View PDF Version - RePub - Erasmus Universiteit Rotterdam
View PDF Version - RePub - Erasmus Universiteit Rotterdam
View PDF Version - RePub - Erasmus Universiteit Rotterdam
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
Summary and conclusion 235<br />
The inference is performed in the Bayesian framework using the Markov chain Monte<br />
Carlo methodology. The methodology is applied to data from the Dutch primary biliary<br />
cirrhosis study.<br />
STATISTICAL MODELS OF EARLY TREATMENT<br />
EFFECTS<br />
Viral dynamics during and after entecavir therapy in patients with chronic hepatitis B are<br />
described in Chapter 4.1.<br />
Nucleoside analogues inhibit HBV replication. Entecavir, a guanine nucleoside, has also<br />
been shown to reduce covalently closed circular DNA (cccDNA) to undetectable levels<br />
in wood chucks chronically infected with hepatitis virus.<br />
Mathematical description of changes in viral load during and after therapy may help to<br />
understand the process that takes place during nucleoside analogue treatment.<br />
Ten chronic hepatitis B patients were evaluated with a mathematical model during<br />
treatment with and after withdrawal of four doses of entecavir. Blood was drawn for<br />
HBV DNA measurement at frequent intervals. Decay and rebound of viral concentration<br />
during and after entecavir therapy, respectively, showed a bi phasic pattern. Non-linear<br />
modelling was used to fit individual patient data.<br />
The median effectiveness in blocking viral production was 96% and the median half-life<br />
of viral turn-over was 16 h. The median half-life of infected hepatocytes was 257 h. Data<br />
on levels of cccDNA in the liver in these patients could be helpful in supporting the<br />
parameters as calculated with the model.<br />
Tenofovir, an antihuman immunodefi ciency virus (HIV) drug, has activity against lamivudine-resistant<br />
HBV mutants. In Chapter 4.2 the effi cacy of tenofovir is described in<br />
patients with lamivudine-resistant hepatitis B. Two investigative approaches based on<br />
mathematical models of viral dynamics were applied: the individual nonlinear fi tting and<br />
the mixed-effect group fi tting approaches.<br />
Eleven chronic HBV patients on lamivudine for a median of 176 weeks (range: 72–382)<br />
with YMDD mutation-related HBV-DNA breakthrough received ‘add-on’ tenofovir 300<br />
mg once-daily, while maintaining their existing therapy. Sequential sera assessing HBV<br />
DNA levels were frequently taken during the fi rst 4 weeks of treatment and every 4<br />
weeks thereafter.<br />
Median baseline log HBV-DNA was 8.62. Tenofovir treatment resulted in a mean log<br />
HBV-DNA decline of 1.37 in the fi rst phase, 2.54 after 4 weeks, and 4.95 log HBV-DNA<br />
after 24 weeks. The median effectiveness of blocking viral replication in the individual