PRESENTATION NME
HIV cure research in Europe Rowena Johnston, Ph.D.
www.amfar.org PRESENTATION NME
Caveats!
• Will not be all-inclusive • As many Euro countries as possible • Concentrating on clinical research
• Apologies if your favorite European researcher/study is not mentioned!
www.amfar.org PRESENTATION NME
www.amfar.org Slide from Steve Deeks PRESENTATION NME
www.amfar.org Slide from Steve Deeks PRESENTATION NME
Ongoing replication?
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Treatment intensification
2011
Decrease in immune activation over time
The 4 patients with detectable reservoir at baseline decreased (p=0.06) at wk 48
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Treatment interruption
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www.amfar.org Slide from Steve Deeks PRESENTATION NME
2007
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Early treatment
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Early treatment
2.1-28.7 months tx (median 9.5)
More CD4 cells Slower decline CD4
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Reservoir skewing
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Reactivation
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Therapeutic vaccination
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Therapeutic vaccination
Low dose
Medium dose
High dose
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Immune therapy
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Gene therapy
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Resources
• Difficult to know • Not comparable between countries
• Engage local governments to ensure funding/support! – Health payoffs – Economic payoffs
www.amfar.org CHERUB' Collabora-on'HIV'Eradica-on'of'Reservoirs:' UK'BRC' ' Plans'for'clinical'studies'in'the'UK' Webinar'AVAC'June'2013' The'Comprehensive'Biomedical' Research'Centres'(CBRCs)' • The'Na-onal'Ins-tute'for'Health'Research'is'charged' 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.' • Funding'is'allocated'through'the'BRCs'and'CBRCs' through'compe--ve'tender.' • In'August'2011,'the'NIHR'invested'a'further'£800' million'in'health'research'over'5'years.' • CHERUB'is'part'of'this'investment.' • CHERUB'–'uniquely'W'combines'the'research'efforts'of' the'five'‘comprehensive’'BRCs' CHERUB'Steering'Commi\ee' 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,'' Kings'College'London' Laboratory'&'Biobank,'' Julie'Fox' clinical'centre' Andrew'Lever,'Mark'Wills' University'of'Cambridge' Viral'replica-on'assay' Jane'Anderson,'Adrian' BHIVA'chair' Palfreman' Mark'Nelson,'Mark'Bower,' C&W'Hospital,'' UK'Clinical'leads' Mar-n'Fisher,'Sabine'Kinloch,' Brighton,'Royal'Free,'' Nneke'Nwokolo,'Caroline' Dean'street,'St'Marys'Hospital,' Foster,'Iain'Williams' Mor-mer'Market' Scien-fic'work'led'by'Dr'John'Frater' Determining'Endpoints:'Assay'Development'
• Development'of'‘stock’'assays' • Proviral'DNA'qPCR'(integrated,'total,'episomal)' – UltraWlow'viral'load'assay'(Steve'Kaye'IC)' – Quan-ta-ve'replica-on'competence'(Andrew'Lever' Cambridge)' – Sequencing'plagorms'' – Immunology'plagorms'' • New'plagorms' Clinical'Cohorts'in'Development'
