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Chemotherapy

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More than 75% of women receiving Nevirapine develop a major resistance mutation ... Requires dosing very precisely every eight hours in order to thwart drug ... – PowerPoint PPT presentation

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Title: Chemotherapy


1
THE AIDS EPIDEMIC HOW CAN WE CURE THE PATIENT?
HOW CAN WE STOP INFECTION?
  • CHEMOTHERAPY
  • VACCINE

2
Anti-Viral Chemotherapy
  • Bacteria
  • Many antibiotics
  • Highly selective
  • Viruses
  • Use host cell metabolism
  • Selectivity difficult
  • Toxicity

3
Anti-Viral Chemotherapy
  • Key is selectivity
  • Other problems
  • Toxicity
  • Rapid excretion
  • Rapid metabolism
  • Poor absorption

Many of these problems have plagued anti-HIV
chemotherapy
4
Anti-Viral Chemotherapy
Ideal Drug
  • Water soluble
  • Chemically and metabolically stable
  • Easily absorbed (apolar)
  • NOT
  • Toxic
  • Carcinogenic
  • Allergenic
  • Mutagenic
  • Teratogenic

5
Anti-Viral Chemotherapy
Therapeutic index (T.I.) Minimum dose toxic to
cell Minimum dose toxic to virus
Effective drug T.I. 100-1000 at least
6
Anti-Viral Chemotherapy
Another consideration Disease severity Rhinovirus
v. Symptomatic rabies or Lassa fever
7
Anti-Viral Chemotherapy
  • Reasons for continuing search for anti-virals
    versus vaccines
  • For many established diseases there is still no
    effective vaccine
  • Rapid mutation (retroviruses) to resistant forms
  • Or there are problems with the current vaccine
  • Reassortment (influenza)
  • New and emerging diseases - no vaccine
    available
  • Vaccine development takes many years
  • Disease that involve immunosuppression (AIDS,
    cancer, transplantation)

At present no drug completely suppresses viral
replication (with possible exception of anti-HIV
protease inhibitors)
8
Anti-Viral Chemotherapy
  • A successful drug must interfere with
  • A specific viral function e.g. enzyme necessary
    for viral life cycle
  • A cellular function that the virus needs in
    order to replicate
  • If it interferes with cellular function either
  • It must be crucial to virus but not the cell or
  • Only the virus-infected cell must be killed
  • (activation of drug in the infected cell only?)

9
Anti-Viral Chemotherapy
  • Viral enzymes
  • Nucleic acid polymerases
  • DNA-dependent DNA polymerase - DNA viruses
  • RNA-dependent RNA polymerase - RNA viruses
  • RNA dependent DNA polymerase (RT)
    Retroviruses HIV
  • Thymidine kinase (activated drug) - Herpes
    viruses
  • Protease retrovirus HIV
  • Integrase retrovirus HIV
  • Neuraminidase (orthomyxovirus)

10
Anti-Viral Chemotherapy
  • 1962 Idoxuridine
  • Pyrimidine analog
  • Toxic
  • Topical - Epithelial herpetic keratitis (cornea)
  • 1983 Acyclovir
  • Purine analog
  • Sugar modification
  • Chain terminator
  • Anti-herpes
  • Selective to virus-infected cells

