Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

Abstract

A fraction of chronic hepatitis C patients treated with direct‐acting antivirals (DAAs) achieved sustained virological responses (SVR), or cure, despite having detectable viremia at the end of treatment (EOT). This observation, termed EOT +/SVR, remains puzzling and precludes rational optimization of treatment durations. One hypothesis to explain EOT +/SVR, the immunologic hypothesis, argues that the viral decline induced by DAAs during treatment reverses the exhaustion of cytotoxic T lymphocytes (CTLs), which then clear the infection after treatment. Whether the hypothesis is consistent with data of viral load changes in patients who experienced EOT +/SVR is unknown. Here, we constructed a mathematical model of viral kinetics incorporating the immunologic hypothesis and compared its predictions with patient data. We found the predictions to be in quantitative agreement with patient data. Using the model, we unraveled an underlying bistability that gives rise to EOT +/SVR and presents a new avenue to optimize treatment durations. Infected cells trigger both activation and exhaustion of CTLs. CTLs in turn kill infected cells. Due to these competing interactions, two stable steady states, chronic infection and viral clearance, emerge, separated by an unstable steady state with intermediate viremia. When treatment during chronic infection drives viremia sufficiently below the unstable state, spontaneous viral clearance results post‐treatment, marking EOT +/SVR. The duration to achieve this desired reduction in viremia defines the minimum treatment duration required for ensuring SVR, which our model can quantify. Estimating parameters defining the CTL response of individuals to HCV infection would enable the application of our model to personalize treatment durations.

Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon‐free treatment era

“…Other studies argue that the reduction in viremia due to DAAs could reverse the exhaustion of cytotoxic T lymphocytes, which then clear the infection. Mathematical models based on both these hypotheses appear to be consistent with patient data and is thus likely to influence outcomes differently depending on which mechanism predominates.…”

“…More recently, multiscale models that couple intracellular viral replication with within‐host kinetics have been constructed to describe the rapid viral load decline observed with some of the new DAAs . Finally, models are now being constructed that explicitly incorporate the influence of the adaptive immune system to describe the intriguing recent observation of patients achieving SVR despite viremia being detected at the end of treatment with DAAs . Several excellent reviews have documented these and other advances and highlighted their contributions to our understanding of HCV pathogenesis and the design of improved treatment protocols .…”

Immunology & Cell Biology's top 10 original research articles 2017–2018

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“…The final article by Baral et al ., like many of the others, focuses on the regulation of immune function during chronic disease. However, unlike all of the other highlighted articles, Baral et al .…”

“…The strength of this work lies in the ability not only to test the original hypothesis but also to predict outcomes under different parameters and to estimate the minimum treatment duration required to achieve sustained virological responses (i.e. cure) …”