• 001':'IVIG'in'PHI' • 003:'Chemotherapy'protocol' • Viral'reservoir'characteriza-on'SPARTAC'study' • Observa-onal'studies'CHERUBWyc,'HEATHER' ' • Future'planned'studies'awai-ng'funding'decision:' • 005:'HDACi'+'Vaccine'in'PHI' • HDACi'+'ART'+'chemotherapy' • HDCAi'+'Vaccine'in'ARTWtreated'acute'infec-on' • Genera-on'of'autologous'HIV'‘vaccine’''' • CHERUB'001:'IVIG'in'Primary'HIV' Infec-on' – Julie'Fox'(King’s'College'London)' ' • Reduc)on%of%the%HIV51%reservoir%in%res)ng%CD4+%T5 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% of%HIV.%%[Mellberg'T,'Gonzalez'VD,'Lindkvist'A,'Edén'A,'Sönnerborg'A,'Sandberg'JK,'Svennerholm'B,'Gisslén'M';'AIDS%Res%Ther.%2011%Jun%28;8:21]' ' N%=%10% Recent%HIV%infec)on% Within%12%weeks%of%infec)on%% Immediate'ART'Truvada'Darunavir'Ritonavir'Raltegrvir' 2x''HIV'VL<50'four'weeks'apart''' Randomisa-on''
ART'+'30g'IVIG'' Con-nue'ART'' 0.4g/kg/day5'days''
Primary%outcome:'quan-fica-on'of'HIV'DNA'week'48' Secondary%outcome:'immune'ac-va-on''Gut''biopsy'sub'study' CHERUB'003'–'‘Chemotherapy’' Prof'Mark'Bower'
• Proof'of'principle'study;'n=25' • AIM:'To'inves-gate'the'impact'of'cytotoxic'chemotherapy'agents'in' addi-on'to'ART'on'surrogate'markers'of'viral'reservoirs.' • Primary%Endpoints% • Comparison'of'proviral%DNA%quan)fica)on%between'baseline'and'at'12' weeks'postWchemotherapy''
• Cytotoxic'agents'used'in'HIV+ve'individuals'with'malignancy'include:' – 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'
SPARTAC'Trial':Design
• Defini-on'of'PHI' – 'laboratory'evidence'of'infec-on'within'6'months'of'a'previous' nega-ve'test,'<3'bands'WB,'RITA'incident,'an-body'nega-ve'PCR+'' • Randomisa-on'to'one'of'three'arms:' – 48Wweek'short'course'ART'(ARTW48)' – 12Wweek'short'course'ART'(ARTW12)' – No'therapy'(Standard'of'Care'SOC)' • Primary'end'point'' – -me'to'CD4'<350'cells/mm3'or'longWterm'ART'ini-a-on'
N'Engl'J'Med.'2013'17;368(3):207W17' SPARTAC:'Time'to'primary'endpoint' 1.00' ART48%HR%0.63% (0.45,0.90),%p=0.01%
0.75' SOC% 0.50' ART12%HR%0.93% (0.67,1.29),%p=0.67%
primary%endpoint% 0.25' Probability%of%not%reaching%
0.00' 0' .5' 1' 1.5' 2' 2.5' 3' 3.5' 4' 4.5' Time%(years)% SOC' 123' 109' 93' 82' 75' 66' 59' 46' 30' 18' ARTW12' 120' 110' 95' 84' 79' 71' 63' 49' 32' 21' ARTW48' 123' 121' 117' 109' 100' 88' 80' 63' 41' 19' N'Engl'J'Med.'2013'17;368(3):207W17' Characterisa-on'of'measures'of'viral' reservoirs'in'SPARTAC' • N='40'par-cipants'randomly'selected'from'ART48' vs'SOC' • Quan-fica-on'of'total'integrated'HIV'DNA'at' baseline'and'week'52' • Results:'HIVW1'reservoir'aser'48'weeks'of' treatment'strongly'predicted'disease' progression,'with'total'HIVW1'levels'being'more' predic-ve'than'integrated'levels.'' • Dr'John'Frater:'will'present'at'KL'July'2013,' Towards'a'cure'mee-ng'and'IAS'oral'late'breaker' Observa-onal'studies'
• HEATHER' • Individuals'with'defined'HIV'acute'infec-on'(<'12'weeks'from' previous'nega-ve'test)'ini-a-ng'immediate'ART'suppressed' on'treatment'for'>'2'years' • CHERUBWyc' • Perinatally'HIV'infected'young'people'age'>'10'years:'either'started'on' ART'within'first'year'of'life'and's-ll'suppressed'vs'ART'started'>1''years'of' age'
• Primary'outcome'' – total'and'integrated'HIV'DNA' Future'studies'planned'
• REACH'' • Genera-on'of'autologous'vaccine'for'future' ex'vivo'studies'from'treated'acute'infec-on' (Eric'Arts'Amfar'applica-on'under'review)' • ART'treated'from'acute'infec-ons'Vaccina-on' plus'HDACi'with'more'potent'agent' Romedepsin':'dependent'on'outcome'of' single'dose'ACTG'Mellors'study' CHERUB%005% REACH:%Recent%HIV%infec)on:%Eradica)on%by% Ac)va)on%of%the%HIV%reservoir:%A%proof%of% concept%trial%'' • Proof'of'principle'pilot'study'n'='50' • Industry'(Merck,'Okairos')'academic' partnership'funding'sought'from'MRC'DCS' • Recent'HIV'infec-on'(<'12'weeks).' – Pa-ents'with'recent'HIV'infec-on' – Start''immediate'ART' – ART'+'Vaccina-on'+'HDACiW'Vorinostat' • Primary'Outcome:'Quan-fica-on'of'HIV'reservoir.'
