Treatment of chronic hepatitis D with peginterferon lambda-the phase 2 LIMT-1 clinical trial.

BACKGROUND AND AIMS: HDV infection leads to the most aggressive form of human viral hepatitis for which there is no FDA-approved therapy. PEG IFN-lambda-1a (Lambda) has previously demonstrated a good tolerability profile in HBV and HCV patients compared to PEG IFN-alfa. The goal of Phase 2 LIMT-1 trial was to evaluate the safety and efficacy of Lambda monotherapy in patients with HDV. APPROACH AND RESULTS: An open-label study of Lambda 120 or 180 mcg, administered once weekly by subcutaneous injections for 48 weeks, followed by 24 weeks of posttreatment follow-up. Thirty-three patients were allocated to Lambda 180 mcg (n=14) or 120 mcg (n=19). Baseline mean values: HDV RNA 4.1 log10 IU/mL (SD±1.4); ALT 106 IU/L (35-364); and bilirubin 0.5 mg/dL (0.2-1.2). Intention-to-treat rates of virologic response to Lambda 180 mcg and 120 mcg, 24 weeks following treatment cessation were 5 of 14(36%) and 3 of 19 (16%), respectively. The posttreatment response rate of 50% was seen in low BL viral load (≤4 log10) on 180 mcg. Common on-treatment adverse events included flu-like symptoms and elevated transaminase levels. Eight (24%) cases of hyperbilirubinemia with or without liver enzyme elevation, leading to drug discontinuation, were mainly observed in the Pakistani cohort. The clinical course was uneventful, and all responded favorably to dose reduction or discontinuation. CONCLUSIONS: Treatment with Lambda in patients with chronic HDV may result in virologic response during and following treatment cessation. Clinical phase 3 development of Lambda for this rare and serious disease is ongoing.

Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics.

Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic patterns, we developed an agent-based model that includes intracellular virion production cycles reflecting the cyclic nature of each individual virus lifecycle. The model fits the data well predicting an increase in production cycles initially starting with a long production cycle of 1 virion per 20 hours that gradually reaches 1 virion per hour after approximately 3-4 days before virion production increases dramatically to reach to a steady state rate of 4 virions per hour per cell. Together, modeling suggests that it is the cyclic nature of the virus lifecycle combined with an initial slow but increasing rate of HBV production from each cell that plays a role in generating the observed multiphasic HBV kinetic patterns in humanized mice.

Mathematical Models of Early Hepatitis B Virus Dynamics in Humanized Mice.

Analyzing the impact of the adaptive immune response during acute hepatitis B virus (HBV) infection is essential for understanding disease progression and control. Here we developed mathematical models of HBV infection which either lack terms for adaptive immune responses, or assume adaptive immune responses in the form of cytolytic immune killing, non-cytolytic immune cure, or non-cytolytic-mediated block of viral production. We validated the model that does not include immune responses against temporal serum hepatitis B DNA (sHBV) and temporal serum hepatitis B surface-antigen (HBsAg) experimental data from mice engrafted with human hepatocytes (HEP). Moreover, we validated the immune models against sHBV and HBsAg experimental data from mice engrafted with HEP and human immune system (HEP/HIS). As expected, the model that does not include adaptive immune responses matches the observed high sHBV and HBsAg concentrations in all HEP mice. By contrast, while all immune response models predict reduction in sHBV and HBsAg concentrations in HEP/HIS mice, the Akaike Information Criterion cannot discriminate between non-cytolytic cure (resulting in a class of cells refractory to reinfection) and antiviral block functions (of up to 99 % viral production 1-3 weeks following peak viral load). We can, however, reject cytolytic killing, as it can only match the sHBV and HBsAg data when we predict unrealistic levels of hepatocyte loss.

Hepatitis D Virus and HBsAg Dynamics in the era of new Antiviral Treatments.

