A multiphase model of the dynamics of HBV infection in BBeAg-negative patients during pegylated interferon-alpha 2a, 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-alpha 2a (peg-IFN-alpha 2a) 180 mg weekly plus 3TC (23 patients), or peg-IFN-alpha 2a 180 mg weekly plus placebo (24 patients). During the first month of therapy most of the 3TC -/+ peg-IFN-alpha 2a 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 log(10) and 2.36 log(10), respectively. At variance, peg-IFN-alpha 2a 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 log(10). 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-alpha 2a and 3TC monotherapy determined a similar reduction of infected hepatocytes (mean: -3.3 log(10)), whereas there was a greater reduction in combination therapy patients (-5.0 versus -3.3 log(10), P=0.039). In conclusion, peg-IFN-alpha 2a, 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.