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Delta Med - Infectious diseases > Infectious diseases - HIV > Flashcards

Infectious diseases - HIV Flashcards

1
Q

What factors increase HIV transmission?

A 
STI in either partner, esp ulcerative
HSV-2
High plasma load
Circumcision protective in heterosexuals
Microbicides
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2
Q

What host genetic factors increase HIV transmission?

A

CCR5 D32 homozygosity

HLA-B alleles - if common between discordant couples, increased transmission

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3
Q

What are subtypes of HIV?

A

retrovirus (lentivirus) with single strand sense RNA
Type 1 M is the most common, >90%
HIV 2 is west africa, e.g. senegal

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4
Q

What is required for entry of HIV?

A

CD4 and a co-receptor i.e. CCR5/CXCR4.

GP120 binds to CD4, and then either CCR5/CXCR4

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5
Q

How can viruses evolve with respect to entry proteins?

A

naive R5 infection can evolve to X4 over time via D/M

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6
Q

What cells are infected by HIV?

A 
CD4+ T-lymphocytes
Monocytes and macrophages
Dendritic cells (allow entry, productive infection rare)
Astrocytes
Thymic progenitor cells
CD34+ progenitor cells
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7
Q

What is the process of infection in HIV?

A

Mucosal exposure to HIV-1
Selective infection by R5 strains
HIV binds to dendritic cell by DC-SIGN
Transport of virus to regional lymph nodes
Spread of infection to activated CD4+ lymphocytes
Entry of infected virus cells into blood stream
Massive depletion of GIT CD4+ t-cells

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8
Q

At what viral loads to specific opportunistic infections occur in HIV?

A

TB at all counts

Pneumocystis

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9
Q

What is the relationship between viral load and development of aids in 3 years?

A

regardless of CD4 count, high viral loads still predispose patients to developing AIDS.
CD4 count still changes risk of developing aids even with ART (

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10
Q

What viral factors determine disease progression?

A

Viral factors:

  • weakened viral strains (e.g. nef gene deletions)
  • CCR5 using viruses
  • Co-infection with CMV accelerates disease regardless of ART
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11
Q

What immunological factors determine disease progression?

A

Immunology
- high tittre neutralising Ab
- high level CD8+ HIV-1 specific t-cells
- high level CD4+ HIV-1 specific proliferative responses
Age - extremes of age lead to poorer prognosis

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12
Q

What genetic factors determine disease progression?

A

Chemokine mutations - CCR5 D32 heterozyg has slower disease progression
CCR2 64I mutation
CCL31 gene duplications

Intracellular factors that limit or restrict viral replication:
APOBEC3, TRIM 5a, tetherin, SAMHD1

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13
Q

What are features of CCR5 mutations?

A

1% of caucasians are homozygous for CCR5delta32
Homozygosity is highly protective
Heterozygotes (20%) have a 2x slower progression to AIDS

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14
Q

What HLA types are associated with good and poor disease progression

A

B13, B27, B51, B57 have slower progression

A23, B37 B49 - rapid progression

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15
Q

What is the effect of ART and viral suppression in HIV patients?

A

Patients who attain viral suppression and a CD4 count of >350 within 1 year of commencing ART have a normal LE compared to controls

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16
Q

What is the primary cause of death in patients treated with ART?

A

Non-aids related malignancy

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17
Q

When should HIV therapy be commenced, according to Australian guidelines?

A

ARV should be commenced in all patients with HIV, irrespective of CD4 count, according to the following principles:

  • ART is recommended in all HIV patients, irrespective of CD4 count
  • Should take into account personal health benefits and risks, and reduced transmission risk
  • Clinicians should discuss current state of knowledge re ART with all patients not already taking it
  • All decisions should be made by the patient with HIV- in a fully informed manner
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18
Q

What were the findings of the START trial?

A

lower rates of serious aids events and non-serious aids events in patients receiving immediate ART vs those in the delayed group (when CD4+ count reaches

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19
Q

What are the 5 classes of HIV medications?