PURPOSE OF REVIEW: Hepatitis D virus (HDV) infection is the most severe form of chronic viral hepatitis, with no FDA-approved therapy. Progress in the development of effective HDV treatments is accelerating. This review highlights how mathematical modeling is improving understanding of HDV-HBsAg-host dynamics during antiviral therapy and generating insights into the efficacy and modes of action (MOA) of new antiviral agents. RECENT FINDINGS: Clinical trials with pegylated-interferon-λ, bulevertide, nucleic acid polymers, and/or lonafarnib against various steps of the HDV-life cycle have revealed new viral-kinetic patterns that were not observed under standard treatment with pegylated-interferon-α. Modeling indicated that the half-lives of circulating HDV and HBsAg are ~ 1.7 d and ~ 1.3 d, respectively, estimated the relative response of HDV and HBsAg during different antiviral therapies, and provided insights into the efficacy and MOA of drugs in development for treating HDV, which can inform response-guided therapy to individualize treatment duration. Mathematical modeling of HDV and HBsAg kinetics provides a window into the HDV virus lifecycle, HDV-HBsAg-host dynamics during antiviral therapy, and the MOA of new drugs for HDV.

Understanding Hepatitis B Virus Dynamics and the Antiviral Effect of Interferon Alpha Treatment in Humanized Chimeric Mice.

Whereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon alpha (IFN-α) is less completely defined. To advance our understanding, we mathematically modeled HBV kinetics during 14-day pegylated IFN-α-2a (pegIFN), LAM, or pegIFN-plus-LAM (pegIFN+LAM) treatment of 39 chronically HBV-infected humanized uPA/SCID chimeric mice. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a multicompartmental mathematical model and simultaneously fit it to the serum and intracellular HBV DNA data. Unexpectedly, even in the absence of an adaptive immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Kinetic analysis and modeling indicate that the first phase represents inhibition of intracellular HBV DNA synthesis and secretion, which was similar under all treatments with an overall mean efficacy of 98%. In contrast, there were distinct differences in HBV decline during the second phase, which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis, with the steepest decline observed during pegIFN+LAM treatment (1.28/day) and the slowest (0.1/day) during pegIFN monotherapy. Reminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of an adaptive immune response. Interestingly, combination treatment did not increase the initial inhibition of HBV production but rather enhanced second-phase decline, providing insight into the dynamics of HBV treatment response and the mode of action of IFN-α against HBV. IMPORTANCE Chronic hepatitis B virus (HBV) infection remains a global health care problem, as we lack sufficient curative treatment options. Elucidating the dynamics of HBV infection and treatment response at the molecular level could facilitate the development of novel, more effective HBV antivirals. Currently, the only well-established small animal HBV infection model available is the chimeric uPA/SCID mice with humanized livers; however, the HBV inhibition kinetics under pegylated IFN-α-2a (pegIFN) in this model system have not been determined in sufficient detail. In this study, viral kinetics in 39 humanized mice treated with pegIFN and/or lamivudine were monitored and analyzed using a mathematical modeling approach. We found that the main mode of action of IFN-α is blocking HBV DNA synthesis and that the majority of synthesized HBV DNA is secreted. Our study provides novel insights into HBV DNA dynamics within infected human hepatocytes.

Epstein-Barr Virus (EBV) Epithelial Associated Malignancies: Exploring Pathologies and Current Treatments.

Epstein-Barr virus (EBV) is one of eight known herpesviruses with the potential to infect humans. Globally, it is estimated that between 90-95% of the population has been infected with EBV. EBV is an oncogenic virus that has been strongly linked to various epithelial malignancies such as nasopharyngeal and gastric cancer. Recent evidence suggests a link between EBV and breast cancer. Additionally, there are other, rarer cancers with weaker evidence linking them to EBV. In this review, we discuss the currently known epithelial malignancies associated with EBV. Additionally, we discuss and establish which treatments and therapies are most recommended for each cancer associated with EBV.

Hepatitis B and Hepatitis D Viruses: A Comprehensive Update with an Immunological Focus.

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) are highly prevalent viruses estimated to infect approximately 300 million people and 12-72 million people worldwide, respectively. HDV requires the HBV envelope to establish a successful infection. Concurrent infection with HBV and HDV can result in more severe disease outcomes than infection with HBV alone. These viruses can cause significant hepatic disease, including cirrhosis, fulminant hepatitis, and hepatocellular carcinoma, and represent a significant cause of global mortality. Therefore, a thorough understanding of these viruses and the immune response they generate is essential to enhance disease management. This review includes an overview of the HBV and HDV viruses, including life cycle, structure, natural course of infection, and histopathology. A discussion of the interplay between HDV RNA and HBV DNA during chronic infection is also included. It then discusses characteristics of the immune response with a focus on reactions to the antigenic hepatitis B surface antigen, including small, middle, and large surface antigens. This paper also reviews characteristics of the immune response to the hepatitis D antigen (including small and large antigens), the only protein expressed by hepatitis D. Lastly, we conclude with a discussion of recent therapeutic advances pertaining to these viruses.

