Hiv: Antiretroviral Therapy

Front 1

HIV disease pathology: HIV virus invades and replicates within what type of human cells?

Back 1

human T-cells (CD4 cells)

Front 2

HIV disease pathology: after invading human T-cells, the virus does this...

Back 2

causes destruction of T-cell (CD4 cell) causing impaired immune function

Front 3

HIV disease pathology: after invading human T-cells --> destruction --> impaired immune function, what happens?

Back 3

impaired immune function enables INFECTIOUS disease progression --> AIDS development

progression --> severe illness --> death

Front 4

HIV replication: HIV virions attach to [these] receptors and coreceptors, and then fuse with [this]

Back 4

HIV virions attach to [CD4] receptors and coreceptors, and then fuse with the [T-cell]

Front 5

HIV replication: upon fusing with the T-cell, what happens?

Back 5

viral RNA duplicates into DNA via reverse transcriptase enzyme

Front 6

HIV replication: upon duplicating, the viral DNA is integrated into host cell using what enzyme?

Back 6

integrase

Front 7

HIV replication: upon integration, what is produced?

Back 7

mRNA is produced, and translated into viral proteins

Front 8

HIV replication: what type of enzymes process HIV proteins into functional (infectious) form????

Back 8

Protease enzymes

Front 9

CD4 count is an indicator of what?

VL measures what?

Back 9

CD4 - an indicator of immune function; cells/mm3

VL - measures amount of virus in blood; copies/mL; PCR

Front 10

do we want high/low CD4 and VL?

Back 10

we want high CD4 and low VL

Front 11

HIV dynamics: how many virions are produced daily?

Back 11

10^9 virions produced QD

Front 12

cell free virus has a t1/2 of how long?

what about productively infected CD4 cells; how long is their t1/2?

Back 12

cell free virus t1/2 = 6h
productively infected CD4 cells t1/2 = 1.6 days

Front 13

time of release of new virion to infection of new cell and release of another new virion is ...

Back 13

2.6 days

Front 14

in 4-6 weeks after infection; what happens to VL, CD4? do they decrease/increase by themselves?

Back 14

VL increases; will go down by itself

CD4 decreases; will NOT increase by itself

Front 15

time frame: viral transmission --> acute viral syndrome

Back 15

2-3 weeks

Front 16

time frame: acute viral syndrome --> recovery + seroconversion

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2-3 wks

Front 17

time frame: recovery + seroconversion --> asymptomatic chronic HIV infection

Back 17

2-4wks

Front 18

time frame: asymptomatic chronic HIV infection --> symptomatic HIV infection/AIDS

Back 18

avg 8 years

Front 19

time frame: symptomatic HIV infection/AIDS --> death

Back 19

avg 1.3 years

Front 20

making a diagnosis of HIV is a two step process; what are the two steps?

Back 20

Enzyme Immunoassay (EIA) followed by a confirmatory western blot (WB)

Front 21

most common symptoms of acute viral syndrome include (5)

Back 21

1. fever
2. lymphadenopathy
3. pharyngitis
4. rash
5. other: myalgia, arthralgia, N/V/D, ha, weight loss, thrush

Front 22

how would one define acquired immunodeficiency syndrome (AIDS)?? HIV infection has these two guidelines: (CD4 count) +/- ??

Back 22

CD4 <200 +/- presence of specific clinical conditions (AIDS defining illnesses)

Front 23

AIDS defining illnesses: many!

Back 23

Candidiasis, Isoporosis with wasting, Cervical Cancer, Kaposi’s sarcoma, Coccidioidomycosis, Lymphoma, Cryptococcus, Mycobacterium avium Complex, Cryptosporidiosis, Mycobacterium tuberculosis, Cytomegalovirus, Pneumocystis carinii (jiroveci), Herpes simplex, Pneumonia (recurrent), Histoplasmosis, Progressive multifocal leukoencephalopathy, HIV-associated dementia, Salmonella septicemia, HIV-associated wasting, Toxoplasmosis

Front 24

HIV disease progression and time frame:

Back 24

1. primary infection
2. constitutional symptoms (~7 years)
3. opportunistic dx (~8 yrs)
4. death (11yrs)

patients may live for a much longer time -- each pt will react differently!

