HIV Flashcards
What are the structural genes in HIV? Which is sequenced for resistance testing? Which encodes gp41 and gp120? Which encodes the core and matrix proteins?
gag, pol and env
pol encodes the RT, integrase, and protease
env encodes the surface glycoproteins
gag encodes core and matrix
What are the receptors for HIV?
gp120 binds to CD4 and uses CCR5 as a co-receptor (or CXCR4 in later infection)
What is the epidemic strain of HIV?
HIV-1, group M. Sub-type B (historically in MSM)
What percentage of patients will have HIV meningitis at seroconversion?
5-10% (or up to 30% in some papers)
What is the window period for HIV-1 in 4th generation assays?
45 days
What is the window period for HIV-1 in Western Blot?
90 days
Which HIV-2 bands are present on the BioRad Geenius?
Only envelope bands - gp36 and gp140
What bands are present in an HIV-1 Western blot?
env = gp160 (precursor), gp120, gp41
gag = p55 (precursor), p24 (core), matrix (p17), nucleocapsid (p15)
pol = p66 and p51 (RT) and p31 endonuclease
Which bands on the WB come up the earliest, and which the latest?
p24 and p55 (it’s precursor) come up earliest
p31 comes up latest (Fiebig lab stage 6)
What is the conversion of HIV copies/ml to IU/ml
Around 0.6 copies = 1 IU but it is assay dependent
Name some commonly used NRTIs
Zidovudine, emtricitibine, abacavir, lamivudine, TDF, TAF
Name some commonly used NNRTIs
Doravirine, efavirenz, neviripine, rilpirivine
How are integrase inhibitors and protease inhibitors identified by their names?
Integrase strand transfer inhibitors = -gravir
Protease inhibitors = - navir
What are HIV ‘booster drugs’? Give two examples
Used at subtherapeutic doses to inhibit cytochrome P450 (CYP3A) and increase half life
Cobicistat and ritonavir
Which drug is a CCR5 inhibitor? What testing is needed before this is prescribed? What would make CCR5 inhibitors ineffective?
Miraviroc
Testing is performed to see if HIV is CCR5 tropic (performed on whole blood - sequencing V3 loop)
If CXCR4 or dual tropic, miraviroc is not indicated
Name examples of HIV - fusion inhibitors, attachment inhibitors, post-attachment inhibitors, capsid inhibitors
Enfuvirtide
Fostemsavir
Ibalizumab
Lenacapavir
What HIV drugs are available as long acting injectables?
How often is it given?
How often do you need to have VLs?
What genotype is contraindicated?
Cabotegravir and rilpivirine
Injection every 8 weeks and VL every 8 weeks
Not for use in A1/6 genotype
Cabotegravir is an analogue of dolutegravir
What are first line treatments for HIV?
Bictegravir/emtricitibine/TAF
Dolutegravir/emtricitibine/TDF or TAF
Dolutegravir/lamivudine/abacavir
Dolutegravir/lamivudine (not if HBV)
Which class of HIV drug have the lowest and highest barrier to resistance?
Lowest = NNRTIs (only require 1 or 2 mutations)
Highest = Boosted PIs
What region of the genome is sequenced for drug resistance?
pol (RT and protease at baseline)
When is integrase resistance tested for?
When any mutation in other drug classes
Diagnosed in pregnancy
?transmitted INSTI resistance
Failing on INSTI treatment
What is defined as HIV virological failure?
<1 log reduction in VL after 4 weeks
> 200 copies/ml on two samples
What database is used for cumulative resistance reports?
Stanford Database
What level of HIV resistance mutation can Sanger and NGS detected?
20-25%
0.1-1%
What are HIV TAMs?
Thymidine Analogue Mutations - mainly affects AZT but accumulation of TAMs causes increased resistance to NRTIs
In elite controllers who are not on cART, how often do they require monitoring and what tests are performed?
6 monthly VL, CD4, CD4:CD8 ratio, clinical assessment
What additional test is required if abacavir is being considered?
HLA B*5701 (only give abacavir in neg patients due to risk of hypersensitivity)
Would the following receive PEPSE?
1) Unknown HIV status, high risk group
- receptive anal sex
- insertive anal sex
- vaginal sex
2) HIV positive - detectable or unknown VL
- receptive anal sex
- insertive anal sex
- receptive vaginal sex
- insertive vaginal sex
3) HIV positive - undetectable VL on cART for >6m
1)
- Give PEP
- Consider PEP
- Generally not recommended
2)
- Give PEP
- Give PEP
- Give PEP
- Consider PEP
3) No PEP
What is the risk of HIV acquisition from a) penetrative sharps injury b) splash injury from an HIV patient with detectable VL
a) 0.3%
b) 0.1%
Would the following receive PEP in sharps/splash injury?
