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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Hepatic Enzyme Alterations in HIV Patients on Antiretroviral Therapy: A Case-Control Study in a Hospital Setting in Ghana</title><author><name sortKey="Osakunor, Derick Nii Mensah" sort="Osakunor, Derick Nii Mensah" uniqKey="Osakunor D" first="Derick Nii Mensah" last="Osakunor">Derick Nii Mensah Osakunor</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Molecular Medicine, School of Medical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Obirikorang, Christian" sort="Obirikorang, Christian" uniqKey="Obirikorang C" first="Christian" last="Obirikorang">Christian Obirikorang</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Molecular Medicine, School of Medical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fianu, Vincent" sort="Fianu, Vincent" uniqKey="Fianu V" first="Vincent" last="Fianu">Vincent Fianu</name><affiliation><nlm:aff id="aff002"><addr-line>Department of Medical Laboratory Technology, Faculty of Allied Health Sciences, Kwame Nkrumah University of Sciences and Technology, Kumasi, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Asare, Isaac" sort="Asare, Isaac" uniqKey="Asare I" first="Isaac" last="Asare">Isaac Asare</name><affiliation><nlm:aff id="aff003"><addr-line>Medical Laboratory Department, St. Dominic Catholic Hospital, Akwatia, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dakorah, Mavis" sort="Dakorah, Mavis" uniqKey="Dakorah M" first="Mavis" last="Dakorah">Mavis Dakorah</name><affiliation><nlm:aff id="aff003"><addr-line>Medical Laboratory Department, St. Dominic Catholic Hospital, Akwatia, Ghana</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26247879</idno><idno type="pmc">4527699</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527699</idno><idno type="RBID">PMC:4527699</idno><idno type="doi">10.1371/journal.pone.0134449</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000023</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000023</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hepatic Enzyme Alterations in HIV Patients on Antiretroviral Therapy: A Case-Control Study in a Hospital Setting in Ghana</title><author><name sortKey="Osakunor, Derick Nii Mensah" sort="Osakunor, Derick Nii Mensah" uniqKey="Osakunor D" first="Derick Nii Mensah" last="Osakunor">Derick Nii Mensah Osakunor</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Molecular Medicine, School of Medical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Obirikorang, Christian" sort="Obirikorang, Christian" uniqKey="Obirikorang C" first="Christian" last="Obirikorang">Christian Obirikorang</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Molecular Medicine, School of Medical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fianu, Vincent" sort="Fianu, Vincent" uniqKey="Fianu V" first="Vincent" last="Fianu">Vincent Fianu</name><affiliation><nlm:aff id="aff002"><addr-line>Department of Medical Laboratory Technology, Faculty of Allied Health Sciences, Kwame Nkrumah University of Sciences and Technology, Kumasi, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Asare, Isaac" sort="Asare, Isaac" uniqKey="Asare I" first="Isaac" last="Asare">Isaac Asare</name><affiliation><nlm:aff id="aff003"><addr-line>Medical Laboratory Department, St. Dominic Catholic Hospital, Akwatia, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dakorah, Mavis" sort="Dakorah, Mavis" uniqKey="Dakorah M" first="Mavis" last="Dakorah">Mavis Dakorah</name><affiliation><nlm:aff id="aff003"><addr-line>Medical Laboratory Department, St. Dominic Catholic Hospital, Akwatia, Ghana</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>Diagnosing hepatic injury in HIV infection can be a herculean task for clinicians as several factors may be involved. In this study, we sought to determine the effects of antiretroviral therapy (ART) and disease progression on hepatic enzymes in HIV patients.</p></sec><sec id="sec002"><title>Methods</title><p>A case-control study conducted from January to May 2014 at the Akwatia Government Hospital, Eastern region, Ghana, The study included 209 HIV patients on ART (designated HIV-ART) and 132 ART-naive HIV patients (designated HIV-Controls). Data gathered included demography, clinical history and results of blood tests for hepatic enzymes. We employed the Fisher’s, Chi-square, unpaired t-test and Pearson’s correlation in analysis, using GraphPad Prism and SPSS. A <italic>P</italic> value < 0.05 was considered significant.