HIV

Question 1

When was AIDS first named
How did humans first contract HIV

Answer 1

1983

Studies show that HIV may have jumped from chimpanzees to humans as far back as the late 1800s. The chimpanzee version of the virus is called simian immunodeficiency virus. It was probably passed to humans when humans hunted these chimpanzees for meat and came in contact with their infected blood.

Question 2

The history of HIV

Answer 2

Researchers believe the first transmission of SIV to HIV in humans that then led to the global pandemic occurred in 1920 in Kinshasa, the capital and largest city in the Democratic Republic of Congo.

The virus spread may have spread from Kinshasa along infrastructure routes (roads, railways, and rivers) via migrants and the sex trade.

In the 1960s, HIV spread from Africa to Haiti and the Caribbean when Haitian professionals in the colonial Democratic Republic of Congo returned home. The virus then moved from the Caribbean to New York City around 1970 and then to San Francisco later in the decade.

In 1981, the Centers for Disease Control and Prevention (CDC) published a report about five previously healthy homosexual men becoming infected with Pneumocystis pneumonia, which is caused by the normally harmless fungus Pneumocystis jirovecii. This type of pneumonia, the CDC noted, almost never affects people with uncompromised immune systems.

The following year, The New York Times published an alarming article about the new immune system disorder, which, by that time, had affected 335 people, killing 136 of them. Because the disease appeared to affect mostly homosexual men, officials initially called it gay-related immune deficiency, or GRID.

Though the CDC discovered all major routes of the disease’s transmission—as well as that female partners of AIDS-positive men could be infected—in 1983, the public considered AIDS a gay disease. It was even called the “gay plague” for many years after.

In September of 1982, the CDC used the term AIDS to describe the disease for the first time. By the end of the year, AIDS cases were also reported in a number of European countries.

Question 3

Incidence
Deaths

Answer 3

Incidence: 5m/year

Prevalence: Number of people in a population who have a disease or other health outcome at one point in time.
Incidence: Number of people in a population who develop a disease or other health outcome over a period of time (i.e. new cases over a period of time)

Deaths: 3m/year

Question 4

Types of virus?

Answer 4

HIV-1 - most prevalent in Europe [95% of infections are HIV-1]
HIV-2 similar disease but longer latency period, less infectious, uncommon outside of Africa

Question 5

UK incidence

Answer 5

6000/year
75% are MSM

Question 6

Modes of transmission

Answer 6

Sex
Blood products
IVDU
Needlestick injury
Vertical transmission

Question 7

Risks in vertical transmission

Answer 7

Child birth - 15% chance of transmission
Child birth + breast feeding - 25%

Question 8

HIV is transmissed by sex mostly - what is the incidence

Answer 8

75%

Question 9

What type of virus is HIV

Answer 9

Single stranded RNA retrovirus

Question 10

How is HIV incorporated into the host cell?

Answer 10

The virus gains entry by attaching to two things:
- the CD4 receptor and
- to a separate co-receptor [CCR5 or CXCR4]

The HIV connects via the its envelope glycoproteins (gp120 glycoprotein).

Once it is inside: it uses reverse transcriptase to make itself into DNA. It then takes itself over to the cells nucleus and evilly itegrates itself into the host DNA. Ready to be transcribed into new viruses.

Question 11

How may people have natural immunity?

Answer 11

If their co-receptor on the cell membrane (which HIV needs to attach to) has a mutation

Question 12

Why is HIV called a retrovirus?

Answer 12

It’s called a retrovirus because it encodes the enzyme reverse transcriptase allowing transcription of the HIV’s RNA to DNA.

Question 13

How does HIV mutate?

Answer 13

The reverse transcriptase is error prone, resulting in high rates of HIV mutation and viral resistance.

Question 14

Which cells in the human body are susceptible to take over by HIV?

Answer 14

Any cells with a CD4 receptor. This includes:
CD4+ T cells
Macrophages
Monocytes
Neurons

What is CD4 receptor? It is a glycoprotein that serves as a co-receptor (a protein on the surface of a cell that serves as a second binding site for a virus or other molecule) for the T-cell receptor. CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells.

CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. They are called helper cells because one of their main roles is to send signals to other types of immune cells, including CD8 killer cells, which then destroy the infectious particle. If CD4 cells become depleted, for example in untreated HIV infection, or following immune suppression prior to a transplant, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight.

Question 15

Once HIV is in a host cell, how does it spread?

