA
Cas9 cuts invading virus DNA and disables virus from replicating
what is Cas9
nuclease
what is a nuclease
enzyme which cuts DNA
how is EBT-101 administered
a one-time dose using an adeno-associated virus (AAV)
AAV delivers CRISPR-Cas9 and two gRNAs
targets 3 sites in HIV genome
excises large portions of HIV genome
removes HIV proviral DNA
how many subtypes of HPV exist
over 120
when does aciclovir work
before forming scab
how many worldwide live with HIV/AIDS
33 million
genital warts are also known as ___ ____
condylomata acuminata (CA)
therapy for genital warts
pt specific, no definitive first line
imiquimod is available as a cream in ___% and ___%
3.75
5
imiquimod cream side effects include
ulceration, muscle aches
imiquimod cream wart clearance rate at 5%
56%
interferons
last resort therapy as needs local anaesthesia and is expensive
systemic wart treatment, interferes with viral replication
recent development
injected, conflicting studies on effectiveness
phodophyllotoxin is administered as a
cream/ gel/ solution
phodophyllotoxin works within ____ days
3-5 post admin
side effects of phodophyllotoxin
inflammation, erosion, itching
gardasil vaccine is admin as
intramuscular injection
3 doses
gardasil vaccine is ___% effective
99
no long term evidence of waning immunity over time
cervarix vaccine
hpv 16,18 - responsible for 70% of cervical cancers
stimulates immune response as contains VLP virus like particles of HPV that mimic outer shell of virus, but do not contain viral DNA
body creates antiboidies that protect against VLPs, and if needed, actual HPV as immunity is long term built
3 injection dose
high efficacy esp, generally no side effects
LA-ART - ___ in HIV-linked mortality rates
sig. reduction
rilpivirine is administered at
oral dose of 25mg once daily
rilpivirine animal studies
in rats and dogs, 100% bioavailability
carbotegravir is a
HIV-1 integrase strand transfer inhibitor
carbotegravir is administered at
200 mg/ml PrEP
ibalizumab
in development trial phase 2
intravenous infusion every 2-4 weeks
atazanivir
in pre clinical rodent/ mammal testing stage
protease inhibitor
dapivirine PrEP study - antiretroviral therapy
vaginal ring, releases antiretroviral drug dapivirine over time to prevent HIV- long acting microbicide
well tolerated with a favourable safety profile and reduced HIV-1 incidence by 31% vs placebo in one study
mechanism:
dapivirine is an NNRTI non-nucleoside reverse transcriptase inhibitor, inhibits reverse transcriptase stage in HIV cycle
local protection via ring
designed to be replaced monthly
in clinical trials but approved for use in some countries - not UK
shit to do with viral that u gots to treat (4)
HPV - wart treatment also HPV can cause cancer
Herpes - HSV- 1 , HSV-2 (both cause gential herpes), epstein barr, varicella-zoster
we dont care abt treating it but abacavir + HLAB701 allele - hypersensitivity reactions whihc can worsen to systemic lupus erthematosus, stevens-johnson syndrome, toxic epidermal necrolysis
HIV
all the old/ current meds (9)
HPV: imiquimod, podophyllotoxin (warts) gardasil vaccine
Herpes: aciclovir
HIV: Pre-exposure prophylaxis (PrEP) - Emtricitabine & Tenofovir
Post-exposure prophylaxis (PEP) - Emtricitabine, Tenofovir & Raltegravir
new/ developing shit - 6
HPV: cervarix vaccine
HIV: atazanivir, LA-ART carbotegravir with aciclovir or raltegravir, dapivirine, new but used EBT-101
Herpes: potentially EBT 101, charcoal drug delivery topical, vaccines not yet successful
