Clinical group

1

Final Presentation

• Clinical group
• Marketing group
• Production group
• New Approach group
• Ethics group

2
HIV Treatment

• Duangrat Inthron
• Tawit Suriyo
• Pronpat Intarasunanont
• Somjed Sahasitiwat
• Peerakarn Banjerdkij
• Ormrat Kampeerawipakorn

3
Outline

• Overview
• Content
• Animal model for HIV
• Life Cycle of HIV
• Anti-HIV Drugs
• Combination Therapy
• Summary

4
History of HIV

• Some scientists believed HIV spread from monkeys
  to human between 1926-1943.
• In 1981, a rare cancer-Kaposis 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.

5
History of HIV

• 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

6
AIDS Animal models

• 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

7
Types of AIDS animal models

• Non-human primate models
• Chimpanzee
• Macaque monkeys
• Murine models
• Transgenic mice
• SCID mice
• Feline models
• Cats

8
Overview of HIV

• 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)

9
Overview of HIV

• 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
• Kaposis sarcoma
• Lymphomas

10
Types of HIV

• HIV type 1 (HIV-1)
• is a cause of the current pandemic
• HIV type 2 (HIV-2)
• is found in West Africa but rarely
• elsewhere
• is closely related to SIV

11
Life Cycle of HIV
12
Anti-HIV Drugs

• Types of anti-HIV drugs
• Reverse Transcriptase Inhibitors
• Nucleoside Analogues
• E.g. AZT, ddI, ddC and d4T
• Non-nucleoside Reverse Transcriptase Inhibitors
• E.g. Nevirapine, Delavirdine
• Protease Inhibitors
• E.g. Ritonavir, Indinavir, Saquinavir

13
Reverse Transcriptase Inhibitors

• Nucleoside Analogues
• 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

14
Reverse Transcriptase Inhibitors

• Non-nucleoside Reverse Transcriptase Inhibitors
• structurally heterogeneous
• selectively inhibit HIV-1 replication
• do not need metabolism before function
• interact with a non-substrate binding site
• non-competitive inhibitors

15
HIV Protease Enzyme

• 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-Thr-Gly)
• cleaves polyproteins to functional proteins

16
Protease Inhibitors

• slow down the action of HIV protease
• interact with catalytic residues and displace a
  structural water molecule
• lack cross-reactivity with human protease enzyme

17
Ritonavir Indinavir

• Ritonavir
• inhibits HIV-1 and HIV-2 protease.
• is active in acutely infected cells
• no direct anti-HIV effect in the brain

• Indinavir
• inhibits HIV-1 protease.
• is active in both acutely and chronically
  infected cells.
• can reduce viral loads in the nervous system.

18
Ritonavir Indinavir

• Ritonavir
• The emergence of viral resistance requires the
  presence of one or more mutations.

• Indinavir
• 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.

19
Ritonavir Indinavir

• Ritonavir
• Drug Interaction
• increases plasma level of drugs that are
  metabolized by CYP-450,

• Indinavir
• Drug Interaction
• plasma level of IDV can alter when its taken
  with drugs that can inhibit or enhance activity
  of CYP-450

20
Ritonavir Indinavir

• Ritonavir
• Side Effects
• - nausea, vomiting,diarrhea
• - numbness, tangling and burning sensation
• - allergic reaction
• - increase liver toxicity

• Indinavir
• Side Effects
• - nausea,vomiting,diarrhea
• - Kidney Stones
• - Hyperbilirubinemia

21
Why does the combination therapy make sense?

• 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.

22
Combinations of Nucleosides Analogues

• 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.

23
Combinations of NRTIs and NNRTIs

• NNRTIs have same target and activity as in NRTIs.
• The incorporation of NRTIs and NNRTIs shows
  synergistic effect and is active against
  AZT-resistant HIV isolates.

24
Combination of NRTIs/NNRTIs can reduce HIV-1 RNA
level
25
Combinations of PIs and RTIs

• Protease inhibitors were used in combination with
  nucleoside analogues.
• The triple drugs (PIs2 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.

26
Combination of PI/NRTI can reduce HIV RNA levels
AZT/3TC
IDV
IDV/AZT/3TC
27
Summary

• Anti-HIV drugs are developed by targeting the
  various stages of HIVs 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.

28
Summary

• 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.