1) Unknown HIV status, high risk group
2) HIV positive - detectable VL or not suppressed for >6 m
3) HIV positive - undetectable VL on cART for >6m
4) NSI in community
1) Generally not recommended
2) Give PEP
3) No PEP (but can consider)
4) No PEP (if freshly discarded needle, can consider)
Would the following receive PEP?
1) HIV positive - detectable VL - spitting exposure
2) HIV positive - undetectable VL - bite exposure
3) HIV positive - detectable VL - bite exposure
1) No PEP (no risk)
2) Generally not recommended (risk negligible)
3) Generally not recommended but can consider if:
- visible blood in saliva
- VL >log 3
- severe/deep injury
Would the following receive PEP following shared injecting drug use?
1) Unknown HIV status, high risk group
2) HIV positive - detectable VL
3) HIV positive - undetectable VL for >6 m
1) Generally not recommended (but consider local outbreaks)
2) Give PEP
3) No PEP
What is prescribed for HIV PEP? When to start? Duration of course?
TDF/emtricitibine/raltegravir
Start asap, ideally within 24 h (can consider up to 72 h)
28 days
What baseline testing is performed when receiving PEP?
What testing is performed for follow up and when?
Kidney function
ALT
HBV
HIV
+/- pregnancy test, syphilis, HCV
Follow up with 4th gen assay at 45 days post stopping PEP
What antivirals are used for PrEP?
Tenofovir and emtricitibine (TDF can be used alone in heterosexuals if emtricitibine contraindicated)
*note PrEP in HBV needs specialist input re: starting and stopping
When can PrEP be used as:
1) On demand
2) Daily
1) MSM only - double dose 2-24 h before sex and daily until 48 h after last risk (rectal tissue protection)
2) Vaginal sex - daily 7 d before to 7 d after risk (as vaginal protection takes longer)
Requires at least 4 doses per week
What baseline testing is performed when receiving PrEP?
What monitoring is required?
What testing is required after stopping?
4th gen HIV test (or VL if risk in the last 4-6 weeks)
HBV/HCV/STI
Renal function
HIV test every 3 months - 4th gen or POC
STI test every 3 months
Renal function
HIV test at 45 d post stopping
What is cabotegravir?
What is lenacapavir?
How can they be used in PrEP?
Cabotegravir is an INSTI, injection every 8 weeks, being assessed for use as PrEP. Currently used as an injectable with rilpivirine for treatment.
Lenacapavir is a capsid inhibitor, injection every 6 months, PURPOSE-1 trial demonstrated zero new infections
What is first line for treatment in pregnant patients? (if not already on cART)
When would an INSTI be used?
First line = TDF/emtricitibine/efavarenz
Needs 2x NRTI (tenofovir/emtricitibine or abacavir/lamivudine) and efavirenz/raltegravir/dolutegravir/ritonavir boosted duranavir
Add INSTI if high VL or not suppressing (as works quickly)
When should ART be started in pregnancy? When is VL testing required?
Asap, but by 24 weeks of pregnancy at the latest
VL testing every 2 months, at 36 weeks and at delivery
What birth plan would be made for a pregnant woman at 36 w with:
a) VL <50
b) VL >400
a) vaginal birth
b) c-section
What ART is given to a women presenting in labour with HIV?
Zidovudine/lamivudine/raltegravir
At labour, preload foetus with:
IV zidovudine for duration of labour
Oral nevirapine
Add in oral double dose of TDF if preterm
How to manage a pregnant woman with a VL >50 at delivery?
Optimise regimen - consider 4 drug regimen, include dolutegravir
Oral nevirapine and double dose TDF
Add in IV zidovudine if VL >1000 cp/ml (can consider in 50-1000 cp/ml)
When should PEP start post birth?
Within 4 hours
In HIV, how are infants designated as, and PEP’d in:
1) Very low risk
2) Low risk
3) High risk
1)
- Baby born at >34 w
- ART >= 10 weeks prior to delivery
- <50 cp/ml x2 at least 4 weeks apart
- <50 cp/ml at 36 w
2 weeks oral zidovudine (even if resistance known)
2)
- Baby born <34 w
- Doesn’t fit above but <50 cp/ml at 36 w
4 weeks oral zidovudine (even if resistance known)
3) Doesn’t fit above
4 weeks zidovudine, lamivudine and neviripine (or raltegravir if HIV-2)
What testing is performed in infants born to mother’s with HIV if:
a) Breastfed
b) non breastfed
a) VL -
Within 48 h of birth
Prior to discharge
At 2 weeks
Monthly whilst breastfed (for mum too)
4-8 weeks post stopping breastfeeding
Ab test at 24 m
b) VL -
Within 48 h of birth
Prior to discharge
At 2 weeks (ONLY IF HIGH RISK)
At 6 weeks (at least 2 weeks post stopping PEP)
At 12 weeks (at least 8 weeks post stopping PEP
Ab test at 24 m
What are the requirements for EPP clearance in HIV?
