Infectious diseases - HIV

Question 1

What factors increase HIV transmission?

Answer 1

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

Question 2

What host genetic factors increase HIV transmission?

Answer 2

CCR5 D32 homozygosity

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

Question 3

What are subtypes of HIV?

Answer 3

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

Question 4

What is required for entry of HIV?

Answer 4

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

GP120 binds to CD4, and then either CCR5/CXCR4

Question 5

How can viruses evolve with respect to entry proteins?

Answer 5

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

Question 6

What cells are infected by HIV?

Answer 6

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

Question 7

What is the process of infection in HIV?

Answer 7

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

Question 8

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

Answer 8

TB at all counts

Pneumocystis

Question 9

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

Answer 9

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

Question 10

What viral factors determine disease progression?

Answer 10

Viral factors:

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

Question 11

What immunological factors determine disease progression?

Answer 11

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

Question 12

What genetic factors determine disease progression?

Answer 12

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

Question 13

What are features of CCR5 mutations?

Answer 13

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

Question 14

What HLA types are associated with good and poor disease progression

Answer 14

B13, B27, B51, B57 have slower progression

A23, B37 B49 - rapid progression

Question 15

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

Answer 15

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

Question 16

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

Answer 16

Non-aids related malignancy

Question 17

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

Answer 17

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

Question 18

What were the findings of the START trial?

Answer 18

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

Question 19

What are the 5 classes of HIV medications?

Answer 19

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

Question 20

What are examples of nucleoside/nucleotide RTIs?

Answer 20

Nucleoside

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

Nucleotide
- tenofovir

Question 21

What are reverse transcriptase inhibitors (Non nucleoside)?

Answer 21

nevirapine
efavirenz
etravirine
rilpivirine

Question 22

What are examples of protease inhibitors?

Answer 22

Lopinavir/ritonavir
atazanavir
fosamprenavir
saquinavir
tipranavir
darunavir

(ritonavir - p450 inhibitor, booster)

Question 23

What are examples of entry inhibitors?

Answer 23

Fusion inhibitors -enfuvirtide

CCR5 inhibitors - Maraviroc

Question 24

What are examples of integrase inhibitors?

Answer 24

ralegravir
dolutegravir
elvitegravir/cobiscistat

Question 25

What determines choice of ART regime?

Answer 25

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

Question 26

What are recommended regimes per DHHS 2015 guidelines?

Answer 26

Truvada + Raltegravir/Dolutegravir/Elvitegravir+cobicistat/darunavir+ritonavir Abacavir + lamivudine + dolutegravir

Question 27

What is the goal of HIV therapy?

Answer 27

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

Question 28

What is virologic/immunologic failure?

Answer 28

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

Question 29

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

Answer 29

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)

Question 30

What are features of HIV genotype testing?

Answer 30

``` 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

Question 31

When should resistance testing be performed?

Answer 31

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

Question 32

What are toxicities associated with tenofovir?

Answer 32

Renal toxicity - Fanconi syndrome - RTA due to loss of bicarb, phosphate, glucose and AA - GFR decline without Fanconi's - Decreased BMD

Question 33

What are toxicities associated with abacavir?

Answer 33

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)

Question 34

What are toxicities associated with efavirenz?

Answer 34

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

Question 35

What are toxicities associated with nevirapine?

Answer 35

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

Question 36

What are toxicities assocaited with atazanavir?

Answer 36

hyperbilirubinaemia and renal stones

Question 37

What are features of lipodystrophy?

Answer 37

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

Question 38

What medications are at highest risk of lipoatrophy?

Answer 38

didanosine, stavudine

Question 39

What are intermediate and low risk medications for lipoatrophy?

Answer 39

zidovudine - intermediate risk emtricitibine, abacavir, tenofovir and lamivudine

Question 40

What other factors contribute to lipoatrophy?

Answer 40

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

Question 41

What is the management of lipodystrophy?

Answer 41

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

Question 42

What is management of lipohypertrophy?

Answer 42

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

Question 43

What class of medications have the greatest metabolic impact?

Answer 43

PIs, especially tipinavir/ritonavir and indivnavir/ritonavir NRTI - stavudine (abacavir, tenofovir, emtricitibine, lamivudine ok) Low risk with integrase inhibitors

Question 44

What ART medications are metabolised by P4503A4 enzymes?

Answer 44

PIs and NNRTIs | ritonavir is the most potent P4503A4 inhibitor (also 2D6, 2C9, 2C19)

Question 45

What are P4503A4 inducers?

Answer 45

nevirapine induces P4503A4 efavirenz induces and inhibits P4503A4 - unpredictable drug interactions Raltegravir has no p450 act (all UGT1A1), dolutegravir minor p450

Question 46

What medications are absolutely contraindicated with P4503A4 inhibitors?

Answer 46

C/I with ritonavir, cobicistat Cisapride - aLQTs - torsades Lovastatin, simvastatin - rhabdo Midazolam, triazolam - prolonged sedation - use propofol

Question 47

What medications are cautioned with P4503A4 inhibitors?

Answer 47

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

Question 48

What opiate is metabolised by a P450 enzyme?

Answer 48

methadone is metabolised by P4503A4 - nevirapine causes methadone withdrawal - cessation of nevirapine - potential for OD

Question 49

What occurs when atazanavir is prescribed with PPIs?

Answer 49

decreased absorption of atazanavir

Question 50

What medications are implicated in ART related hepatotoxicity?

Answer 50

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

Question 51

What is the efficacy of treatment as prevention?

Answer 51

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

Question 52

What is the effectiveness of PrEP in the real world?

Answer 52

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.

Question 53

What is the efficacy of on demand PrEP?

Answer 53

effective! NNT of 18 for 1 year

Question 54

What are significant HIV latent reservoirs?

Answer 54

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

Question 55

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

Answer 55

Cell to cell infection, as in lymphoid tissue

Question 56

What re reservoirs for infection?

Answer 56

CNS Lymphoid tissue Genitalia (immunologically privileged) GUT