</p></sec><sec id="sec003"><title>Results</title><p>Median CD4 lymphocyte count of HIV-ART participants (604.00 <italic>cells/mm<sup>3</sup></italic>) was higher than that of HIV-Controls (491.50 <italic>cells/mm3; P</italic> = 0.0005). Mean values of ALP, ALT, AST and GGT did not differ between the two groups compared (P > 0.05). There was a significant positive correlation between hepatic enzymes (ALP, ALT, AST and GGT) for both groups (p < 0.01 each). Duration of ART correlated positively with ALT (p < 0.05). The effect size of disease progression on hepatic enzymes for both groups was small.</p></sec><sec id="sec004"><title>Conclusion</title><p>Antiretroviral therapy amongst this population has minimal effects on hepatic enzymes and does not suggest modifications in therapy. Hepatic injury may occur in HIV, even in the absence of ART and other traditional factors. Monitoring of hepatic enzymes is still important in HIV patients.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Palella, Fjj" uniqKey="Palella F">FJJ Palella</name></author><author><name sortKey="Delaney, Km" uniqKey="Delaney K">KM Delaney</name></author><author><name sortKey="Moorman, Ac" uniqKey="Moorman A">AC Moorman</name></author><author><name sortKey="O, Lm" uniqKey="O L">LM O</name></author><author><name sortKey="Fuhrer, J" uniqKey="Fuhrer J">J Fuhrer</name></author><author><name sortKey="Satten, Ga" uniqKey="Satten G">GA Satten</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berns, Js" uniqKey="Berns J">JS Berns</name></author><author><name sortKey="Kasbekar, N" uniqKey="Kasbekar N">N Kasbekar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kontorinis, N" uniqKey="Kontorinis N">N Kontorinis</name></author><author><name sortKey="Dieterich, D" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26247879</article-id><article-id pub-id-type="pmc">4527699</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0134449</article-id><article-id pub-id-type="publisher-id">PONE-D-15-02558</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Hepatic Enzyme Alterations in HIV Patients on Antiretroviral Therapy: A Case-Control Study in a Hospital Setting in Ghana</article-title><alt-title alt-title-type="running-head">Hepatic Enzymes in HIV/ART</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Osakunor</surname><given-names>Derick Nii Mensah</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref rid="cor001" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Obirikorang</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fianu</surname><given-names>Vincent</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Asare</surname><given-names>Isaac</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dakorah</surname><given-names>Mavis</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Molecular Medicine, School of Medical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Department of Medical Laboratory Technology, Faculty of Allied Health Sciences, Kwame Nkrumah University of Sciences and Technology, Kumasi, Ghana</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Medical Laboratory Department, St. Dominic Catholic Hospital, Akwatia, Ghana</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Ceccherini-Silberstein</surname><given-names>Francesca</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Rome Tor Vergata, ITALY</addr-line></aff><author-notes><fn fn-type="conflict" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: DNMO CO VF. Performed the experiments: DNMO CO VF IA MD. Analyzed the data: DNMO CO VF. Contributed reagents/materials/analysis tools: DNMO CO VF IA MD. Wrote the paper: DNMO CO VF.</p></fn><corresp id="cor001">* E-mail: <email>osakunor@gmail.com</email></corresp></author-notes><pub-date pub-type="epub"><day>6</day><month>8</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>10</volume><issue>8</issue><elocation-id>e0134449</elocation-id><history><date date-type="received"><day>19</day><month>1</month><year>2015</year></date><date date-type="accepted"><day>10</day><month>7</month><year>2015</year></date></history><permissions><copyright-year>2015</copyright-year><copyright-holder>Osakunor et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="pone.0134449.