HIV and anti-retroviral Flashcards
what is the cause of HIV (: Human Immunodeficiency Virus)
reasons for low levels of cd4+
Lentivirus (type of retrovirus), Group VI ssRNA-RT, enveloped
Predominant type is HIV-1 (HIV-2 is less virulent/infective)
Infects immune cells: CD4+ T cells (helper), macrophages & dendritic cells
Leads to low levels CD4+ T cells via:
1)Direct viral killing of infected cells
2)Increased apoptosis infected cells
3)Killing infected CD4+ T cells by CD8 cytotoxic lymphocytes
As CD4+ T cells decrease below critical level, cell-mediated immunity lost, more susceptible to opportunistic infections
HIV Life-cycle
1 Virus binds to CD4 receptor (glycoprotein on immune cells) and co-receptor CCR5 via gp120 and fuses with host cell membrane
2 Virus uncoated and viral RNA and other proteins enter host cell
3 Viral DNA is transcribed via reverse transcriptase
4 Viral DNA enters nucleus, integrates into host genome using viral integrase
5 New viral RNA is transcribed from host genome and new viral proteins are generated and processed
6 Viral RNA and proteins assemble at the membrane
7Budding leads to generation of mature viral particle released from the cell
what are the transmission routes of HIV?
Unprotected sex (vaginal, anal, oral)
Mother-to-baby
Intravenous drug use – sharing of needles / needle-stick injuries
Blood transfusions / medical procedures
how can you prevent HIV
HIV testing and awareness of risk factors
Condoms
PEP (post-exposure prophylaxis),
PrEP (pre-exposure prophylaxis) and TasP (treatment as prevention) – all use anti-retrovirals
Needle-exchange programmes / clean needles
Blood screening, other measures
Diagnosis HIV Infection
By an ELISA/EIA (immunoassay): the latest tests detect antibodies against HIV
and p24 antigen – testing both reduces period from infection to testing positive to 1 month
Antibodies take several weeks to be produced so can initially test negative for antibodies – older tests may not detect until up to 3 months after infection
There are ‘rapid tests’ (point of care testing, POCT) – can give results within minutes (need confirm later with full blood test)
Patients can self-sample (take own blood/saliva sample to send for testing) or self-test
Tests are available in a range of Healthcare settings: sexual health clinics, hospitals, GP surgeries and some community pharmacies
If HIV+ test, this will be followed up with immunoassay to differentiate between HIV-1 and HIV-2 and an HIV NAT (nucleic acid test)
HIV infection stages
primary infections
acute HIV syndrome
clinical latency
constitutional symptoms - symptoms of aids begins
opportunist disease
death
Seroconversion (acute infection stage)
On initial infection may get some flu-like symptoms (fever, headache, rash)
Initially if tested will not be HIV+ve as antibodies starting to be made against virus
After infection virus replicates and get initial high viral load, CD4 cell count declines
Clinical Latency (chronic infection, asymptomatic stage)
Viral load starts to drop with reciprocal increase in CD4 count as immune system fights infection
This reverses as immune system unable cope with infection (CD4 count drops, viral load increases) until a threshold where start to see symptoms In initial symptomatic stages may see common infections as well as other symptoms (e.g. weight loss)
AIDS
Immune system can no longer fight infection, low CD4 count and high viral load
Get opportunistic infections and AIDS-defining disorders
Untreated patient will die
what are AIDS-Defining Conditions
If HIV is untreated/poorly controlled, can lead to developing AIDS. A number of infections, cancers and other disorders are considered ‘AIDS defining’ including the following:
Infections
Mycobacterium tuberculosis - TB
Pneumocystis jiroveci pneumonia
