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Predicting Disease Progression with HIV-1 DNA Levels Post Antiretroviral Therapy: SPARTAC Trial Findings

The SPARTAC Trial is a significant study comparing short-course ART with no ART in Primary HIV infection. Monitoring HIV DNA levels can predict disease progression and inform treatment decisions. This analysis reveals correlations between HIV-1 DNA levels and clinical outcomes, including viral rebound time and viral load. The study emphasizes the importance of assessing total and integrated proviral DNA levels for predicting treatment outcomes and the primary clinical trial endpoint. Results suggest that baseline viral load influences HIV DNA levels, while proviral load is not directly associated with viral rebound time. ART significantly reduces cell-associated HIV DNA, highlighting its impact in managing HIV infection.

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Predicting Disease Progression with HIV-1 DNA Levels Post Antiretroviral Therapy: SPARTAC Trial Findings

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  1. HIV-1 DNA levels after antiretroviral therapy in primary infection predict disease progression: the SPARTAC Trial James Williams1,2,3, Jacob Hurst1,2,3, Nicola Robinson1,2,3, Sarah Fidler4, Jonathan Weber4, Abdel Babiker5, Rodney Phillips1,2,3, Kersten Koelsch6*, Tony Kelleher6*, John Frater1,2,3* On behalf of the SPARTAC Trial Investigators *contributed equally 1Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford; 2Institute for Emerging Infections, The Oxford Martin School, Oxford, UK; 3Oxford National Institute of Health Research Biomedical Research Centre, Oxford, UK; 4Division of Medicine, Wright Fleming Institute, Imperial College, London, UK; 5Medical Research Council Clinical Trials Unit, London, UK; 6The Kirby Institute, UNSW, Sydney, Australia.

  2. The SPARTAC Trial • Design: Largest randomised clinical trial investigating the effect of short-course ART compared with no ART in Primary HIV infection. • Definition of PHI Lab evidence of infection within 6 months since seroconversion • Randomisation to 3 arms: • 48-week short course ART (ART-48) • 12-week short course ART (ART-12) • No therapy (Standard of Care, SOC) • Composite primary end point • time to CD4 <350 cells/mm3 or long-term ART initiation • Findings: 48 weeks of ART: • Significantly delayed disease progression, although not for longer than the period of treatment • Delayed viral rebound Fidleret al, NEJM, 2013

  3. Cell associated HIV-DNA levels • Measuring HIV DNA levels: • ‘Total’ HIV-1 qPCR : measures all HIV-1 DNA (integrated and unintegrated) • ‘Integrated’ HIV-1 qPCR: measures integrated HIV-1 DNA • Input DNA enriched CD4+ T cells • Patient selection • UK • Predominantly subtype B • Cross-clade compatible primers and probes HIV DNA levels can predict clinical outcome - High total HIV-DNA predicts a shorter rebound time (Pikettyet al J.Med.Virol, 2010). • - Proviral and total HIV DNA predicts viral rebound and viral setpoint after STI (Swiss Cohort Study) in acutes (Yerlyet al, AIDS, 2004)

  4. Results of Proviral Analysis Associations of HIV cell associated DNA levels with: • Baseline plasma VL • Estimated time since seroconversion • Time to plasma VL rebound on stopping ART • Clinical progression (Trial primary endpoint)

  5. Quantification of the proviral load in the SPARTAC Trial ART48 Total ART48 Integrated

  6. Correlation of HIV-1 DNA with plasma viral load r2 = 0.18 r2 = 0.34 Baseline VL vs Baseline cell-associated HIV-1 DNA (Total Assay) ART12 (wk12) r2 = 0.34 r2 = 0.30 r2 = 0.23 ART48 (wk48)

  7. Association of HIV-1 DNA levels with the estimated time since seroconversion Baseline HIV-DNA vs ETS • No evidence for a statistical association between HIV DNA levels and ETS at time of enrolment • No association between plasma HIV-1 viral load and ETS (p=0.55) (not shown) r2 = 0.04

  8. No evidence to associate HIV-1 DNA levels with time to viral rebound at wk48. Total Time on ART is associated with time to VL rebound on stopping P = 0.31, r2 = 0.03 But, no evidence for an association between proviral load and time to rebound Integrated P = 0.74, r2 = 0.003 Stohret al; unpublished

  9. Association of proviral load with primary endpoint after STI. TOTAL (Wk48)INTEGRATED (Wk48) • Univariate Cox Regression Analyses • (log total) vs survival: P = 0.017; Hazard Ratio: 7.22 (1.42-36.84) • (log integrated) vs survival: P = 0.041; Hazard Ratio: 2.68 (1.04-6.90) • (log baseline VL) vs survival: P = 0.022; Hazard Ratio: 1.81 (1.09-3.00) • (wk48 CD4 count) vs survival: P = 0.684; Hazard Ratio: 0.97 (0.83-1.13)

  10. Conclusions • 12 or 48 weeks of ART significantly decreases the cell associated HIV-DNA. • Viral Load at ‘baseline’ associates with HIV DNA levels at baseline and after therapy. • Viral load and HIV DNA levels are not determined by estimated time since seroconversion. • No evidence to suggest proviral load is associated with time to viral rebound. • Total and Integrated proviral levels both predict primary endpoint of the clinical trial.

  11. Acknowledgements • PETER MEDAWAR BUILDING FOR PATHOGEN RESEARCH, OXFORD, UK • John Frater • Rodney Phillips • Jacob Hurst • Nicola Robinson • MRC CTU, LONDON, UK • Wolfgang Stöhr • Abdel Babiker • UNSW, SYDNEY, AUSTRALIA • Tony Kelleher • KerstenKoelsch • IMPERIAL COLLEGE, LONDON, UK • Jonathan Weber • Sarah Fidler • UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, USA • UnaO’Doherty • The SPARTAC trial Investigators • Participants of SPARTAC

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