Front 25

5 drug targets for HIV and type of drug class used for each...

Back 25

1. viral fusion with host cell
a. entry inhibitors
2. CCR5 receptors on CD4 cells
a. entry inhibitors - CCR5 antagonists
3. reverse transcriptase process
a. NRTIs
b. NNRTIs
4. integrase
a. integrase inhibitors
5. protease viral cleavage
a. protease inhibitors

Front 26

5 classes of antiretroviral meds

Back 26

1. nucleoside reverse transcriptase inhibitors (NRTI's)/nucleotide RTI (tenofovir)
2. non-nucleoside reverse transcriptase inhibitors (NNRIT's)
3. pretease inhibitors (PI)
4. entry inhibitors: enfuviritde, CCR5 antagonists (maraviroc)
5. integrase inhibitors (raltegravir)

Front 27

list NRTIs

Back 27

retrovir (zidovudine)
videx (didanosine)
zerit (stavudine)
epivir (lamivudine)
ziagen (abacavir)
viread (tenofovir)
emtriva (emtricitabine)

Front 28

list NRTIs that are combo products

Back 28

combivir (zidovudine+lamivudine),

trizivir (zidovudine+lamivudine+abacavir)

truvada (tenofovir+emtricitabine)

epzicom (abacavir+lamivudine)

Front 29

list NNRTIs

Back 29

Viramune (nevirapine)

Rescriptor (delavirdine)

Sustiva (efavirenz)

Front 30

list PIs

Back 30

Invirase (saquinavir HGC)

Crixivan (indinavir)

Norvir (ritonavir)

Viracept (nelfinavir)

Lexiva (fosamprenavir)

Kaletra (lopinavir/ritonavir)

Reyataz (atazanavir)

Tipranavir (Aptivus)

Darunavir (Prezista)

Front 31

list 2 entry inhibitors

Back 31

Fuzeon (enfuvirtide, T20)

Selzentry (Maraviroc)

Front 32

what is an integrase inhibitor?

Back 32

raltegravir (isentress)

Front 33

how do NRTI's work?

Back 33

chain termination; RT can no longer do its job

they mimic different DNA analogs (incorporated into chains so that no subsequent analogs can be added)

Front 34

nucleosides have to undergo what to become active?

Back 34

phosphorylation

nucleoTides already have this step done (tenofovir)

Front 35

NRTI's that pose as thymidine analogs are:

Back 35

zidovudine (retrovir)
stavudine (zerit)

Front 36

NRTIs that pose as adenosine analogs are:

Back 36

didanosine (videx)
tenofovir (viread)

Front 37

NRTIs that pose as cytosine analogs are:

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lamivudine (epivir)
emtricitabine (emtriva)

Front 38

NRTIs that pose as guanine anoalogs are:

Back 38

abacavir (ziagen)
amdoxovir (?)

Front 39

Resistnace to NRTI can occur via:

Back 39

interference with the incorporation of a nucleoside analogue

Front 40

does it matter which NRTI is used??? why???

Back 40

YES!
there is a diffirence in drugs in: dosing frequency, side effect potential, drug interactions, potency, resistance profile**, and the ability to work well with others

Front 41

these side effects are common w/ALL NRTIs:

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N/V/D*

lactic acidosis with hepatic statosis -- rare, but serious

Front 42

bone marrow suppression is a possible side effect of this NRTI

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zidovudine (retrovir)

Front 43

pancreatitis is a common side effect of this NRTI

this NRTI should be taken 1/2 before or 2 hrs after a meal

Back 43

didanosene (videx)

Front 44

this NRTI is associated with minmal toxicity

Back 44

Lamivudine (Epivir)

Front 45

there is an increased risk of hypersensitivity reaction with this NRTI and alcohol will increase its levels by 41%

Back 45

Abacavir (ziagen)

Front 46

this NRTI works best if taken WITH FOOD; one of its SE if renal insufficiency (rare)

this NRTI is also a nucleoTide

Back 46

tenofovir (viread)

Front 47

these two combination NRTIs are dosed QD; and these two are dosed BID

Back 47

QD: combivir, trizivir
BID: epzicom, truvada

Front 48

this is the first combination product that spans antiretroviral drug classes: it includes 2NRTIs and 1NNRTI

Back 48

Atripla
NRTI: emtricitabine, tenofovir
NNRTI: efavirenz

Front 49

this NRTI is associated with lypoatrophy

Back 49

stavudine (zerit)

Front 50

this NRTI is associated with hyperpigmentation

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emtricitabine (emtriva)

Front 51

mitochnodrial toxicity is most common with which class of antiretrovirals?

