Modeling Hepatocellular Carcinoma Cells Dynamics by Serological and Imaging Biomarkers to Explain the Different Responses to Sorafenib and Regorafenib.

In advanced HCC, tyrosine-kinase inhibitors obtain partial responses (PR) in some patients and complete responses (CR) in a few. Better understanding of the mechanism of response could be achieved by the radiomic approach combining digital imaging and serological biomarkers (α-fetoprotein, AFP and protein induced by vitamin K absence-II, PIVKA-II) kinetics. A physic-mathematical model was developed to investigate cancer cells and vasculature dynamics in three prototype patients receiving sorafenib and/or regorafenib and applied in seven others for validation. Overall four patients showed CR, two PR, two stable-disease (SD) and two progressive-disease (PD). The rate constant of cancer cells production was higher in PD than in PR-SD and CR (median: 0.398 vs. 0.325 vs. 0.316 C × day-1). Therapy induced reduction of neo-angiogenesis was greater in CR than in PR-SD and PD (median: 83.2% vs. 29.4% and 2.0%), as the reduction of cell-proliferation (55.2% vs. 7.6% and 0.7%). An additional dose-dependent acceleration of tumor vasculature decay was also observed in CR. AFP and cancer cells followed the same kinetics, whereas PIVKA-II time/dose dependent fluctuations were influenced also by tissue ischemia. In conclusion, pending confirmation in a larger HCC cohort, modeling serological and imaging biomarkers could be a new tool for systemic therapy personalization.

A multiphase model of the dynamics of HBV infection in HBeAg-negative patients during pegylated interferon-alpha2a, lamivudine and combination therapy.

Using a multiphase bio-mathematical model, we studied the dynamics of hepatitis B virus (HBV) infection in 72 HBeAg-negative patients who received 48 weeks of either lamivudine (3TC; 25 patients); pegylated interferon-alpha2a (peg-IFN-alpha2a) 180 mg weekly plus 3TC (23 patients), or peg-IFN-alpha2a 180 mg weekly plus placebo (24 patients). During the first month of therapy most of the 3TC -/+ peg-IFN-alpha2a treated patients showed a multiphase decay of viral load: during the first two phases, where we hypothesized a direct inhibition of virus production, the mean viral production per infected cell was reduced by 2.22 log10 and 2.36 log10, respectively. At variance, peg-IFN-alpha2a treated patients had a biphasic profile: the first phase HBV DNA decline was slower than that observed in 3TC patients (mean HBV DNA t(1/2) = 1.6 +/- 1.1 days and 9.5 +/- 3.0 h, respectively) and the direct antiviral effect reduced virus production by 1.14 log10. From day 14 onwards (third or second phase according to multi- or biphasic patterns), HBV DNA declined mainly because of the infected hepatocyte clearance that slowed down in approximately 50% of the patients from day 35, possibly because of a negative feedback on the immune system activity. Computing the number of infected cells at the end of therapy we found that peg-IFN-alpha2a and 3TC monotherapy determined a similar reduction of infected hepatocytes (mean: -3.3 log10), whereas there was a greater reduction in combination therapy patients (-5.0 versus -3.3 log10, P = 0.039). In conclusion, peg-IFN-alpha2a, in spite of having direct antiviral activity lower than that of 3TC, achieved a comparable reduction of infected hepatocytes, possibly because of a higher infected cell clearance rate.

Sustained response to interferon-ribavirin combination therapy predicted by a model of hepatitis C virus dynamics using both HCV RNA and alanine aminotransferase.

BACKGROUND AND AIMS: Standard models simulate the dynamics of hepatitis C virus (HCV) infection using HCV RNA kinetics and show a correlation between the clearance of infected hepatocytes and response to interferon. However, they are unable to predict whether the response will be maintained. The aim of our work was to identify criteria by which sustained responses may be predicted and defined. METHODS: In our model the clearance rate of infected cells is a function of their number and the baseline rate is computed by the alanine aminotransferase (ALT) kinetics during the first month of therapy. We simulated the variations of viral and infected cell loads in 31 consecutive patients treated with IFN-alpha2b 3-5 MU every other day, with or without ribavirin, for 6 or 12 months depending on HCV genotype. RESULTS: At baseline the computed (in 28 of 31 cases) percentage of infected cells was lower in seven sustained responders (mean: 11.7%, range: 1-24.6%) than in 14 transient responders (mean: 28.2%, range: 7.4-75.5%) and in seven non-responders (mean: 41%, range: 8.8-86%) (P=0.036). At the end of therapy the computed infected cell number was <100 cells/ml of extracellular fluid in all sustained responders (mean: 18.4, range: 1.7-48), in three transient responders (mean: 3500, range: 1.52-17500) and in none non-responders (mean: 28500, range: 1200-96000) (P=0.003). Overall of 10 patients with less than 100 infected cells/ml at the end of therapy seven (six had combination therapy) showed sustained response. All three relapsers received interferon monotherapy. CONCLUSION: The analysis of infected cells dynamics using the new model might be useful to tailor treatment duration in patients with combination therapy.