Transcript HIV Treatment I

“The sovereign Lord has filled me with his spirit.
He has chosen me and sent me
to bring good news to the poor,
To heal the broken-hearted,
to announce release to the captives,
And freedom to those in prison.
He has sent me to proclaim that the time will come
When the Lord will save his people and defeat their enemies”
Excerpt from the passage from Isaiah 61
read at the inauguration of
Jean Bertrand Aristide
Throughout the class we will explore how
we can use basic science to guide the design
of new treatments for disease
A series of basic science discoveries have
given us substantial insight into the cause of AIDS
Retroviruses reverse the central dogma
A retrovirus causes AIDS
http://www.avert.org/his81_86.htm
Potential Therapies- Life Cycle of HIV-1
Let’s start where the field started: with reverse transcriptase
Here’s the enzyme synthesizing a DNA complement
To the HIV RNA genome
Let’s zoom in on this step
RT adds a DNA nucleotide complementary to
Each RNA nucleotide in the HIV genome
Here’s the chemistry:
http://www.avert.org/his81_86.htm
If we get rid of this hydroxyl group,
the enzyme can’t add another nucleotide
http://www.avert.org/his81_86.htm
AZT (azidothymidine) is an exact match
to the T nucleotide but
without the hydroxyl group!
http://www.avert.org/his81_86.htm
The result…
http://www.avert.org/his81_86.htm
How did we get here?
http://www.avert.org/his81_86.htm
The success of sulfa drugs in inhibiting bacterial metabolism
inspired two scientists at Wellcome Research Labs
to investigate other metabolic pathways
George Hitchings
Gertrude Elion
Nobelprize.org and www.chemheritage.org
The success of sulfa drugs in inhibiting bacterial metabolism
inspired two scientists at Wellcome Research Labs
to investigate other metabolic pathways
George Hitchings
They started just as
people figured out
That DNA is the genetic material!
Gertrude Elion
Nobelprize.org and www.chemheritage.org
They looked for derivatives of nucleotides
That inhibited synthesis of DNA and RNA
George Hitchings
Gertrude Elion
Nobelprize.org and www.chemheritage.org
They looked for derivatives of nucleotides
That inhibited synthesis of DNA and RNA
First drugs against leukemia
George Hitchings
Gertrude Elion
Nobelprize.org and www.chemheritage.org
Suppresses immune system
(first kidney transplants)
When Hitchings became Vice President for Research
Elion was promoted to Head of the
Department of Experimental Therapy (without a Ph.D!)
and her group continued to explore these pathways
George Hitchings
Gertrude Elion
Nobelprize.org and www.chemheritage.org
When Hitchings became Vice President for Research
Elion was promoted to Head of the
Department of Experimental Therapy (without a Ph.D!)
and her group continued to explore these pathways
Treats gout and being tested against
the Leishmania parasite
George Hitchings
Gertrude Elion
They also explored mechanism of action
Of acyclovir and its affect on Herpes virus
Nobelprize.org and www.chemheritage.org
For all this hard work ….
George Hitchings
Gertrude Elion
Nobelprize.org and www.chemheritage.org
Others followed their lead
http://www.avert.org/his81_86.htm
Jerome Horwitz--first synthesized AZT in 1964
as a possible anticancer drug
http://www.avert.org/his81_86.htm
But it failed!
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The first treatment option: a time line
Februrary 1985
Scientists at National Cancer Institute and at Burroughs Wellcome
Collaborate to study effect of AZT on HIV in cell culture
http://www.avert.org/his81_86.htm
The first treatment option: a time line
Februrary 1985
Scientists at National Cancer Institute and at Burroughs Wellcome
Collaborate to study effect of AZT on HIV in cell culture
September 1986
Early clinical trials showed that AZT slowed down the attack of HIV.
http://www.avert.org/his81_86.htm
The first treatment option: a time line
Februrary 1985
Scientists at National Cancer Institute and at Burroughs Wellcome
Collaborate to study effect of AZT on HIV in cell culture
September 1986
Early clinical trials showed that AZT slowed down the attack of HIV.
The AZT clinical trial: one group of patients received AZT
and the other received placebo. At the end of six months, only one patient
in the AZT group was dead, whilst there were 19 deaths among the placebo group.
The clinical trial was stopped early, because it was thought to be
unethical to deny the patients of the placebo groups a better chance of survival.
Fischl M. A., et al. (1987)''The Efficacy of azidothymidine (AZT) in the treatment of patients
with AIDS and AIDS-related complex, a double-blind, placebo-controlled trial',
The New England Journal Of Medicine, Vol. 317: 185-191, Number 4
FDA approved March 20, 1987!
http://www.avert.org/his81_86.htm
The first treatment option: a time line
August 1989
First large clinical trial of AZT in asymptomatic patients showed that
it slowed progression of disease
The day after the press conference, Burroughs Wellcome stock rose 32%.
http://www.avert.org/his81_86.htm
The first treatment option: a time line
August 1989
First large clinical trial of AZT in asymptomatic patients showed that
it slowed progression of disease
The day after the press conference, Burroughs Wellcome stock rose 32%.
The high price of AZT angered many people; a year's supply cost ~$7,000
In September, the cost of the drug was cut by 20%.
http://www.avert.org/his81_86.htm
Thus the early response of HIV to AZT was superb
Does this sound familiar?
Does it make you worried?
The bad news came quickly and was not
unexpected
The bad news came quickly and was not
unexpected
Mutations altering amino acids
In the AZT binding site of
Reverse transcriptase
Led to resistance
By the early 1990s resistance was a serious problem
How do we get around this???
Same concept, new drugs!
Inosine
ddI
Used in patients by October 1989
http://www.avert.org/his81_86.htm
Same concept, new drugs!
Cytodine
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ddC
FDA approved Summer 1991
If you treat patients with ddI or ddC ALONE
What will happen?
Cytodine
http://www.avert.org/his81_86.htm
ddC
FDA approved Summer 1991
So how do you get around this??
Cytodine
http://www.avert.org/his81_86.htm
ddC
FDA approved Summer 1991
If it worked for TB…..
http://www.avert.org/his81_86.htm
If it worked for TB…..
September 1995
Two clinical trials, the Delta trial and the ACTG175 trial,
showed that combinations of AZT with ddI or ddC
were more effective than AZT alone
in delaying disease progression and prolonging life.
http://www.avert.org/his81_86.htm
Chemists keep
Tinkering with nucleotides
To make new drugs
Retroviruses. CSHL Press Fig. 13-10
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