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>Diagnosing hepatic injury in HIV infection can be a herculean task for clinicians as several factors may be involved. In this study, we sought to determine the effects of antiretroviral therapy (ART) and disease progression on hepatic enzymes in HIV patients.</p></sec><sec id="sec002"><title>Methods</title><p>A case-control study conducted from January to May 2014 at the Akwatia Government Hospital, Eastern region, Ghana, The study included 209 HIV patients on ART (designated HIV-ART) and 132 ART-naive HIV patients (designated HIV-Controls). Data gathered included demography, clinical history and results of blood tests for hepatic enzymes. We employed the Fisher’s, Chi-square, unpaired t-test and Pearson’s correlation in analysis, using GraphPad Prism and SPSS. A <italic>P</italic> value < 0.05 was considered significant.</p></sec><sec id="sec003"><title>Results</title><p>Median CD4 lymphocyte count of HIV-ART participants (604.00 <italic>cells/mm<sup>3</sup></italic>) was higher than that of HIV-Controls (491.50 <italic>cells/mm3; P</italic> = 0.0005). Mean values of ALP, ALT, AST and GGT did not differ between the two groups compared (P > 0.05). There was a significant positive correlation between hepatic enzymes (ALP, ALT, AST and GGT) for both groups (p < 0.01 each). Duration of ART correlated positively with ALT (p < 0.05). The effect size of disease progression on hepatic enzymes for both groups was small.</p></sec><sec id="sec004"><title>Conclusion</title><p>Antiretroviral therapy amongst this population has minimal effects on hepatic enzymes and does not suggest modifications in therapy. Hepatic injury may occur in HIV, even in the absence of ART and other traditional factors. Monitoring of hepatic enzymes is still important in HIV patients.</p></sec></abstract><funding-group><funding-statement>The authors have no support or funding to report.</funding-statement></funding-group><counts><fig-count count="0"></fig-count><table-count count="7"></table-count><page-count count="10"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper.</p></notes></front><body><sec sec-type="intro" id="sec005"><title>Introduction</title><p>Antiretroviral Therapy (ART), a term that refers to the use of the combination of three or more antiretroviral agents, since its introduction, has dramatically altered the treatment and life expectancy of Human Immunodeficiency Virus (HIV) patients for the better [<xref rid="pone.0134449.ref001" ref-type="bibr">1</xref>, <xref rid="pone.0134449.ref002" ref-type="bibr">2</xref>]. In spite of the benefits of ART, adverse effects [<xref rid="pone.0134449.ref003" ref-type="bibr">3</xref>], of which hepatotoxicity is a common finding can lead to discontinuation, switch and non-adherence to therapy [<xref rid="pone.0134449.ref004" ref-type="bibr">4</xref>].</p><p>Diagnosing hepatic injury in HIV infection can be a herculean task for clinicians, as several factors may be involved. That which includes HIV itself, hepatitis viruses (B and C), systemic opportunistic infections, malignancies and drug-induced hepatotoxicity [<xref rid="pone.0134449.ref005" ref-type="bibr">5</xref>].</p><p>Mechanisms of hepatotoxicity from ART may result from the interaction between anti-retroviral agents and other drugs metabolized in the liver. Dose-dependent toxicity, increased half lives (decreased clearance rate) of antiretroviral agents resulting from treatment with drugs like antibiotics and increase in the levels of anti-fungal agents to hepatotoxic levels by anti-retroviral agents themselves, are amongst other mechanisms [<xref rid="pone.0134449.ref003" ref-type="bibr">3</xref>].</p><p>Studies have shown that in patients commencing ART, 14–20% will experience elevations in hepatic enzymes [<xref rid="pone.0134449.ref006" ref-type="bibr">6</xref>]. Upon initiation of therapy however, most studies have found that mild hepatotoxicity exists amongst patients co-infected with hepatitis B or C virus [<xref rid="pone.0134449.ref007" ref-type="bibr">7</xref>–<xref rid="pone.0134449.ref009" ref-type="bibr">9</xref>] and after commencement of treatment for tuberculosis [<xref rid="pone.0134449.ref010" ref-type="bibr">10</xref>]. In Tanzania, efavirenz and rifampicin-based hepatotoxicity occurred in HIV patients with or without Tuberculosis (TB) co-infection but these were reported to be mild and did not require modifications in therapy [<xref rid="pone.0134449.ref011" ref-type="bibr">11</xref>].