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Medicine year 2 semester 1 > Case 17- HIV > Flashcards

Case 17- HIV Flashcards

1
Q

Transmission of HIV

A

Blood; IVDU, blood ticks, needlestick injures. Sexual transmission. Mother to baby transmission at birth or when breast feeding
• Leads to severe immunodeficiency through infection

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2
Q

HIV

A

1) Human retrovirus

2) Leads to severe immunodeficiency through infection and destruction of CD4 cells. Can cause AIDs.

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3
Q

How HIV infects the cells

A

1) HIV binds to CD4 through gp120
2) Cell wall of the HIV virus breaks down releasing the genome
3) Reverse transcriptase converts the RNA into DNA and its integrated into the human genome
4) Synthesis of HIV proteins
5) Integrase assists with the assembly of the virion core structure
6) Budding and release of mature virion

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4
Q

What causes increased risk of HIV transmission in pregnancy

A
  • High viral load
  • Advanced immunodeficiency
  • IVDU
  • Malnutrition
  • Complicated labour
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5
Q

When does HIV transmission occur during pregnancy

A

Third trimester, during the birth process, when breast feeding, mixed feeding

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6
Q

HIV undetectable

A

1) When the viral load is undetectable <200 copies/ml it is untransmissable
2) Decreased risk with crcumcision
3) Increased risk with STI’s

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7
Q

Seroconversion

A
  • 2-6 weeks after exposure, can be asymptomatic
  • Symptomatic (80%)- Rash, lymphadenopathy, fever, sore throat, headaches, diarrhoea
  • Rarely neurological- encephalitis, mononeuritis
  • Rarely an AID’s defining illness
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8
Q

Clinical stage 1 of HIV

A

Asymptomatic, Generalised lymphadenopathy. Performance scale 1: asymptomatic, normal activity

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9
Q

Clinical stage 2 of HIV

A

Weight loss <10% of body weight. Minor mucocutaneous manifestations (seborrheic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations, angular cheilitis). Herpes zoster within the last 5 years. Recurrent upper respiratory tract infections i.e. bacterial sinusitis. And/or performance scale 2: symptomatic, normal activity

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10
Q

Clinical stage 3 of HIV

A
  • Weight loss >10% of body weight
  • Unexplained chronic diarrhoea >1 month
  • Unexplained prolonged fever (intermittent or constant), >1month
  • Oral candidiasis (thrush)
  • Oral hairy leucoplakia
  • Pulmonary tuberculosis
  • Sever bacterial infections i.e. pneumonia, pyomyositis
  • And/or performance scale 3: bedridden <50% of the day during the last month
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11
Q

Clinical stage 4 of HIV- AID’s examples

A
  • HIV wasting syndrome
  • Pneumocystic carinii pneumonia (PCP)
  • Toxoplasmosis of the brain
  • Cryptosporidiosis with diarrhoea >1 month
  • Cryptococcosis, extrapulmonary
  • Cytomegalovirus disease of an organ other than the liver, spleen or lymph node
  • Herpes simplex virus infection, mucocutaneous (>1month) or visceral
  • Progressive multifocal leukoencephalopathy
  • Any disseminated endemic mycosis
  • Candidiasis of oesophagus, trachea or bronchi
  • Atypical mycobacteriosis, disseminated or pulmonary
  • Non-typhoid salmonella septicaemia
  • Extrapulmonary tuberculosis
  • Lymphoma
  • Kaposi’s sarcoma
  • HIV encephalopathy
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12
Q

HIV- population testing

A

1) In high prevalence areas consider population testing.
2) Test patients with indicator conditions i.e. shingles, tuberculosis, oral candidiasis, OHL, test if seroconversion illness is suspected.
3) Testing should be routine, there is a long period between seroconversion and illness.
4) AID’s can occur as CD4 drops and is a collection of multiple infections which can present in an organ.

