HIV Flashcards
where is the highest HIV/AIDS population
sub-Saharan Africa
initial risk groups
-men who have sex with men (MSM) (account for most)
-injecting drug users
- recipient of blood products
what is HIV
human Immunodeficiency Virus
-an RNA virus which has to recode itself into a double stranded DNA to insert into a host DNA
how does HIV replicate
convert their genetic material into host genetic material via reverse transcription by viral enzyme reverse transcriptase
what is AIDS
Acquired Immune Deficiency Syndrome
- observed as Pneumocystis jiroveci (PCP) infection in homosexual men & injecting drug users
what is PCP
-rare opportunistic infection which occurs in immune compromised pts
what happens if HIV is left untreated
AIDS
what is HIV-2
- has five phylogenetically distinct forms most common in west Africa
- subtypes less virulent and transmissible in humans
what is HIV 1
-most commonly referred to when talking about HIV
- has 4 groups: MNOP, which represent Simian Immunodeficiency Virus (SIV) into humans
what is group M of HIV1
- Has 9 genetic sub types (clades)
-subtype C most common as it accounts for more than 55% of HIV1 infections
what is circulating recombinant forms (CRFs)
- 2 subtypes meet in same host cell & share genetic code ….. most dont survive
e.g. CFR A/E = A and a parent subtype E (not a pure E subtype)
can someone be infected with multiple distinct HIV1 strains
yes…… reported cases of people co- infected with 2+ strains
simultaneously before their immune system could react
what is the structure of HIV
-fatty membrane with 72 protein spikes made up of gp41(mediates fusion between viral and cellular membranes) and gp120 (for movement to bind to target cell)
-2 identical strands of RNA and reverse transcriptase, integrase and protease for replication
how does HIV replicate
- once in cell, gp120 binds to CD4 (found on T cell surface) receptors on host cells
- Gp120 conformational change = bind to a chemokine co-receptor (CCR5 on macrophages or CXCR4 on T helper cells)
- GP41 interacts with the host cell & fuse HIV particle to host
- HIV RNA and replication enzymes enter cell
- viral reverse transcriptase converts RNA to DNA in host cytoplasm
- viral DNA moves into host cell nuclues and becomes part of host DNA = Provirus & viral integrase facilitates this
- messenger RNA produced and host mRNA is used to produce viral proteins/ enzymes (translation)
- precursor proteins from immature core cut into smaller functional proteins by viral protease= viral particle
- viral particle leaves cell and is released into blood
what is the name of drugs that work at the stage of Gp120 conformational change
entry inhibitors
what is the name of drugs that work at the sage of HIV RNA in host and give examples
fusion inhibitors e.g. Enfuvirtide
what drugs target convertion of RNA to DNA process
Nucleoside non-nucleoside reverse transcriptase inhibitors
what drugs target integration of HIV DNA with host DNA (think enzyme involved here) & give examples
Integrase inhibitors:
Bictegravir
Cabotegravir
Dolutegravir
Elvitegravir
Raltegravir
what drugs are involved in final process of HIV replication (think of protein + enzymes involved) and give examples
Protease inhibitors:
Atazanavir
Darunavir
Lopinavir
Ritonavir
Tipranavir
what are the 4 categorise in HIV testing
-Third generation tests
- Fourth generation tests
- Rapid HIV tests
- Polymerase Chain Reaction (PCR) Tests
what are 3rd generation tests
-enzyme linked immunosorbent assay (ELISA) antibody test
-inexpensive, accurate and very sensitive
- disad: only become accurate after 12 weeks as takes a person 6-12 weeks to raise antibodies against HIV
-
what are 4th generation tests
-ELISA to detect antibodies and p24 antigens
- detect 1 month post exposure and possibly 11 days post
-BASHH recommend this for anyone presenting for test 4 weeks post exposure
- 4 week post exposure follow up recommended because highly infectious in 1st few weeks
-
what are self testing kits
- work as ELISA tests
-e.g. OraQuick HIV-1 and HIV-2 rapid test kit
-results in 20mins
-use blood or oral fluids sample
-positive results = confirmatory stands ELISA test
what are Polymerase Chain Reaction (PCR)
-detects HIV genetic material
-identify HIV in blood samples within 2-3 weeks of infection
-usually used for babies born to mothers with HIV because have maternal HIV antibodies for several months after birth= false positive ELISA test
-expensive & require training
how often are Gay, bisexual and other men who have sex with men are advised to test
every 3 months or if having sex with new partner
what does HIV actually do
-attacks the immune system by destroying CD4 positive T cell (CD4 cells)
-CD4 cells co-ordinate immune responses…. destruction = vulnerable to opportunistic infections + other complications
which 2 parameters used to monitor progression
-CD4 cell count: for the health of an individual’s immune system. normal= 800 and 1500 cells/µl.