Answer 15

HIV sneaks it’s way into the host cell DNA (an immune cell of some kind). When the immune cell is then activated they start transcribing and translating proteins needed for the immune response. Ironically this means that whenever the immune cells are exposed to something which ignites an immune response, it inadvertently transcribes and translates new HIV viruses, which bud off from the cell membrane to infect more cells.

Question 16

In for example, sexual transmission of HIV, how would it spread?

Answer 16

Most common way of spread. Usually dendritic cells are in the epithelial cells or mucosal tissue where the virus enters the body. It will then capture HIV and travel to the lymph nodes where a lot of immune cells live. HIV then infects these.

Question 17

Stages of HIV

Answer 17

Acute 0-12w (first part flu like sex, second part counter attack and control of viral replication)
Chronic phase 12w up to 2-10 years. Gradually t cells reduce and viral load increases.

1. Seroconversion - 2-6w after exposure, 50% get flu like sx.
   Initially the CD4 count drops and viral load increases. As immune system kicks in sx may develop and the 2 even out.
2. Pts then go onto asymptomatic infection - 5y or more. 30% will have persistent generalised lymphadenopathy.
3. AIDs related complex (ARC) - night sweats, high sweats, diarrhoea, opportunistic infections (candida, herpes) [200-500 T cells / mm3]
4. AIDS <200 t cells / mm3

Question 18

AIDS defining infections

Answer 18

Candida of resp tract or oesophagus
Chronic HSV
Disseminated TB
Toxoplasmosis of the brain
Recurrent salmonella
Pneuomocystis jiroveci pneumonia
Lymphoma of the brain
Invasive cervical cancer

Question 19

What tests are used for diagnosis of HIV

Answer 19

Initially:
HIV antibody test e.g. enzyme linked immunosorbent assay (ELISA) most frequently, but newer antibody/ antigen-based assay tests are being used now

A positive result from this is then confirmed by a secondary test:
HIV RNA or viral load

Question 20

When a patient is newly diagnosed with HIV, what other tests should be done?

Answer 20

Lymphocyte subset panel including CD4 count
Hepatitis screen
STI screen
TB skin test
FBC / U+Es / LFTs / fasting blood glucose / lipids / urinalysis
HIV viral load

Drug resistance testing in settings where there is high levels of resistance

Question 21

Common symptoms of HIV

Answer 21

• Fevers & night sweats
• Weight loss
• Skin rashes and post inflammatory scars - rashes are the most common sign of WHO stage 2 disease (incl herpes zoster [shingles], seborrhoeic dermatitis, fungal skin and nail infections [tinea corportis])
• Oral ulcers, oral thrush, angular cheilitis, oral hairy leukoplakia-
• Diarrhoea
• Lymphadenopathy

Question 22

HIV differentials

Answer 22

• Infectious mononucleosis [EBV –> fever, lymphadenopathy, pharyngitis, maculopapular rash] - do IgM serology for EBV / Paul Bunnell positive
• CMV [fever, lymphadenopathy, rash, splenomegaly] - CMV serology positive
• Influenza infection
• Common cold
• Viral hepatitis [RUQ pain, jaundice]
• Secondary syphilis [fever, malaise, pharyngitis, lymphadenopathy, maculopapular rash, condylomata lata on genital areas and oral ulcers]
• Covid 19

Question 23

WHO stage 1

Answer 23

Acute seroconversion syndrome

• Primary infection usually presents within the first month of infection with fever and lymphadenopathy. Other sx might include: pharyngitis, maculopapular rash, orogenital ulcers, meningoencephalitis. Other oportunistic infections may occur due to the transient lymphopenia. CD4 count may drop profoundly.
• Persistent generalised lymphadenopathy - painless
• Asymp - no sx at all
• Performance status 1 (fully active and asymp)

Question 24

WHO stage 2

Answer 24

• Weight loss of less than 10% body weight
• Herpes zoster (shingles)
• Minor mucocutaneous manifestations
• Recurrent URTIs
• Performance status 2 (symptomatic but near fully active)

Question 25

WHO stage 3

Answer 25

• Weight loss of more than 10% body weight
• Chronic diarrhoea for more than 1 month
• Prolonged fever for more than 1 month
• Oral candida, chronic vaginal candadiasis
• Oral hairly leukoplakia
• Severe bacterial infections
• Pulmonary TB
• Performance status 3 (in bed less than 50% of the past month)

