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Www.ias2015.org What are possible biomarkers for cure-related interventions ? Lars Ostergaard, MD, Ph.D., DMSc Prof/Head Dept of infectious diseases Aarhus.

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Presentation on theme: "Www.ias2015.org What are possible biomarkers for cure-related interventions ? Lars Ostergaard, MD, Ph.D., DMSc Prof/Head Dept of infectious diseases Aarhus."— Presentation transcript:

1 www.ias2015.org What are possible biomarkers for cure-related interventions ? Lars Ostergaard, MD, Ph.D., DMSc Prof/Head Dept of infectious diseases Aarhus University Hospital, Aarhus, Denmark E-mail: larsoest@rm.dk

2 www.ias2015.org Disclosures –Gilead –Pfizer –Sanofi-Pasteur –Bionor –ViiV –Roche –MSD –BMS –Janssen

3 www.ias2015.org

4 Definition of a biomarker A biological analysis that predicts a clinically relevant outcome

5 www.ias2015.org What are clinical relevant outcomes in cure research ? “I want my disease not to progress and not being transmitted to others without taking any pills – and maybe someday I can say that I am cured”.

6 www.ias2015.org What are clinical relevant outcomes in cure research ? Having undetectable viral load is the best predictor of “no progress” and “no transmission” With courtesy of Jonathan Li But without any “pills” the virus rebound – so the clinical relevant goal of any cure intervention is to delay the time to rebound

7 www.ias2015.org It is difficult to make predictions - especially about the future ! Piet Hein. Danish author (1905-96)

8 www.ias2015.org BUT – we can. However, we need to know the exact outcome of an intervention (i.e. time to viral rebound) Outcome Intervention Possible biomarker

9 www.ias2015.org This implies that we need intervention studies with the outcome of ”time to viral rebound” - otherwise we can not determine the predictive value of any test

10 www.ias2015.org CONCLUSION 1 A NEED FOR STUDIES WITH ”TIME TO VIRAL REBOUND” AS THE OUTCOME IN ORDER TO ASSESS THE PREDICTIVE VALUE OF POTENTIAL CLINICALLY RELEVANT BIOMARKERS

11 www.ias2015.org AVAILABLE DATA WHAT ARE THE DATA ON POTENTIAL BIOMARKERS FROM STUDIES LOOKING AT TIME TO VIRAL REBOUND AFTER TREATMENT INTERRUPTIONS ATCG (compiled data) ANRS SPARTAC CLEAR STUDY (Biomarkers associated with elite controllers)

12 www.ias2015.org Factors associated with elite controllers Host factors Protective alleles HLA-B*27 and B*5701 Risk alleles HLA-B*07 and B*35 CD8 cytotoxicity capacity T-helper cells Regulatory T-cells NK cells Coexpression of CD160 and 2B4 Th17 and Th17/Treg ratio Cell-intrinsic type I interferon secretion Soluble CD14 IFN-γ IP-10 IL-4 IL-10 sCD40L GM-CSF ( Viral factors Anti-APOBEC3 Vif activity NEF deletion/truncation, Residual viral activity

13 www.ias2015.org ATCG treament interruption trials 124 patients pooled from A5170, A5197, A5068, A5024, ATCG371 Behzad Etemad et al, CROI 2015 Low grade viremia and CA-RNA are associated with time to viral rebound

14 www.ias2015.org SPARTAC trial Frater J. CROI 2015, Fidler IAS 2015 47 patients with primary HIV. Treatment interruption after 48 weeks 18 immunological and virological parameters At the time of treatment interruption: Total - but not integrated - DNA At the time of ART initiation (acute infection) CD4/CD8 ratio, CD4 count, plasma viral load CD8 CD38, CD8 PD1, CD8 HLA DR, CD4 HLA DR, CD8 Lag-3 and d-dimer

15 www.ias2015.org ANRS 116 SALTO Assoumou AIDS 2015 95 patients treated early in their course of HIV-infection. 12 variables tested Total-DNA at treatment interruption > 150 pmPBMC HR: 2.08

16 www.ias2015.org Panobinostat trial (Clear) Rasmussen et al HIV Lancet 2014 9 patients stopped cART after panobinostat Rx Measured every third day Association between the drop in Total-DNA during panobinostat Rx and time to rebound – but not Total-DNA at time of panobinostat Drop in DNA associated with NK-cell activity Olesen et al. J. Virol (in press)

17 www.ias2015.org CONCLUSION 2 PREDICTORS OF TIME TO REBOUND TOTAL HIV-DNA IN CD4+ CELLS CA-RNA Hs-VIRAL LOAD (single copy assay)

18 www.ias2015.org CONCLUSION 2 PREDICTORS OF TIME TO REBOUND TOTAL HIV-DNA IN CD4+ CELLS CA-RNA Hs-VIRAL LOAD (single copy assay) Probably a reflection of reservoir size and ”idle”-activity

19 www.ias2015.org CONCLUSION 2 PREDICTORS OF TIME TO REBOUND TOTAL HIV-DNA IN CD4+ CELLS CA-RNA Hs-VIRAL LOAD (single copy assay) Probably a reflection of reservoir size and ”idle”-activity

20 www.ias2015.org FUTURE RESEARCH Avoid expressing results as “associations” Use ROC Multiple comparisons Advanced statistical analyses are needed Algorithms (combination of parameters) Needs to be applied on other data set. Collect as much material and data as possible Collaborate

21 www.ias2015.org Thank you

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