HIV Flashcards
What does HIV stand for?
Human Immunodeficiency Virus
Describe the brief early history of HIV
~1900 HIV-1 Group M(ain) emerges in west Africa
- Zoonotic transmission event from Pan troglodytes troglodytes (SIV chimpanzee)
– closest to HIV is seen in chimpanzee’s
~1950 HIV-1 clades begin to diverge in humans
~1966 HIV-1 clade B introduced to Haiti
~1972 HIV-1 clade B introduced to USA
- 1981 unusually high rates of rare pneumonia and cancer in young gay men reported (GRID - Gay Related Immuno Disorder - thought it was but it’s not)
- 1983 HTLVIII/LAV described as causative agent of AIDS
– Nobel prize in Physiology or Medicine 2008 (Joint with HPV) - 1985 FDA approves first HIV test (antibody test)
- 1987 FDA approves AZT
- 1996 triple therapy licensed (HAART) (still the therapy today)
- 2002 US FDA approves the first HIV rapid antigen test
– Produces results in <20min - 2004 the first Phase 3 HIV vaccine trials conclude
– Two candidates fail to show protection from infection (still no HIV vaccine) - 2008 the “Swiss Statement” is issued
– Undetectable = Untransmissible - 2009 the RV144 HIV vaccine study shows modestprotection (~30%) (mostly in Thailand)
– Follow-up studies have not replicated the protection - 2012 Truvada® approved as first “one pill once a day” HIV therapy (before it was a complicated regiman)
- 2016 Swiss statement becomes widely accepted after PARTNER study shows 0 transmissions in 1,593 eligible couple-years of follow-up (1 partner HIV + & 1 HIV -)
- 2021 FDA approves cabotegravir, the first long-acting injectable anti-hiv drug
(all based on historical samples)
When you are ______ with keeping up with your regimen it is WAY LESS likely to transmit HIV to your partner
consistant
What is the prevalence of HIV?
majority in Sub-Sahara desert in Africa
~65 000 living in Canada with HIV
~2000 new infections in Canada
~100 new in Manitoba
What is the Global HIV Prevalence?
of people living with HIV in 2017
19.6 million - East & Southern Africa (MAJORITY)
Western & Central Africa - 6.1 million
Asia & Pacific - 5.2 million
W. & C. Europe & N. America - 2.2 million
Latin America - 1.8 million
East Europe & Central Asia - 1.4 million
Caribbean - 310, 000
Middle East & North Africa - 220, 000
What are the top 3 countries that result in 33% of ALL INFECTIONS?
- South Africa
- Nigeria
- India
What are the top 10 countries that result in 61% of ALL INFECTIONS?
- South Africa
- Nigeria
- India
- Kenya
- Mozambique
- Uganda
- Tanzania
- Zimbabwe
- USA
- Zambia
Annual HIV incidence is _____
declining
BUT we’re still not on target (far behing - b/c not been as accessible to HIV care & tests)
What does the Canadian HIV Prevalence look like?
Saskatchewan has the HIGHEST prevalence in Canada
Describe the Canadian HIV hotspot
There is a sort of small community in SASKATCHEWAN called Ahtahkakoop that has comparable African HIV rates by population
Ahtahkakoop (in Saskatchewan) = 3.5%
In Africa:
- Guinea-Bissau = 3.74%
- Central African Republic = 3.82%
- Nigeria = 3.17%
- Rwanda = 2.85%
What is the HIV virology in terms of Taxonomy?
Family: Retroviridae (takes RNA genome & reverse transcribes it to DNA?)
Subfamily: Orthoretrovirinae
Genus: Lentivirus
Species: Human Immunodeficiency Virus(-1)
What is the HIV virology in terms of Structure?
- Enveloped virus (lipid bilayer)
– gets when it exits host cell - Matrix proteins (p17)
- Conical capsid (p24) (tested protein for antigen test ?)
– Carries 2 genome copies/virion
– Positive sense single-stranded RNA (messenger RNA)
– ~9kb in length
– Encodes 9 genes
Describe the HIV Life Cycle
- Attach to host cell (CD4+ & needs a co-receptor (CCR5/CXCR4) - involved in immune signalling
- Membrane fuses together - brings in proteins to start transcribing
- Integrate into DNA
- Makes new copies
- Gets brought up & packaged
(*can also get direct transfer from cell to cell?)
Describe the different ways for HIV Transmission
- Peron-to-person through body fluids
- Blood, semen, pre-seminal fluid, rectal fluid, vaginal fluid, breast milk (esp. places where they don’t have access to formula), saliva (?) (can detect viral genome) - Routes of transmission
- Sexual contact, injection drug use, perinatally, breastfeeding, transfusion of infected blood products - Majority of HIV infections globally are through heterosexual contact
- Varies dramatically by region
- Heterosexual – AB, MB
- Injection drug use – SK
- Men who have sex with men – BC, ON, QC, Atlantic Canada
Describe the New HIV Infections in Canada
Canada doesn’t have a single HIV epidemic. New infections are concentrated in different populations across the country.
Main way globally is through MSM (46.6%) but varies b/t provinces
slide 14
Describe the Early Events in HIV Infection
- HIV is poorly transmitted if there is a mucousal membrane
- resides mostly in lymphatics (lymphatic disease)
add to this
Although many cell types are infectible in vitro, the major cell population targeted by…
HIV in vivo are CD4+ T cells (T helper cells)
Describe the HIV disease progression
Up until 2007 traits were investigated by candidate gene studies, thereafter more by GWAS, I’ll focus mainly on the latter for reasons that I hope will become obvious.