Toxoplasmosis, brain
Histoplasmosis
Candidiasis (oesophageal, lung)
Cytomegalovirus disease (CMV)
Cryptococcosis, extrapulmonary
Cryptosporidiosis (chronic)
Chronic herpes simplex
Cancers
Lymphoma (Burkitt’s, brain, immunoblastic)
Kaposi’s sarcoma
Invasive cervical cancer
Other
Progressive multifocal leukoencephalopathy
HIV-related encephalopathy
Wasting syndrome
what is the aims of ART (Antiretroviral Therapy)
- treating HIV
-reduce viral load
increase cd4 count
prevent transmission
increase life expectancy and quality of life
decrease risk infections
decrease risk progression
Treatment Targets HIV Life-cycle
1 Virus binds to CD4 receptor (glycoprotein on immune cells) and co-receptor CCR5 via gp120 and fuses with host cell membrane - Entry / Fusion Inhibitors
2 Virus uncoated and viral RNA and other proteins enter host cell - Entry / Fusion Inhibitors
3 Viral DNA is transcribed via reverse transcriptase- RT Inhibitors
4 Viral DNA enters nucleus, integrates into host genome using viral integrase- Integrase Inhibitors
5 New viral RNA is transcribed from host genome and new viral proteins are generated and processed- Protease Inhibitors
6 Viral RNA and proteins assemble at the membrane
7Budding leads to generation of mature viral particle released from the cell
moa of Entry Inhibitors:
examples
CCR5 antagonist: Maraviroc (not common, only for certain tropism)
Fusion inhibitor: Enfuvirtide (not common, injectable)
Post-attachment inhibitor: Ibalizumab (monoclonal Ab binds CD4) – approved EMA Sept 2019
Attachment inhibitor: Fostemsavir (binds gp120 on HIV) – not yet in UK
moa of Reverse Transcriptase Inhibitors
NRTIs: act as analogues of dNTPs and cause DNA chain termination: abacavir, tenofovir, emtricitabine, lamivudine, zidovudine
NNRTIs: direct inhibition HIV reverse transcriptase: efavirenz, nevirapine, rilpivirine
moa of Protease Inhibitors:
Directly interacts and inhibits HIV protease, preventing formation mature viral particles: atazanavir, darunavir, lopinavir [-navir]
moa of Integrase Inhibitors:
Directly interact and inhibit HIV integrase, preventing host integration: raltegravir, dolutegravir, elvitegravir, bictegravir [-gravir]
what is HIV Treatment
Combination therapy essential treating HIV, typically:
2 NRTIs plus 1 NNRTI or
1b/PI or
1INI
Vaccines are in development with several in/working towards clinical trials
Triple combination therapy essential – examples are:
2 NRTIs: tenofovir disproxil fumarate (DF) + emtricitabine (Truvada)
or tenofovir alafenamide (AF) + emtricitabine
abacavir + lamivudine (Kivexa) - alternative
plus
1 NNRTI: Tenofovir/emtricitabine + Efavirenz (‘alternative’ 3rd agent)*
Tenofovir/emtricitabine + rilpivirine
or
1b/PI: *Tenofovir/emtricitabine + Darunavir (ritonavir-boosted, rB)
*Tenofovir/emtricitabine + Atazanavir (ritonavir-boosted, rB)
or
1INI: * Tenofovir/emtricitabine + Raltegravir
* Tenofovir/emtricitabine + Dolutegravir
* Tenofovir/emtricitabine + Elvitegravir/c
Interim Update Feb 2022
A 2 drug Injectable, long-acting regimen (for use in very specific cases)
Long-acting Cabotegravir (INI) and rilpivirine (NNRTI) - LA-CAB/RPV
Patients start on oral forms as a lead-in
Switch to IM prolonged-release injections (monthly or every 2 months)
Pregnancy and HIV treatment
Many ARVs known to be safe in pregnancy
If not on ARVs, start treatment according to guidance
Preferred (safety): either backbone + efavirenz or atazanavir/r
Aim for undetectable viral load prior to delivery
Integrase inhibitor may be given for rapid viral load suppression (e.g. if VL>100,000)
Baby to have zidovudine treatment (duration depends on risk)
V low risk 2 weeks, low risk 4 weeks (high risk neonatal PEP)
HIV testing
Antenatal screening has significantly reduced rates of mother to child transmission