1990s Protease inhibitors
11
LIFE CYCLE OF HIV POSSIBLE TARGETS
12
INTERACTION WITH SURFACE RECEPTOR
Binding of gp120 To CD4
Interaction of co-receptor with gp120
?
?
CD4
13
CHANGES IN GP120 CONFORMATION
Gp120 conformational change
?
CD4
14
INTEACTION OF EXPOSED GP41 WITH LIPID BILAYER
Interaction of fusogen (gp41) with membrane
?
CD4
15
FUSION OF VIRAL MEMBRANE WITH CELL MEMBRANE
Membrane fusion
?
CD4
16
REVERSE TRANSCRIPTION
CD4
nucleus
17
UNCOATING OF CAPSID ENTRY INTO NUCLEUS
Uncoating
?
18
INTEGRATION OF HIV DNA TRANSCRIPTION OF DNA TO
RNA SPLICING OF RNA
Pol II
19
TRANSLATION OF RNA TO POLYPROTEIN CLEAVAGE OF
POLYPROTEIN
Proteolysis of polyprotein
20
ASSEMBLY AT THE CELL SURFACE
Assembly
21
BUDDING THROUGH CELL MEMBRANE MATURALION
22
BLOCKING INTERACTIONS OF HIV AT THE CELL SURFACE
Gp120 CD4 antigen interactions Gp120
Chemokine receptor interactions Gp41 membrane
protein or lipid bilayer interactions
23
Anti-HIV Chemotherapy
CD4 Antigen
  • Soluble CD4 - May make HIV more infective as
    results in chemokine receptor being the only
    necessary receptor
  • Could change gp120 conformation

CD4-Ig2 (PRO542) - A more stable version of
soluble CD4 is a tetrameric fusion protein of
immunoglobulin G and CD4. It can reduce levels of
virus in vivo
Chemokine Receptors
AMD3100 (Plerixafor) - appears to bind to CXCR4
(fusin)
None of these commercially viable Little
activity in clinical trials
24
Chemokine Receptors
Maraviroc
Pfizer
Maraviroc (brand-named Selzentry, or Celsentri
outside the U.S.) Approved August 2007
Maraviroc blocks the chemokine receptor CCR5
Because HIV can use another co-receptor, CXCR4,
HIV tropism test is performed to see if the drug
will be effective
Compared to HAART alone, HAART Maraviroc gave
twice as many patients with HIV lt50 copies/ml and
doubles CD4 cell number
25
Membrane Fusion
T-20 Fuzeon (enfuvirtide)
Trimeris
Peptides derived from gp41 can inhibit
infection Probably block interaction of gp41
with cell membrane proteins during fusion
T-20 In clinical trials, a nearly two log
reduction in plasma HIV levels achieved
Ac-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-
Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-
Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-
Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn- Trp-Phe-NH2
26
Anti-HIV Chemotherapy
Membrane Fusion
Trimeris
T-20 FUZEON (enfuvirtide)
  • Enfuvirtide therapy costs an estimated 25,000
    per year in the United States
  • Inconvenient dosing regimen (Lyophilized
    injectable - 2x per day)
  • Used as a reserve, for "salvage" therapy in
    patients with multi-drug resistant HIV

T-1249 Next generation Different site from T-20
27
Anti-HIV Chemotherapy
Trimeris Merke
Membrane Fusion
T-1249
Peptides derived from gp41 can inhibit infection
Works in people who have developed resistance to
Fuseon 2 log drop in some people in clinical
trials
Unstable peptide Difficulty of administration
Daily injection 20,000 per year Disappointing
sales! Development suspended
28
BLOCKING HIV REVERSE TRANSCRIPTION
Competitive inhibitors of RT Nucleoside analogs
29
Anti-HIV Chemotherapy
Nucleoside analogs Sugar modifications Base
modifications
  • Selectivity
  • Activated drug is more active against viral
    reverse transcriptase than against cell
    polymerases
  • However, may still inhibit cell enzymes
  • HIV does not have the enzyme used by herpesvirus
    to activate nucleoside analogs (thymidine kinase)
    Activated by cell enzymes (phosphorylation)

Side effects
30
Anti-HIV Chemotherapy
  • AZT
  • Chain terminator
  • Anti-HIV drug because it inhibits reverse
    transcriptase
  • Selectivity because inhibits RT at lower
    concentration than it inhibits cell DNA polymerase

