Eric S. Rosenberg, M.D.

Associate Professor of MedicineMassachusetts General Hospital

Harvard Medical Schoolerosenberg1@partners.org

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

47 year old male Additional history:MSMRecent unprotected sex with an HIV infected partnerPMH: prior hx of syphilisExam:

FeverCervical lymphadenopathy Rash (started on torso spread to limbs and scalp)

47 year old male Diagnostics:

Test for EBV, CMV, influenza were negative

HIV ELISA PositiveWestern Blot negative (no bands)HIV RNA > 750,000 copies/ml

1:100 dilution 47,000,000 copies/mlCD4 count = 432 cells

Diagnosis

Acute HIV infection

Framing the QuestionMGH-NCSU collaboration

Should this individual be treated with antiretroviral therapy??

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

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?

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

The Dynamics of Acute HIV Infection

HIV

Vira

l Loa

d

6-12 months

Rapid Progression

Slow Progression

28, 240

59, 987

11,843

Interquartileranges

Lyles et al, 2000

CTL

HIV Ab

2-8 weeks

Since the level of HIV in the blood predicts progression, What factors

influence viral replication?

Viral factors

Host immune responses

Host genetic factors

New virusassembly

2-3 Days

CTL

SolublefactorsCellular Immune Responses

If CTL are present, why is the immune response not more effective

in HIV infection?

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

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 infectionHypothesis (opportunity):• Treatment with ARV during acute

infection will protect these responses from being lost

Activation

&

Expansion

ImpairmentInfectionCD4 cells

Class II

CD4

TCR

Activation

&

Expansion

Antiretroviral therapyCD4 cells

Class II

CD4

TCR

Characteristic Acute Early total nMedian age (years)

[IQR]35

[31,39]37

[34,43] 102

Male gender (%) 94 94 102HIV 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

control chronic acute acute LTNP1

10

100

1000

RxNo Rx

Stim

ulat

ion

inde

x

Rosenberg et al, Science 1997

Spontaneously control virus

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 immunitySTI Hypothesis

RXRX RXRX RXRX RXRX

TimeTime

Mag

nitu

deM

agni

tude

CTLCTL

ThTh

Viral LoadViral Load

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 2000Kaufmann 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.