-viral load: measure of plasma HIV RNA
HIGH CD4 = LOW viral load
what are the 3 clinical presentations of HIV
primary HIV infection, chronic HIV infection and AIDS.
what happens during the primary infection
-dynamic equilibrium between virus replication and its destruction by the immune system
- viral load increase in first few months and then decreases = highly infectious
-very few symptoms
-Seroconversion (loss of antibody detectability) illness = recognisable symptoms in first 2 months
- symptoms disappear within couple weeks, when HIV antibodies start being produced by Bcells
-symptoms mistaken for flu
what are the symptoms of primary HIV infection
Rash
Fever
Weight loss
Persistent lymphadenopathy
Diarrhoea for longer than four days
Malaise
Headaches
what happens in chronic HIV
-remain asymptomatic for while before progression
-after diagnosis… CD4 count and viral count monitored to determine severity
what are the non- specific symptoms of HIV
Rapid weight loss
Recurring fever
Profuse night sweats
Prolonged swelling of the lymph
glands
Immunosuppression related
conditions
what happens in diagnosis of AIDS
-HIV infected person presents with one or more AIDS defining illnesses (opportunistic infections and
malignancies) because destruction the immune system, and prevention of normal immune
responses
- CD4 count below 200 cells/µl
give examples of AIDS defining illnesses
Cryptococcal meningitis
Cytomegalovirus disease
Mycobaterium avium complex (MAC)
Pneumocystis pneumonia (PCP)
Progressive multifocal leucoencephalopathy
(PML)
Toxoplasmosis encephalitis
Tuberculosis
Cervical cancer
Kaposi’s sarcoma
Non-Hodgkin’s lymphoma
Primary cerebral lymphoma
what are the HIV treatment goals as they do no cure it
-Prevention of morbidity and mortality associated with HIV
- Improving physical and psychological well-being of a person living with HIV (PLWH)
- Prevention of onward sexual transmission to others
- Prevention of maternal transmission (where applicable)
- Restoring or maintaining immune function
what is the choice of drug based on
-likelihood of success against the current viral strain
-tolerability
-likelihood of patients to adhere
how does point at which treatment is started affect life expectancy
-starting late can cause up to 15 years of reduced life expectancy
when should Antiretrovirals (ART) be started
- on day of diagnosis
-if presenting with AIDS defining illness or other serious bacterial infection with a CD4 count ≤200cells/μL
=ART 2 weeks after antibacterial chemo
what to screen before ART regimen
-HIV resistance
-Hepatitis B and C co-infection
- Cardiovascular risk
- Diabetes
- Renal problems
- Psychiatric problems
- Alcohol use
- Recreational drug use
what are the 4 possible combination first line drugs in ART
-Tenofovir/emtricitabine (Truvad or Descovy) with dolutegravir (Tvicay) – two tablets daily
-Abacavir/lavivudine/dolutegravir (Triumeq) – one tablet daily
- Tenofovir/emtricitabine/bictegravir (Biktarvy) – one tablet daily
-Doutegravir/lamivudine (Dovato) – one tablet daily
when should you change ART regimens
when viral load starts to increase…. shows resistance
what are the main problems with HAART regimen (highly active antiretroviral therapy)
- life long
-side effects
-compliance issues
-poor penetration into brain = local proliferation of virus
give examples of Nucleoside
reverse transcriptase inhibitors (NRTIs)
Abacavir
Darunavir
Emtricitabine
Lamivudine
Tenofovir
Zidovudine
give examples of Non-nucleoside
reverse transcriptase inhbitors
(NNRTIs)
Doravirine
Efavirenz
Etravirine
Nevirapine
Rilpivirine
what is the MOA of NRITS
-become incorporated into viral DNA = act as chain terminators in HIV reverse transcriptase reaction
- dideoxy-nucloside analogues which lack a second hydroxyl group = essential addition of subsequent bases for DNA elongation
-inhibit HIV-1, HIV-2,human T-cell leukaemia/lymphoma
what is the MOA of NNRITS
- bind at a different site on reverse transcriptase and inhibit the
movement of protein domains necessary for DNA synthesis
-non-competitive inhibitors
of reverse transcriptase
what are two mechanisms of NRTI resistances
-increased drug discrimination: active site amino acid changes = decreased affinity of enzyme for drug
- increased rate of primer unblocking AKA offloading: combination of amino acid changes= removal of the chain terminator and replacement with a natural nucleoside (pyrophosphorylysis)
what do NRTIS use for activation and causes toxicity & which drug least toxic
-use cellular rather than viral enzymes for activation to the triphosphate form
-toxicity due to the inhibition of mitochondrial DNA polymerase by the triphosphates
