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Cell-associated HIV-RNA as a superior marker of treatment success or failure
The goal of combination antiretroviral therapy (cART) in HIV infected individuals is to suppress viral replication. The biomarker that is traditionally used to measure this replication is the concentration of free virions in blood plasma (viral load, VL). In most treatment adherent patients VL is suppressed to levels below the limit of detection (LOD) of current commercial assays (i.e. <20 copies/ml) (1). Nevertheless, even when VL is clinically undetectable, there may still be residual viral activity. Therefore, new virological markers are needed to better monitor the response to treatment. The cellular fraction of blood contains several forms of viral DNA and RNA, all representing possibly useful HIV biomarkers. Research indicates that the unspliced form of mRNA (usRNA) might be a particularly interesting marker (2). In patients with clinically undetectable plasma VL levels, usRNA is often still detectable in peripheral blood mononuclear cells (PBMCs) (3). Furthermore, higher amounts of usRNA are correlated with suboptimal adherence, increased immune activation and viral failure (VF) (4-6). However, no quantitative assay for usRNA or any other cell-associated biomarker for that matter, are currently in clinical use. Further research on the predictive value of viral cell-associated usRNA for treatment failure is needed to determine the added value of this extra biomarker in the follow-up of patients on treatment. Besides the unspliced form of viral RNA, other forms, including multiple-spliced (ms) RNA that are found in cells, deserve further investigation as well. At first view, an extra bio-marker can only be considered in affluent countries with financially strong health systems. Nevertheless, cell-associated biomarkers such as viral RNA can also have important benefits in limited resource settings (LRS), where most HIV positive people live. In LRS routine VL testing is generally unavailable due to its high cost and logistical difficulties associated with the isolation and storage of plasma (7). However, VL can be tested on whole blood (WB) as well (8, 9), which is either spotted on filter paper first (dried blood spots, DBS) or tested immediately on a point-of-care (POC) instrument. This obviates the need for electricity, centrifuges, a cold chain or efficient sample transport systems to prepare and transport plasma. On the other hand, since WB does not only contain plasma viral RNA, but all cell-associated viral nucleic acids as well, plasma VL and WB VL correlate poorly in the lower ranges (10). Consequently, as LRS are currently constrained to using WB samples instead of the gold standard plasma, it is crucial to elucidate the clinical significance of WB VL, including the cell-associated viral RNA, so that it can be correctly interpreted. Taken together, it becomes apparent that both in high resource, as well as in low resource settings, the role of plasma VL as the only and best indicator of treatment failure needs to be re-examined. Therefore, the predictive value of cell-associated viral RNA (caRNA) levels for treatment failure needs further investigation. In this context, the influence of sub-optimal treatment adherence remains to be taken into account. Finally, further research is urgently needed to understand how caRNA influences the correlation of VL results between plasma and WB so that the quality of and access to VL testing can be improved for the millions of people living with HIV/AIDS in LRS.
Datum:29 apr 2015 → 19 sep 2019
Project type:PhD project