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13
Q

Rationale for testing for HIV

A
  • A large number of undiagnosed patients
  • Patients being diagnosed late in the disease process
  • Late diagnosis increases mortality, morbidity and cost
  • Routine testing is cost effective
  • Testing reduced onwards transmission
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14
Q

How to test for HIV

A
  • Consent the patient- explain the benefits of the test, details of how the results will be given
  • Detailed discussion should occur if the patient refuses and high concern that the patient may be positive
  • Document offer and reason for refusal is refused
  • Written consent is not necessary
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15
Q

HIV outcomes CD4 <25

A
  • Viral load >100,000
  • Age >50
  • Predicted probability of death at 5 years is 30%
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16
Q

HIV outcomes CD4>350

A
  • Viral load <100,000
  • CDC A or B
  • Age >50
  • Predicted probability of death at 5yrs is 3%
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17
Q

Tumours in HIV

A

Most are virally induced and driven
• Kaposi’s sarcoma- human herpes virus 8
• Lymphomas- Epstein Barr virus
• Cervical carcinoma- Human Papilloma virus
• Anal carcinoma- Human Papilloma virus
• Overall increased risk of many other cancer i.e. lung cancer, squamous cell carcinoma, bowel cancer, breast cancer etc

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18
Q

Kaposi’s sarcoma

A

• Induced by HHV8
• In USA and northern Europe 95% in gay men
• In sub Saharan Africa the sex incidence is equal
• Rates of HIV associated KS reflects the seroprevalence in the population
Vascular tumours on the skin and mouth. Typically red/purple and raised, can spread to lungs and liver

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19
Q

Pneumocystitis carinii pneumonia (PCP)

A

• Occurs in CD4 levels <200
• The most common AID’s defining illness
• Usually subacute presentation with dry cough, night sweats and increased shortness of breath
• Desaturation on exercise is relatively specific
• Chest signs are often minimal
• CXR can be normal
Pneumonua caused by fungi- pneumocystitis jiroveci

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20
Q

PCP treatment

A

First line: cotrimoxazole 120mg/kg in 3 divided doses

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21
Q

Prevention of PCP

A

Cotrimoxazole 960mg three times a week. Primary prophylaxis when CD4 <250, secondary prophylaxis after PCP. On Highly Active Antiretroviral Therapy (HAART) continue until sustained undetectable viral load and CD4>200.

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22
Q

Tuberculosis HIV

A
  • Very high association with HIV in the developing world- up to 65%
  • Presents with fever, sweats (often severe and at night), weight loss, respiratory symptoms or localised symptoms depending on the organ affected
  • Increased smear negative infections which may impair diagnosis
  • Requires scrupulous attention to control of infection and adherence issues
  • TB further impairs immune function in HIV infection
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23
Q

Mycobacterium avium complex infections

A

• CD4 counts less than 100
• Presents with fever, weight loss, late presentation with bone marrow failure
• Intrinsic resistance to first line Tb drugs
• Usually bacteraemia and multiorgan involvement
• Heavy bacterial load
• Outcome considerably improved by HAART, macrolides and quinolones
Can affect the lungs

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24
Q

CMV disease in HIV infection

A
  • Occurs in advanced immunodeficiency, CD4 less than 50
  • Viraemia predicts onset of clinical disease
  • Eye is the commonest site of localised CMV disease- presents with rapid onset visual loss
  • Other organs- bowel (diarrhoea), brain (encephalitis), lung (pneumonitis)
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25
Q

CNS disease in AIDs

A
  • Opportunistic infections Cryptococcus, CMV, MAC, PML, Toxoplasmosis
  • Primary cerebral lymphoma
  • HIV dementia complex
  • Spinal cord disease
  • Peripheral and autonomic neuropathy
26
Q

Groups of people with HIV

A

54% are gay men
22% in heterosexual women
15% in heterosexual men
3% in IVDU

27
Q

Primary HIV infections

A

HIV replicates significantly
Reaches very high viral load
Results in acute HIV syndrome
Might get non specific flu like symptoms

