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Flashcards in Antivirals Deck (63):
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HAART

highly active antiretroviral therapy
increase survivability

1

Goals of ART?

reduce HIv infection-related morbidity and prolong duration and quality of survival
resotre and preserve immunologic function
maximally and durably suppress viral load
prevent vertical HIV transmission
Key - achieve and maintain durable viral suppression

2

how would you determine which drugs to choose?

-Pre ART - determine CD4 count, measure HIV RNA and perform resistance testing
-determine viral tropism - prior to initiation of CCr5 antagonist
HLAB*5701 testing - prior to initiation of abacavir (ABC) due to risk of hypersensitivity reaction

3

What shows success of ART treatment?

high potency of ARV regimen
excellent adherence to treatment regimen
low baseline viremia
higher baseline CD4 count - >200 cells/mm3
rapid reduction of viremia in response to treatment

4

Classes of Antiretrovirals

Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease Inhibitors
Integrase inhibitor
Fusion inhibitors
Chemokine receptor antagonists - CCR5 antagonists

5

What can Antiretrovirals NOT do?

do not cure HIV infection or AIDS
do not eliminate risk of passing HIV to other
HIV medicines must be taken in combination with other HIV medicines
not all medicines are right for all ppl and treatments may be different for each person

6

Mechanism of Nucleoside reverse transcriptase inhibitors

-competitively inhibit RT effectively blocking ability of virus to make a provirus copy
-the NRTIs gets added to the growing proviral chain by RT leading to chain termination
-bind at the RT active site

7

Zidovudine

ZDV (was AZT)
Thymidine analogue

8

When ZDV was used as monotherapy

HIV quickly became resistant
so currently used in combination drug regimens

9

Side effects of ZDV

anemia and granulocytopenia
avoid using with other myelosuppressive drugs

10

Examples of Nucleoside reverse transcriptase inhibitors

Zidovudine - AZT,ZDV
Lamivudine
Abacavir (this is the one associated with hypersens. reaction)
Didanosine
Emtricitabine
Stavudine
Tenofovir

11

Non nucleoside Reverse transcriptase inhibitors mechanism?

bind to and alter reverse transcriptase
bind directly to RT
can be used synergistically with NRTIs due to differences in binding location

12

what is a concern with NNRTI?

whether the virus will be susceptible or resistant

13

Examples of NNRTIs

Efavirenz*
Delavirdine
Nevirapine
Rilpivirine
Etravirine - has anti HIV-2 activity as well

14

Mechanism of Protease Inhibitors

binds to HIV protease (which essential for proteolytic processing of nascentt polypeptides into individual proteins during maturation)

15

Activity of PIs

against HIV-1 and HIV-2

16

Mechanism of resistance to PIs

due to mutations inside and outside the active protease domain

17

Examples of Protease Inhibitors

Ritonavir*
Darunavir
Atazanavir
Fosamprenavir
Indinavir
Nelfinavir
Saquinavir
Tipranavir

18

Potency of NRTI

less potent than NNRTIs and PIs

19

Mechanism of ZDV/AZT resistance?

mutations remove ZDV from DNA chain
a conformational change allowed Thymine to continue to bind but disabled
ZDVs ability to bind RT
also able to remove ZDV from the proviral DNA

20

NRTI is active against?

HIV-1 and HIV-2

21

Efavirenz

preferred drug for combination therapy in treatment naive individuals

22

Etravirine

has anti-HIV-2 activity as well

23

Ritonavir side effects?

inhibits host protein cytochrome P450 3A4 which results in failure to metabolize other drugs, including other PIs, this leads to higher serum levels and sometime an increase in toxicity

24

Lipodystrophy

Fat wasting - fat is lost from arms, legs, face and buttocks
fat redistribution due to PIs (&NNRTIs)
disturbs the way the body produces, uses, and stores fat

25

Hyperadiposity

fat accumulation
fat builds up in belly, breasts and back of the neck

26

Clinical signs of Lipodystrophy

back of neck and upper shoulders - buffalo hump
abdomen - protease paunch or crixivan potbelly
breasts - both men and women
Lipomas - fatty growths in different parts of the body

27

Proviral integration

Proviral integration is 2 step process
-3'-processing in host cell cytoplasm to prepare proviral strands for attachment
-strand transfer where proviral DNA is covalently linked to cellular DNA

28

Mechanism of Integrase Inhibitors (INSTI)

competitively inhibits Mg+2 or Mn+2 both essential cofactors for integrase binding to proviral DNA

29

Examples of INSTIs

Raltegravir
Elvitegravir
Dolutegravir

30

INSTI resistance

mutations in integrase gene associated with resistance to raltegravir and elvitegravir

31

which step of proviral integration do INSTIs block?

