WEBINAR: CHERUB collaboration & UK research towards HIV cure


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Webinar June 2013 AVAC/NAM

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  • Spartac was an open RCT 1:1:1 randomisation across 8 different countries The planned sample size of 360 participants was estimated using CASCADE data,19,20 providing 90% power with significance level 5% to detect a relative reduction in the risk of progression to the original primary endpoint (CD4 <350 cells/mm3) of 50% and 25% in ART-48 and ART-12, respectively, versus SOC, assuming recruitment over 18 months with minimum 3.5 years follow-up and 10% lost to follow-up.
  • This graph compares the actual time difference in weeks to reach primary endpoint between the armsART48 delayed time to primary endpoint by 65 weeks compared with SOC. This was however, not significantly longer than time spent on therapy
  • WEBINAR: CHERUB collaboration & UK research towards HIV cure

    1. 1. CHERUBCollaboration HIV Eradication ofReservoirs: UK BRCPlans for clinical studies in the UKWebinar AVAC June 2013
    2. 2. The National Institute for Health Research is charged withdeveloping and supporting a health research system inwhich the NHS supports leading edge research focused onthe needs of patients and the public.Funding is allocated through the BRCs and CBRCs throughcompetitive tender.In August 2011, the NIHR invested a further £800 million inhealth research over 5 years.CHERUB is part of this investment.CHERUB – uniquely - combines the research efforts of thefive ‘comprehensive’ BRCsThe Comprehensive BiomedicalResearch Centres (CBRCs)
    3. 3. CHERUB Steering CommitteeName Institution RoleJohn Frater University of Oxford Scientific leadSarah Fidler Imperial College London Clinical leadJonathan Weber Imperial College Chair of TSCJames Williams, Lucy Dorrel University of Oxford LaboratorySteve Kaye Imperial College LaboratorySimon Collins i-Base People living with HIVRepresentationDeenan Pillay, Ravi Gupta University College London LaboratoryPaul Kellam Sanger Institute / UCL Deep sequencingMike Malim,, John Cason,Julie FoxKings College London Laboratory & Biobank,clinical centreAndrew Lever, Mark Wills University of Cambridge Viral replication assayJane Anderson, Adrian Palfreman BHIVA chairMark Nelson, Mark Bower, Martin Fisher,Sabine Kinloch, Nneke Nwokolo, CarolineFoster, Iain WilliamsC&W Hospital,Brighton, Royal Free,Dean street, St Marys Hospital, Mortimer MarketUK Clinical leads
    4. 4. Development of ‘stock’ assaysProviral DNA qPCR (integrated, total, episomal)Ultra-low viral load assay (Steve Kaye IC)Quantitative replication competence (Andrew LeverCambridge)Sequencing platformsImmunology platformsNew platformsScientific work led by Dr John FraterDetermining Endpoints: Assay Development
    5. 5. 001 : IVIG in PHI003: Chemotherapy protocolViral reservoir characterization SPARTAC studyObservational studies CHERUB-yc, HEATHERFuture planned studies awaiting funding decision:005: HDACi + Vaccine in PHIHDACi + ART + chemotherapyHDCAi + Vaccine in ART-treated acute infectionGeneration of autologous HIV ‘vaccine’Clinical Cohorts in Development
    6. 6. CHERUB 001: IVIG in Primary HIV InfectionJulie Fox (King’s College London)Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenousimmunoglobulin treatment in ART treated acuteinfection : a proof-of-concept studyCHERUB 001Rebound of residual plasma viremia after initial decrease following addition of intravenous immunoglobulin to effective antiretroviraltreatment of HIV.Mellberg T, Gonzalez VD, Lindkvist A, Edén A, Sönnerborg A, Sandberg JK, Svennerholm B, Gisslén MAIDS Res Ther. 2011 Jun 28;8:21
