Transcript HIV Pathogenesis 2000: Clinical implications

Eric S. Rosenberg, M.D.
Associate Professor of Medicine
Massachusetts General Hospital
Harvard Medical School
[email protected]
47 year old male
• Present to MGH ED with an 8 day
history of :
Fever to 102.5
Headache
Photophobia
Myalgias and arthralgias
Nausea and vomiting
3rd visit to health care system
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)
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
Diagnosis
Acute HIV infection
Framing the Question
MGH-NCSU collaboration
Should this individual be treated
with antiretroviral therapy??
Acute HIV infection
Goals
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
Should individuals with Acute HIV-1 infection be
treated with antiretroviral therapy?
Advantages
Preservation of HIV-specific
cellular immune responses
Opportunity for structured
treatment interruption
Lowering of HIV-1 set point
Limitation of viral evolution and
diversity
Decreased transmission
Mitigation of acute retroviral
symptoms
Disadvantages
Toxicities and unknown longterm risks
Short- and long-term clinical
benefits are not well-defined
Resistance acquisition
Limitation of future antiretroviral
therapy options
Quality of life impact
Cost
Kassutto et al, CID 2006
Understanding the terminology
and variables that can be measured
Viral Load = Speed of the train
CD4 count = Distance from cliff
Antiviral therapy = Brakes
HIV
infection
J. Coffin, XI International Conf. on AIDS, Vancouver, 1996
The Dynamics of Acute HIV
Infection
HIV Viral Load
Interquartile
ranges
Rapid Progression
59, 987
HIV Ab
Slow Progression
2-8 weeks
6-12 months
28, 240
11,843
Lyles et al, 2000
Since the level of HIV in the blood
predicts progression, What factors
influence viral replication?
Viral factors
Host genetic
factors
Host immune
responses
Cellular Immune Responses
New virus
assembly
2-3 Days
Soluble
factors
If CTL are present, why is the
immune response not more effective
in HIV infection?
HIV-Specific T Helper Cells are impaired in all
stages of disease
Class II
1. Activation
2. Clonal expansion
TCR
CD4
Antigen
Presenting
Cell
CD4+
Th Cell
3. Cytokine
secretion
Critical relationship between CD4 and CD8
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
CD4 cells
Activation
&
Expansion
Class II TCR
CD4
Infection
Impairment
CD4 cells
Activation
&
Expansion
Class II TCR
CD4
Antiretroviral therapy
Characteristic
Median age (years)
[IQR]
Male gender (%)
HIV Risk Factor MSM
(%)
White race (%)
Mean baseline VL
(copies/mL)
(range)
Mean baseline CD4
(cells/mm3)
(range)
Acute
Early
total n
35
[31,39]
37
[34,43]
102
94
94
102
82
81
94
77
78
102
382,000
(2800-2.95
million)
75
567
(170-981)
100
5.61
million
(11,000-95
million)
445
(42-1093)
Kassutto et al, CID 2006
Spontaneously
control virus
Stimulation index
1000
100
10
1
control chronic acute
No Rx
acute
LTNP
Rx
Rosenberg et al, Science 1997
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
Can treatment be initiated during
acute HIV infection and then
discontinued?
Lessons from Berlin
Lisziewicz et al, NEJM 340 (21), 1999
Augment HIV-specific immunity
STI Hypothesis
RX
RX
RX
CTL
Magnitude
RX
Th
Viral Load
Time
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?
Structured treatment interruption
• Several patterns have emerged
• Failure
• Transient control of viremia with sudden
loss of containment
• Control (durability?)
Rosenberg et al, Nature 2000
Kaufmann et al, PLoS Med 2004
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
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.