Modeling-Based Response-Guided Glecaprevir-Pibrentasvir Therapy for Chronic Hepatitis C to Identify Patients for Ultrashort Treatment Duration.

We recently showed in a proof-of-concept study that real-time modeling-based response-guided therapy can shorten hepatitis C virus treatment duration with sofosbuvir-velpatasvir, elbasvir-grazoprevir, and sofosbuvir-ledipasvir without compromising efficacy, confirming our retrospective modeling reports in >200 patients. However, retrospective modeling of pibrentasvir-glecaprevir (P/G) treatment has yet to be evaluated. In the current study, modeling hepatitis C virus kinetics in 44 cirrhotic and noncirrhotic patients predicts that P/G treatment might have been reduced to 4, 6, and 7 weeks in 16%, 34%, and 14% of patients, respectively. These results support the further evaluation of a modeling-based response-guided therapy approach using P/G.

Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics.

Chimeric urokinase type plasminogen activator (uPA)/severely severe combined immunodeficiency (SCID) mice reconstituted with humanized livers are useful for studying hepatitis B virus (HBV) infection in the absence of an adaptive immune response. However, the detailed characterization of HBV infection kinetics necessary to enable in-depth mechanistic studies in this in vivo HBV infection model is lacking. To characterize HBV kinetics post-inoculation (p.i.) to steady state, 42 mice were inoculated with HBV. Serum HBV DNA was frequently measured from 1 minute to 63 days p.i. Total intrahepatic HBV DNA, HBV covalently closed circular DNA (cccDNA), and HBV RNA was measured in a subset of mice at 2, 4, 6, 10, and 13 weeks p.i. HBV half-life (t1/2 ) was estimated using a linear mixed-effects model. During the first 6 hours p.i., serum HBV declined in repopulated uPA/SCID mice with a t1/2 = 62 minutes (95% confidence interval [CI] = 59-67). Thereafter, viral decline slowed followed by a 2-day lower plateau. Subsequent viral amplification was multiphasic with an initial mean doubling time of t2 = 8 ± 3 hours followed by an interim plateau before prolonged amplification (t2 = 2 ± 0.5 days) to a final HBV steady state of 9.3 ± 0.3 log copies (cps)/mL. Serum HBV and intrahepatic HBV DNA were positively correlated (R2 = 0.98). CONCLUSION: HBV infection in uPA/SCID chimeric mice is highly dynamic despite the absence of an adaptive immune response. Serum HBV t1/2 in humanized uPA/SCID mice was estimated to be ∼1 hour regardless of inoculum size. The HBV acute infection kinetics presented here is an important step in characterizing this experimental model system so that it can be effectively used to elucidate the dynamics of the HBV life cycle and thus possibly reveal effective antiviral drug targets. (Hepatology 2018).

Early HCV viral kinetics under DAAs may optimize duration of therapy in patients with compensated cirrhosis.

BACKGROUND & AIMS: Detailed hepatitis C virus (HCV) kinetics modelling is scarce in patients with advanced liver disease receiving direct-acting antivirals (DAAs). Due to budget restrictions, patients and health systems would benefit from the shortest possible treatment course. We investigated whether modelling very early HCV kinetics in cirrhotic patients under DAAs therapy could be used to individualize care and reduce treatment duration to achieve cure. METHODS: We included 74 patients with HCV-related cirrhosis who received interferon-free treatments for 12-24 weeks. HCV genotype, liver disease stage and treatment regimen were recorded. Viral load was determined prospectively at very frequent intervals until target not detected (TND, <15 IU/mL). A viral kinetic model was used to predict time to cure based on HCV clearance in extracellular body fluid (CL-EF). RESULTS: Sixty-eight patients (92%) achieved cure. Thirteen (18%) had MELD ≥15, 35 (47%) were Child-Pugh (CTP) ≥7. Median time to reach TND was 2 weeks (IQR: 1-4 weeks). Modelling indicated an average DAAs efficacy in blocking viral production of ε = 99.1%. HCV half-life (t1/2 ) was significantly shorter in patients with CTP <7, LSM <21 kPa or MELD <15 (1.5 vs 2.5 hours; P = 0.0057). The overall median CL-EF was 5.6 weeks (4.1-7.8). A CTP >7 and a LSM ≥21 kPa were significantly (P = 0.016) associated with longer CL-EF. CONCLUSIONS: The study provides insights into HCV dynamics during DAAs therapy in patients with compensated and decompensated cirrhosis. Viral kinetics modelling suggests that treatment duration may be optimized in patients with compensated cirrhosis.

