HIV cure research in Europe Rowena Johnston, Ph.D. www.amfar.org - - PowerPoint PPT Presentation
PRESENTATION NME HIV cure research in Europe Rowena Johnston, Ph.D. www.amfar.org www.amfar.org www.amfar.org PRESENTATION NME Caveats! Will not be all-inclusive As many Euro countries as possible Concentrating on clinical
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Rowena Johnston, Ph.D.
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The 4 patients with detectable reservoir at baseline decreased (p=0.06) at wk 48 Decrease in immune activation over time 2011
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2007
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2.1-28.7 months tx (median 9.5)
More CD4 cells Slower decline CD4
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Low dose Medium dose High dose
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– Health payoffs – Economic payoffs
with'developing'and'suppor-ng'a'health'research' system'in'which'the'NHS'supports'leading'edge' research'focused'on'the'needs'of'pa-ents'and'the' public.'
through'compe--ve'tender.'
million'in'health'research'over'5'years.'
the'five'‘comprehensive’'BRCs'
Name% Ins)tu)on% Role% John'Frater' University'of'Oxford' Scien-fic'lead' Sarah'Fidler' Imperial'College'London' Clinical'lead' Jonathan'Weber' Imperial'College' Chair'of'TSC' James'Williams,'Lucy'Dorrel' University'of'Oxford' Laboratory' Steve'Kaye' Imperial'College' Laboratory' Simon'Collins' iWBase' People'living'with'HIV' Representa-on' Deenan'Pillay,'Ravi'Gupta' University'College'London' Laboratory' Paul'Kellam' Sanger'Ins-tute'/'UCL' Deep'sequencing' Mike'Malim,,'John'Cason,'' Julie'Fox' Kings'College'London' Laboratory'&'Biobank,'' clinical'centre' Andrew'Lever,'Mark'Wills' University'of'Cambridge' Viral'replica-on'assay' Jane'Anderson,'Adrian' Palfreman' BHIVA'chair' Mark'Nelson,'Mark'Bower,' Mar-n'Fisher,'Sabine'Kinloch,' Nneke'Nwokolo,'Caroline' Foster,'Iain'Williams' C&W'Hospital,'' Brighton,'Royal'Free,'' Dean'street,'St'Marys'Hospital,' Mor-mer'Market' UK'Clinical'leads'
Scien-fic'work'led'by'Dr'John'Frater' Determining'Endpoints:'Assay'Development'
– UltraWlow'viral'load'assay'(Steve'Kaye'IC)' – Quan-ta-ve'replica-on'competence'(Andrew'Lever' Cambridge)' – Sequencing'plagorms'' – Immunology'plagorms''
'
'
lymphocytes%by%high%dosage%intravenous% immunoglobulin%treatment%in%ART%treated%acute% infec)on%:%a%proof5of5concept%study'
'
' ' '
Rebound%of%residual%plasma%viremia%aEer%ini)al%decrease%following%addi)on%of%intravenous%immunoglobulin%to%effec)ve%an)retroviral%treatment%
'
Immediate'ART'Truvada'Darunavir'Ritonavir'Raltegrvir' 2x''HIV'VL<50'four'weeks'apart''' Randomisa-on'' ART'+'30g'IVIG'' 0.4g/kg/day5'days'' Con-nue'ART'' Primary%outcome:'quan-fica-on'of'HIV'DNA'week'48' Secondary%outcome:'immune'ac-va-on''Gut''biopsy'sub'study'
Prof'Mark'Bower'
addi-on'to'ART'on'surrogate'markers'of'viral'reservoirs.'
