Molecular diagnostic and predictive tests in the evolution of chronic hepatitis C anti-viral therapies
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Since the discovery of HCV, polymerase chain reaction (PCR) has significantly contributed to the understanding of the virus life cycle and its replicative kinetics during anti-viral therapy. Parallel to the progression of dual and triple combination treatment, real-time PCR molecular tests have constantly improved in their ability to monitor viral load and drive personalized management schedules. The current sensitivity, accuracy and dynamic range of the available assays fulfil the requirement of “companion diagnostics” and support the development of new directly acting antiviral (DAA)-based regimens.
KeywordsSustained Virological Response Boceprevir Polymerase Chain Reaction Test Rapid Virological Response Triple Combination Treatment
The development of polymerase chain reaction (PCR) in the eighties was instrumental, a few years later, to the discovery of HCV, the first infectious disease agent identified by a reverse genetic approach. Using a library of primers and concentrated plasma from individuals with non-A, non-B hepatitis, M. Houghton et al. amplified and identified the first HCV sub-genomic fragments whose products were specifically reactive with circulating antibodies from infected patients . Proteins derived from the initial HCV clones served as target antigens in the first serological assay and, once validated in large cohorts of patients with non-A, non-B hepatitis, they were further developed into standardized immunoassays for screening blood donations and blood derived products to prevent transmission.
Development of molecular methods in the diagnosis of HCV
The evidence available at that time on the clinical utility of viral load in the area of HIV/AIDS suggested similar indications also for the management of chronic hepatitis C and led to the development of quantitative PCR tests based on end-point dilution. These provided the initial tools to investigate the association between viral load and disease progression, as well as response to therapy.
Different response profiles were identified during interferon (IFN) based therapies and a first, viral kinetics based, predictive criterion was introduced in clinical practise which identified, at week 12 on treatment, patients with no probability of sustained virological response (SVR). SVR is defined by a negative HCV RNA test 6 months after end of treatment and indicate virus eradication. A decrease of less than 2 logarithms at week 12, the threshold required for the early virological response (EVR), was found to have a very high negative predictive value and was proposed and validated as a “stopping rule” for treatment discontinuation.
Using these tests, an additional, important viral load parameter was identified at week 4 on treatment, the rapid virological response (RVR), characterized by undetectable HCV RNA, with a high positive predictive value for SVR so as to serve as a main driver for treatment individualization.
The recent development of DAA and the approval of the first, boceprevir- and telaprevir-based triple-therapy regimes, have brought new hopes for higher virus eradication rate across different disease settings. This calls for even more accurate and sensitive quantitative HCV RNA tests able to monitor faster virus kinetics and promptly detect treatment failures. Indeed, subtle differences between a HCV RNA negative (reported as target not detected) and a borderline HCV RNA positive result (reported as detected <15 IU/ml), below the limit of detection (LOD) of the most widely used real-time PCR tests, were found to influence the RVR rate and potentially lead to more relapses.
With new viral load tests acting as “companion diagnostic”, the clinical development and applications of the new generation DAA can be fully supported for a more effective management of chronic hepatitis C and its long-term complications.
Publication of this supplement was partly supported by an unrestricted grant provided by Roche. The articles were independently prepared by the authors with no input from Roche. Roche were not involved in selecting the articles for the supplement.
This article has been published as part of BMC Infectious Diseases Volume 12 Supplement 2, 2012: Proceedings of the Second Workshop of the Regional Study Group on HCV in the Calabria Region (Southern Italy). The virus-host-therapy pathway in HCV disease management: from bench to bedside in the era of Directly Acting Antivirals. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcinfectdis/supplements/12/S2.
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