-Lamivudine least toxic
Side effects of NRTIs
-GI disturbances (nausea, vomiting, abdominal pain, flatulence, diarrhoea)
-Anorexia
- Pancreatitis
- Liver damage (hepatomegaly with hepatic steatosis)
- Lactic acidosis
- Dyspnoea
- Cough
- Headache
-Insomnia, dizziness, fatigue,
- Blood disorders (anaemia, neutropenia, thrombocytopenia)
- Myalgia, arthralgia
- Rash, urticaria
- Fever
- Fatal hypersensitivity (with abacavir)
side effects of NNRTIs
-rash within first 2 weeks of treatment (6 weeks for nevirapine)
-rash more common in women with etravirine & this drug can cause severe hypersensitivity reactions
-Potentially life-threatening hepatotoxicity in first 6 weeks of treatment with nevirapine= monitor liver function
-suicidal ideation, psychosis and severe depression with Efavirenz
MOA for protease inhibitors
-prevent the release of the mature infectious virus particle from the host cell
-competitively inhibit or reduce the activity of viral protease resulting in the production of inactive viral proteins
-prevents the maturation of virioins infecting other cells
-used in HIV1 AND 2
what causes resistance to protease inhibitors
-use as single agents in the treatment of HIV
side effects of protease inhibitors
-same as NNRTIs and NRTIs
-also associated with hyperglycaemia = used with caution in diabetics
interaction of protease inhibitors
-may be both inhibitors and inducers of CYP450…. combined use with ritonavir = change degree of inhibition/ induction
- monitor use with drugs that are affected by CYP450 conc changes
MOA of fusion inhibitors
-interacts with the viral surface glycoprotein gp41= prevent fusion of viral and host cell membranes
-Enfuvirtide 36 amino acid peptide…. structurally very similar to gp41 segment
-administered by sub-cutaneous (BD)
-Enfuvirtide only licensed to treat resistant HIV infection in combination to other ARTs or for pts intolerant to other ARTs
key counselling point for enfuvirtide
-how to recognize the signs and symptoms of a hypersensitivity reaction & to seek medication attention if so.
Integrase inhibitors MOA
- inhibit integrase, which stitches HIV DNA into the host cell’s DNA
-integrase attractive target for therapy because no similar enzyme in human cells
CCR5 inhibitors MOA e.g. maraviroc
-only one licensed drug in this class
-used in combination with other antiretrovirals in pts previously with ARTs
-blocks the activity of the co-receptor CCR5 on macrophages
-need for tropism assay to determine whether the infection is CCR5-trophic before treatment can be initiated
examples of combination products
-Kaletra: Lopinivir/ritonavir
-Kivexa: Abacavir/lamivudine
-Truvada: Emtricitabine/tenofovir disoproxil
-Atripla: Tenofovir disoproxil/emtricitabine/efavirenz
-Eviplera: Tenofovir disoproxil/emtricitabine/rilpivirine
-Stribild: Tenofovir disoproxil/emtricitabine/elvitegravir/cobicistat
-Combivir: Zidovudine/lamivudine
-Trizivir Dascovy Genvoya
Odefsey:
Abacavir/lamivudine/zidovudine Emtricitabine/ tenofovir
alafenamide
Tenofovir alafenamide/ emtricitabine/elvitegravir/cobicistat
what are injectable long-acting treatments 2022 & who is it recommended for
-cabotegravir and rilpivirine (given as two separate injections every two months)
-recommended for pts with virological suppression (HIV-1 RNA fewer than 50 copies/mL)
-must be on stable antiretroviral regimen and without viral resistance & no previous virological failure with any NNRTIs or integrase inhibitors
PK of Zidovudine
- given Oral/ IV with half life of 1hr
-Metabolized to inactive glucuronide in
liver
-20% active form excreted in urine
PK of didanosine
- oral
- half life of 1.5hrs
-Renal clearance by glomerular filtration and active tubular secretion - 20% of active form excreted in urine
PK of Emtricitabine
-Excreted largely unchanged in urine (some in faeces)
-half life of 10hrs
PK of Lamivudine
-Excreted mainly unchanged by active renal secretion
- 5-7hrs
PK of Stavudine
-Renal clearance by glomerular filtration
and active tubular secretion
- half life 1-1.5hrs
PK of Abacavir
- half life 1.5hrs
- Hepatic metabolism primarily by alcohol dehydrogenase and by glucuronidation
-metabolites excreted in urine
PK of Efavirenz
- half life 52-76 hrs
- 14 to 34% of a dose is excreted in the
urine
-most excreted in faeces
PK of Nevirapine
- half like 45 hours (after single dose)
- Excreted in urine as glucuronide conjugates of the hydroxylated metabolites
PK of rilpivirine
-45 hours half life
-Primarily metabolized and eliminated in Liver
- 25% in excreted unchanged in the faeces
pk of protease inhibitors
-mainly eliminated in faeces as metabolites