How often do patients get VL monitoring?
Must be engaged in care
On cART = 2x IVS 12-14 weeks apart with HIV VL <200 cp/ml
Elite controller = undetectable VL for >12 months with at least 3 separate VLs
Monitoring every 12 weeks
Workers with VL 50-200 cp/ml will be reviewed on a case by case basis
If a HCW with HIV is cleared for EPP, what would happen at the following VL at 12 week monitoring test?
a) <50 cp/ml
b) 50-200 cp/ml
c) 200-1000 cp/ml
d) >1000 cp/ml
a) No action. Retest in 12 w
b) Case by case approach based on clinical judgement
c) Repeat test in 10 d
d) Cease EPP immediately, repeat test in 10 d (if >1000 cp/ml full risk assessment and PH intervention)
What is the window period for HIV-2?
90 d (as 4th gen assay is essentially Ab only assay for HIV-2)
What commercial assay is available for qualitative HIV-1/2 RT-PCR?
cobas (Roche)
What should be the approach if HIV-1 and HIV-2 antibodies are detected on confirmatory Ab test?
Possibly dual infection
Possibly cross-reactive Ab
Ideally would test for HIV-2 by WB however not available in UK
Test for HIV-2 VL - however if negative (remember 25-40% of people are undetectable without ART) then proviral DNA testing
Which HIV drugs is HIV-2 intrinsically resistant to?
NNRTIs - due to differing structure of the NNRTI binding pocket
The fusion inhibitor enfuvirtide
First line treatment for HIV-2 infection?
TDF/emtricitibine/dolutegravir or r/darunavir
What is the risk of vertical HIV-2 transmission?
<4%
Are recombination events common in a) HIV-1 b) HIV-2
a) very common
b) rare
Which ART should be used in pregnancy for HIV1?
- If already on ART then this should be continued
- Ideal first regime
– TDS/ABC
with 3TC/FTC
And Efavirenz or r/atazanavir or dolutegravir if >6/40
Mum is taking dtg 400mg as part of her ART. What advice should she be given?
Take supplemental 5mg folic acid
Management of HIV positive untreated mum who presents at labour?
Stat - nevirapine 200mg
Oral AZT (zidovudine) and lamivudine (3TC)
Oral raltegravir
IV zidovudine for duration of labour
A woman requires an invasive diagnostic procedure during pregnancy and isn’t on HIV ART. What should be done?
If possible delay until good viral suppression has been achieved.
If not the patient should commence ART which includes raltegravir and be given a single dose of nevirapine 2-4 hours pre procedure.
Well controlled HIV in preg. <50 at 36/40. What delivery method?
Normal birth
HIV viral load >50 at 36 weeks. Whatdelivery method
Pre labour c section
HIV in pregnancy - Who should receive IV zidovudine?
Untreated mums in labour (i.e. unknown viral load)
Viral load >1000
“consider if 50-1000”
HIV in pregnancy
- HIV very low risk neonate. Definition and management?
Mum on ART for >10 weeks and 2 viral loads <50, at least 4 weeks apart, one of which is at or after 36 weeks
Management - 14 days AZT
HIV in pregnancy
- HIV low risk neonate. Definition and management?
Mum on ART for >10 weeks and maternal viral load is <50 after 36 weeks (but not on two occasions)
Or if baby born <34 weeks but most recent viral load <50
Management - 28 days AZT
HIV in pregnancy
- HIV high risk neonate. Definition and management?
Most recent viral load >50
Combination PEP advise
- Lamivudine (NRTI)
- Nevirapine (NNRTI)
- Zidovudine (NRTI)
Additional medication given to HIV pos mums who are not breastfeeding?
Cabergoline - suppresses lactation
Post natal testing of baby born to HIV pos mum who is not breastfeeding?
PCR at birth, 6 weeks, 12 weeks
Ag/ab test at 22 months (to demonstrate loss of maternal ab)
Post natal testing of baby born to HIV pos mum who is breastfeeding?
HIV PCR – at birth, 2 weeks, then monthly whist breastfeeding. Then 4 and 8 weeks after cessation of breastfeeding.
Ag/ab testing at 22 months or minimum of 8 weeks after stopping breast feeding, which ever is later
Risk of postnatal acquisition of HIV due to breast feeding in well controlled patient with HIV.
Risk of breast feeding in mum on cART is 0.3% at 6 months and 0.6% at 12 months
NB higher risk if extreme prematurity due to leaky gut.
HIV 2 PEP for high risk baby born to hiv pos mum?
zidovudine, lamivudine and raltegravir
HIV PEP - First line treatment?
TDF/FTC + raltegravir 1200mg OD (400mg BD in pregnant women)
HIV PEP - definite indications for giving?