'38'weeks'total'
RANDOMISATION% At%wk%24%
Recruitment' ChAd' MVA' and' HIVcon' HIVcon' screening' prime' boost'
24'weeks' 8'weeks' 12'days' 4.2'weeks'
3'Drug'HAART'+'Raltegravir' Arm'1:' Control' HAART'only' 2'Days' 3'Drug'HAART'+'Raltegravir' Vaccinate;' Commence' FollowWup'period' Arm'2:' HAART' vorinostat'400mg' 4.2'weeks;' HAART'+SAHA' con-nues' od'for'10'day;' HAART'con-nues' +'Vaccine' ' HAART'con-nues'
Week:' 0'''''''''2'''''''4 ''''''''''8''''''''''12'''''''2324'''''''''''28''''''''''''32''''32+2''32+5'''''33+1''''''33.4'34 '''''''''''''''''''''''''38'&'40' ''''''''
Primary'Study'end'point' Comparison'between'arms'Log10'integrated'proviral'HIV'DNA'/CD4'cell'at'week'38'&'40' Why'might'you'be'interested?'
• All'interes-ng'UK'health'care'professionals' providing'care'for'PLWHA'may'see'pa-ents' who'ask'ques-ons'about'UK'HIV'“cure”' research' • May'refer'poten-ally'interested'pa-ents'into' ongoing'studies'' • May'be'interested'in'working'with'the' collabora-on'in'laboratory'based'research'or' developing'new'clinical'trial'ideas'' Towards an HIV Cure : Can Immunity to HIV control the reservoirs ?
Pr Brigitte Autran Inst. of Researches Immunity, Cancer and Infection , Université Pierre et Marie Curie - Hôpital Pitié-Salpêtrière, France Why do we need a Cure for HIV ? To control the HIV pandemics How ?
Current Can we AntiRetroVirals NO AIDS decrease the HIV Reservoirs Persistence of and stop ART? HIV Functional Cure Reservoirs 2 models: Elite Controlers Post-treatment Controlers or eradicate HIV: Sterilizing Cure ? Berlin patient
B Autran
Obstacles to Eradication of the HIV Reservoirs
Residual Immune Replication Activation
HIV Latency
B Autran Very early kinetics of Constitution of durable HIV Reservoirs
Immune Responses to HIV: The Optiprim ANRS-147 « Too little, too late » substudy
From A Haase et al. 2008 HIV Reservoirs in Heterogeneous and
long-lived CD4 T cells (up to 1/10 cells) Massive and Early memoryCentral memory effector Establishment Memory Transitionaleffector Turnover CD4 cell Memory Naive CD4 T of the HIV Reservoirs CD4+cell in CD4 cells memoryEffector Effector memory Apoptosis 30 d post inf. memorymemory CD4 T Memory B Autran CD4 T Why does HIV persist despite treatment & immune responses ?
