Virology B5: Anti-Retroviral Therapy In Aids

Front 1

When did AIDS therapy begin? Why did the number of deaths still rise?

Back 1

1996 - so many people infected, they were in end stage of disease and were ready to go

Front 2

What are the 4 targets of HIV therapy?

Back 2

1) Entry inhibitors - virus-cell fusion, CD4, CCR5, CXCR4 (chemokine inhibitors),

2) Reverse transcriptase inhibitors - NRTI (nucleoside), NNRTIs (non-nucleoside)

3) Protease inhibitors

4) Integrase inhibitors (in nucleus)

Front 3

NRTIs:

1) What are they?
2) What is the main drug?
3) What activates these drugs?
4) How do they work?

Back 3

1) Nucleoside reverse transcriptase inhibitors - nucleoside analogs
2) AZT (azidoTHYMIDINE), then tenofuvir and lamivudine
3) Phosphorylation by host kinases
4) Taken up preferentially by HIV reverse transcriptase, blocks active site of RT, terminates DNA synthesis

Front 4

NNRTIs:

1) What are they?
2) Main drugs?
3) How do they work?

Back 4

1) Non-nucleoside reverse transcriptase inhibitors
2) Efavirenz, Nevirapnie, delaviridine
3) Bind to RT in a pocket distant from active site, not incorporated into DNA, **non-competitive**

Front 5

NNRTIs:

1) What strains are susceptible?
2) Synergistic with?
3) Toxicity?

Back 5

1) NRTI-resistant
2) Nucleoside analogs
3) Minimal toxicity

Front 6

Protease inhibitors:

1) What are the drugs?
2) How do they work?
3) What happens to infected cells?

Back 6

1) RINSA-avir (Ritonavir, indinavir, nelfinavir, saquinavir, amprenovir)

2) Synthetic, non-hydrolysable peptides compete for HIV protease, inhibits it from binding to multiprotein molecule.

3) Accumulate polyproteins, which leads to cell death. Need cleavage of proteins for maturation of virion.

Front 7

What is TNX-355 and what does it do?

Back 7

Investigational drug that prevents binding of gp120 to CD4.

Front 8

What is Maraviroc and what does it do?

Back 8

Approved CCR5 antagonist, inhibits co-receptor binding of HIV

Front 9

What does enfuvirtide do?

Back 9

Approved drug that blocks virus-cell fusion.

Front 10

What does Raltegravir do?

Back 10

Inhibition of DNA integrase - inhibits irreversible strand transfer step of DNA integration.

Front 11

What are the five categories of approved anti-retroviral drugs?

Back 11

1) NRTI
2) NNRTI
3) PI
4) Fusion inhibitor
5) CCR5 Antagonist
6) Integrase inhibitor

Front 12

HAART:

1) What is it a combination of?
2) Increases patient survival by how long?

Back 12

1) 3 anti-retroviral agents blocking different stages of viral replication cycle
2) 13.3 years

Front 13

What is the current standard of care for AIDS?

Back 13

HAART

Front 14

What are the 3 types of patients that are indicated for therapy with HAART?

Back 14

1) HIV+ with AIDS defining illness OR CD4 count <350/ul

2) Preggo HIV+ patients regardless of CD4 count to prevent transmission to fetus

3) HIV post-exposure prophy

Front 15

How strong of a recommendation for HAART treatment are:

CD4+ 350-500/ul

Back 15

Strong/moderate

Front 16

How strong of an indication for HAART therapy is:

CD4+ >500/ul

Back 16

Recommended, optional

Front 17

How strong of an indication for HAART therapy is:

HBV/HCV coinfection

Back 17

Recommended

Front 18

How strong of an indication for HAART therapy is:

HIV associated nephropathy

Back 18

Recommended

Front 19

How strong of an indication for HAART therapy is:

Acute HIV infection

Back 19

Optional

Front 20

Clinical outcome of HAART therapy is improved by?

Back 20

Starting therapy at higher CD4+ count. Lower risk of disease/death at 351-500 cells/mm^3

Front 21

What is the preferred regimen for NNRTI-based HAART therapy? Who do you avoid with this treatment?

Back 21

Efavirenz (NNRTI) + lamivudine (NRTI) or zidovudine (NRTI), 2-5 pills a day. Avoid in preggo women or women with high preggo potential

Front 22

What is the preferred regimen for PI based HAART therapy?

Back 22

Lopinavir or ritonavir (PI) + lamivudine (NRTI) or zidovudine (NRTI), 8-10 pills/day

Front 23

What is the probability of vertical transmission in HIV and pregnancy?

Back 23

15-25%

Front 24

How does vertical transmission occur in HIV and pregnancy?

Back 24

Ante-partum, **delivery (60-75%)**, breastfeeding

Front 25

Vertical transmission in HIV and pregnancy is more likely when?

Back 25

1) High maternal viral load, low CD4 count
2) Very early or very late disease
3) Premature rupture of membranes

Front 26

Risk of perinatal transmission in HIV and pregnancy is significantly reduced (<2%) with?

Back 26

1) Effective antiretroviral therapy 2) C section at 38 weeks when HIV RNA levels >1000 copies/ml or viral levels unknown 3) formula feeding

Front 27

What year saw a peak in perinatally acquired AIDS cases? How have levels been since then?

