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<dochead>Debate</dochead>
<bibl>
<title>
<p>On fractional order models for Hepatitis C</p>
</title>
<aug>
<au ca="yes" id="A1"><snm>Ahmed</snm><fnm>E</fnm><insr iid="I1"/><email>magd45@yahoo.com</email></au>
<au id="A2"><snm>El-Saka</snm><mi>A</mi><fnm>H</fnm><insr iid="I2"/><email>halaelsaka@yahoo.com</email></au>
</aug>
<insg>
<ins id="I1"><p>Mathematics Department, Faculty of Science, Mansoura University, 35516, Mansoura, Egypt</p></ins>
<ins id="I2"><p>Mathematics Department, Faculty of Science, Mansoura University, 34517, New Damietta, Egypt</p></ins>
</insg>
<source>Nonlinear Biomedical Physics</source>
<issn>1753-4631</issn>
<pubdate>2010</pubdate>
<volume>4</volume>
<issue>1</issue>
<fpage>1</fpage>
<url>http://www.nonlinearbiomedphys.com/content/4/1/1</url>
<xrefbib><pubidlist><pubid idtype="pmpid">20236553</pubid><pubid idtype="doi">10.1186/1753-4631-4-1</pubid></pubidlist></xrefbib>
</bibl>
<history><rec><date><day>30</day><month>12</month><year>2009</year></date></rec><acc><date><day>18</day><month>3</month><year>2010</year></date></acc><pub><date><day>18</day><month>3</month><year>2010</year></date></pub></history>
<cpyrt><year>2010</year><collab>Ahmed and El-Saka; licensee BioMed Central Ltd.</collab><note>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</note></cpyrt>
<abs>
<sec>
<st>
<p>Abstract</p>
</st>
<p>In this paper we present a fractional order generalization of Perelson et al. basic hepatitis C virus (HCV) model including an immune response term. We argue that fractional order equations are more suitable than integer order ones in modeling complex systems which include biological systems. The model is presented and discussed. Also we argue that the added immune response term represents some basic properties of the immune system and that it should be included to study longer term behavior of the disease.</p>
</sec>
</abs>
</fm><bdy>
<sec>
<st>
<p>1. Introduction</p>
</st>
<p>Hepatitis C is one of many serious infectious diseases affecting humans. An estimated about 170 million people worldwide are infected with hepatitis C. No vaccine against hepatitis C is available. Egypt has the highest rate of infections by hepatitis C virus (HCV) genotype 4. Chronic HCV infection is the main cause leading to liver transplant or death <abbrgrp>
<abbr bid="B1">1</abbr>
</abbrgrp>. Antiviral therapy has been used to treat chronically HCV infected patients. Relatively successful treatment contains pegylated interferon (PEG-IFN) and ribavirin (RBV). Typical response ate biphasic beginning with rapid viral decline phase followed by slower decline phase. Sometimes there is more complicated behavior but they will not be discussed here. Extensive and impressive studies have been done by Perelson and his group <abbrgrp>
<abbr bid="B2">2</abbr>
<abbr bid="B3">3</abbr>
<abbr bid="B4">4</abbr>
<abbr bid="B5">5</abbr>
</abbrgrp>. Here we present a fractional order generalization of a basic HCV model <abbrgrp>
<abbr bid="B2">2</abbr>
</abbrgrp> including the immune response (Ir) term proposed in <abbrgrp>
<abbr bid="B3">3</abbr>
</abbrgrp>.</p>
<p>In sec. 2 we argue that fractional order equations are more suitable than integer order ones in modeling complex systems which include biological systems. In sec.3 the model is presented and discussed. Also we argue that the added immune response term represents some basic properties of the immune system and that it should be included to study longer term behavior of the disease.</p>
</sec>
<sec>
<st>
<p>2. Fractional Equations</p>
</st>
<p>Caputo's definition for derivative of order 0 &lt; &#945; &#8804; 1 is given by <abbrgrp>
<abbr bid="B6">6</abbr>
</abbrgrp>
</p>
<p>
<display-formula>
<graphic file="1753-4631-4-1-i1.gif"/>
</display-formula>
</p>
