HIV Flashcards
Pathogenesis of HIV-1 infection
HIV-1 infection –> enters and replicates in CD4+ cells i.e. helper T lymphocytes –> infected CD4+ cells are recognised and attacked by CD8 (cytotoxic) cells –> progressive loss of CD4+ T cells –> AIDS
Typical course of HIV-1 infection
1) Acute HIV syndrome
- HIV viral load spikes
- CD4+ dips (killing of CD4+ cells by CD8+ cytotoxic cells = seroconversion illness)
- B lymphocytes also make ab to HIV (seroconversion illness)
2) Clinical latency
- HIV viral load suppressed
- CD4+ recovers slightly then falls over time
- CD4+ is going to be WNL
3) AIDS symptoms
- HIV viral load increases exponentially
- CD4+ continues to fall
What’s seroconversion illness in HIV?
Phase 1) Acute HIV syndrome
10 days to 6 weeks post acquisition of HIV-1
Non-specific symptoms similar to glandular fever
Typically self limiting
Non-specific characteristics typical of viral infections
- Fever, pharyngitis, myalgia/arthralgia
- Lymphadenopathy & maculopapular rash
- Aseptic meningoencephalitis; GBS
What’s AIDS?
Final stage of untreated HIV-1 infection
Terminal without treatment
Uncommon but not rare
Marked by:
1) CD4+ ≤200 cells
2) AIDS-defining conditions
- Opportunistic infection e.g. PJP, candida
- Malignancy
What’s the clinical latency phase?
Most patients are asymptomatic for long periods of time
CD4+ ≥500
Various symptoms not uncommon Not usually directly caused by HIV - Psoriasis - Persistent generalised lymphadenopathy - Herpes zoster - Apthous ulcers
AIDS CD4+ ≤200 associated conditions
Oesophageal candidiasis - usually candida albicans
PJP
TB
Lymphoma
Kaposi’s sarcoma
- Extremely vascular tumour
- Skin most common - lung, gut occasional
AIDS CD4+ ≤~100 associated conditions
Cerebral toxoplasmosis
- Seizures
- From cat faeces or uncooked meat
Cryptococcal meningitis
- Respiratory entry –> haematogenous spread
- Screened by serum cryptococcal antigen
- Can be triggered starting anti-retroviral therapy
Cryptosporidiosis
- Chronic diarrhoea
- Difficult to treat//eradicate
Can occur at higher CD4 counts
AIDS CD4+ ≤50 associated conditions
CMV infection
- Usually reactivation
- Broad manifestation - retinitis (blindness), enteritis, pneumonitis, encephalitis
MAC
- Lymphadenitis, pulmonary infection
Primary brain lymphoma
- Seizure
- Skin most common (lung, gut occasional)
PML
- Reactive disease, caused by the JC virus
- No effective treatment
- Fatal unless HIV controlled
How is HIV transmitted?
1) Blood
2) Seminal
3) Vaginal secretions
4) Breast milk
5) Mother to child vertical transmission
- Basically eradicated due to effective anti-viral therapy
Life cycle of HIV
HIV virion –> attaches to CD4+ helper T cells via surface molecules (CD4 protein + coreceptor) –> virion fuses with host cell membrane –> contents of virion spill out into cytoplasm –> RNA is reverse transcribed into DNA –> viral DNA is actively transported into nucleus and integrated into cell genome –> host+viral DNA is transcribed and translated to viral proteins –> proteins get packaged up to make new virion –> bud off from cell –> uses protease to mature –> infect other helper T cells
Why do we use combination ART rather than monotherapy?
To prevent resistance
Should we start ART immediately or wait until CD4+ ≤50?
Immediately
Reduce AIDS events, death, malignancy
Higher mean CD4+ count
What are the 4 key ART classes?
1) Nucleoside reverse transcriptase inhibitors (NRTIs)
2) Non-Nucleoside reverse transcriptase inhibitors (NNRTIs)
3) Protease inhibitors (PIs)
- Always need booster (CYP450 inhibitors) to increase PI drug level
- High barrier to resistance
- May increase cholesterol levels
4) Integrase strand transfer inhibitors (INSTIs)
- Preferred anchor option
How to start ART in HIV?
TRIPLE THERAPY
2 NRTIs + one of
- NNRTI
- PI (boosted)
- Integrase inhibitor
Which ART to start in HIV?
TRIPLE THERAPY
TRIPLE THERAPY
x2 NRTI backtone + x1 integrase inhibitor (anchor)
1) Preferred NRTI backbone options
Tenofovir alafenamide + emtricitabine (preferred)
Abacavir + lamivudine
Come in combination tablet
Researched most in clinical trials
2) Integrase inhibitors are the preferred anchor drug class
- Very potent, drop viral load quickly
- Well tolerated, low drug-drug interactions
- Bictegravir or dolutegravir (2nd gen integrase inhibitor)
Current approved integrase inhibitors
1st gen
- Raltegravir
- Elvitegravir
2nd gen (less resistance) preferred
Dolutegravir
Bictegravir
What’s high and low HIV viral load?
> 100,000 high
<100,000 low
Why is HLAB5701 important in HIV?
1) If positive, associated with hypersensitivity to abacavir (NRTI)
= Contraindicated
2) People with HLAB5701 is able to hold the HIV peptide (presents it to the cytotoxic T cell) more strongly which strongly stimulates cytotoxic T cell response
Why is CV disease/risk important to consider in HIV?
Avoid abacavir
Increased risk of myocardial infarction
Which NRTI to choose if there is renal impairment or osteoporosis?
Tenofovir alafenamide (TAF) Minimal effects on kidneys and bone
Avoid Tenofovir disoproxil fumarate (TDF) - older version of tenofovir - associated with renal toxicity and bone density loss
What about 2 drug cART?
Dolutegravir (integrase inhibitor) + lamivudine (NRTI)
NEW double therapy approved for initial cART
Emerging evidence
Logic to use 2 instead of 3 drugs is reduce side effects and drug interactions however not recommended with
- Plasma viral load >500,000 copies/mL
- Hep B coinfection
- No available resistance genotyping results
HIV diagnosis + baseline investigations
Screening test (P24 Ag/Ab ELISA test) If positive, do confirmatory test (Western blot)
Others
HIV-1 RNA plasma viral load
CD4+ lymphocyte count
HIV-1 resistance genotyping
Specialised testing
TB-IGRA (latent TB)
HLAB5701 (for abacavir hypersensitivity)
Other
STIs - hep B, C coinfection
What’s a confirmatory test for HIV?
HIV-1 Western blot
If you have a certain combination of bands = confirmed
Reported by visual inspection (degree of subjectivity)
Highly specific, poor sensitivity
Can you use viral load to diagnose HIV?
No
