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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 (t 1/2 ) 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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Viral kinetic models have proven useful in characterizing treatment effectiveness during HCV therapy with interferon (IFN) as well as with direct-acting antivirals (DAAs)., Methods: Here we use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with setrobuvir, a non-nucleosidic inhibitor of the HCV NS5B polymerase enzyme. Using PK data from three studies in healthy volunteers and PK and VK data from a Phase I study, where setrobuvir was administered for 3 days, we fitted a two-compartment PK model with first-order absorption and lag-time, an Emax pharmacodynamics model and a standard biphasic VK model., Results: Setrobuvir's EC 50 and Hill coefficient and the viral clearance rate were significantly different (P=0.014, P<0.001 and P=0.004, respectively) between patients infected with HCV subtypes 1b and 1a, leading to an increased viral load decline in patients infected with genotype 1b virus., Conclusions: Understanding the combined effects of PK/VK on the performance of a non-nucleoside polymerase inhibitor such as setrobuvir could provide valuable insights into their use in combination with other DAAs as well as to optimize future therapy. Further, our work suggests that patients infected with subtype 1a would need higher doses than those infected with subtype 1b to achieve the same effectiveness. Whether this is true for other non-nucleoside polymerase inhibitors needs to be examined.

Background & Aims: High cure rates are achieved in HCV genotype-1b patients treated with daclatasvir and asunaprevir, DCV/ASV. Here we analyzed early HCV kinetics in genotype-1b infected Japanese subjects treated with DCV/ASV and retrospectively projected, using mathematical modeling, whether shorter treatment durations might be effective., Methods: HCV RNA levels were measured frequently during DCV/ASV therapy in 95 consecutively treated patients at a single center in Japan. Mathematical modeling was used to predict the time to cure, i.e, <1 virus copy in the extracellular body fluid. Patients with HCV<15 IU/ml at week 1 (n = 27) were excluded from modeling analysis due to insufficient HCV RNA data points., Results: Eighty nine of the 95 included patients (94%) achieved cure, 3 (3%) relapsed due to treatment-emergent resistance, and 3 (3%) completed therapy but were lost during follow up. Model fits from 68 patients with sufficient data points indicate that after a short pharmacological delay (15.4 min [relative standard error, rse = 26%]), DCV/ASV effectiveness in blocking HCV production was 0.999 [rse~0%], HCV half-life in blood was t1/2 = 1.7 hr [rse = 21%], and HCV-infected cell loss rate was 0.391/d [rse = 5%]. Modeling predicted that 100% and 98.5% of patients who had HCV<15 IU/ml at days 14 and 28 might have been cured with 6 and 8 weeks of therapy, respectively. There was a trend (p = 0.058) between younger age and shorter time to cure., Conclusion: Modeling early HCV kinetics under DCV/ASV predicts that most patients would achieve cure with short treatment durations, suggesting that 24 weeks of DCV/ASV treatment can be significantly shortened.

Legalon SIL (SIL) is a chemically hydrophilized version of silibinin, an extract of milk thistle (Silybum marianum) seeds that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus (HCV) in patients leading to viral clearance in combination with ribavirin. To elucidate the incompletely understood mode of action of SIL against HCV, mathematical modelling of HCV kinetics and human hepatocyte gene expression studies were performed in uPA-SCID-chimeric mice with humanized livers. Chronically HCV-infected mice (n = 15) were treated for 14 days with daily intravenous SIL at 469, 265 or 61.5 mg/kg. Serum HCV and human albumin (hAlb) were measured frequently, and liver HCV RNA was analysed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3 and 14 of treatment. While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a second slower phase (or plateau with the two lower SIL dosings). SIL effectiveness in blocking viral production was similar among dosing groups (median ε = 77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated (r = 0.66, P = 0.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and antiproliferative gene expression in human hepatocytes in SIL-treated mice. The results suggest that SIL could lead to a continuous second-phase viral decline, that is potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and antiproliferative gene expression in human hepatocytes., (© 2016 John Wiley & Sons Ltd.)

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., Competing Interests: Disclosures: None of the authors has any financial interest or conflict of interest related to this research. Writing Assistance: None., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Modelling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness., Methods: Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor, and mericitabine, a nucleoside polymerase inhibitor, for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data., Results: The average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg three times daily of danoprevir and 500 mg twice daily of mericitabine and 0.9998 for 600 mg twice daily of danoprevir and 1,000 mg twice daily of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low sustained virological response rates obtained in a more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks., Conclusions: This suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.

Background: Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis., Methods: In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585., Findings: Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups., Interpretation: Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV., Funding: National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct-acting antivirals., Methods: We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a Phase I study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naive and 8 were non-responders to prior pegylated IFN-α/ribavirin treatment., Results: In all patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg twice daily) and 0.99 at the highest dose (200 mg three times daily). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg twice daily). The second phase decline showed two different behaviours, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 day(-1)), whereas the viral decline was slower in the other patients., Conclusions: Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.

Viral kinetic (VK) modeling has led to increased understanding of the within host dynamics of viral infections and the effects of therapy. Here we review recent developments in the modeling of viral infection kinetics with emphasis on two infectious diseases: hepatitis C and influenza. We review how VK modeling has evolved from simple models of viral infections treated with a drug or drug cocktail with an assumed constant effectiveness to models that incorporate drug pharmacokinetics and pharmacodynamics, as well as phenomenological models that simply assume drugs have time varying-effectiveness. We also discuss multiscale models that include intracellular events in viral replication, models of drug-resistance, models that include innate and adaptive immune responses and models that incorporate cell-to-cell spread of infection. Overall, VK modeling has provided new insights into the understanding of the disease progression and the modes of action of several drugs. We expect that VK modeling will be increasingly used in the coming years to optimize drug regimens in order to improve therapeutic outcomes and treatment tolerability for infectious diseases.

Several studies have proven oseltamivir to be efficient in reducing influenza viral titer and symptom intensity. However, the usefulness of oseltamivir can be compromised by the emergence and spread of drug-resistant virus. The selective pressure exerted by different oseltamivir therapy regimens have received little attention. Combining models of drug pharmacokinetics, pharmacodynamics, viral kinetics and symptom dynamics, we explored the efficacy of oseltamivir in reducing both symptoms (symptom efficacy) and viral load (virological efficacy). We simulated samples of 1000 subjects using previously estimated between-subject variability in viral and symptom dynamic parameters to describe the observed heterogeneity in a patient population. We simulated random mutations conferring resistance to oseltamivir. We explored the effect of therapy initiation time, dose, intake frequency and therapy duration on influenza infection, illness dynamics, and emergence of viral resistance. Symptom and virological efficacies were strongly associated with therapy initiation time. The proportion of subjects shedding resistant virus was 27-fold higher when prophylaxis was initiated during the incubation period compared with no treatment. It fell to below 1% when treatment was initiated after symptom onset for twice-a-day intakes. Lower doses and prophylaxis regimens led to lower efficacies and increased risk of resistance emergence. We conclude that prophylaxis initiated during the incubation period is the main factor leading to resistance emergence.