</p><p>Meanwhile, other researchers have reported an increased incidence of hepatic injury in ART-treated patients and have identified hepatotoxic events [<xref rid="pone.0134449.ref004" ref-type="bibr">4</xref>, <xref rid="pone.0134449.ref012" ref-type="bibr">12</xref>, <xref rid="pone.0134449.ref013" ref-type="bibr">13</xref>] including life-threatening episodes [<xref rid="pone.0134449.ref014" ref-type="bibr">14</xref>] in patients on ART. In Uganda, there is documented evidence of the absence of hepatotoxicity during ART [<xref rid="pone.0134449.ref008" ref-type="bibr">8</xref>].</p><p>These confirm that incidence rates of hepatotoxicity during ART may vary across different populations and with different drug combinations. Giving the different definitions used in different studies, the overall frequency of grade 3 or 4 liver toxicity induced by ART in HIV patients ranges from 1% to 18% [<xref rid="pone.0134449.ref015" ref-type="bibr">15</xref>, <xref rid="pone.0134449.ref016" ref-type="bibr">16</xref>].</p><p>In Ghana, there was more than a 200-fold increase in the number of HIV patients receiving ART from 197 in 2003 to over 45,000 in 2010 [<xref rid="pone.0134449.ref017" ref-type="bibr">17</xref>]. With the increasing access to ART, there is the need to assess and monitor a plethora of co-morbidities that often present at the initiation or with the ageing of ART-treated patients.</p><p>To the best of our knowledge, this study is the first of its kind in Ghana. Thus, data on the extent of ART-related liver disease and the role of hepatic enzymes in monitoring this event, is limited.</p><p>In this study, we hypothesize that ART or HIV infection itself has hepatotoxic effects on HIV patients receiving treatment in Ghana. The purpose of this study was to determine the effect of ART and disease progression on hepatic enzymes, in a hospital setting in Ghana.</p></sec><sec sec-type="materials|methods" id="sec006"><title>Materials and Methods</title><sec id="sec007"><title>Study design/site</title><p>This case-control study was conducted at the Akwatia Government Hospital in the Eastern region of Ghana, from January to May 2014. The site is a district hospital that serves inhabitants of Akwatia and its surrounding areas.</p></sec><sec id="sec008"><title>Study population</title><p>Three hundred and forty-one (341) participants were involved in the study, that which consisted of 209 patients on ART (designated HIV-ART) and 132 ART-naive patients (designated HIV-Controls).</p><p>Patients were included in the study if they met the following criteria; diagnosed and confirmed HIV-positive, age ≥ 18 years, followed up by the Akwatia Government Hospital with frequent visits, and on ART for at least three (3) months. Patients were excluded if they had active or chronic viral hepatitis, were pregnant, on concurrent hepatotoxic drugs or on treatment with liver supportive drugs.</p></sec><sec id="sec009"><title>Ethical consent</title><p>The study was approved by the Committee on Human Research, Publication and Ethics (CHRPE) of the School of Medical Sciences (SMS), Kwame Nkrumah University of Science and Technology (KNUST) / the Komfo Anokye Teaching Hospital (KATH). Participation was voluntary and written informed consent was obtained from each participant.</p></sec><sec id="sec010"><title>Data Collection and laboratory analysis</title><p>Demographic characteristics and clinical history were gathered using findings from a structured questionnaire and concurrent review of patient records.</p><p>About five (5) ml venous blood sample was taken from each participant, and dispensed into serum separator (SST) (3 ml) and ethylenediaminetetraacetic acid (EDTA) tubes (2ml). Serum biochemical assays [Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline Phosphatase (ALP) and Gamma-glutamyltransferase (GGT)] were performed immediately on the BT-3000 Plus Chemistry Analyser (Diamond Diagnostics, USA). CD4 lymphocyte count estimation was done on the BD FACS Count System (Becton Dickenson and Company, USA).