A Parameter Estimation Method for Multiscale Models of Hepatitis C Virus Dynamics.

Mathematical models that are based on differential equations require detailed knowledge about the parameters that are included in the equations. Some of the parameters can be measured experimentally while others need to be estimated. When the models become more sophisticated, such as in the case of multiscale models of hepatitis C virus dynamics that deal with partial differential equations (PDEs), several strategies can be tried. It is possible to use parameter estimation on an analytical approximation of the solution to the multiscale model equations, namely the long-term approximation, but this limits the scope of the parameter estimation method used and a long-term approximation needs to be derived for each model. It is possible to transform the PDE multiscale model to a system of ODEs, but this has an effect on the model parameters themselves and the transformation can become problematic for some models. Finally, it is possible to use numerical solutions for the multiscale model and then use canned methods for the parameter estimation, but the latter is making the user dependent on a black box without having full control over the method. The strategy developed here is to start by working directly on the multiscale model equations for preparing them toward the parameter estimation method that is fully coded and controlled by the user. It can also be adapted to multiscale models of other viruses. The new method is described, and illustrations are provided using a user-friendly simulator that incorporates the method.

High-Risk Geographic Mobility Patterns among Young Urban and Suburban Persons who Inject Drugs and their Injection Network Members.

Young people in the USA who inject drugs, particularly those at a risk of residence instability, experience the highest incidence of hepatitis C (HCV) infections. This study examined associations between geographic mobility patterns and sociodemographic, behavioral, and social network characteristics of 164 young (ages 18-30) persons who inject drugs (PWID). We identified a potential bridge sub-population who reported residence in both urban and suburban areas in the past year (crossover transients) and higher-risk behaviors (receptive syringe sharing, multiple sex partners) compared to their residentially localized counterparts. Because they link suburban and urban networks, crossover transients may facilitate transmission of HIV and HCV between higher and lower prevalence areas. Interventions should address risk associated with residential instability, particularly among PWID who travel between urban and suburban areas.

HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir.

BACKGROUND & AIMS: Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. METHODS: 58 chronic HCV patients were treated with 12-week sofosbuvir+simeprevir (n=19), sofosbuvir+daclatasvir (n=19), or sofosbuvir+ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12weeks post EOT. Mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid. RESULTS: All but one patient who relapsed achieved SVR. Mean age was 60±11years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV<15IU/ml, with 27%, 74% and 91% of observations having target not detected, respectively. Modeling results predicted that 23 (43%), 16 (30%), 7 (13%), 5 (9%) and 3 (5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir+ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43-45% and 17-30% in subjects who had HCV<15IU/ml at weeks 2 and 4, respectively. CONCLUSIONS: The use of early viral kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost saving of 16-20% per 100-treated persons.

Quantification of Hepatitis C Virus Cell-to-Cell Spread Using a Stochastic Modeling Approach.