weeks'postWchemotherapy''
– Kaposi’s'sarcoma'–'Liposomal'doxorubicin'(Caelyx)'or'liposomal'daunorubicin' (Daunoxome)'or'Paclitaxel' – NonWHodgkin’s'Lymphoma'–'‘RCHOP’:'Rituximab,'Cyclophosphamide,' Doxorubicin,'Vincris-ne,'Prednisolone' – Hodgkin’s'Disease'–'‘ABVD’:'Doxorubicin,'Bleomycin,'Vinblas-ne,'Dacarbazine'
– 'laboratory'evidence'of'infec-on'within'6'months'of'a'previous' nega-ve'test,'<3'bands'WB,'RITA'incident,'an-body'nega-ve'PCR+''
– 48Wweek'short'course'ART'(ARTW48)' – 12Wweek'short'course'ART'(ARTW12)' – No'therapy'(Standard'of'Care'SOC)'
– -me'to'CD4'<350'cells/mm3'or'longWterm'ART'ini-a-on'
N'Engl'J'Med.'2013'17;368(3):207W17'
123' 121' 117' 109' 100' 88' 80' 63' 41' 19' ARTW48' 120' 110' 95' 84' 79' 71' 63' 49' 32' 21' ARTW12' 123' 109' 93' 82' 75' 66' 59' 46' 30' 18' SOC'
0.00' 0.25' 0.50' 0.75' 1.00' Probability%of%not%reaching% primary%endpoint% 0' .5' 1' 1.5' 2' 2.5' 3' 3.5' 4' 4.5' Time%(years)% ART48%HR%0.63% (0.45,0.90),%p=0.01% ART12%HR%0.93% (0.67,1.29),%p=0.67% SOC% N'Engl'J'Med.'2013'17;368(3):207W17'
previous'nega-ve'test)'ini-a-ng'immediate'ART'suppressed'
ART'within'first'year'of'life'and's-ll'suppressed'vs'ART'started'>1''years'of' age'
– total'and'integrated'HIV'DNA'
– Pa-ents'with'recent'HIV'infec-on' – Start''immediate'ART' – ART'+'Vaccina-on'+'HDACiW'Vorinostat'
ChAd' HIVcon' prime' MVA' HIVcon' boost' 24'weeks' 8'weeks' 12'days' 3'Drug'HAART'+'Raltegravir' 4.2'weeks'
Recruitment' and' screening'
'38'weeks'total'
3'Drug'HAART'+'Raltegravir'
Vaccinate;' HAART' con-nues' ' Commence' vorinostat'400mg'
HAART'con-nues' FollowWup'period' 4.2'weeks;' HAART'con-nues'
Arm'1:' Control' HAART'only' Arm'2:' HAART'+SAHA' +'Vaccine' Week:'
0'''''''''2'''''''4 ''''''''''8''''''''''12'''''''2324'''''''''''28''''''''''''32''''32+2''32+5'''''33+1''''''33.4'34 '''''''''''''''''''''''''38'&'40' ' ' ' ' ' ' ''
RANDOMISATION% At%wk%24%
2'Days' Primary'Study'end'point' Comparison'between'arms'Log10'integrated'proviral'HIV'DNA'/CD4'cell'at'week'38'&'40'
Pr Brigitte Autran
Université Pierre et Marie Curie - Hôpital Pitié-Salpêtrière, France
NO AIDS Persistence of HIV Reservoirs Current AntiRetroVirals Functional Cure
2 models: Elite Controlers Post-treatment Controlers
eradicate HIV: Sterilizing Cure ?
Berlin patient
Can we decrease the HIV Reservoirs and stop ART?
B Autran
Obstacles to Eradication of the HIV Reservoirs Residual Replication Immune Activation HIV Latency
B Autran
Very early kinetics of Constitution of durable HIV Reservoirs
Massive and Early Establishment
in CD4 cells 30 d post inf.
From A Haase et al. 2008 Immune Responses to HIV:
HIV Reservoirs in Heterogeneous and long-lived CD4 T cells (up to 1/10 cells)
Naive CD4+cell
Apoptosis
Turnover
effector effector
Transitional Memory CD4 T
memory memory Effector Memory CD4 T memory memory Central Memory CD4 cell memory memory Effector CD4 T
The Optiprim ANRS-147 substudy
B Autran
Why does HIV persist despite treatment & immune responses ?
