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Acute HIV InfectionTranslating Pathogenesis into Opportunity
Eric S. Rosenberg, M.D.
Associate Professor of Medicine
Massachusetts General Hospital
Harvard Medical School
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
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
• Viral debris
• Rapid evolution and diversification of HIV (horse is already out of the barn)
• Inadequate T cell “help”
Why do neutralizing antibodies fail?
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
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
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
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
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
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
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
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.