eric s. rosenberg, m.d. associate professor of medicine massachusetts general hospital harvard...
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Eric S. Rosenberg, M.D.
Associate Professor of Medicine
Massachusetts General Hospital
Harvard Medical School
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47 year old male
• Present to MGH ED with an 8 day history of :Fever to 102.5HeadachePhotophobiaMyalgias and arthralgiasNausea and vomiting
3rd visit to health care system
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47 year old male Additional history:
MSM
Recent unprotected sex with an HIV infected partner
PMH: prior hx of syphilis
Exam:Fever
Cervical lymphadenopathy
Rash (started on torso spread to limbs and scalp)
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47 year old male Diagnostics:
Test for EBV, CMV, influenza were negative
HIV ELISA Positive
Western Blot negative (no bands)
HIV RNA > 750,000 copies/ml
1:100 dilution 47,000,000 copies/ml
CD4 count = 432 cells
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Diagnosis
Acute HIV infection
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Framing the QuestionMGH-NCSU collaboration
Should this individual be treated with antiretroviral therapy??
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Acute HIV infectionGoals
1. To discuss the advantages and disadvantages of treating individuals with acute HIV
2. To review the early biological events of acute HIV infection
3. To review the immunologic rationale for treatment during acute infection and possible treatment interruption
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Advantages Disadvantages
Preservation of HIV-specific cellular immune responses
Toxicities and unknown long-term risks
Opportunity for structured treatment interruption
Short- and long-term clinical benefits are not well-defined
Lowering of HIV-1 set point Resistance acquisition
Limitation of viral evolution and diversity
Limitation of future antiretroviral therapy options
Decreased transmission Quality of life impact
Mitigation of acute retroviral symptoms
Cost ? ? ? ? ?
Kassutto et al, CID 2006
Should individuals with Acute HIV-1 infection be treated with antiretroviral therapy?
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HIVinfection
J. Coffin, XI International Conf. on AIDS, Vancouver, 1996
Viral Load = Speed of the train Viral Load = Speed of the train CD4 count = Distance from cliffCD4 count = Distance from cliff
Antiviral therapy = BrakesAntiviral therapy = Brakes
Understanding the terminology and variables that can be measured
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The Dynamics of Acute HIV Infection
HIV
Vir
al L
oad
6-12 months
Rapid Progression
Slow Progression
28, 240
59, 987
11,843
Interquartileranges
Lyles et al, 2000
CTL
HIV Ab
2-8 weeks
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Since the level of HIV in the blood predicts progression, What factors
influence viral replication?
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Viral factors
Host immune responses
Host genetic factors
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New virusassembly
2-3 Days
CTL
SolublefactorsCellular Immune Responses
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If CTL are present, why is the immune response not more effective
in HIV infection?
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Antigen Presenting
Cell
Class II
CD4+Th Cell
CD4
HIV-Specific T Helper Cells are impaired in all stages of disease
TCR
1. Activation2. Clonal expansion
3. Cytokine secretion
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Critical relationship between CD4 and CD8
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What happens to HIV-specific T helper cells? The acute infection hypothesis
Hypothesis (pathogenesis):
• HIV-specific T helper cell (CD4) responses are impaired during acute infection
Hypothesis (opportunity):
• Treatment with ARV during acute infection will protect these responses from being lost
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Activation
&
Expansion
ImpairmentInfectionCD4 cells
Class II
CD4
TCR
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Activation
&
Expansion
Antiretroviral therapyCD4 cells
Class II
CD4
TCR
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Characteristic Acute Early total n
Median age (years)
[IQR]
35[31,39]
37[34,43] 102
Male gender (%) 94 94 102
HIV Risk Factor MSM (%)
82 81 94
White race (%) 77 78 102
Mean baseline VL (copies/mL)
(range)
5.61 million
(11,000-95 million)
382,000(2800-2.95
million)75
Mean baseline CD4 (cells/mm3)
(range)
445(42-1093)
567(170-981) 100
Kassutto et al, CID 2006
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control chronic acute acute LTNP1
10
100
1000
RxNo Rx
Sti
mu
lati
on
in
dex
Rosenberg et al, Science 1997
Spontaneously control virus
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Observation
• Immune damage occurs in the earliest stages of acute HIV infection, but there appears to be a “window of opportunity” to reverse this damage with treatment
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Can treatment be initiated during acute HIV infection and then
discontinued?
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Lessons from Berlin Lisziewicz et al, NEJM 340 (21), 1999
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Augment HIV-specific immunitySTI Hypothesis
RXRX RXRX RXRX RXRX
TimeTime
Mag
nitu
deM
agni
tude
CTLCTL
ThTh
Viral LoadViral Load
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Can therapy be discontinued?
• Will HIV-1-specific immune responses generated and maintained during acute infection be enough to control viremia?
• If virus returns once therapy is discontinued, can this “snap-shot” of autologous virus further boost the immune system?
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Structured treatment interruption
• Several patterns have emerged
• Failure
• Transient control of viremia with sudden loss of containment
• Control (durability?)
Rosenberg et al, Nature 2000Kaufmann et al, PLoS Med 2004
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Is the “possibility” of STI enough reason to treat individuals during
acute HIV infection?
Enough question exists regarding the use of STI as a management strategy that the most relevant question in 2008 is whether or not to treat during acute infection
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Conclusions
• It is not known whether treatment during acute infection is the correct thing to do
• STI may have a role in management of individuals treated during acute infection but optimal approach not known.
• Robust mathematical and statistical modeling (NCSU-MGH) to inform the design of the first randomized trial of treatment versus no treatment during acute HIV.