28
Q

HIV latency

A

After acute HIV syndrome, virus enters clinical latency
Resulting in a balance between HIV replication and CD4 cell stability
Tends to be around for 10 years
Very rarely any symptoms during this time

29
Q

HIV dementia

A

Dementia that occurs due to cortical atrophy, inflammation and demyelination caused by direct infection with HIV

30
Q

Diagnosis of HIV

A

ELISA

HIV antibody test

31
Q

DC-SIGN

A

A lectin on the dendritic cell surface
HIV can bind to this - becoming attached to dendritic cell
Transported to the lymph nodes with the dendritic cell - ends up in close proximity to CD4 cells that it wants to attack

32
Q

Receptors in HIV

A

Primary receptor- CD4

Secondary receptor- CCR5 or CXCR4, these are chemokine co-receptors which help HIV to fuse and enter the cell

33
Q

CCR5

A

Chemokine co-receptor that allows HIV virus to enter T cells
Macrophage tropic
Implicated in M-tropic/R5- tropic HIV
R5 strains usually indicate early infection

34
Q

CCR5 receptor agonists

A

Maraviroc
Prevents HIV from binding to CCR5
Prevents HIV from entering the host cell

35
Q

CXCR4

A

Chemokine receptor that allows HIV to enter T cells
T cell tropism
Implicated in T-tropic/R4-tropic HIV
HIV infection typically switches to this strain from M tropic
Associated with faster T cell clearance and more severe immunodeficiency

36
Q

How does HIV enter T cells

A

Viral and cellular membrane fuse
Gp120 complex on HIV attaches with CD4 receptor
Conformational shape change in the virus
Exposing Gp41 complex on HIV

This complex promotes fusion of viral and cellular membrane - co-membrane and viral genome and proteins are in host cell

37
Q

HIV medication Enfuvirtide

A

Fusion inhibitor

38
Q

HIV medication Enfuvirtide

A

Fusion inhibitor

39
Q

HIV medication Enfuvirtide

A

Fusion inhibitor T20. Prevents fusion of HIV virus to CD4 cell. By preventing hair pining of the gp41 molecule thereby preventing erasure of the HIV virion and CD4 cells

40
Q

HIV- integration

A

Integrate enzyme allows movement of viral DNA in to the host nucleus - inserted into the chromosome
The virus lives in the host

41
Q

HIV viral maturation

A

HIV DNA is now in the hosts genome - transcription and translation
New viral proteins can be made - new HIV virion
Proteins get cleaved by viral proteases to become mature
Now the virion is infectious
Virus buds off from the hosts membrane

42
Q

Virucides, antivirals and immunomodulatora

A
  • Virucides- direct effect against virions (too toxic for use)
  • Antivirals- have virus specific effects i.e. cell attachment or virus detected macromolecular synthesis
  • Immunomodulators- may either replace deficient immune system (i.e. immunoglobulins) or augment host response to pathogens (i.e. interferon)
43
Q

Chemotherapeutic index (CI)

A

Maximum tolerable dose per kilogram of body weight / Minimum dose per kilogram body weight that will cure the disease.

The higher the CI the better, it will be specific to the virus and not attack cellular function

44
Q

Factors affecting drug resistance in antivirals

A

• High viral replication (RNA>DNA viruses)
• Adherence to medication
• Effectiveness of drugs
• Mutations in virus that lead to resistance and don’t effect fitness
In the virus point mutations occur at every point along the genome at least once a day.

45
Q

History of HIV medication

A
  • 1987: AZT approved by FDA.
  • 1992: multiple drugs attempted
  • 1995: protease inhibitors discovered
  • 1996: NNRTIs discovered; HAART used for first time.
46
Q

Rationale drug design

A

Determine the structure of your target in a complex with a known inhibitor. Use this and other knowledge to design a better inhibitor, make it and test it

47
Q

Combinatorial chemistry

A

Use robotic techniques to make an enormous number of different compounds from a limited number of subunits. The individual components are then assayed for bioactivity, any active compounds identified can be used as a lead compound.