    7. 7. Primary outcome: quantification of HIV DNA week 48Secondary outcome: immune activation Gut biopsy sub studyStudy profileN = 10Recent HIV infection within 12 weeks of infectionImmediate ART Truvada, Darunavir, Ritonavir, Raltegrvir2x HIV VL<50 four weeks apartRandomisationART + 30g IVIG0.4g/kg/day5 days Continue ART
    8. 8. Proof of principle study N=25AIMTo investigate the impact of cytotoxic chemotherapy agents in addition to ART onsurrogate markers of viral reservoirs.Primary EndpointsComparison of proviral DNA quantification between baseline and at 12 weeks post-chemotherapyCytotoxic agents used in HIV+ve individuals with malignancy include:Kaposi’s sarcoma – Liposomal doxorubicin (Caelyx) or liposomal daunorubicin(Daunoxome) or PaclitaxelNon-Hodgkin’s Lymphoma – ‘RCHOP’: Rituximab, Cyclophosphamide, Doxorubicin,Vincristine, PrednisoloneHodgkin’s Disease – ‘ABVD’: Doxorubicin, Bleomycin, Vinblastine, DacarbazineCHERUB 003 – ‘Chemotherapy’Prof Mark Bower
    9. 9. Study Regimen
    10. 10. Definition of PHIlaboratory evidence of infection within 6 months of aprevious negative test, <3 bands WB, RITA incident, antibodynegative PCR+Randomisation to one of three arms:48-week short course ART (ART-48)12-week short course ART (ART-12)No therapy (Standard of Care SOC)Primary end pointtime to CD4 <350 cells/mm3 or long-term ART initiationSPARTAC: Trial DesignN Engl J Med. 2013 17;368(3):207-17
    11. 11. SPARTAC: Time to primary endpoint
    12. 12. N= 40 participants randomly selected from ART48 vs SOCQuantification of total integrated HIV DNA at baseline andweek 52Results: HIV-1 reservoir after 48 weeks of treatmentstrongly predicted disease progression, with total HIV-1levels being more predictive than integrated levels.Dr John Frater: will present at KL July 2013, Towards a curemeeting and IAS oral late breakerCharacterisation of measures of viralreservoirs in SPARTAC
    13. 13. HEATHERIndividuals with defined HIV acute infection (< 12 weeks fromprevious negative test) initiating immediate ART suppressed ontreatment for > 2 yearsCHERUB-ycPerinatally HIV infected young people age > 10 years: eitherstarted on ART within first year of life and still suppressed vs ARTstarted >1 years of agePrimary outcometotal and integrated HIV DNAObservational studies
    14. 14. REACHGeneration of autologous vaccine for future ex vivostudies from treated acute infection (Eric Arts-Amfarapplication under review)ART treated from acute infections Vaccination plusHDACi with more potent agent Romedipsin :dependent on outcome of single dose ACTG MellorsstudyFuture studies planned
    15. 15. Proof of principle pilot study n = 50Industry (Merck, Okairos ) academic partnershipfunding sought from MRC DCSRecent HIV infection (< 12 weeks).Patients with recent HIV infectionStart immediate ARTART + Vaccination + HDACi- VorinostatPrimary Outcome: Quantification of HIV reservoir.CHERUB 005REACH: Recent HIV infection: Eradication by Activation of theHIV reservoir: A proof of concept trial
    16. 16. REACH Principle
    17. 17. Primary Study end pointComparison between arms Log10 integrated proviral HIV DNA /CD4 cell at week 38 & 40REACH RegimenWeek 0 2 4 8 12 23 24 28 32 33 34 38 40Day in week 1 1 1 1 1 1 1 1 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 1 1(V)accine V VVorinostat 1 2 3 4 5 6 7 8 9 10
    18. 18. All interesting UK health care professionals providingcare for PLWHA may see patients who ask questionsabout UK HIV “cure” researchMay refer potentially interested patients into ongoingstudiesMay be interested in working with the collaborationin laboratory based research or developing newclinical trial ideasWhy might you be interested?http://www.cherub.uk.net/@ukcherub