step 1 - 3' processing in host-cell cytoplasm

32

1 pill with 4 drugs

Raltegravir
Elvitegravir
both have same mechanism - blocks Mg binding

(only told two of them)

33

Mechanism of Fusion Inhibitors

prevent HIV from entering
binds gp41 and prevents fusion to host cell and viral entry
ONLY for HIV-1
used in combo with other ART drugs

34

Enfuvirtide (T-20)

36 AA peptide derived from EC domain of gp41 of HIV-1 envelop
given when other drugs have failed

35

Mechanism of chemokine receptor antagonists

blocks binding of virus to target cell
directly competes with gp120 for site

36

Maraviroc

its a CRA
blocks gp120 from binding CCR5
only works for CCR5 tropic viruses

37

What viruses are there antivirals available for?

Influenza viruses
Herpes viruses - HSV-1, and 2 VZV, CMV
Respiratory syncytial virus (RSV)
Hep B virus
Hep C virus
Papillomaviruses
HIV

38

Inhibiting Antiviral drugs can target

attachment/adsorption
penetration/entry
nucleic acid synthesis
release

39

A drug that affects viral inhibition of cellular processes could do so by

prevent viral inhibition by interferon production

40

How could anti virals support the immune system to combat viral infections?

by affecting antibodies and immune modulators
-polyclonal antisera
-monoclonal antibodies
-Imiquimod

41

Anti-Influenza drugs

Permavir
Oseltamivir (Tamiflu)
Zanamivir (Relenza)
-these inhibit cleavage of HA-SA bonds by NA - thus no viral release
Amantadine
Rimantadine
-these block M2 ion channel - no viral coating

42

Neuraminidase inhibitors for Inf A and B

inhibits viral release and virion clumping promoted
must be started
reduces severity and shortens duration of symptoms

-Peramivir - IV adults only
-Oseltamivir
-Zanamivir

43

H+ ion channel (M2) inhibitors for Influenza A

not currently rec. due to high levels of resistance to circulating strains of Influenza A
interfers with H+ transport, necessary component for uncoating to occur thus RNA transcription cannot happen

-Adamantes
-Rimantadine

44

M2

required by Influenza to uncoat and release its genome

45

Activation of Nucleoside Analogues for HSV,VZV

converted to active drug by 3 phosphorylation steps in viral-infected cells
1-first phosphorylation step by viral thymidine kinase
2-Next 2 phosphorylation steps by host cell enzymes
3-Acyclovir tri phosphate added to growing chain of herpes virus DNA - results in chain termination

46

Mechanism of Nucleoside Analogues for HSV

Acyclovir - prodrug
Added to growing chain of virus DNA

47

Acyclovir related compounds

Valacyclovir - better bioavaible than oral acyclovir
Famciclovir - higher intracellular levels
Penciclovir - higher intracellular levels

48

CMV is opportunisitc in IC pts, clinical manifestations of infection

AIDS pts tend to be infected, pts may be on myelosuppressive (AZT) or nephrotoxic drugs
Retinitis
Esophagitis
Coliis
Encephalitis
Pneumonia

49

HIV+ patients are resistance to

Acyclovir

50

CMV doesnt encode

Thymidine Kinase

51

Nucleoside Analogues for CMV

Acyclovir and related not active because uses different enzymes to initiate phosphorylation
Ganciclovir - bone marrow toxicity - leads to neutropenia, CMV retinitis
Valganciclovir
Cidofovir - cytosine analog

52

Foscarnet

...

53

Fomivirsen

...

54

Palivizumab

monoclonal antibody to RSV F protein

55

Ribavirin mechanism

Broad spectrum antiviral
synthetic nucleoside analog - GTP analog
interferes with viral RNA-dep RNA polymerase (RdRP)

56

Side effects of Ribavirin

dose dep hemolytic anemia
dry cough, dyspnea
Teratogenic

57

Indications for Ribavirin

RSV - hospitalized infants
Hep C
Vaccinia, Monkeypox

58

Nucleoside analogues for HBV -RT inhibitor

Lamivudine, telbivudine
blocks HBV DNA synthesis by incorporating into the growing DNA chain, causing premature chain termination

59

NA -RT AND DNA poly inhibitor - HBV

Adefovir - rare cases Renal toxic
Tenofovir - rare cases Hepatotoxic
Entecavir

60

what does cellular release of Type 1 IFN

induces antiviral state in uninfected cells - induces enzymes that block viral replication
Increases expression of MHC I on infected cells to accelerate killing by CTLs

61

Type 1 IFN for HCV

IFN given to up general cellular responses to viral infection
Immunomodulatory - increases MHC I expression on infected cells to enhance killing

63

Hep C antivirals Protease Inhibitors

Boceprevir
Telaprevir
block production of structural proteins