Normal DNA synthesis
31
Anti-Viral Chemotherapy
  • AZT
  • Chain terminator

Termination
32
AZT Side Effects
  • Nausea
  • Headache
  • Changes in body fat (lipodystrophy buffalo
    hump)
  • Myopathy
  • Discoloration of fingernails and toenails
  • Anemia and bone marrow suppression (treated with
    erythropoietin or darbepoetin)

Sensitivity of the ?-DNA polymerase in the cell
mitochondria may be responsible for side effects
Works additively or synergistically with many
antiviral agents E.g. acyclovir and
interferon BUT ribavirin decreases the antiviral
effect of AZT Should not be taken with d4T
Rapid resistance in monotherapy
33
Anti-HIV Chemotherapy
Sugar modifications
AZTazidothymidine
DDCdideoxycytidine
DDIdideoxyinosine
34
Anti-Viral Chemotherapy
  • Cidofovir
  • DNA chain terminator
  • DNA polymerase inhibitor
  • A acyclic nucleoside phosphonate (not a
    phosphate) - C-O-P bond in a nucleoside
    monophosphate replaced by a phosphonate (C-P)
  • More stable

Cidofovir
35
Anti-Viral Chemotherapy
Indicated CMV retinitis May be useful Pox
molluscum contagiosum virus Polyoma JC -
progressive multifocal leukoencephalopathy
Adenovirus - gastroenteritis
Cidofovir
Vaccinia in immunocompromisation? Used in on
case Eczema vaccinatum
36
Anti-Viral Chemotherapy
Cidofovir
37
BLOCKING HIV REVERSE TRANSCRIPTION
Non-competitive inhibitors of RT Non-Nucleoside
analogs
38
Anti-HIV Chemotherapy
Non-nucleoside Non-competitive RT
inhibitors Combination therapy with
AZT Resistance mutations will be at different
sites
The most potent and selective RT
inhibitors Nanomolar range Minimal toxicity (T.I.
10,000-100,000) Synergistic with nucleoside
analogs (AZT) Good bio-availability Resistant
mutants - little use in monotherapy
39
Anti-Viral Chemotherapy
DuPont
Nevirapine
Sustiva
(S) -6- chloro-4-(cyclopropylethynyl)-1,4-dihydro-
4-(trifluoromethyl)-2H-3, 1-benzoxazin-2-one.
40
Anti-HIV Chemotherapy
Nevirapine Approved for AIDS patients
About one third to one half of HIV infected
babies acquire HIV from breast feeding Others HIV
in maternal blood etc Rate depends on maternal
viral load Mostly in third world countries Very
rare in western counties
41
Anti-HIV Chemotherapy
  • Nevirapine
  • Good blocker of mother to child transmission
    peri-natal - breast feeding
  • Single dose when mother in labor
  • Single dose to baby by 72 hours
  • Reduces HIV transmission by 50
  • Short course of AZT plus 3TC, with single dose
    Nevirapine 6-week transmission rates below 5 in
    population in which 40 breast-feed.
  • More than 75 of women receiving Nevirapine
    develop a major resistance mutation prohibiting
    subsequent use in the treatment of the mother

42
Anti-HIV Chemotherapy
  • Efavirenz (Sustiva, DMP266)
  • In combination therapy (with AZT and 3TC) may
    suppress viral load as well as standard
    combination of
  • AZT
  • 3TC
  • Indinavir (protease inhibitor)
  • Approved for AIDS patients

43
Anti-HIV Chemotherapy
Efavirenz (Sustiva, DMP266)
  • Efavirenz in combination with
  • Lamivudine (3TC)
  • Zidovudine (AZT) (Combivir)
  • OR
  • Tenofovir (Nucloside inhibitor)
  • Emtricitabine (Nucloside inhibitor) (Truvada)
  • are preferred NNRTI-based HAART regimens in
    adults and adolescents in US
  •  
  • Efavirenz also used with other anti-retroviral
    agents in post-exposure prophylaxis