</p></sec><sec id="sec011"><title>Data management and analysis</title><p>Data was entered into a Microsoft Excel spread sheet and analysed using GraphPad Prism version 6.0 (GraphPad software, San Diego, California, USA) and Statistical Package for the Social Sciences (SPSS) version 20 (SPSS Inc. Chicago, USA).</p><p>Case definitions for the various hepatic enzymes were as follows; ALT > 40.0 U/L for male or > 31.0 U/L for female, AST > 37.0 U/L for male or > 31.0 U/L for female, GGT > 51.0 U/L for male or > 33.0 U/L for female and ALP > 117.0 U/L for adults [<xref rid="pone.0134449.ref018" ref-type="bibr">18</xref>]. Disease progression as indicated by CD4 lymphocyte count was; Stage1 (≥ 500 cells/mm<sup>3</sup>), Stage 2 (200–499 cells/mm<sup>3</sup>) and Stage 3 (< 200 cells/mm<sup>3</sup>) as per recommendations of the Centres for Disease Control and Prevention (CDC) [<xref rid="pone.0134449.ref019" ref-type="bibr">19</xref>–<xref rid="pone.0134449.ref021" ref-type="bibr">21</xref>]. Patients on ART were placed in three groups, based on duration of therapy; Group 1 (< 2 years), Group 2 (2–4 years) and Group 3 (> 4 years).</p><p>Categorical variables were expressed as frequencies and proportions and compared using the Fisher’s exact test or Chi-square test. Continuous variables were expressed as means ± SEM and compared using the unpaired t-test. To establish the relationship between variables, we performed the Pearson’s correlation co-efficient test. The Cohen's guidelines for eta squared was used in assessing the effect size of disease progression as follows; small = 0.02, medium = 0.06 and large = 0.13 [<xref rid="pone.0134449.ref022" ref-type="bibr">22</xref>]. A <italic>P</italic> value of < 0.05 was considered statistically significant.</p></sec></sec><sec sec-type="results" id="sec012"><title>Results</title><p><xref rid="pone.0134449.t001" ref-type="table">Table 1</xref> shows the demographic and clinical characteristics of the study population. Mean age was 40.85 ± 0.63 and majority were female (76.8%). Amongst the HIV-ART population, 45.5% had been on ART for less than 2 years. Median CD4 lymphocyte count of HIV-ART participants (604.00 <italic>cells/mm</italic><sup><italic>3</italic></sup>) was higher than that of HIV-Controls (491.50 <italic>cells/mm3; P</italic> = 0.0005). About half the population (50.1%) had CD4 counts ≥ 500 <italic>cells/mm</italic><sup><italic>3</italic></sup> with a significant difference between proportions of the two groups (<italic>P</italic> < 0.0001).</p><table-wrap id="pone.0134449.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0134449.t001</object-id><label>Table 1</label><caption><title>Demographic and clinical characteristics of study population.</title></caption><alternatives><graphic id="pone.0134449.t001g" xlink:href="pone.0134449.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Parameter</th><th align="left" rowspan="1" colspan="1">Total (n = 341)</th><th align="left" rowspan="1" colspan="1">HIV-ART (n = 209)</th><th align="left" rowspan="1" colspan="1">HIV-Controls (n = 132)</th><th align="left" rowspan="1" colspan="1"><italic>P-value</italic></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Age (years)</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Mean age</td><td align="left" rowspan="1" colspan="1">40.71 ± 0.63</td><td align="left" rowspan="1" colspan="1">41.05 ± 0.73</td><td align="left" rowspan="1" colspan="1">39.95 ± 1.27</td><td align="char" char="." rowspan="1" colspan="1">0.4593</td></tr><tr><td align="left" rowspan="1" colspan="1">Young Adulthood (18–40 yrs)</td><td align="left" rowspan="1" colspan="1">184 (54.0)</td><td align="left" rowspan="1" colspan="1">119 (56.9)</td><td align="left" rowspan="1" colspan="1">65 (49.2)</td><td align="char" char="." rowspan="1" colspan="1">0.3783</td></tr><tr><td align="left" rowspan="1" colspan="1">Middle Adulthood (41–65 yrs)</td><td align="left" rowspan="1" colspan="1">152 (44.6)</td><td align="left" rowspan="1" colspan="1">87 (41.6)</td><td align="left" rowspan="1" colspan="1">65 (49.2)</td><td align="char" char="." rowspan="1" colspan="1">0.3783</td></tr><tr><td align="left" rowspan="1" colspan="1">Maturity (66 yrs—death)</td><td align="left" rowspan="1" colspan="1">5 (1.5)</td><td align="left" rowspan="1" colspan="1">3 (1.4)</td><td align="left" rowspan="1" colspan="1">2 (1.5)</td><td