Back 27

1993, levels have been on steady decline since.

Front 28

What are the recommendations for pregnant HIV+ women?

Back 28

1) 3 part regimen REGARDLESS of viral load or CD4 cell count, including zidovudine (AZT) if possible.

2) AZT after 12 weeks gestation, IV during labor

Front 29

What is Rx for a newborn born to an HIV+ mom?

Back 29

AZT for first 6 weeks of life

Front 30

What is the risk of acquiring HIV from infected patient by percutaneous exposure?

Back 30

~0.3%

Front 31

What is the risk of acquiring HIV from infected patient by mucous membrane exposure?

Back 31

~0.9%

Front 32

Risk of getting HIV post-exposure is increased by what 3 things?

Back 32

1) Larger quantity of blood
2) Procedure involving insertion of needle into blood vessel
3) Deep injury

Front 33

As of Dec. 2006, how many cases are there of documented occupational HIV infections in the US? Possible?

Back 33

57, 0 dentists. 140 possible, 6 dentists. No new cases since 2000.

Front 34

What is the main route for HIV transmission?

Back 34

Percutaneous

Front 35

What is the 2 drug PEP regimen?

Back 35

1) 2 NRTIs (like AZT + lamivudine)
2) NtRTI + NRTI (tenofovir, lamivudine)

Front 36

What is the >3 drug PEP regimen?

Back 36

2-drug PEP + PI (ritonavir)

Front 37

How long do you continue PEP for? PEP failure to date?

Back 37

4 weeks. 6 cases worldwide

Front 38

What kind of PEP do you give someone if:

Less severe, solid needle superficial injury with HIV+ asymptomatic, low viral load?

Back 38

2 drug

Front 39

What kind of PEP do you give someone if:

Less severe, solid needle superficial injury with HIV+ symptomatic, AIDS, high viral load

Back 39

3 drug

Front 40

What kind of PEP do you give someone if:

More severe deep puncture, visible blood, HIV+ asymptomatic, low viral load

Back 40

3 drug

Front 41

What kind of PEP do you give someone if:

More severe deep puncture, visible blood, HIV+ symptomatic, AIDS, high viral load

Back 41

3 drug

Front 42

What kind of PEP do you give someone if:

Mucous membrane, small volume, HIV+ asymptomatic, low viral load

Back 42

Consider 2 drug PEP

Front 43

What kind of PEP do you give someone if:

Mucous membrane, small volume, HIV + symptomatic, AIDS, high viral load

Back 43

2 drug PEP

Front 44

What kind of PEP do you give someone if:

Mucous membrane, large volume, HIV+ asymptomatic, low viral load

Back 44

2-drug PEP

Front 45

What kind of PEP do you give someone if:

Mucous membrane, large volume, HIV+ symptomatic, AIDS, high viral load

Back 45

3 drug PEP

Front 46

What is the success of HAART determined by? How do CD4+ cell counts react?

Back 46

Decrease of HIV mRNA levels below the level of detection (<50 copies/ml). CD4+ counts rise slowly, recovery is directly associated with baseline CD4 count.

Front 47

What is immune reconstitution syndrome? Flares of which disease are common?

Back 47

Infections flare up shortly after beginning ART because CD4 cells are increasing - flares of mycobacterial disease common (eg tuberculous lymphadenopathy)

Front 48

What is the main cause of HAART failure?

Back 48

Toxicity (58%), noncompliance (20%), virologic (14%)

Front 49

What are the side effects of NRTIs?

Back 49

Pancreatitis, neuropathy, GI, marrow suppression

Front 50

What are the side effects of NNRTIs?

Back 50

Rash, hypersensitivity reactions

Front 51

What are the side effects of PIs?

Back 51

Glucose intolerance (diabetes), hyperlipidemia, lipodystrophy, breast hypertrophy, GI, paresthesia, rashes

Front 52

What are the side effects of fusion inhibitors?

Back 52

Hypersensitivity, increased risk of bacterial pneumonia

Front 53

Lipodystrophy:

1) What is it a side effect of?
2) What are the four things that happen?

Back 53

1) PI therapy
2) a) Fat buildup - buffalo hump, increase in fat in neck/shoulders. Crix belly - abdominal fat

b) Fat loss - arms, legs, buttocks, face

c) Increased fat levels in blood (triglycerides, cholesterol)

d) Increase in blood sugar (diabetes)

Front 54

Resistance to therapy:

1) What causes it?
2) How can we counter that?

Back 54

1) ~ 10 billion viral particles made daily, 1 mutation per new HIV RNA copy

2) Multi-drug therapy reduces risk of development of resistance - 3 class is best > NNRTI > PI > 2 class

Front 55

Ancillary therapies:

1) What are they used for?
2) 3 main examples?
3) Immunotherapy?
4) How do you deal with AIDS patients and live vaccines?

Back 55

1) Treat opportunistic infections
2) Erythropoeitin - AZT associated red cell dysplasia

Granulocyte Colony Stimulating Factor - for neutropenia

Inerferon alpha - Kaposi's sarcoma

3) IL-2
4) DO NOT give live vaccines

Front 56

What did they see in a stem cell transplant from a CCR5delta32 donor in an AIDS patient with leukemia?

Back 56

HIV-1 RNA decreased, CD4+ T cells went up