Obstacles towards an HIV Cure :
The Sleeping Beauty & The Trojan Horse
Central memorymemory Memory Transitionaleffectoreffector Turnover CD4 cell Memory CD4 T Naive CD4+cell memoryEffector Effector memory Apoptosis memorymemory CD4 T Targeted by ARV Memory CD4 T anti-HIV CTLs Abs 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 )
UN-TREATED UN-TREATED Post-treatment controlers PTC 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 12 months post TI
• Age 40 years (IQR: 36–45). • All had CD4 cell >500/mm3 • Pre-cART values 7/95 patients still had a VL<400 cp/ml • CD4 : 454 /mL (392–576) (KP: 7.5%, CI: 3.7-14.6)
• VL : 4.3 log cp/ml (3.9 – 4.5) 10 4 kept a VL<400 copies/mL • CD4 nadir : 382 /mL (340–492). up to 36 months;
• Duration of cART : 5.3 y (4.0–6.0) HIV DNA was the only significant • Baseline values predictor of maintaining VL < 400 cp/ml • CD4 : 813 cells/µL (695–988) (median: < 10 vs 233 cp / 106PBMCs, 6 • DNA : 206 copies/10 PBMCs p < 0.001 ) (IQR: 53–556)
B Autran Piketty et al, J Med Virol, 2010; Assoumou et al, CROI 2013 Post-treatment Controllers: new hope for a functional cure
ANRS Visconti cohort
- Long-term remission of 14 patients treated at ~39 days p.i. for a median of 3.5 years and controlling off therapy for > 4 years
Mississippi Baby
- Infant treated with early, intense antiretroviral treatment within 30 hours of birth. - Plasma HIV RNA undetectable, despite ART discontinuation
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 of 3.5 years and controlling off therapy for > 4 years
Post-treatment controllers do not Low reservoir levels which further have a favorable MHC background decreased after treatment interruption in some cases 60 4
B27
50 B57
B35 1 DNA 3 40 B07 - PBMC) PBMC)
6 30 2 20
10 1 Allele frequency frequency Allele(%) (Log (Log copies/10
0 HIV associated Cell France HIC PTC 0 0 30 60 90 120 Time after treatment B Autran interruption (months) 9
Potential strategies to reduce HIV reservoirs From C. Katlama et al. Lancet 2013
CD8 NKT
APC Anti-HIV immunity
Systemic Inflammation Immune Residual Viral Co- Activation Replication Infections
Disruption of Pre/post- HIV transcriptional HIV Reservoirs latency in quiescent CD4T cells Latency - IL7 - HDACi B Autran - HMBA … Therapeutic immunization against HIV : Changes in paradigms
The 2000s years : The 2010s years : To re-immunize against HIV : To re-immunize against HIV : - while on ART - while on ART - before virus relapse, - in association with anti-latency agents In order to limit : In order to : - time on therapy - reduce or purge the HIV reservoirs - disease progression during time « off ART » - allow functional cure of HIV
HAART HART + + X +
vaccine Vaccine HIV DNA HIV HIV RNA HIV
Help CTL Murphy et al. Science 2009; Trono D. et al Nat.Med. 2010; the IAS Working Scientific group on HIV Cure, NRI 2012 Autran et al NRI 2003, Science 2004, Exp. Rev. on HIV Vaccines 2004 Katlama C. et al. The Lancet 2013 A new therapeutic concept : Can therapeutic vaccines help at purging the HIV Reservoirs?
Lessons from : • Elite Controllers: Anti-latency Immune control of the Purging the HIV Reservoirs HIV by anti-HIV CD8 T cells reservoirs ? ( Martinez et al. J.Inf. Dis. 2005, Almeida JR et al , J.Exp. Med 2007; CTLs/Abs Xie J. et al. AIDS 2011; Descours B. et al. Clin. Inf. Dis. 2012)
D Richmann et al. Science 2009 • Therapeutic vaccines trials against HIV
A Therapeutic Vaccine should induce - Limited capacity to control virus anti-HIV CD8 T cells or Abs relapse in the absence of to kill the residual replicating cells CD8 T cells or Abs or block cell to cell HIV spreading (B Autran et al. AIDS 2008 Papagno et al. AIDS 2011)
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 Elite Controllers
Anti-HIV CD8 T Lymphocytes : Key for the control of HIV Reservoirs in Centra-Memory CD4 T cells
HLA-B27/57 neg Critical protection of long-lived
Central- Memory CD4 TN Antigens TCM Antigens TTM Antigens TEM HLA-B27/57pos T Lymphocytes (TCM):
required for maintaining TCM TN TTM TEM T cell Numbers and Function
memoryEffector Apoptosis memory effector in the long term
CCR7 Memory effector
CCR7 Effector CD4 T cells CD4 T
Naive CD45RA cells CD45RA CD4+cell preserved in LTNP / Controllers
CCR7 memory CCR7 memory Central Transitionnal CD45RA memorymemory
CD4 T cells Memory Turnover CCR7 CD4 T cells CD27
CD45RA
HIV Transcriptionally active HIV Transcriptionally inactive B Descours et al CID 2012. Anti gag CD8 T cells Can a Therapeutic vaccine against HIV decrease the HIV reservoirs ?