48
Q

NRTI

A
  • Reverse transcriptase is used to convert viral RNA into DNA
  • NRTI’s look like nucleotides that are used to form DNA
  • Once an NRTI is mistaken for a nucleotide and is placed in the growing chain, further growth stops.
49
Q

NRTI side effects

A

Also inhibits mitochondrial replication. Potent inhibitors of DNA polymerase which is essential for mitochondrial replication: Lactic acidosis, Steatosis, Lipoatrophy, metabolic syndrome.

50
Q

NRTI mechanism of resistance

A

The process of adding a new building block involves 3 steps:
• Binding of the next nucleoside or nucleoside analogue (NRTI) triphosphate
• Incorporation onto the end of the growing viral DNA chain and release of pyrophosphate
• Translocation of the incorporated nucleoside to a different position to allow room for addition of the next nucleoside residue
Nucleoside analogues are removed by mutant reverse transcriptase by a cleavage process called pyrophosphorylysis (PPi), translocation cannot happen, and the analogue is removed. No binding of reverse transcriptase to analogue.

51
Q

NNRTI

A

NNRTI’s bind directlty to reverse transcriptase

The binding stops the ability of the reverse transcriptase to add new nucleotides to the growing DNA chain

52
Q

Protein inhibitors (PI)

A
  • Protease is an enzyme that breaks up the proteins made by mRNA
  • These proteins are used to assemble new viruses
  • By blocking the breakup of these proteins the necessary building blocks of new viruses are not available
  • Resistance is through confirmational change in the Protease
53
Q

CCR5 inhibitor MoA

A
  • Homozygous CCR5 Δ32 mutation is associated with lack of infection.
  • CCR5 tropic virus require CCR5 for cell entry- it is a co-receptor.
  • CCR5 inhibitors therefore prevent virion entry.
  • Resistance occurs when virus switches to be CXCR4 tropic.
54
Q

Integrase inhibitors

A

1) Unknown exact mode of action

2) Prevents integration of viral DNA into the human genome

55
Q

Medication combinations given for HIV

A
  • Dual NRTI and single Integrase
  • Dual NRTI and single PI
  • Dual NRTI and single NNRTI
56
Q

HIV resistance

A

1) Suspected when viral load increases or lack of virology suppression.
2) Resistance testing may be carried out.
3) However, patients need to be taking drugs as scheduled.
3) Resistance can be archived, cross resistance may occur.
4) Transmitted or prior resistance may reduce how effective future treatment is.
5) Monotherapy does not work due to resistance.

57
Q

HIV drug interactions

A

All PI and NNRTI are metabolised through CYP P450 in liver. Ritonavir is a major inhibitor of CYP P450. There are intra-retroviral interactions as well as with TB medication, sedatives and statins.

58
Q

HIV the main causes of drug resistance

A

Poor adherence and drug interactions

59
Q

Likelihood of HIV transmission

A 
Needle stick injury = 1 in 300
Mucous membranes = 1 in 111
Vaginal receptive = 1 in 500
Vaginal insertive - 1 in 1111-3333
Anal receptive = 1 in 33-1000
Anal insertive = 1 in 1666
Mother to foetus
60
Q

HIV post exposure prophylaxis

A

Raltegravir (integrase) and Truvada (2 NRTI- tenofovir and emtricictabine). Test for HIV needs to be done post exposure. If the partner has an undetectable load then it will be untransmissible.

61
Q

Pre-exposure prophylaxis

A
  • Truvada (2NRTI Tenofovir and Emtricitabine) reduces risk of transmission in high risk population such as men who have sex with men and partners of positive patients who have a detectable virus.
  • Daily or Event based dosing
  • Reduces incidence of new HIV diagnosis significantly

Medicine year 2 semester 1 (53 decks)

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