<p>where &#915; (&#945;) is the Gamma function and <it>f</it>'(<it>s</it>) is the first derivative. It is known that FO is more suitable in describing complex adaptive systems e.g. biological systems since they naturally represent fractal, memory and non-locality effects <abbrgrp>
<abbr bid="B7">7</abbr>
<abbr bid="B8">8</abbr>
<abbr bid="B9">9</abbr>
</abbrgrp>.</p>
</sec>
<sec>
<st>
<p>3. The model and conclusions</p>
</st>
<p>The fractional order hepatitis C virus (HCV) model is given by</p>
<p>
<display-formula id="M1">
<graphic file="1753-4631-4-1-i2.gif"/>
</display-formula>
</p>
<p>Where 0 &lt; &#945; &#8804; 1, <it>T </it>represents uninfected hepatocytes, <it>I </it>represents infected hepatocytes and <it>V </it>represents virus. The model assumes that uninfected hepatocytes are produced at a constant rate <it>s</it>, die at rate, <it>d</it>, per cell and are infected at constant rate &#946;. Infected hepatocytes are lost at a rate &#948; per cell. Viral particles (virions) are produced at rate <it>p </it>per infected hepatocyte and cleared at rate <it>c </it>per virion. Chronic HCV infection is treated using interferon-a in combination with the antiviral drug ribavirin. Interferon-a acts primarily by blocking the production/release of new virus, although we also allow for a treatment effect in blocking <it>de novo </it>infection. The efficacy of treatment in blocking virion production and reducing new infections are described by two parameters, &#949;<sub>
<it>p </it>
</sub>and &#951;, respectively. For example, a treatment efficacy in blocking virion production of 95% corresponds to &#949;<sub>
<it>p </it>
</sub>= 0.95.</p>
<p>The approximate solutions displayed in Figs. <figr fid="F1">1</figr>, <figr fid="F2">2</figr>, <figr fid="F3">3</figr> for different &#945; and <it>s </it>= 2.6 &#215; 10<sup>4</sup>, <it>d </it>= 0.0026, &#951; = 0.95, &#946; = 2.25 &#215; 10<sup>-7</sup>, &#948; = 0.26, <it>c</it>
<sub>2 </sub>= 5 &#215; 10<sup>6</sup>, <it>c </it>= 6.0, &#949;<sub>
<it>p </it>
</sub>= 0.99, <it>p </it>= 2.9</p>
<fig id="F1"><title><p>Figure 1</p></title><caption><p></p></caption><text>
   <p/>
</text><graphic file="1753-4631-4-1-1"/></fig>
<fig id="F2"><title><p>Figure 2</p></title><caption><p></p></caption><text>
   <p/>
</text><graphic file="1753-4631-4-1-2"/></fig>
<fig id="F3"><title><p>Figure 3</p></title><caption><p></p></caption><text>
   <p/>
</text><graphic file="1753-4631-4-1-3"/></fig>
<p>We have the following conclusions:</p>
<p indent="1">i) Mathematical models, when done by a group of mathematicians and HCV specialists give relevant results e.g. explaining the role of RBV <abbrgrp>
<abbr bid="B4">4</abbr>
</abbrgrp>, explaining the observed two phase decline hence deriving the role of the drug in initially blocking the viral secretion more than blocking the cells' infection etc. <abbrgrp>
<abbr bid="B4">4</abbr>
</abbrgrp>.</p>
<p indent="1">ii) The term added in equation (1) represents the well known high and low zone tolerance of the immune response (There is no Ir if the antigen number is either too high or too low <abbrgrp>
<abbr bid="B10">10</abbr>
</abbrgrp>) since it vanishes for both limits <it>I </it>&#8594; 0 and <it>I </it>&#8594; <it>c</it>
<sub>2</sub>. Immune response is significant for long time virus dynamics.</p>
<p indent="1">iii) Fractional order results show the realistic biphasic decline behavior of HCV but at a slower rate.</p>
<p indent="1">iv) Since multi-drugs are strongly recommended to avoid drug resistance it is proposed that a further drug should be used in addition to Peg-IFN and RBV. Notice that RBV may not be considered as independent drug since, when used alone, it has no effect on HCV.</p>
</sec>
</bdy><bm>
<ack>
<sec>
<st>
<p>Acknowledgements</p>
</st>
<p>We thank Prof. A. S. Perelson for sending us copies of his work.</p>
</sec>
</ack>
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</bm></art>