Targeted by ARV anti-HIV CTLs Abs
Obstacles towards an HIV Cure :
The Sleeping Beauty & The Trojan Horse
Naive CD4+cell
Apoptosis
Turnover
effector effector
Transitional Memory CD4 T
memory memory Effector Memory CD4 T memory memory Central Memory CD4 cell memory memory Effector CD4 T
UN-TREATED UN-TREATED Post-treatment controlers PTC
How to measure the HIV Reservoirs? Levels of total cell-associated HIV-DNA in the peripheral blood at various stages of the HIV infection (Data from the french ANRS Cohorts )
Peripheral Blood HIV-DNA levels : same magnitude and correlation to gut tissue reservoirs (Avettand-Fenoel AIDS 2008, Descours B et al. J.AIDS 2012
B Autran
Levels of HIV Reservoirs : the best predictors for long term control of HIV after stopping cART in early treated patients
(the SALTO ANRS 116)
95 patients
(IQR: 53–556)
12 months post TI
(KP: 7.5%, CI: 3.7-14.6)
up to 36 months;
predictor of maintaining VL < 400 cp/ml
(median: < 10 vs 233 cp / 106PBMCs, p < 0.001 )
Piketty et al, J Med Virol, 2010; Assoumou et al, CROI 2013 B Autran
ANRS Visconti cohort
Mississippi Baby
birth.
B Autran
Long-term Remission of HIV after Interruption of Very Early ART in Adults-ANRS EP47 VISCONTI The probability of patients treated since PHI for >12 months to control for >24 months after treatment interruption is ~ 8-15%.
Hocqueloux et al 2010; Goujard et al 2012; Saez-Cirion et al 2013
EP 47 VISCONTI: 14 patients treated at ~39 days p.i. for a median
France HIC
Allele frequency (%)
10 20 30 40 50 60 PTC B27 B57 B35 B07
Post-treatment controllers do not have a favorable MHC background
9
Time after treatment interruption (months) Cell associated HIV-1 DNA (Log copies/106 PBMC)
30 60 90 120 1 2 3 4
Low reservoir levels which further decreased after treatment interruption in some cases
B Autran
Potentia
l str strate tegies gies to r to reduc educe H e HIV r IV res eser ervoir
Residual Replication Immune Activation HIV Reservoirs Latency
Systemic Inflammation Viral Co- Infections
Anti-HIV immunity
NKT CD8 APC
Disruption of Pre/post- HIV transcriptional latency in quiescent CD4T cells
From C. Katlama et al. Lancet 2013
B Autran
The 2000s years :
Help CTL
HAART + vaccine HART + X + Vaccine
HIV RNA HIV DNA
The 2010s years :
Therapeutic immunization against HIV : Changes in paradigms
Autran et al NRI 2003, Science 2004, Exp. Rev. on HIV Vaccines 2004 Murphy et al. Science 2009; Trono D. et al Nat.Med. 2010; the IAS Working Scientific group on HIV Cure, NRI 2012 Katlama C. et al. The Lancet 2013
D Richmann et al. Science 2009
Purging the HIV reservoirs ?
Anti-latency
CTLs/Abs
A new therapeutic concept : Can therapeutic vaccines help at purging the HIV Reservoirs?
Autran et al NRI 2003, Science 2004, Murphy et al. Science 2009; D Richman Nat.Med. 2009; the IAS Working Scientific group on HIV Cure, NRI 2012
Lessons from :
Immune control of the HIV Reservoirs by anti-HIV CD8 T cells
( Martinez et al. J.Inf. Dis. 2005, Almeida JR et al , J.Exp. Med 2007; Xie J. et al. AIDS 2011; Descours B. et al. Clin. Inf. Dis. 2012)
relapse in the absence of CD8 T cells or Abs
(B Autran et al. AIDS 2008
Papagno et al. AIDS 2011)
B Descours et al CID 2012.
