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 research • Apologies if your favorite European researcher/study is not mentioned! www.amfar.org www.amfar.org

PRESENTATION NME www.amfar.org www.amfar.org Slide from Steve Deeks www.amfar.org

PRESENTATION NME www.amfar.org www.amfar.org Slide from Steve Deeks www.amfar.org

PRESENTATION NME Ongoing replication? www.amfar.org www.amfar.org

PRESENTATION NME Treatment intensification 2011 Decrease in immune activation over time The 4 patients with detectable reservoir at baseline decreased (p=0.06) at wk 48 www.amfar.org www.amfar.org

PRESENTATION NME Treatment interruption www.amfar.org www.amfar.org

PRESENTATION NME www.amfar.org www.amfar.org Slide from Steve Deeks www.amfar.org

PRESENTATION NME 2007 www.amfar.org www.amfar.org www.amfar.org

PRESENTATION NME Early treatment www.amfar.org www.amfar.org

PRESENTATION NME Early treatment 2.1-28.7 months tx (median 9.5) More CD4 cells Slower decline CD4 www.amfar.org www.amfar.org

PRESENTATION NME Reservoir skewing www.amfar.org www.amfar.org

PRESENTATION NME Reactivation www.amfar.org www.amfar.org

PRESENTATION NME Therapeutic vaccination www.amfar.org www.amfar.org

PRESENTATION NME Therapeutic vaccination Low dose Medium dose High dose www.amfar.org www.amfar.org

PRESENTATION NME Immune therapy www.amfar.org www.amfar.org

PRESENTATION NME Gene therapy www.amfar.org www.amfar.org

PRESENTATION NME Resources • Difficult to know • Not comparable between countries • Engage local governments to ensure funding/support! – Health payoffs – Economic payoffs www.amfar.org 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/mm 3 '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% Probability%of%not%reaching% 0.75' primary%endpoint% SOC% 0.50' ART12%HR%0.93% (0.67,1.29),%p=0.67% 0.25' 0.00' 0' .5' 1' 1.5' 2' 2.5' 3' 3.5' 4' 4.5' Time%(years)% SOC ' 109 ' 93 ' 82 ' 75 ' 66 ' 59 ' 46 ' 30 ' 18 ' 123' 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% ChAd' MVA' Recruitment' HIVcon' HIVcon' and' prime' boost' screening' 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' 0'''''''''2'''''''4 ''''''''''8''''''''''12'''''''2324'''''''''''28''''''''''''32''''32+2''32+5'''''33+1''''''33.4'34 '''''''''''''''''''''''''38'&'40' Week:' ' ' ' ' ' ' ' ' Primary'Study'end'point' Comparison'between'arms'Log 10 'integrated'proviral'HIV'DNA'/CD4'cell'at'week'38'&'40'