align="char" char="." rowspan="1" colspan="1">0.3783</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold><italic>Gender</italic></bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Male</td><td align="left" rowspan="1" colspan="1">79 (23.2)</td><td align="left" rowspan="1" colspan="1">55 (26.3)</td><td align="left" rowspan="1" colspan="1">24 (18.2)</td><td align="char" char="." rowspan="1" colspan="1">0.0882</td></tr><tr><td align="left" rowspan="1" colspan="1">Female</td><td align="left" rowspan="1" colspan="1">262 (76.8)</td><td align="left" rowspan="1" colspan="1">154 (73.7)</td><td align="left" rowspan="1" colspan="1">108 (81.8)</td><td align="char" char="." rowspan="1" colspan="1">0.0882</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold><italic>CD4 cell count (cells/mm</italic></bold><sup><bold><italic>3</italic></bold></sup><bold><italic>)</italic></bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Median (IQR)</td><td align="left" rowspan="1" colspan="1">563.00 (362–928)</td><td align="left" rowspan="1" colspan="1">604.00 (384–4360)</td><td align="left" rowspan="1" colspan="1">491.50 (331–664)</td><td align="char" char="." rowspan="1" colspan="1"><bold>0.0005</bold></td></tr><tr><td align="left" rowspan="1" colspan="1">< 200</td><td align="left" rowspan="1" colspan="1">33 (9.7)</td><td align="left" rowspan="1" colspan="1">20 (9.6)</td><td align="left" rowspan="1" colspan="1">13 (9.8)</td><td align="char" char="." rowspan="1" colspan="1"><bold>< 0.0001</bold></td></tr><tr><td align="left" rowspan="1" colspan="1">200–499</td><td align="left" rowspan="1" colspan="1">137 (40.2)</td><td align="left" rowspan="1" colspan="1">113 (31.6)</td><td align="left" rowspan="1" colspan="1">24 (18.2)</td><td align="char" char="." rowspan="1" colspan="1"><bold>< 0.0001</bold></td></tr><tr><td align="left" rowspan="1" colspan="1">≥ 500</td><td align="left" rowspan="1" colspan="1">171 (50.1)</td><td align="left" rowspan="1" colspan="1">76 (58.9)</td><td align="left" rowspan="1" colspan="1">95 (72.0)</td><td align="char" char="." rowspan="1" colspan="1"><bold>< 0.0001</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ART duration (years)</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Median (IQR)</td><td align="left" rowspan="1" colspan="1">3.00 (1.7–4.0)</td><td align="left" rowspan="1" colspan="1">3.00 (1.7–4.0) -</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Group 1 (< 2)</td><td align="left" rowspan="1" colspan="1">95 (27.9)</td><td align="left" rowspan="1" colspan="1">95 (45.5)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Group 2 (2–4)</td><td align="left" rowspan="1" colspan="1">74 (21.7)</td><td align="left" rowspan="1" colspan="1">74 (35.4)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Group 3 <bold>(></bold> 4)</td><td align="left" rowspan="1" colspan="1">40 (11.7)</td><td align="left" rowspan="1" colspan="1">40 (19.1)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold><italic>ART regimen</italic></bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">AZT-3TC-EFV</td><td align="left" rowspan="1" colspan="1">48 (14.1)</td><td align="left" rowspan="1" colspan="1">48 (23.0)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">AZT-3TC-LOP</td><td align="left" rowspan="1" colspan="1">7 (2.1)</td><td align="left" rowspan="1" colspan="1">7 (3.3)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">AZT-3TC-NVP</td><td align="left" rowspan="1" colspan="1">29 (8.5)</td><td align="left" rowspan="1" colspan="1">29 (13.9)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">AZT-EFV-NVP</td><td align="left" rowspan="1" colspan="1">9 (2.6)</td><td align="left" rowspan="1" colspan="1">9 (4.3)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">TDF-3TC-EFV</td><td align="left" rowspan="1" colspan="1">82 (23.3)</td><td align="left" rowspan="1" colspan="1">76 (36.4)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">TDF-3TC-NVP</td><td align="left" rowspan="1" colspan="1">27 (7.9)</td><td align="left" rowspan="1" colspan="1">27 (12.9)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">TDF-3TC-LOP</td><td align="left" rowspan="1" colspan="1">7 (2.1)</td><td align="left" rowspan="1" colspan="1">7 (3.3)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">TDF-3TC-EFV</td><td align="left" rowspan="1" colspan="1">6 (1.8)</td><td align="left" rowspan="1" colspan="1">6 (2.9)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>Data is presented as mean ± SEM or n (%), ART = Antiretroviral Therapy; TDF = Tenofovir Disoproxil Fumarate; FTC = Emtricitabine; LOP = Lopinavir/ritonavir, EFV = Efavirenz, AZT = Zidovudine; NVP = Nevirapine. P value < 0.05 was considered significant.