Transcript Final Presentation

Final Presentation
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Clinical group
Marketing group
Production group
New Approach group
Ethics group
HIV & Treatment
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Duangrat Inthron
Tawit Suriyo
Pronpat Intarasunanont
Somjed Sahasitiwat
Peerakarn Banjerdkij
Ormrat Kampeerawipakorn
Outline
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Overview
Content
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Animal model for HIV
Life Cycle of HIV
Anti-HIV Drugs
Combination Therapy
Summary
History of HIV
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Some scientists believed HIV spread from
monkeys to human between 1926-1943.
In 1981, a rare cancer-Kaposi’s Sarcoma-was
found in healthy gay men. This was called GRID
(Gay Related Immune Deficiency).
In 1982, the Gay Men Heath Crisis was found in
New York City.
History of HIV
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The term AIDS or Acquired Immune Deficiency
Syndrome was used for the first time in 1982
In 1983, HIV or Human Immunodeficiency Virus
(HIV) was first identified.
4,749 cases of AIDS in the U.S. and 2,112 died
in 1983
AIDS Animal models
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useful for studying HIV infection
help scientists to know about HIV genetics and
mechanism of pathogenesis including developing
potent anti-HIV drugs and vaccines to suppress
HIV replication
Types of AIDS animal models
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Non-human primate models
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Murine models
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Chimpanzee
Macaque monkeys
Transgenic mice
SCID mice
Feline models
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Cats
Overview of HIV
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HIV is a lentivirus, a class of retrovirus.
HIV can infect a number of different cells
within the host such as:
 CD4 lymphocytes (T-helper lymphocytes)
 Monocytes and Macrophages
 Dendritic cells (Lymph node and Central
nervous system)
Overview of HIV
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During HIV infection, the number of CD4
lymphocytes in blood progressively declines.
Because of the reduction, AIDS patients become
ill and eventually die from the opportunistic
infections and cancers such as
 Pneumocyatis carnii together with Herpes
simplex, cytomagalovirus and candida
 Kaposi’s sarcoma
 Lymphomas
Types of HIV
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HIV type 1 (HIV-1)
: is a cause of the current pandemic
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HIV type 2 (HIV-2)
: is found in West Africa but rarely
elsewhere
: is closely related to SIV
Life Cycle of HIV
Reverse transcriptase
Inhibitor
Fusion Inhibitors
Integrase Inhibitors
Protease Inhibitors
Anti-HIV Drugs
Types of anti-HIV drugs
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Reverse Transcriptase Inhibitors
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Nucleoside Analogues
E.g. AZT, ddI, ddC and d4T
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Non-nucleoside Reverse Transcriptase
Inhibitors
E.g. Nevirapine, Delavirdine
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Protease Inhibitors
E.g. Ritonavir, Indinavir, Saquinavir
Reverse Transcriptase Inhibitors
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Nucleoside Analogues
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are both inhibitors and substrates of RT
need metabolism before function
competitive inhibition with natural dNTP
incorporate into the growing viral DNA leads to
DNA chain termination
Reverse Transcriptase Inhibitors
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Non-nucleoside Reverse Transcriptase
Inhibitors
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structurally heterogeneous
selectively inhibit HIV-1 replication
do not need metabolism before function
interact with a non-substrate binding site
non-competitive inhibitors
HIV Protease Enzyme
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is an aspartyl protease
consists of 99 amino acids
exists as a C2-symmetric
homodimer with a single
active site
catalytic site contains
catalytic triads (Asp-ThrGly)
cleaves polyproteins to
functional proteins
Protease Inhibitors
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slow down the action of
HIV protease
interact with catalytic
residues and displace a
structural water molecule
lack cross-reactivity with
human protease enzyme
Ritonavir & Indinavir
Indinavir
Ritonavir
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inhibits HIV-1 and HIV2 protease.
is active in acutely
infected cells
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no direct anti-HIV
effect in the brain
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inhibits HIV-1 protease.
is active in both acutely
and chronically infected
cells.
can reduce viral loads in
the nervous system.
Ritonavir & Indinavir
Ritonavir
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The emergence of viral
resistance requires the
presence of one or more
mutations.
Indinavir
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The emergence of viral
resistance requires the
presence of three or
more mutations.
If resistance to IDV
occurs, it can also
increase the probability
of resistance to other
PIs.
Ritonavir & Indinavir
Ritonavir
Drug Interaction:
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increases plasma level of
drugs that are
metabolized by CYP450,
Indinavir
Drug Interaction:
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plasma level of IDV can
alter when it’s taken
with drugs that can
inhibit or enhance
activity of CYP-450
Ritonavir & Indinavir
Ritonavir
Indinavir
Side Effects :
- nausea, vomiting,diarrhea
Side Effects:
- nausea,vomiting,diarrhea
- Kidney Stones
- Hyperbilirubinemia
- numbness, tangling and
burning sensation
- allergic reaction
- increase liver toxicity
Why does the combination therapy
make sense?
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Combination therapy can decrease HIV progression
better than monotherapy.
Different anti-HIV drugs can attack the virus in
different ways.
Different drugs can attack virus in different types
of cells and in different parts of the body.
Combinations of anti-HIV drugs may overcome or
delay resistance.
Combinations of Nucleosides Analogues
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Based on differences in the intracellular
activity, NRTIs that work in actively infected
cells are given with those that work in resting
cells.
ACTG 175 trial showed the CD4 cell count
increased significantly in the combinations of
AZT/ddI and AZT/ddC group, compared with
AZT monotherapy.
Combinations of NRTIs and NNRTIs
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NNRTIs have same target and activity as in
NRTIs.
The incorporation of NRTIs and NNRTIs shows
synergistic effect and is active against AZTresistant HIV isolates.
Percent with HIV-1 RNA Level of <400 copies/ml
Combination of NRTIs/NNRTIs can reduce HIV1 RNA level
100
80
60
40
20
0
0
2
4
8
12
16
20
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36
48
Week
Efavirenz+zidovudine and lamivudine
Efavirenz+indinavir
Efavirenz+indinavir and lamivudine
Combinations of PIs and RTIs
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Protease inhibitors were used in combination
with nucleoside analogues.
The triple drugs (PIs+2 NRTIs) given together
resulted in a large and longer-lasting reduction in
the amount of virus in blood compared with 2
NRTIs combinations or with PIs alone.
Combination of PI/NRTI can reduce HIV RNA
levels
AZT/3TC
IDV
IDV/AZT/3TC
Summary
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Anti-HIV drugs are developed by targeting the
various stages of HIV’s life cycle , e.g., RTIs
inhibit RT enzyme in the early stage of
replication.
Initially, a single anti-HIV drug was used to
treat patient living with AIDS , but it was not
successful because of frequent development of
viral resistance to anti-HIV drugs.
Summary
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The combinations of anti-HIV drugs are used
to treat AIDS patients because of their high
potency in viral suppression and a delay in drug
resistance.
Indinavir is our “CHOSEN” drug.
Engineers do not understand biology! - They
chose Ritonavir.