Recent Advances in Antiretroviral Therapy

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Recent Advances in Antiretroviral Therapy

• Hail M. Al-Abdely, MD
• Consultant, Infectious Diseases

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Rationale for Drug Combinations
CD4 cell
NRTIs Work here
NNRTIs Work here
PIs Work here
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Development of AIDS is like an impending train
wreck Viral Load Speed of the train CD4
count Distance from cliff
HIV infection
J. Coffin, XI International Conf. on AIDS,
Vancouver, 1996
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Perelson et.al. Science 2711582 (1996)
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Viral dynamics

• it takes 2.6 days to produce a new generation of
  viral particles
• estimated total HIV production is 10.3 x 109
  virions per day
• at least 99 of the virus pool is produced by
  recently infected cells
• retroviral therapy should be able to reduce viral
  load within a few days

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GOALS OF THERAPY

• Clinical goals Prolongation of life and improved
  quality of life
• Virologic goals Reduction in viral load as much
  as possible for as long as possible to 1) halt
  disease progression, and 2) prevent/reduce
  resistant variants
• Immunologic goals Achieve immune reconstitution
  that is quantitative (CD4 to normal range) and
  qualitative (pathogen-specific immune response)
• Therapeutic goals Rational sequencing of drugs
  in a fashion that achieves virologic goals, but
  also 1) maintains therapeutic options 2) is
  relatively free of side effects and 3) is
  realistic in terms of probability of adherence
• Epidemiologic goals Reduce HIV transmission

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Trends in Age-Adjusted Rates of Death due to HIV
Infection, USA, 1982-1998
Using the age distribution of the projected
year 2000 US population as the standard.
Preliminary 1998 data
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Good News
Highly active antiretroviral therapy has Changed
our view toward HIV from inevitably fatal to a
manageable disease over several decades
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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Cross resistance
• Drug-drug interactions

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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Cross resistance
• Drug-drug interactions

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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Cross resistance
• Drug-drug interactions

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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Cross resistance
• Drug-drug interactions

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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Cross resistance
• Drug-drug interactions

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Bad News

• Incomplete response
• Complete RNA suppression and sustained CD4
  increase happens only in 60-80.
• Effectiveness is even lower in patients with high
  replication rates and extensive antiretroviral
  experience.
• Complexity of treatment
• Short and long term side effects
• Cross resistance
• Drug-drug interactions

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Immunotherapy
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Immunotherapy

• Directions
• Augmentation of specific immune response to
  control viral replication.
• Preventive Vaccines.

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Clues to immune control of HIV?
Subject JP Sx Fever, Rash, Headache Dx
HIV ELISA Neg. HIV RNA gt700,000 F/U
Extensive Rx AIDS at 11 mo. Rapid CD4 cell
decline Viral Load gt750,000
Subject 161J Sx Fever, Rash, Headache Dx
HIV ELISA Neg. HIV ELISA Pos. F/U No
Rx Well at 19 yrs. CD4 1000 Viral Load lt 500
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Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4
cells (Helper cells)
Generation of HIV-1-specific killer cells (CTL)
Infection of activated helper cells
Loss of CTL function due to inadequate
HIV-1-specific helper cells
Loss of HIV-1-specific helper cells
Progression
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T helper cells are the central orchestrator of
the immune system
CTL Function
NK Cell Function
T helper cell
APC Function
B Cell Function
Cytokine production
Antibody Production
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Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4
cells (Helper cells)
Antiviral Rx
Generation of HIV-1-specific killer cells (CTL)
Protection of activated helper cells
Maintenance of CTL function due to adequate
HIV-1-specific helper cells
Maintenance of HIV-1-specific helper cells
Nonprogression
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HIV-1-specific T helper cells in individuals
treated during acute infection (n7)
1
0
0
1
0
1
M
B
J
C
K
M
N
D
S
J
D
K
K
S
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Barriers to the Development of an Effective AIDS
Vaccine

• Sequence variation
• Protective immunity in natural infection not
  clearly established
• Desire to achieve sterilizing immunity
• Lack of adequate animal model to study vaccine
  protection with HIV
• Latency and integration of HIV into host genome
• Transmission by cell-associated virus
• Limited knowledge about mucosal transmission and
  immune responses
• Financial disincentives
• Ethical issues