</p></fn></table-wrap-foot></table-wrap><p>There was no significant difference in mean ALP (<italic>P</italic> = 0.8750), ALT (<italic>P =</italic> 0.6511), AST (<italic>P =</italic> 0.6128) and GGT (<italic>P</italic> = 0.0543) between the two groups (HIV-ART and HIV-Controls). [<xref rid="pone.0134449.t002" ref-type="table">Table 2</xref>]</p><table-wrap id="pone.0134449.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0134449.t002</object-id><label>Table 2</label><caption><title>Biochemical characteristics (hepatic enzymes) of study participants.</title></caption><alternatives><graphic id="pone.0134449.t002g" xlink:href="pone.0134449.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Parameters</th><th align="left" rowspan="1" colspan="1">HIV-ART (n = 209)</th><th align="left" rowspan="1" colspan="1">HIV- Controls (n = 132)</th><th align="left" rowspan="1" colspan="1"><italic>P-value</italic></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>ALP</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">125.4 ± 3.33</td><td align="left" rowspan="1" colspan="1">126.5 ± 6.11</td><td align="char" char="." rowspan="1" colspan="1">0.8750</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ALT</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">24.85 ± 1.33</td><td align="left" rowspan="1" colspan="1">26.08 ± 2.36</td><td align="char" char="." rowspan="1" colspan="1">0.6511</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>AST</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">33.97 ± 1.64</td><td align="left" rowspan="1" colspan="1">35.82 ± 3.92</td><td align="char" char="." rowspan="1" colspan="1">0.6128</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>GGT</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">66.47 ± 4.47</td><td align="left" rowspan="1" colspan="1">89.51 ± 15.81</td><td align="char" char="." rowspan="1" colspan="1">0.0543</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>Data is presented as mean ± SEM. ALP = Alkaline Phosphatase; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma-glutamyltransferase. P value < 0.05 was considered significant.</p></fn></table-wrap-foot></table-wrap><p>In <xref rid="pone.0134449.t003" ref-type="table">Table 3</xref>, there was no significant difference between proportion of individuals with elevated hepatic enzymes, when compared between HIV-ART and HIV-Controls (P > 0.05).</p><table-wrap id="pone.0134449.t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0134449.t003</object-id><label>Table 3</label><caption><title>Participants with elevated hepatic enzymes.</title></caption><alternatives><graphic id="pone.0134449.t003g" xlink:href="pone.0134449.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Parameters</th><th align="left" rowspan="1" colspan="1">Total (n = 341)</th><th align="left" rowspan="1" colspan="1">HIV-ART (n = 209)</th><th align="left" rowspan="1" colspan="1">HIV-Controls (n = 132)</th><th align="left" rowspan="1" colspan="1"><italic>P-value</italic></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>ALP</bold></td><td align="left" rowspan="1" colspan="1">172 (50.4%)</td><td align="left" rowspan="1" colspan="1">106 (50.7%)</td><td align="left" rowspan="1" colspan="1">66 (50.0%)</td><td align="char" char="." rowspan="1" colspan="1">0.9119</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ALT</bold></td><td align="left" rowspan="1" colspan="1">60 (17.6%)</td><td align="left" rowspan="1" colspan="1">34 (16.3%)</td><td align="left" rowspan="1" colspan="1">26 (19.7%)</td><td align="char" char="." rowspan="1" colspan="1">0.4661</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>AST</bold></td><td align="left" rowspan="1" colspan="1">113 (33.1%)</td><td align="left" rowspan="1" colspan="1">65 (31.1%)</td><td align="left" rowspan="1" colspan="1">48 (36.4%)</td><td align="char" char="." rowspan="1" colspan="1">0.3454</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>GGT</bold></td><td align="left" rowspan="1" colspan="1">226 (66.3%)</td><td align="left" rowspan="1" colspan="1">138 (66.0%)</td><td align="left" rowspan="1" colspan="1">88 (66.7%)</td><td align="char" char="." rowspan="1" colspan="1">1.0000</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t003fn001"><p>Data is presented as n (%). ALP = Alkaline Phosphatase; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma-glutamyltransferase. P value < 0.05 was considered significant.