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Eric S. Rosenberg, M.D. Associate Professor of Medicine Massachusetts General Hospital Harvard Medical School erosenberg1@partners.org. 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

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eric s rosenberg m d

Eric S. Rosenberg, M.D.

Associate Professor of Medicine

Massachusetts General Hospital

Harvard Medical School

erosenberg1@partners.org

47 year old male
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 male3
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 male5
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
Diagnosis

Acute HIV infection

framing the question mgh ncsu collaboration
Framing the QuestionMGH-NCSU collaboration

Should this individual be treated with antiretroviral therapy??

acute hiv infection goals
Acute HIV infectionGoals
  • To discuss the advantages and disadvantages of treating individuals with acute HIV
  • To review the early biological events of acute HIV infection
  • 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
Should individuals with Acute HIV-1 infection be treated with antiretroviral therapy?

? ? ? ? ?

Kassutto et al, CID 2006

slide10

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

CTL

6-12 months

The Dynamics of Acute HIV Infection

Interquartile

ranges

Rapid Progression

59, 987

HIV Viral Load

HIV Ab

28, 240

11,843

Slow Progression

2-8 weeks

Lyles et al, 2000

slide12
Since the level of HIV in the blood predicts progression, What factors influence viral replication?
slide13

Host genetic factors

Viral factors

Host immune responses

slide14

Soluble

factors

CTL

New virus

assembly

2-3 Days

Cellular Immune Responses

slide16

HIV-Specific T Helper Cells are impaired in all stages of disease

1. Activation

2. Clonal expansion

Class II

TCR

CD4

3. Cytokine secretion

Antigen Presenting Cell

CD4+

Th Cell

what happens to hiv specific t helper cells the acute infection hypothesis
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
slide19

CD4 cells

Activation

&

Expansion

Infection

Impairment

Class II

TCR

CD4

slide20

CD4 cells

Activation

&

Expansion

Antiretroviral therapy

Class II

TCR

CD4

slide22

Spontaneously control virus

1000

100

Stimulation index

10

1

control

chronic

acute

acute

LTNP

No Rx

Rx

Rosenberg et al, Science 1997

observation
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
slide25

Lessons from Berlin

Lisziewicz et al, NEJM 340 (21), 1999

augment hiv specific immunity sti hypothesis
Augment HIV-specific immunitySTI Hypothesis

RX

RX

RX

RX

CTL

Th

Magnitude

Viral Load

Time

can therapy be discontinued
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
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

is the possibility of sti enough reason to treat individuals during acute hiv infection
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
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.
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