AIDS 2011
19 young adults (23 y.o) on ART, HIV RNA < 50 cp/mL
vaccine: HIV env, gag, tat, rev, nef, RT recombinant MVA +FowlPoxV - 2 MVA: D0, W4 - 1 FPV: W8
Transient decrease in latently infected CD4+ T cells The EraMune-02 Trial : Study Design
International, multicenter, randomized, non-comparative Hyper-ART + controlled study of therapeutic intensification Immune plus vaccine in HIV-infected patients
interventions with long-term viral suppression
(USA, PI: R Murphy) HIV DNA ERAMUNE-02 HIV RNA Primary objective: SCREENING Decrease in the HIV-1 viral W -4 ARM A ARM B (n=14) reservoir (n=14) D0 3 ARV + (cell-associated HIV-DNA) Rationale : Intensification Results end Q2 2013 3 ARV (raltegravir + TOC study combining Randomization maraviroc) - ARV intensification + + Intensification - immune intervention + VRC Vaccine: Next steps ? (raltegravir + W8 inducing HIV-specific maraviroc) 3x HIVDNA016-00-VP To combine a therapeutic (W8,12, 16) CD8 T cells to target vaccine with an anti-latency residual HIV replication: 1x rAd5 (W32) VRC-HIVADV014-00-VP agent capable to induce Eramune-02 => HIV antigen expression
Other Strategies ? Primary Evaluation W56 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 RFH Group M Youle, S Kinloch et al. AM Geretti
NIH VRC: G Nabel R Koup J Cassazza funding for HIV Cure
• Although no specific earmarked funds for HIV Cure, the ANRS funds numerous projects
• Funding, including basic research, preclinical studies and clinical research (therapeutic trials and cohorts)
• 2012 for specific HIV Cure research (very narrow definition) and HIV controllers: 1,4 million € (1,8 M USD)
• Total amount includes some post-doc salaries and PhD studentships, but excludes all other salaries
Scientific coordination surrounding HIV Cure
• AC 32: Viral reservoirs – 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
• AC 5: Therapeutic clinical trials – President: Jean-Michel Molina, St Louis Hospital, Paris – Review and discussion of all therapeutic clinical trials, including trials on primary infection, treatment intensification, etc…
Selected key projects
• ANRS EP47 Visconti: Distribution of the HIV reservoir in patients spontaneously controlling HIV infection after treatment interruption (PLoS Pathogens, 2013)
• ANRS CO6 Primo cohort: some rare patients show persistent control of HIV following treatment interruption (Antiviral Therapy 2012)
• ANRS 147 Optiprim: Evaluation of treatment intensification at AHI on viral reservoirs (poster presentation at ICAAC 2012)
• ANRS CODEX CO21 - Multicentric Cohort of HIV Patient With Extreme Profile
• More than 30 ongoing projects in basic science
Upcoming ANRS events
• “ What can we learn from Post-therapy controllers?” IAS 2013 Satellite, Kuala Lumpur
Tuesday 2nd July 2013, 6.30pm – 8.30pm
• ANRS sponsorship of IAS HIV Cure symposia (AIDS2010, AIDS2012, IAS2013 in Kuala Lumpur)
• Annual ANRS Basic Science Meeting
“Relationship between immune activation/inflammation and cure (HIV and HBV)
Montpellier, April 2014 ANRS and the International Scene of HIV Cure research
NIAID: Statement of Intent (HIV Cure research) (Dr A. Fauci) - July 2013
Member of IAS Towards an HIV Cure Advisory Board Your logo
CURE: The point of view of people living with HIV Fred Verdult
Volle Maan Amsterdam, The Netherlands Presented by Kevin Fisher AVAC Research questions
! ! ! From!the!PERSPECTIVE!of!people!living! with!HIV:!
• How!important!is!a!cure?! !WHY?! ! • WHICH!cure!is!preferred?! Respondents
! • Database!of!1,002!names!contacted! ! ! • Response:!n=!458!(=!46%)!! • May!15–31!2012(+!4!respondents!in!
June)! ! ! !! ! ! ! !! !! ! ! ! !! !! ! ! ! !! !! ! ! ! !! !! ! ! ! !! !! ! ! ! !! !!!! Gggggg Ggg!! ! !Gggh H! H !! H O O O
!! ! ! ! !! !! ! ! ! !! !! ! ! ! !! !!!!