A

1) reverse transcriptase inhibitors - nucleoside/nucleotide inhibitors
2) reverse transcriptase inhibitors - non-nucleoside
3) protease inhibitors
4) entry inhibitors
5) integrase inhibitors

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20
Q

What are examples of nucleoside/nucleotide RTIs?

A

Nucleoside

  • zidovudine
  • didanosine
  • stavudine
  • lamivudine
  • emtricitabine
  • abacavir

Nucleotide
- tenofovir

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21
Q

What are reverse transcriptase inhibitors (Non nucleoside)?

A

nevirapine
efavirenz
etravirine
rilpivirine

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22
Q

What are examples of protease inhibitors?

A 
Lopinavir/ritonavir
atazanavir
fosamprenavir
saquinavir
tipranavir
darunavir

(ritonavir - p450 inhibitor, booster)

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23
Q

What are examples of entry inhibitors?

A

Fusion inhibitors -enfuvirtide

CCR5 inhibitors - Maraviroc

24
Q

What are examples of integrase inhibitors?

A

ralegravir
dolutegravir
elvitegravir/cobiscistat

25
Q

What determines choice of ART regime?

A

patient/lifestyle preference
transmitted drug resistance - baseline HIV genotype
presence of comorbidities exac by HIV
pharmacogenetic screening (HLA-B5701 for abacavir HSR)
RFs for CVD/metabolic syndrome

26
Q

What are recommended regimes per DHHS 2015 guidelines?

A

Truvada + Raltegravir/Dolutegravir/Elvitegravir+cobicistat/darunavir+ritonavir

Abacavir + lamivudine + dolutegravir

27
Q

What is the goal of HIV therapy?

A

complete suppression of HIV viral load (confirmed by undet level on RNA PCR)

28
Q

What is virologic/immunologic failure?

A

Incomplete virologic response - RNA >200 after 24/52 ART
Virologic rebound - RNA>200 after previous suppression

Immunologic failure - CD4 fall below baseline on therapy

Clinical failure - occurence of HIV related events after 3/12 on therapy, excluding IRIS

29
Q

When should drug resistance testing be performed in a treatment experience patient?

A

Whilst on failing regime or within 4 weeks of discontinuing treatment
Should design a new regime with 2 or more active agents (from another class)

30
Q

What are features of HIV genotype testing?

A 
require >1000 copies/ml for test
Genotype testing - mutations which are associated with resistance:
RT gene (NRTI/NNRTI resistance)
Protease gene (resistance to PI)
Integrase gene (resistance to InSTIs)

Phenotype testing is like Ab resistance testing, not avail in Australia

31
Q

When should resistance testing be performed?

A

When commencing treatment (even in chronic infection)
Pregnant women
Virological failure (on Rx or within 4 weeks of discont)

32
Q

What are toxicities associated with tenofovir?

A

Renal toxicity

  • Fanconi syndrome - RTA due to loss of bicarb, phosphate, glucose and AA
  • GFR decline without Fanconi’s
  • Decreased BMD
33
Q

What are toxicities associated with abacavir?

A

3-5% allergic reaction - GIT symptoms, myalgia, +/- rash, cough
Stop drug and do not rechallenge - strong assoc with HLAB5701
Doubling of AMI risk reported (also in older PIs, not other NRTIs)

34
Q

What are toxicities associated with efavirenz?

A

40% CNS SEs including vivid dreams, sleep changes, headache
Rash
TERATOGENIC!

35
Q

What are toxicities associated with nevirapine?

A

Rash 5-10% (usually mild, treated with antihistamines) - reports of SJS and death, 7 fold higher risk of serious rash in women
Hepatotoxicity - 12x in women with CD4 cells >250 and men with CD4 >400

36
Q

What are toxicities assocaited with atazanavir?

A

hyperbilirubinaemia and renal stones

37
Q

What are features of lipodystrophy?