Question 26

WHO stage 4

Answer 26

• Extrapulmonary TB
• Pneumocystis jirovecii [yirovetzee] pneumonia
• HSV ulcer for more than 1mo
• Oesophageal candida
• Toxoplasmosis
• CMV
• HIV encephalopathy
• Kaposis sarcoma
• Lymphoma
• Recurrent pneumonia
  + more
• Performance status 4 (confined to bed more than 50% of the time)

Question 27

WHO stage - advanced HIV disease

Answer 27

• CD4 <200 at presentation
• Seriously ill adult - resp rate >30, HR >120bpm, unable to walk unaided, T >39
• Seriously ill child - lethargy or unconsciousness, unable to drink / breast feed, vomitting, high RR, high HR, T>39
• Severely immunocompromised: CD4 count <50

Question 28

When should ART be started? Why?

Answer 28

Immediately after diagnosis

• To increase the uptake of ART and linkage to care
• Decrease the time to viral suppression
• Reduce risk of transmission
• Improve rate of virological suppression

Question 29

Classes of ARTs

Answer 29

1. NRTIs - nucleoside reverse transcriptase inhibitors
2. NNRTIs - non nucleoside reverse transcriptase inhibitors
3. PIs - protease inhibitors
4. INSTIs - integrase strand transfer inhibitors [generally only available in the developed world]
5. Pharmacokinetic boosters [improve the pharmacokinetic profiles of some antiretrovirals and increase their effectiveness, resulting in lower doses of the ARTs being needed]

Question 30

First line ART regimine would consist of:

Answer 30

2x nucleoside reverse transcriptase inhibitors [NRTIs]
In combination with a 3rd agent- usually an INSTI if available, or a NNRTI or PI

Question 31

NRTIs MOA

Answer 31

When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation, to reproduce the virus. RTIs block reverse transcriptase’s enzymatic function and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying.

A similar process occurs with other types of viruses. The hepatitis B virus, for example, carries its genetic material in the form of DNA, and employs an RNA-dependent DNA polymerase to replicate. Some of the same compounds used as RTIs can also block HBV replication; when used in this way they are referred to as polymerase inhibitors.

Question 32

What is a nucleotide
What is a nucleoside

Answer 32

• Organic molecule consisting of a nucleoside and a phosphate.
• Building blocks for nucleic acid polymers - DNA and RNA.
• 5 carbon sugar deoxyribose at centre, a nucleobase [which will be one of guanine, adenine, cytosine or thymine- DNA stuff, in RNA uracil is used in place of thymine] and phosphate group [either 1, 2 or 3] [a nucleoside is this but without the phosphate group].
• In DNA / RNA T & A are connect by double carbon bonds, and G & C are connected by triple carbon bonds. The individul nucleotides are joined at their sugar and phosphate molecules forming 2 backbones ‘double helix’ of nucleic acid
• They also play a central role in metabolism and provide chemical energy in the form of ATP and others

Question 33

How do NRTIs work?

Answer 33

• The antiviral effect of NRTIs and NtRTIs (nucleoTide transcriptase inhib) are essentially the same; they are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA chain.
• However, unlike the natural deoxynucleotides substrates, NRTIs and NtRTIs lack a 3′-hydroxyl group on the deoxyribose moiety. As a result, following incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide cannot form the next 5′–3′ phosphodiester bond needed to extend the DNA chain.
• These nucleosides compete to be binded to the RNA by the HIV’s reverse transciptase. ‘Chain termination’ occurs, and HIV DNA is not fully formed and cannot be incorporated into the DNA of the host cell.
• In order to be incorporated into the viral DNA, NRTIs must be activated in the cell by the addition of three phosphate groups to their deoxyribose moiety, to form NRTI triphosphates. This phosphorylation step is carried out by cellular kinase enzymes.

Question 34

Examples of NRTIs

Answer 34

• Truvada, made of emtricitabine and tenofovir disoproxil fumarate [both NRTIs] - used to treat and prevent HIV [prep].
• Zidovudine (trade name Retrovir)
• Didanosine (trade name Videx - it is an analog of adenosine)
• Stavudine (trade names Zerit)
• Lamivudine (trade name Zeffix and Epivir). It is approved for the treatment of both HIV and hepatitis B. Emtricitabine is another drug that is structurally similar to this.
• Abacavir (trade name Ziagen - is an analog of guanosine)

Question 35

MOA non-nucleoside reverse transcriptase inhibitors

Answer 35

NNRTIs block enzyme activity by binding directly to reverse transcriptase (RT) enzyme.