Tenofovir Emtricitabine
44
BLOCKING HIV PROTEIN SYNTHESIS
Protein Synthesis Inhibitors None
45
BLOCKING HIV PROTEIN PROCESSING
Proteolysis
46
Anti-HIV Chemotherapy
GAG/POL polyprotein
GAG
Integrase
Polymerase
Protease
GAG
POL
47
Anti-HIV Chemotherapy
GAG
Integrase
Polymerase
Protease folds and cuts itself free
48
Anti-HIV Chemotherapy
GAG
Integrase
Polymerase
Protease cuts at a site between the integrase and
polymerase
49
Anti-HIV Chemotherapy
GAG
Integrase
polymerase
50
Anti-HIV Chemotherapy
Saquinavir (Invirase)
51
Anti-HIV Chemotherapy
Indinavir (Merke) INDINAVIR AZT
3TC (HAART) No detectable HIV by PCR Before
20,000 - 11,000,000 RNA copies /ml After lt
200-400 copies Lasts several yearsNo replication
No resistance
52
Anti-HIV Chemotherapy
Indinavir
  • Indinavir level drops quickly after dosing
  • Requires dosing very precisely every eight hours
    in order to thwart drug resistant mutations
  • These mutation may give resistance to other
    protease inhibitors
  • Restrictions on what sorts of food may be eaten
    concurrently

53
Anti-HIV Chemotherapy
HIV aspartyl protease inhibitors
IndinavirAZT3TC
54
Anti-HIV Chemotherapy
HIV aspartyl protease inhibitors
Newer protease inhibitors Provoke less
resistance Less binding to serum
proteins Lopinavir (Abbott)
  • Atazanavir (Reyataz - Bristol-Myers)
  • Once-daily (rather than requiring multiple doses
    per day)
  • Lower effect on lipid profile
  • Used only in combination with other HIV
    medications

55
HAART Highly Active Anti-Retroviral Therapy
56
Preferred NNRTI-Based Regimens ? Efavirenz
(zidovudine or tenofovir) (lamivudine or
emtricitabine) (except during first trimester of
pregnancy or in women with high pregnancy
potential)Alternative NNRTI-Based Regimens?
Efavirenz (didanosine or abacavir or stavudine)
(lamivudine or emtricitabine) (except during
pregnancy, particularly the first trimester, or
in women with high pregnancy potential)  or?
Nevirapine-based regimens may be used as an
alternative in adult females with CD4 T cell
counts lt250 cells/mm3 and adult males with CD4
T cell counts lt400 cells/mm3 .
57
Preferred PI-based regimens
Lopinavir/ritonavir zidovudine (lamivudine or
emtricitabine) Alternative PI-based regimens
may include Atazanavir, fosamprenavir,
ritonavir-boosted fosamprenavir,
ritonavir-boosted indinavir), nelfinavir, or
ritonavir-boosted saquinavir  all used in
combination with (zidovudine or stavudine or
tenofovir or abacavir or didanosine)
(lamivudine or emtricitabine)
Lopinavir/ritonavir (abacavir or stavudine or
tenofovir or didanosine) (lamivudine or
emtricitabine)
58
BLOCKING HIV INTEGRATION
59
Anti-HIV ChemotherapyIntegrase Inhibitor
Isentress (Raltegravir ) Approved for use in
adults by the USFDA in October, 2007
60
Anti-HIV ChemotherapyIntegrase Inhibitor
Isentress Part of a HAART regimen when the
patient is resistant to other drugs such as
protease inhibitors In combination therapy,
similar to standard HAART
Metabolized away via glucuronidation
61
CHEMOTHERAPY OF HIV PROBLEMS
Population polymorphism (use of RNA pol II and
RT) leads to resistance to all drugs unless
replication ceases
62
HIV VACCINES
  • Problems
  • Population Polymorphism
  • Hidden epitopes (glycosylation)
  • Some critical epitopes formed only on HIV
    binding
  • Retrovirus Cancer potential
  • Antibodies against HIV elicited by a vaccine may
    increase uptake by macrophages
  • Antibodies against HIV elicited by vaccine may
    give rise to autoimmunity