Back 51

NRTIs

Front 52

major offenders (NRTIs) associated with mitochondrial toxicity

Back 52

stavudine (zerit)
didanosine (videx)

Front 53

clinical manifestations of mitochondrial toxicity

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lactic acidosis, microvascular steatosis (mostly in liver), anemia, myopathy, neuropahty, pancreatitis

Front 54

how does mitochondrial toxicity occur?

Back 54

drugs inhibit DNA polymeraseY --> leads to impaired oxidative phosphorylation

Front 55

s/sx of abacavir hypersensitivity reaction:

Back 55

rash, fever, fatigue, malaise, GI (N/V/abdominal pn)


less common sx: arthralgias, edema, cough, dyspnea

Front 56

with abacavir hypersensitivity reaction - are the symptoms long term?

Back 56

no, symptoms resolve upon d/c of therapy

Front 57

abacavir hypersensitivity reaction; can patient be rechanllenged?******KNOW

Back 57

no! there is a real danger -- may lead to severe life-threatening hypotension --> death***

Front 58

is there testing available to evaluate pts at greatest risk for abacavir hypersensitivity reaction?

Back 58

yes, HLA-5701*B is a genetic test available

Front 59

abacavir hypersensitivity reaction presents at a median of how many days?

Back 59

9 days
(93% of cases occur w/in first 6 weeks of therapy)

Front 60

black box warning on ALL NRTIs

Back 60

lactic acidosis + hepatic steatosis

Front 61

black box warning on Lamivudine/emtricitabine/tenofovir:

Back 61

hepatic flare with acute removal of agents in pts co-infected w/hepB

Front 62

black box warning on abacavir:

Back 62

hypersensitivity reaction

Front 63

black box warning on didanosine:

Back 63

reports of fatal pancreatitis

Front 64

black box warning on zidovudine:

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hematologic toxicity including granulocytopenia and severe anemia

Front 65

NNRTI mechanism of action

Back 65

bind DIRECTLY to reverse transcriptase and inhibit its action

Front 66

this NNRTI produces CNS symptoms such as vivid dreams, drowsiness..it is also teratogenic if used in pregnant patients

Back 66

efavirenz (sustiva)

Front 67

this NNRTI should be taken on an EMPTY stomach(due to increased levels and incidence of AE if taken with food)

Back 67

efavirenz (sustiva)

Front 68

this NNRTI causes hepatic necrosis and requires dose escalation upon initiation of treatment
its also an auto inducer

Back 68

nevirapine (viramune)

Front 69

headaches are associated with use of this NNRTI + it is rarely used

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delavirdine (rescriptor)

Front 70

class side effects associated with NNRTIs (black box warning exists for both of these side effects)

Back 70

1. Hepatotoxicity: elevated LFTs +/- hepatitis, hepatic necrosis

2. Rash: steven johnson's syndrome

Front 71

what monitoring parameter is most important for pts on nevirapine?

Back 71

LFT's

Front 72

nevirapine (viramune) hepatotoxicity is more common in women w/ what CD4 count? what about men?

what is the time frame in which hepatotoxicity occurs?

Back 72

women: CD4>250
men: CD4>400

time frame: typically occurs w/in 1st 12 weeks: hypersensitivity and hepatic necrosis*

Front 73

mechanism of action of PI

Back 73

bind w/in active pocket of PROTEASE, inhibiting binding of virus
w/o protease cleavage, virus canNOT cause infection

Front 74

this PI is associated with GI intolerance, N/V/D, increased LFTs, hypERglycemia, increased lipids, fat redistribution

Back 74

Darunavir (prezista)

Front 75

these are the only PIs that should be taken on an EMPTY stomach, all others should be taken with food...