UNLABELLED: It has been proposed that viral cell-to-cell transmission plays a role in establishing and maintaining chronic infections. Thus, understanding the mechanisms and kinetics of cell-to-cell spread is fundamental to elucidating the dynamics of infection and may provide insight into factors that determine chronicity. Because hepatitis C virus (HCV) spreads from cell to cell and has a chronicity rate of up to 80% in exposed individuals, we examined the dynamics of HCV cell-to-cell spread in vitro and quantified the effect of inhibiting individual host factors. Using a multidisciplinary approach, we performed HCV spread assays and assessed the appropriateness of different stochastic models for describing HCV focus expansion. To evaluate the effect of blocking specific host cell factors on HCV cell-to-cell transmission, assays were performed in the presence of blocking antibodies and/or small-molecule inhibitors targeting different cellular HCV entry factors. In all experiments, HCV-positive cells were identified by immunohistochemical staining and the number of HCV-positive cells per focus was assessed to determine focus size. We found that HCV focus expansion can best be explained by mathematical models assuming focus size-dependent growth. Consistent with previous reports suggesting that some factors impact HCV cell-to-cell spread to different extents, modeling results estimate a hierarchy of efficacies for blocking HCV cell-to-cell spread when targeting different host factors (e.g., CLDN1 > NPC1L1 > TfR1). This approach can be adapted to describe focus expansion dynamics under a variety of experimental conditions as a means to quantify cell-to-cell transmission and assess the impact of cellular factors, viral factors, and antivirals. IMPORTANCE: The ability of viruses to efficiently spread by direct cell-to-cell transmission is thought to play an important role in the establishment and maintenance of viral persistence. As such, elucidating the dynamics of cell-to-cell spread and quantifying the effect of blocking the factors involved has important implications for the design of potent antiviral strategies and controlling viral escape. Mathematical modeling has been widely used to understand HCV infection dynamics and treatment response; however, these models typically assume only cell-free virus infection mechanisms. Here, we used stochastic models describing focus expansion as a means to understand and quantify the dynamics of HCV cell-to-cell spread in vitro and determined the degree to which cell-to-cell spread is reduced when individual HCV entry factors are blocked. The results demonstrate the ability of this approach to recapitulate and quantify cell-to-cell transmission, as well as the impact of specific factors and potential antivirals.

Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life.

The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir's mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents. Here, we show that understanding the effects of daclatasvir in vivo requires a multiscale model that incorporates drug effects on the HCV intracellular lifecycle, and we validated this approach with in vitro HCV infection experiments. The model predicts that daclatasvir efficiently blocks two distinct stages of the viral lifecycle, namely viral RNA synthesis and virion assembly/secretion with mean effectiveness of 99% and 99.8%, respectively, and yields a more precise estimate of the serum HCV half-life, 45 min, i.e., around four times shorter than previous estimates. Intracellular HCV RNA in HCV-infected cells treated with daclatasvir and the HCV polymerase inhibitor NM107 showed a similar pattern of decline. However, daclatasvir treatment led to an immediate and rapid decline of extracellular HCV titers compared to a delayed (6-9 h) and slower decline with NM107, confirming an effect of daclatasvir on both viral replication and assembly/secretion. The multiscale modeling approach, validated with in vitro kinetic experiments, brings a unique conceptual framework for understanding the mechanism of action of a variety of agents in development for the treatment of HCV.

Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling.

UNLABELLED: There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-α therapy. Here a mathematical model was developed and fitted to frequent HDV and HBsAg kinetic data from 10 patients during the first 28 weeks of pegylated-interferon-α2a (peg-IFN) therapy. Three patients achieved a complete virological response (CVR), defined as undetectable HDV 6 months after treatment stopped with loss of HBsAg and anti-HBsAg seroconversion. After initiation of therapy, a median delay of 9 days (interquartile range [IQR]: 5-15) was observed with no significant changes in HDV level. Thereafter, HDV declined in a biphasic manner, where a rapid first phase lasting for 25 days (IQR: 23-58) was followed by a slower or plateau second phase. The model predicts that the main effect of peg-IFN is to reduce HDV production/release with a median effectiveness of 96% (IQR: 93-99.8). Median serum HDV half-life (t1/2 ) was estimated as 2.9 days (IQR: 1.5-5.3) corresponding to a pretreatment production and clearance of about 10(10) (IQR: 10(9.7) -10(10.7) ) virions/day. None of the patients with flat second phase in HDV achieved CVR. HBsAg kinetics of decline paralleled the second phase of HDV decline consistent with HBsAg-productive-infected cells being the main source of production of HDV, with a median t1/2 of 135 days (IQR: 20-460). The interferon lambda-3 polymorphism (rs12979860) was not associated with kinetic parameters. CONCLUSION: Modeling results provide insights into HDV-host dynamics, the relationship between serum HBsAg levels and HBsAg-infected cells, IFN's mode of action, and its effectiveness. The observation that a flat second phase in HDV and HBsAg kinetics was associated with failure to achieve CVR provides the basis to develop early stopping rules during peg-IFN treatment in HDV-infected patients.

Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics.

BACKGROUND & AIMS: Intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR. METHODS: A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR. RESULTS: Based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV was feasible, safe and achieved SVR (week-33). CONCLUSIONS: We report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.