Acute HIV InfectionTranslating Pathogenesis into Opportunity

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 102.5HeadachePhotophobiaMyalgias and arthralgiasNausea and vomiting

3rd visit to health care system

47 year old male

Additional history:Recent unprotected sex with an HIV infected

partner

PMH: prior history 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 Negative

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 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/host immune response = BrakesAntiviral therapy/host immune response = Brakes

Understanding the terminology and variables that can be measured

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

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

Humoral immune responseNeutralizing Antibodies

B cell

• Viral debris

• Rapid evolution and diversification of HIV (horse is already out of the barn)

• Inadequate T cell “help”

Why do neutralizing antibodies fail?

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

Opportunity #1Rescue of HIV-specific T helper cells

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

Activation

&

Expansion

ImpairmentInfectionCD4 cells

Class II

CD4

TCR

Activation

&

Expansion

Antiretroviral therapyCD4 cells

Class II

CD4

TCR

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

control chronic acute acute LTNP1

10

100

1000

RxNo Rx

Sti

mu

lati

on

in

dex

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

Opportunity #2

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

Opportunity #3

There is more translating to do… Each patient tells a different story

0 5 10 15 20 25 300

50000

100000

150000

200000

Days off therapy

VIr

al lo

ad

AC-02

STI cycle #1

0 500 1000 1500 20000

50000

100000

150000

200000

Days off therapy

Vir

al lo

adAC-02

STI cycle #2

AC-10

0 500 1000 1500 20000

10000

20000

30000

40000

50000

Days off therapy

Vir

al

loa

d

0 50 100 150 200 2501

10

100

1000

HIV-1 RNA

0100020003000400050006000Autol Nab

AC-10 (1.5 years on therapy)

Days off therapy

Neu

tral

izin

g a

nti

bo

dy

tite

r Plasm

a HIV

-1 RN

A

Montefiori, J Virology 2001

1h

2h

5j6e

Jrfl

Hxb2NL43 2b

100

100

89-6

1a1c

1b

2c1d

100

77

5g6h

5a6c

5e3a

6m2f

1k1l

6i

5c3e

5b5h

2k6l

5d1b3b3h4a5k

2e6d

103d3g

6f2b2i1m1j1i

6g6j6k

1a3f

1n5m 5f

6n1e

2c3c 2d

5i5n 4b

2a1d

2g1c

2j1f

5l1g

6b5o

99

96

99

97

Chronic pt.

Acute pt.

Acute pt.

1a

1b1c1d1e1f1g2a2b2c2d2h

2f

What is unique about treated acute infection?Lack of viral diversification

AC-06

50000

100000

1500008.8 x 106

< 50

12 months 24 months 36 months 48 months

New virusassembly

2-3 Days

CTL

SolublefactorsCellular Immune Responses

gagpol

vifvpr

vpu

envnef

tatrev

1 631

793 2295

2088 5099

5044 5622

5562 5853

6070 6302

6230 8805

8807 9431

5834 6048 8368 8458

5973 6048 8368 8663

WEKIRLRPGGKKKYK16 30

SPRTLNAWVKVVEEK148 162

GATPQDLNTMLNTV178 191

HPVHAGPIAPGQMREPR216 232

TACQGVGGPGHKAPVL348 363

WRKLVDFRELNKRTQDFW226 243

FWEVQLGIPHPAGLKKK242 259

WKGSPAIFQSSMTKI308 322

SQIYPGIKVRQLCKL423 437

LKTGKYARMRGAHTNDVK504 521

AVFIHNFKRKGGIGGYSA894 911

VRHFPRIWLHGLGQH31 45

ERILSTYLGRSAEPV57 71

QVDRMRIRTWKSLVK12 26

KSLVKHHMYISKKAK22 36

THPRVSSEVHIPLG47 60

KKTKPPLPSVKKLT157 170

NCTRPNNNTRKSIHI295 309

FSYRRLRDLLLIAAR766 780

HIPRRIRQGLERALL842 856

EVGFPVTPQVLRPM65 79

VTPQVPLRPMTYKAA70 84

PLRPMTYKAAVDLSH75 89

TYKSSVDLSHFLKEK80 94

RRQDILDLWIYHTQG105 119

AC-06

50000

100000

1500008.8 x 106

< 50

12 months 24 months 36 months 48 months

AC-06

50000

100000

1500008.8 x 106

< 50

12 months 24 months 36 months 48 months

N

T

V

AT

L

Y

L

S

Viral peptide in HLA Binding Groove

HLA Class I molecule

HLA Class I molecule

N

Y

F

S

T

V

TAL

Immune escape in anchor residues

Viral Variation in Gag

KIRLRPGGK-A03 RLRPGGKKKY-A03Day 18 MGARASVLSGGELDKWEKIRLRPGGKKKYRLKHIVWASRELERFALNPSLLETSGGCRQILGQLQPSLQTGSEELKSLFNTIAVLYCVHQRIDVKDTKEA>Day 1170 ..........................T.K...............V..G............K..H.............Y..V.T........EIR.....>

SPRTLNAWV-B07 TPQDLNTML-B07Day 18 LDKIEEEQNKTKKKAQQAAADTGNSSQVSQNYPIVQNLQGQMVHQPISPRTLNAWVKVVEEKAFSPEVIPMFTALSEGATPQDLNTMLNTVGGHQAAMQM>Day 1170 .........C..RE..............................S..........................S...........................>

HPVHAGPIA-B07Day 18 LKETINEEAAEWDRLHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIAWMTNNPPIPVGDIYKRWIILGLNKIVRMYSPSSILDIKQGPKEPFRDYVDRF>Day 1170 .............M.......V........................Q...S...V...E...................T....................>

GPGHKARVL-B07Day 18 YKTLRAEQASQDVKNWMTETLLVQNSNPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVLAEAMSQMTSPANIMMQRGNFKNQRKIVKCFNCGKEGH>Day 1170 ..........E..G..........A.............G.............................V.NS.T........R....T...........>

Day 18 IARNCRAPRKKGCWKCGQEGHQMKDCTERQANFLGKIWPSHKGRPGNFLQSRPEPTAPPAESLMFGEETTTPPQKQEPRDKELYPPLASLRSLFGNDPSSQ>Day1170...........................................................E..VR.....A..S...GTI......-...............>

Altfeld et al , Nature

Presence of Two Distinct Viruses

Altfeld et al , Nature

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.

• Mathematical and statistical modeling (NCSU-MGH) to inform the design of the first randomized trial of treatment versus no treatment during acute HIV.