HIV

Question 1

What does HIV stand for?

Answer 1

Human Immunodeficiency Virus

Question 2

Describe the brief early history of HIV

Answer 2

~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)

Question 3

When you are ______ with keeping up with your regimen it is WAY LESS likely to transmit HIV to your partner

Answer 3

consistant

Question 4

What is the prevalence of HIV?

Answer 4

majority in Sub-Sahara desert in Africa

~65 000 living in Canada with HIV

~2000 new infections in Canada

~100 new in Manitoba

Question 5

What is the Global HIV Prevalence?

of people living with HIV in 2017

Answer 5

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

Question 6

What are the top 3 countries that result in 33% of ALL INFECTIONS?

Answer 6

1. South Africa
2. Nigeria
3. India

Question 7

What are the top 10 countries that result in 61% of ALL INFECTIONS?

Answer 7

1. South Africa
2. Nigeria
3. India
4. Kenya
5. Mozambique
6. Uganda
7. Tanzania
8. Zimbabwe
9. USA
10. Zambia

Question 8

Annual HIV incidence is _____

Answer 8

declining

BUT we’re still not on target (far behing - b/c not been as accessible to HIV care & tests)

Question 9

What does the Canadian HIV Prevalence look like?

Answer 9

Saskatchewan has the HIGHEST prevalence in Canada

Question 10

Describe the Canadian HIV hotspot

Answer 10

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%

Question 11

What is the HIV virology in terms of Taxonomy?

Answer 11

Family: Retroviridae (takes RNA genome & reverse transcribes it to DNA?)

Subfamily: Orthoretrovirinae

Genus: Lentivirus

Species: Human Immunodeficiency Virus(-1)

Question 12

What is the HIV virology in terms of Structure?

Answer 12

• 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

Question 13

Describe the HIV Life Cycle

Answer 13

1. Attach to host cell (CD4+ & needs a co-receptor (CCR5/CXCR4) - involved in immune signalling
2. Membrane fuses together - brings in proteins to start transcribing
3. Integrate into DNA
4. Makes new copies
5. Gets brought up & packaged

(*can also get direct transfer from cell to cell?)

Question 14

Describe the different ways for HIV Transmission

Answer 14

1. 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)
2. Routes of transmission
   - Sexual contact, injection drug use, perinatally, breastfeeding, transfusion of infected blood products
3. 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

Question 15

Describe the New HIV Infections in Canada

Answer 15

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

Question 16

Describe the Early Events in HIV Infection

Answer 16

• HIV is poorly transmitted if there is a mucousal membrane
• resides mostly in lymphatics (lymphatic disease)

add to this

Question 17

Although many cell types are infectible in vitro, the major cell population targeted by…

Answer 17

HIV in vivo are CD4+ T cells (T helper cells)

Question 18

Describe the HIV disease progression

Answer 18

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

Question 19

Describe the Primary HIV infection

Answer 19

~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

Question 20

Describe the Chronic infection of HIV

Answer 20

~ 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

Question 21

Describe a note on setpoint viral load

Answer 21

• 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)

Question 22

What does AIDS stand for?

Answer 22

Acquired Immune Deficiency Syndrome

Question 23

Describe Acquired Immune Deficiency Syndrome (AIDS)

Answer 23

• 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

Question 24

What are the 3 types of HIV Testing?

Answer 24

1. HIV antibody testing
2. HIV antibody/antigen testing
3. HIV antibody testing
4. Nucleic acid testing

Question 25

Describe HIV antibody testing

Answer 25

- 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)

Question 26

Describe HIV antibody/antigen testing

Answer 26

- Detects both antibody and antigen (p24) - most abundant protein therefore easy to detect - Results detected earlier than Ab testing alone -- Recommended at 4 weeks

Question 27

Describe HIV antibody testing

Answer 27

- 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

Question 28

Describe Nucleic acid testing

Answer 28

- 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

Question 29

Describe Clinical management

Answer 29

- 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

Question 30

Available antiretrovirals target almost every part of the HIV life cycle...

Answer 30

- 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))

Question 31

Describe Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

Answer 31

1. Recommended optimal first line - Bictegravir/TAF/emtricitabine - Dolutegravir/abacavir/lamivudine - Dolutegravir + TAF/emtricitabine 2. 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 ?)

Question 32

What does Undetectable = Untransmissible mean?

Answer 32

- “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

Question 33

What are prospects going forward?

Answer 33

- 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)

Question 34

The End of AIDS?

Answer 34

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