- Latent phase - CD4+ cells goes up & down & then lose it over time
- Everyone has a certain amount of time before that they are susceptible - *not everyone is equally susceptible to HIV
- Look at CD4+ T-cell count & HIV viral mode
- Loss of gut cells, esp. in gut
Describe the Primary HIV infection
~0 – 4 weeks post infection (most likely to transmit b/c more viral material, more likely to transmit)
- Characterized by high viral load (acute viremia) and loss of T cells (mainly in the gut mucosa)
- Accompanied by one or more (or no) mild, non-specific ”flu-like” clinical symptoms
– Fatigue, fever, myalgia, nausea, RASH (separate it from general viral illness), sore throat, etc… - Highly infectious during this time
Describe the Chronic infection of HIV
~ 4 weeks to many years
- Viral latency is established (huge variability)
- Viral load remains relatively stable
– Viral load ”set point” - Steady decline in CD4+ T cells
- Generally asymptomatic
- Transmissability depends on SETPOINT VIRAL LOAD
Describe a note on setpoint viral load
- Normally distributed in infected population
– Log10 RNA copies/ml of plasma - Highly variable (increase virus, faster progression & more likely to transmit)
- Correlates with transmissibility
– 1.8-2.2 -fold risk for each log10 HIV increase - Correlates with rate of progression
– 2 fold increase in risk of AIDS and 2.5 fold increased risk of death for each log10 HIV increase
(# of copies of viral genome that can be found in blood)
What does AIDS stand for?
Acquired Immune Deficiency Syndrome
Describe Acquired Immune Deficiency Syndrome (AIDS)
- Originally termed GRID
– Gay Related Immune Disorder - State of severe immune deficiency caused by HIV infection
- Clinical definition requires HIV infection and EITHER:
– AIDS defining illness
— E.g. Pneumocystis Jiroveci Pneumonia, Kaposi’s sarcoma, Burkitt lymphoma Cytomegalovirus retinitis, Invasive cervical cancer, etc… (in an immunocompromised person)
– CD4+ T cell count < 200 cells/mm3 - Fatal if untreated
What are the 3 types of HIV Testing?
- HIV antibody testing
- HIV antibody/antigen testing
- HIV antibody testing
- Nucleic acid testing
Describe HIV antibody testing
- Oldest and most widely used
- Detects anti-HIV antibody generated by immune
response
– Does not detect acute infection
– Recommended at 6 weeks, re-test at 12 weeks - ELISA
- Western blot
(detecting for an immune response)
Describe HIV antibody/antigen testing
- Detects both antibody and antigen (p24) - most abundant protein therefore easy to detect
- Results detected earlier than Ab testing alone
– Recommended at 4 weeks
Describe HIV antibody testing
- Oldest and most widely used
- Detects anti-HIV antibody generated by immune
response
– Does not detect acute infection
– Recommended at 6 weeks, re-test at 12 weeks - ELISA
Describe Nucleic acid testing
- PCR (polymerase chain reaction)
- Detect viral genetic material
- Can detect infection as early as 3 DAYS
- Generally only used in specific circumstances
– recent high risk exposure and symptoms of acute
HIV infection
Describe Clinical management
- Previously antiretrovirals (ARVs) initiated based on monitoring of patient CD4+ T cell count
– Therapy initiated at T cell threshold (commonly CD4 < 350 cells/mm3)
– Drugs has many adverse events
– Difficult to take
– Concerns surrounding drug resistance - Currently “test and treat” (right away)
– Ensure patient leaves with ARVs in their system
– Modern formulations are much more convenient
—One pill once a day - Ongoing management includes CD4 and viral load measurements (decrease viral load, healthy)
– U = U
Available antiretrovirals target almost every part of the HIV life cycle…
- Integrase Inhibitors
-*Reverse transcriptase Inhibitors
- Protease Inhibitors
(Entry Inhibitors & Maturation Inhibitors)
(Includes nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non- nucleoside reverse transcriptase inhibitors (NNRTIs))
Describe Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults
- Recommended optimal first line
- Bictegravir/TAF/emtricitabine
- Dolutegravir/abacavir/lamivudine
- Dolutegravir + TAF/emtricitabine - Optional first line (if 1 are unavailable/contraindicated)
- Darunavir/cobicistat + TAF (or TDF)/emtricitabine
- Darunavir + ritonavir + TAF (or TDF)/emtricitabine
- Efavirenz/TDF/emtricitabine
- Elvitegravir/cobicistat/TAF (or TDF)/emtricitabine
- Raltegravir + TAF (or TDF)/emtricitabine
- Rilpivirine/TAF (or TDF)/emtricitabine
(don’t memorize names ?)
What does Undetectable = Untransmissible mean?
- “People living with HIV with an undetectable viral load cannot transmit HIV sexually” – UNAIDS
- “HIV is no longer a death sentence, but it’s still a life sentence” – Dr Paul Sandstrom (Director, NHRL, PHAC)
(no practical way to treat) - Current drugs are well tolerated and work well
– Still many challenges to widespread uptake
What are prospects going forward?
- 90-90-90 (if achieved by 2025)
(90% of pop. diagnosed, 90% on treatment, 90% virally suppressed) - Anti-HIV biologics (bNAbs)
- PrEP (taking anti-HIV drugs while (-) to prevent
- Patients receiving daily oral FTC/TDF ? (biggest hope)
- HIV vaccines
- Cure (took stem cells from a person who didn’t have CCR5 & it cured his leukemia & HIV)
The End of AIDS?
Triple therapy introduced
Dramatic increase in efficacy compared to monotherapy
Treatment as prevention
Pre-exposure prophylaxis (PrEP)
Estimated 25% of HIV+ don’t know their status
NIGERIA – 37,000 mother to child transmission in 2016
RUSSIA – Fast growing infection in IDUs, no gov’t support of harm reduction
FLORIDA – 3 of top 10 US cities for new infections -> Miami #1