Lessons from Elite Controllers Anti-HIV CD8 T Lymphocytes : Key for the control
Central- Memory CD4 T Lymphocytes (TCM):
T cell Numbers and Function in the long term
HIV Transcriptionally active HIV Transcriptionally inactive Anti gag CD8 T cells
TN TTM TEM
Antigens Antigens Antigens
HLA-B27/57 neg TCM HLA-B27/57pos TN
TCM
TTM TEM
Naive CD4+cell
CD45RA CCR7Apoptosis
Turnover
effector effector Effector CD4 T cells
CD45RA CCR7memory memory Central Memory CD4 T cells
CD45RA CCR7 CD45RA CCR7memory memory Effector Memory CD4 T cells
CD27 CCR7memory memory Transitionnal CD4 T cells
19 young adults (23 y.o)
vaccine: HIV env, gag, tat, rev, nef, RT recombinant MVA +FowlPoxV
Can a Therapeutic vaccine against HIV decrease the HIV reservoirs ?
AIDS 2011
ERAMUNE-02 (USA, PI: R Murphy)
SCREENING Primary Evaluation ARM A
(n=14)
3 ARV + Intensification
(raltegravir + maraviroc)
W -4 D0
Randomization
W8 W56
ARM B (n=14) 3 ARV + Intensification
(raltegravir + maraviroc)
+ VRC Vaccine:
3x HIVDNA016-00-VP
(W8,12, 16)
1x rAd5 (W32)
VRC-HIVADV014-00-VP
International, multicenter, randomized, non-comparative controlled study of therapeutic intensification plus vaccine in HIV-infected patients with long-term viral suppression
Decrease in the HIV-1 viral reservoir
(cell-associated HIV-DNA)
vaccine with an anti-latency agent capable to induce HIV antigen expression
Hyper-ART + Immune interventions
HIV RNA HIV DNA
Rationale :
TOC study combining
inducing HIV-specific CD8 T cells to target residual HIV replication: Eramune-02 => B Autran
Univ Pierre et Marie Curie , Pitié-Salpétrière,
IFR Immunité-Cancer-Infection
CRIV (Centre de Recherches Intégrées sur le VIH)
INSERM U945 INSERM U943 Immunity & immunogenetics to viruses Clinical Research /Virology /Epidemiol
A Samri B Descours I Theodorou C Katlama V Calvez D Costagliola A Guihot V Martinez J Guergnon et al. et al. et al. G Carcelain C Bacchus B Autran
ANRS CO15, CO-21 Cohorts, VISCONTI, OPTIPRIM and Reservoir study groups:
Virology and serology : C Rouzioux, V Avettand , Univ. Paris-5 Viro-Immunology: A Saez-Cirion, Inst. Pasteur Clinics: JP Clauvel, Saint-Louis Hosp. Univ Paris-7 ; D Sicard, Cochin Hosp. Univ. Paris-5 L Hoqueloux, CH Orléans; A Cheret CHU Lille-Tourcoing, France
ORVACS
(Objectif recherche Vaccins SIDA)
An International Research Platform The Eramune trials
NIH VRC: G Nabel R Koup J Cassazza RFH Group M Youle, S Kinloch et al. AM Geretti
funds numerous projects
clinical research (therapeutic trials and cohorts)
and HIV controllers: 1,4 million € (1,8 M USD)
studentships, but excludes all other salaries
– Co-‑presidents : Christine Rouzioux, Hopital Necker, Paris and Asier Saez-‑Cirion, Institut Pasteur – Created in 2008, this group brings together research from basic sciences, preclinical and clinical studies. – 4 meetings per year
– President: Jean-Michel Molina, St Louis Hospital, Paris – Review and discussion of all therapeutic clinical trials, including trials
spontaneously controlling HIV infection after treatment interruption (PLoS Pathogens, 2013)
HIV following treatment interruption (Antiviral Therapy 2012)
reservoirs (poster presentation at ICAAC 2012)
Profile
IAS 2013 Satellite, Kuala Lumpur
Tuesday 2nd July 2013, 6.30pm – 8.30pm
“Relationship ¡between immune activation/inflammation and cure (HIV and HBV)
Montpellier, April 2014
(AIDS2010, AIDS2012, IAS2013 in Kuala Lumpur)
NIAID: Statement of Intent (HIV Cure research) (Dr A. Fauci) - July 2013 Member of IAS Towards an HIV Cure Advisory Board
Fred Verdult
Volle Maan Amsterdam, The Netherlands Presented by Kevin Fisher AVAC Your logo
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