Back 75

1. fosamprenavir (lexiva)
2. indinavir (crixivan)
3. saquinavir (invirase)

Front 76

this PI is not recommended for use as monotherapy

Back 76

saquinavir (invirase)

Front 77

this PI is used primarily as a boosting agent; and its effects are most see when it is used as an active PI

Back 77

ritonavir (norvir)

Front 78

this is a combination PI regimen

Back 78

Kaletra (lopinavir+ritonavir)

Front 79

PI class side effects

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1. GI intolerance (N,V,D)
2. liver enzyme elevations
3. metabolic complications
(hyperlipidemia, hyperglycemia, lipodystophy - fat redistribution)

Front 80

which PI causes no metabolic complications?? its the exception to the class AEs...

Back 80

Atazanavir (reyataz)

Front 81

increased risk of hyperlipidemia occurs with what classes of antiretrovirals?

Back 81

NNRTIs, PIs and stavudine (NRTI)

PIs are greatest offenders!

Front 82

what is the mechanism of PI induced insulin resistance?

Back 82

GLUT4 is an insulin responsive glucose transporter..in resistnace, these trasnporters are blocked/innactivated

Front 83

black box warning on ritonavir (norvir)

Back 83

co-admin w/certain nonsedating antihistamines, sedative hypnotics, antiarrhythmics, or ergot alkoloid preparations may result in life-threatening adverse events

Front 84

black box warning on tipranavir (aptivus)

Back 84

reports of fatal & non-fatal intracranial hemorrhage; clinical hepatitis, hepatic decompensation including some fatalities

Front 85

this PI is used as a "booster" and why?

Back 85

ritonavir

its the most potent inhibitor of cyp3a4
--all PIs are substrates of 3A4

Front 86

when being used as a booster, high or low dose of ritonavir is used?

Back 86

LOW dose...which causes increased efficacy, less pill burden potentially, less resistance

*more absorpion, better efficacy

Front 87

Two ways Ritonavir acts as a booster...

Back 87

1. by inhibiting cyp3A4
2. by blocking p-glycoprotein transport pump causing SQV to enter circulation

---causes increased mean PI C-trough levels with coadministration w/ritonavir

Front 88

which step of HIV attachment and fusion does enfuvirtide inhibit?

Back 88

it inhibits gp41
(gp41 mediates fusion of the viral and cell membranes (the last step))

Front 89

enfuvirtide is administered via?

Back 89

injection (powder reconstituted with sterile water) 90mg q12h (aka BID)

Front 90

a common AE of enfuvirtide aside from local site injection and hypersensitivity reaction...

Back 90

increased rate of bacterial pneumonia

Front 91

what patient population is enfuvirtide (T20) used in?

Back 91

treatment experienced patients

(NEVER as initial therapy)

Front 92

what is an issue with T20 (enfuvirtide)?

Back 92

resistance!

Front 93

the first approved CCR5 antagonist

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maraviroc (selzentry)

Front 94

MOA of CCR5 antagonists

Back 94

chemokine (c-c motif) receptor 5 inhibitors

Front 95

ccr5 antagonists are often used for what?

Back 95

they are used as co-receptors to enter T-cells; used with TROPISM ASSAY to determine if CCR5 is the predominant co-receptor used by the pt

Front 96

CCR5 antagonists cause these serious AEs

Back 96

hepatotoxicity, rare

Front 97

CCR5 antagonists cause these common AEs

Back 97

cough, fever, UPPER RESPIRATORY TRACT INFECTIONS,rash, musculoskeletal symptoms, abdominal pn, and dizziness, SINUSITIS

Front 98

what patient population are CCR5 antagonists used in?

Back 98

treatment experienced patients with extensive resistance

Front 99

dosing of CCR5 antagonist is based on what?

Back 99

****Dosing is based upon drug interactions with common medications****


With some drugs, have to give lower dose – others can give normal dose or higher dose

given BID

Front 100

what pt population are integrase inhibitors (such as Raltegravir (insentress)) used in?

Back 100

treatment experienced with extensive resistance

Front 101

MOA of integrase inhibitors

Back 101

inhibit viral enzyme: integrase

integrase is necessary for insertion of viral DNA into human genomic DNA

Front 102

dosing of Raltegravir (insentress)

Back 102

400mg po bid

Front 103

common AE of raltegravir

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N, HA, diarrhea, pyrexia

Front 104

rare, serious AE of raltegravir (insentress)

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myopathy and rhabdomyolysis