Unite forces to validate biomarkers in the quest for lasting HIV remission (2016)

With interest, we have read the article by Li et al.[1] on the pooled analysis aiming to identify predictors of viral rebound. By reexamining the aggregated data, the authors convincingly show that lower levels of cell-associated HIV DNA and HIV RNA are associated with longer time to HIV rebound following analytical treatment interruption (ATI). This is in line with predictions on time to virological rebound from earlier modelling studies [2]. This important and clinically relevant finding aids the search for biomarkers for lasting HIV remission. The ability to identify patients who can control HIV in the absence of treatment, either spontaneous or after eradication interventions, will have a global impact. The study of Li et al.[1] unfortunately also shows that the vast majority of participants are still unable to control viraemia. Rebound viraemia can be associated with a retroviral syndrome, additional immune damage, and forward transmission. The improved identification of patients unlikely to remain aviraemic will prevent an unnecessary and potentially hazardous ATI in these patients. Nonetheless, patient-based ATI studies remain necessary to identify biomarkers associated with viral rebound. Sharing data will, however, greatly aid this goal for two principle reasons. First, collaborative research would better support the patients’ sacrifices for the greater good. The justification for researchers to ask their patients to participate in potentially dangerous ATI studies is only appropriate when the nature of the study has been weighed against the importance of the expected outcome. Alternative and less invasive approaches to test a hypothesis should have been considered and excluded as realistic possibilities. These considerations are a moral obligation of every researcher and a pivotal part of ethical committee procedures. Collaborations will further honour the patients’ risks greater than individual projects. Second, collaborations will improve the power to find relevant biomarkers in ATI studies. This helps finding meaningful differences and reduces the risk of false negative results. A biomarker could also facilitate the follow-up after therapy interruption in patients, similar to the correlation between a suppressed plasma HIV-RNA and clinical outcomes. The identification of a validated biomarker for lasting HIV remission will eventually render future ATI studies obsolete. The quest for lasting HIV remission by the identification and validation of biomarkers to replace ATI studies would benefit greatly from a collaboration between investigators, individuals, the pharmaceutical industry, and regulatory authorities. Challenges of this approach can be foreseen. Retrospective analyses must incorporate methods to deal with inconsistencies and differences between studies. Future studies in the field should ideally be a prospectively initiated collaboration, and the design should be shaped to optimally answer the research questions. As a research community, we should define codes of good conduct to prevent inappropriate data abuse. We propose an international collaboration to share the datasets of published work, perform meta-analyses, and initiate well designed prospective studies to validate possible biomarkers. Examples of innovative collaborative research projects that result in relevant findings from other research fields are progressively emerging [3], and are also expanding within the HIV research field [1,4]. HIV researchers from various continents have already gathered together to discuss the future management of HIV [5]. These incentives are increasingly applauded by prominent researchers [6,7]. Future collaborative studies should be conducted between trustworthy pioneering researchers who will acknowledge each other's input by relevant coauthorships. Combining knowledge will further shape hypothesis driven studies to fill important knowledge gaps in the HIV cure research. Together, we have a better and unique chance of finding validated biomarkers that will help us to identify patients who can be given a chance to live antiretroviral free lives, outside the spectrum of clinical ATI trials. Acknowledgements Conflicts of interest There are no conflicts of interest.