63
HIV VACCINES
  • Subunit vaccines
  • Purified proteins (pp160, gp120, gp41) -
    recombinant proteins
  • Do not induce a cell-mediated response
  • Stimulate neutralizing antibodies
  • Response short lived and low titer
  • Many current anti-HIV vaccines fall into this
    category

Since 1986 Many anti-HIV vaccines  based on
gp160/gp120/gp41 using various adjuvants Can
protect chimps HIV under very controlled
conditions but fail to protect against clinical
isolates
64
HIV VACCINES
  • Whole virus (killed) vaccines in animals
  • Showed some degree of protection
  • Experiments were designed for success The
    chimps were vaccinated with a killed laboratory
    strain of the virus and challenged intravenously
    with small doses of the same strain at the peak
    of antibody production
  • No rectal or vaginal immunity
  • Protection only extended to the same strain of
    HIV that was used as the immunogen

65
HIV VACCINES
  • Attenuated Virus Vaccines
  • NEF is not required for HIV replication in vitro
  • NEF is important for a productive infection in
    vivo
  • NEF deletion mutants of SIV can very effectively
    protect monkeys against simian AIDS without
    causing disease
  • NEF deletion of SIV reverted to a virulent
    strain
  • Juvenile monkeys developed AIDS when given a
    high dose of the vaccine

66
HIV VACCINES
  • Recombinant vaccines Vaccinia
  • Anti-HIV vaccine based on the Ankara vaccinia
    strain elicits both humoral and cell-mediated
    immunity
  • Seems effective in animals
  • In humans the results have given less cause for
    optimism
  • There was only limited anti-HIV activity,
    perhaps because most of us have immunity to
    vaccinia a result of vaccination

67
HIV VACCINES
  • Recombinant vaccines - Canarypox
  • Participants show limited development of a
    long-lived cell-mediated response
  • In one trial (2007), a canarypox vaccine was
    tested along with administration of interleukin-2
    to boost the patients' immune response
  • Gp120, expressed by a part of the env gene
  • Anchoring transmembrane domain of gp41
  • p55 polyprotein expressed by the gag gene
  • Part of the pol gene expressing protease
    activity in order to process the p55gag
    polyprotein
  • Genes expressing peptides from pol and nef

No difference between the treatment and the
placebo group
68
HIV VACCINES
STEP STUDY
  • Involved over 3000 people around the world
    receiving a vaccine based on mixture of
    adenovirus 5 vectors which express nef, pol and
    gag from HIV1 clade B
  • Well tolerated - an immune response was elicited
  • Prematurely terminated in late 2007
  • Clear that vaccine would not meet the end points
    set for efficacy
  • People with pre-existing anti-Ad5 neutralizing
    antibodies showed more infections by HIV than the
    controls (placebo)
  • Reason unclear

69
HIV VACCINES
  • RV144 A Possible (Modest) Success?????
  • In September, 2009, the first clinical trial that
    showed any efficacy of an AIDS vaccine was
    reported
  • Thailand
  • 16,402 volunteers over six years
  • Half received placebos and half received the
    vaccine
  • 74 who got placebo became infected
  • 51 who got the vaccine became infected.
  • Small difference (23) statistically significant
  • Suggests that vaccine is 31 effective.
  • Not great Normally an effective vaccine should
    give greater than 80 protection

70
HIV VACCINES
  • RV144
  • Combination of two vaccines
  • Alvac-HIV (Sanofi-Aventis) Canarypox virus with
    three HIV genes cloned into it.
  • Aidsvax (Genentech) Subunit vaccine containing
    purified gp120, prepared in Chinese Hamster Ovary
    cells
  • Neither vaccine had shown no efficacy in
    previous trials when used separately

71
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