Question 36

NNRTIs egs

Answer 36

Efavirenz (Sustiva and Stocrin)
Nevirapine (Viramune)
Etravirine (Intelence)
Rilpivirine (Edurant)
Doravirine -i t is also used in a combination tablet as doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo).

Question 37

Protease inhibitors MOA

Answer 37

Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. These protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

Question 38

Nomenclature protease inhibitors HIV

Answer 38

Antiretroviral HIV-1 protease inhibitors—class stem –navir
e.g. Nelfinavir, Ritonavir, Saquinavir, Tipranavir

Question 39

Nomenclature protease inhibitors hepatitis C

Answer 39

Hepatitis C virus NS3/4A protease inhibitors—class stem –previr
e.g.
Asunaprevir
Boceprevir

Question 40

What is a protease

Answer 40

A protease is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in many biological functions, including digestion of ingested proteins, protein catabolism and cell signaling.

In the absence of functional accelerants, proteolysis would be very slow, taking hundreds of years. Proteases can be found in all forms of life and viruses.

Question 41

Why do we use multiple PI’s at once?

Answer 41

Given the specificity of the target of these drugs there is the risk, like with antibiotics, of the development of drug-resistant mutated viruses. To reduce this risk, it is common to use several different drugs together that are each aimed at different targets.

Question 42

MOA integrase strand transfer inhibitors
What is integrase

Answer 42

They block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell.
Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus.

Question 43

Integrase inhibitor examples

Answer 43

Raltegravir (Isentress)
Elvitegravir (Vitekta), used as part of the fixed dose combination with emtricitabine and tenofovir disoproxil (elvitegravir/ cobicistat/ emtricitabine/ tenofovir).
Dolutegravir (Tivicay),
Bictegravir is one and is in he combination drug bictegravir/ emtricitabine/ tenofovir alafenamide (Biktarvy)

Question 44

Pharmacokinetic boosters / enhancers - which drugs can they enhance and general principle of this

Answer 44

The pharmacokinetic enhancer interferes with the breakdown of the other drug, which allows the drug to remain in the body longer at a higher concentration.

Typically they enhance integrase inhibitors or protease inhibitors.

Question 45

MOA pharmacokinetic (PK) enhancers

Answer 45

PK enhancing is a strategy used to increase exposure of an ARV by concomitantly administering a drug that
inhibits the enzymes that metabolize the ARV. Currently, two agents are used as PK enhancers: ritonavir
(RTV) and cobicistat (COBI). Both drugs are potent inhibitors of the CYP3A4 enzyme, and thus, when
coadministered with ARVs metabolized by the CYP3A4 pathway, the resultant systemic exposure of the ARVs
is higher.

They inhibit enzyme cytochrome P450 3A4, also called CYP3A4. Normally, CYP3A4 metabolises and eliminates some drugs, so when it is inhibited by a PK enhancer, HIV ARV concentration and efficacy may be increased.

Medications like the integrase inhibitor elvitegravir, and the protease inhibitors atazanavir and darunavir can be used with a PK enhancer and potentially have their efficacy improved. PK enhancers used in HIV treatment are also called CYP3A4 inhibitors.

Question 46

Interactions of PK enhancers

Answer 46

PK enhancers may cause side effects such as yellowing of the skin or whites of the eyes. Because PK enhancers impact the way some drugs are broken down, they may have significant drug interactions

Importantly, RTV and COBI have different effects on other CYP- or UGT-metabolizing enzymes and drug transporters. Complex or unknown mechanisms of PK-based interactions preclude extrapolation of RTV drug interactions to certain COBI interactions, such as interactions with warfarin, direct oral anticoagulants, phenytoin, voriconazole, oral contraceptives, and certain HMG-CoA reductase inhibitors (or statins).

ritonavir RTV) and cobicistat (COBI)

Question 47

Pharmacokinetic enhancer drug exampls

Answer 47

Ritonavir (RTV)
Cobicistat (COBI)

Question 48

To do:
1. On bmj good practice: Follow up - monitoring, complications, prognosis
2. HIV emergencies - check for sophies slides on T drive
3. HIV assoc infection - https://www.cdc.gov/hiv/basics/livingwithhiv/opportunisticinfections.html