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Biomarkers to Predict Viral Rebound at Antiretroviral Therapy Interruption in SPARTAC
Jacob Hurst1, James Williams1, John P. Thornhill2, Matthew Pace1, Chris Willberg1, Elizabeth Hamlyn3, Abdel Babiker4, Rodney Phillips1, Sarah Fidler2, John Frater1
1 University of Oxford, Oxford, United Kingdom. 2 St Mary's Hospital–Imperial College Healthcare NHS Trust, London, United Kingdom. 3 King's College London, London, United Kingdom. 4 Medical Research Council Clinical Trials Unit, London, United Kingdom.
Background: Treatment of HIV-1 infection with antiretroviral therapy (ART) in the first few weeks or months following transmission may induce a state of virological remission or ‘post-treatment control' (PTC), in which viraemia remains suppressed when ART is stopped. We present an analysis of 18 immunological and virological biomarkers measured in primary HIV-1 infection (PHI) to determine if they may help predict PTC after treatment interruption (TI).
Methods: We retrospectively analysed a sub-group of samples from SPARTAC - a randomised controlled study of PHI incorporating a TI after 48 weeks of ART. We measured HIV-1 specific CD4 and CD8 T cell ELISpot responses, markers of T cell activation (HLA DR, CD38, CD25, CD69) and exhaustion (Tim-3, Lag-3, PD-1, TIGIT), soluble markers (Il-6, d-dimer), HIV-1 DNA (Total and Integrated), cell-associated unspliced RNA, CD4 count, plasma viral load and the CD4/CD8 ratio. Statistical analyses explored associations between biomarkers and Total HIV-1 DNA and time to viral rebound at TI, with measurements taken, where samples permitted, pre-therapy in all participants and at 48 weeks in those undertaking TI.
Results: We analysed 154 individuals prior to starting ART, a median of 73.8 days from the estimated date of seroconversion. 47 participants undertook a TI after 48 weeks of ART. In univariable regression models undertaken with samples from pre-therapy baseline, CD4/CD8 ratio, CD4 count, plasma viral load, CD8 CD38, CD8 PD-1, CD8 HLA DR, CD4 HLA DR, CD8 Lag-3 and d-dimer were significantly associated (all P<0.05) with HIV-1 DNA levels, but only CD4 count, viral load, CD8 CD38, CD8 Lag-3 and d-dimer survived in multivariable analyses.
When measured pre-therapy, and adjusting for levels of HIV-1 DNA, T cell exhaustion marker expression on CD4 (PD-1, Tim-3 and Lag-3) and CD8 (Tim-3 only) T cells predicted time to the return of viraemia (n=20; Table 1), but notably not when measured at TI. Apart from Total HIV-1 DNA, in this sub-group analysis we found no evidence for any other biomarkers associating with rebound when measured at baseline or at TI.
Conclusions: In the search for an algorithm of biomarkers to help stratify treated PHI patients according to likelihood of PTC, these data indicate that pre-therapy measurements may be informative and that markers of T cell exhaustion should be included alongside HIV-1 DNA levels. This may also open critical new avenues for understanding the mechanisms underlying PTC, which need to be explored in larger cohorts.