A

lipoatrophy - peripheral subq fat wasting, sunken cheeks, skinny arms and legs, prominent veins, flat arse
lipohypertrophy - fat accum - increased abdo girth, breast enlargement, buffalo hump, lipomas
Metabolic abn - usually >=1 are present - high chol, high trigs, low HDL, high LDL, type2 DM, insulin resistance

38
Q

What medications are at highest risk of lipoatrophy?

A

didanosine, stavudine

39
Q

What are intermediate and low risk medications for lipoatrophy?

A

zidovudine - intermediate risk

emtricitibine, abacavir, tenofovir and lamivudine

40
Q

What other factors contribute to lipoatrophy?

A

Age

Severity of illness - AIDS, nadir cell count - 350, 30% if

41
Q

What is the management of lipodystrophy?

A

avoid highest risk drug - d-class drugs and AZT, incl older PIs

Statins - atazanavir and darunavir are best PIs re: lipids
avoid simvastatin/lovastatin
Pravastatin has lowest p450 interaction, but not potent
use caution with atorva and rosuva due to high statin levels when used with PIs- but still recommended agents

Fibrates - decrease TGs - use gemfibrozil 600mg bd

42
Q

What is management of lipohypertrophy?

A

diet and exercise
surgery to remove buffalo hump
liposuction to remove excess fat around upper trunk and neck

43
Q

What class of medications have the greatest metabolic impact?

A

PIs, especially tipinavir/ritonavir and indivnavir/ritonavir

NRTI - stavudine
(abacavir, tenofovir, emtricitibine, lamivudine ok)

Low risk with integrase inhibitors

44
Q

What ART medications are metabolised by P4503A4 enzymes?

A

PIs and NNRTIs

ritonavir is the most potent P4503A4 inhibitor (also 2D6, 2C9, 2C19)

45
Q

What are P4503A4 inducers?

A

nevirapine induces P4503A4
efavirenz induces and inhibits P4503A4 - unpredictable drug interactions

Raltegravir has no p450 act (all UGT1A1), dolutegravir minor p450

46
Q

What medications are absolutely contraindicated with P4503A4 inhibitors?

A

C/I with ritonavir, cobicistat

Cisapride - aLQTs - torsades
Lovastatin, simvastatin - rhabdo
Midazolam, triazolam - prolonged sedation - use propofol

47
Q

What medications are cautioned with P4503A4 inhibitors?

A

ritonavir -tricyclic antidepressants, CCBs
inhaled steroids - cushing’s syndrome, OP, AVN (less in budesonide, not in beclomethasone)
ethonyl oestradiol - 40% reduction with ritonavir

48
Q

What opiate is metabolised by a P450 enzyme?

A

methadone is metabolised by P4503A4

  • nevirapine causes methadone withdrawal
  • cessation of nevirapine - potential for OD
49
Q

What occurs when atazanavir is prescribed with PPIs?

A

decreased absorption of atazanavir

50
Q

What medications are implicated in ART related hepatotoxicity?

A

nevirapine - most in 1st 12/52 of therapy, associated rash (50%) and flu like symptoms, fever.
Dose reduction reduces risk
Increased risk in HBV/HCV, women and higher CD4 counts

protease inhibitors - any time during treatment - ritonavir, sequinavir/ritonavir higher risk than indinavir

51
Q

What is the efficacy of treatment as prevention?

A

93% risk reduction in transmission in sero-discordant couples.

52
Q

What is the effectiveness of PrEP in the real world?

A

PROUD study - shows that there is an NNT of 13 for 1 year to prevent one seroconversion. No actual true seroconversions in the immediate treatment arm.
No difference in STIs between groups.

53
Q

What is the efficacy of on demand PrEP?

A

effective! NNT of 18 for 1 year

54
Q

What are significant HIV latent reservoirs?

A

Resting memory CD4+ T-cells - preintegrated HIV = major reservoir
Prompt rebound in virus when ART is ceased

55
Q

What type of infection in the body is not terminated in ART?

A

Cell to cell infection, as in lymphoid tissue

56
Q

What re reservoirs for infection?

A

CNS
Lymphoid tissue
Genitalia (immunologically privileged)
GUT

Delta Med - Infectious diseases (3 decks)

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