Sexual
- Receptive anal intercourse with someone of unknown HIV status or HIV pos with unknown or detectable HIV viral load
- Receptive vaginal intercourse with someone of unknown HIV status or HIV pos with unknown or detectable HIV viral load
Occupational exposure
– Sharps injury or mucosal splash from someone with a detectable or unknown HIV viral load
Other
- People sharing drug injecting equipment if the index partner is known to be HIV pos with unknown or detectable HIV viral load
HIV PEP - baseline bloods
Creatinine
ALT
HBsAb, HBsAg, HBcAb
Hep C
HIV Ag/Ab
HIV PEP followup
HIV Ag/Ab - min 45 days after finishing PEP
Patient on PrEP who has had unprotected receptive anal sex with UK MSM. When should they get PEP?
Anal – for continuous PrEP where fewer than 4 pills taken in the prior 7 days or when on event based PEP where PrEP has not been taken as recommended
Patient on PrEP who has had unprotected receptive vaginal sex with person with known HIV and a viral load of >200. When should they get PEP?
PEP should be considered if >48h have elapsed since last dosing or one missed dose in the last 7 days
Vaccines contraindicated in HIV?
Absolute
- BCG
- Live typhoid
Consider only if CD4 >200
- Typhoid
- Small pox
- Live VZV (CP or shingles)
- Yellow fever
- MMR
Bands on Geenius
HIV 2
–Gp 36
–Gp 140
HIV 1
–Gp 31
–Gp 160
—-Cleaves to make gp 120 and gp 41
–P24
–Gp 41
Window period for 50th and 99th percentile for HIV 4th gen ag/ab test
45 and 90 days
Common HIV resistance mutations?
M184V - Resistance to lamivudine and emtricitabine
Hypersusceptibility to TDF/AZT
Plus viral fitness cost leads to around 0.5 log fall in viraemia
K65R - TDF resistance with cross resistance to abacavir and lamivudine
Hypersusceptibility to AZT
E138K - Rilpivirine - often seen alongside M184V/I and restores the viral fittness lost with that mutation
K103N - Efanvirenz and nevirapine resistance
HIV - K103N
Efanvirenz and nevirapine resistance
HIV - E138K
Rilpivirine - often seen alongside M184V/I and restores the viral fittness lost with that mutation
HIV - K65R
DF resistance with cross resistance to abacavir and lamivudine
Hypersusceptibility to AZT
HIV - M184V
Resistance to lamivudine and emtricitabine
Hypersusceptibility to TDF/AZT
Plus viral fitness cost leads to around 0.5 log fall in viraemia
HIV viral life cycle
Binding – gp120 binds either CXCR4 or CCR5
Fusion – gp41 binds heparan sulfate on cell plasma membrane and triggers fusion of the viral envelope
Reverse transcription – viral RNA released into cytoplasm following release from the capsid. Viral RNA reverse transcribed into cDNA by RT.
Integration – viral DNA is transported to the nucleus and randomly inserts into host genome – catalysed by the viral enzyme integrase
Replication – viral proteins are made. Several viral pre-proteins are made which are later cleaved in the maturation step to make smaller proteins. This is where protease drugs work. NB – gp120 and gp140 are cleaved from the bigger protein gp160. Gp160 and gp41 are both in the Geenius HIV1/2 biospot. Core proteins are initially translated into pr55 which is then cleaved to make p24 amongst others.
Assembly – Larger proteins migrate to the cell surface and implant into the plasma membrane to form the viral envelope. At this stage the virion is not infectious as the larger proteins have not yet been cleaved into functional proteins.
Budding – the virion crosses the plasma membrane to get is lipid envelope. The Gag proteins, along with the viral RNA and other enzymes, assemble at the inner surface of the host cell’s plasma membrane. The Gag proteins form a lattice-like structure that encapsulates the viral RNA and enzymes, creating a spherical core that will become the mature virion.
Maturation -The viral protease enzyme (which was packaged inside the virion during assembly) cleaves the Gag and Gag-Pol precursor proteins into smaller, functional pieces. This cleavage leads to the rearrangement of the viral proteins, which causes the virion to mature into a fully infectious form. Larger proteins are cleaved into smaller ones. This is where protease drugs work. NB – gp120 and gp140 are cleaved from the bigger protein gp160. Gp160 and gp41 are both in the Geenius HIV1/2 biospot. Core proteins are initially translated into pr55 which is then cleaved to make p24 amongst others.
When should cART be initiated after treatment for opportunistic infection?
2 weeks post treatment of OI
When does IRIS most commonly occur?
What is a risk factor for IRIS?
What should be monitored in patients co-infected with HIV and HBV/HCV when initiating cART
4-8 weeks post initiating treatment (within 2 days to 1 year)
Low CD4 count
Monitor ALT for flares
What drug should HIV treatment include in HBV co-infected patients?
Tenofovir