</p></fn></table-wrap-foot></table-wrap><p>When this was compared within and across gender, all enzymes but the GGT, did not differ significantly between HIV-ART and HIV-Controls. Of both groups compared, there were significantly more males than females with elevated GGT (<italic>P</italic> < 0.0001 each). [<xref rid="pone.0134449.t004" ref-type="table">Table 4</xref>]</p><table-wrap id="pone.0134449.t004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0134449.t004</object-id><label>Table 4</label><caption><title>Comparison of hepatic enzyme levels between HIV-ART and HIV-Controls relative to gender.</title></caption><alternatives><graphic id="pone.0134449.t004g" xlink:href="pone.0134449.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Parameters</th><th align="left" rowspan="1" colspan="1">HIV-ART Male (n = 55)</th><th align="left" rowspan="1" colspan="1">HIV-Controls Male (n = 24)</th><th align="left" rowspan="1" colspan="1"><italic>P value</italic></th><th align="left" rowspan="1" colspan="1">HIV-ART Female (n = 154)</th><th align="left" rowspan="1" colspan="1">HIV-Controls Female (n = 108)</th><th align="left" rowspan="1" colspan="1"><italic>P-value</italic></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold><italic>ALP</italic></bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">27 (49.0)</td><td align="left" rowspan="1" colspan="1">12 (50.0)</td><td rowspan="2" align="char" char="." colspan="1">1.0000</td><td align="left" rowspan="1" colspan="1">76 (49.4)</td><td align="left" rowspan="1" colspan="1">54 (50.0)</td><td rowspan="2" align="char" char="." colspan="1">1.0000</td></tr><tr><td align="left" rowspan="1" colspan="1">Elevated</td><td align="left" rowspan="1" colspan="1">28 (50.9)</td><td align="left" rowspan="1" colspan="1">12 (50.0)</td><td align="left" rowspan="1" colspan="1">78 (50.6)</td><td align="left" rowspan="1" colspan="1">54 (50.0)</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold><italic>ALT</italic></bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">49 (89.00</td><td align="left" rowspan="1" colspan="1">18 (75.0)</td><td rowspan="2" align="char" char="." colspan="1">0.1700</td><td align="left" rowspan="1" colspan="1">126 (81.8)</td><td align="left" rowspan="1" colspan="1">88 (81.5)</td><td rowspan="2" align="char" char="." colspan="1">1.0000</td></tr><tr><td align="left" rowspan="1" colspan="1">Elevated</td><td align="left" rowspan="1" colspan="1">6 (10.9)</td><td align="left" rowspan="1" colspan="1">6 (25.0)</td><td align="left" rowspan="1" colspan="1">28 (18.2)</td><td align="left" rowspan="1" colspan="1">20 (18.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold><italic>AST</italic></bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">38 (69.1)</td><td align="left" rowspan="1" colspan="1">16 (66.7)</td><td rowspan="2" align="char" char="." colspan="1">1.0000</td><td align="left" rowspan="1" colspan="1">106 (68.8)</td><td align="left" rowspan="1" colspan="1">68 (63.0)</td><td rowspan="2" align="char" char="." colspan="1">0.3534</td></tr><tr><td align="left" rowspan="1" colspan="1">Elevated</td><td align="left" rowspan="1" colspan="1">17 (30.9)</td><td align="left" rowspan="1" colspan="1">8 (33.3)</td><td align="left" rowspan="1" colspan="1">48 (31.2)</td><td align="left" rowspan="1" colspan="1">40 (37.0)</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold><italic>GGT</italic></bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">32 (58.2) <xref rid="t004fn004" ref-type="table-fn">***</xref></td><td align="left" rowspan="1" colspan="1">16 (66.7)<xref rid="t004fn004" ref-type="table-fn">†††</xref></td><td rowspan="2" align="char" char="." colspan="1">0.6176</td><td align="left" rowspan="1" colspan="1">39 (25.3)</td><td align="left" rowspan="1" colspan="1">28 (25.9)</td><td rowspan="2" align="char" char="." colspan="1">1.0000</td></tr><tr><td align="left" rowspan="1" colspan="1">Elevated</td><td align="left" rowspan="1" colspan="1">23 (41.8)</td><td align="left" rowspan="1" colspan="1">8 (33.3)</td><td align="left" rowspan="1" colspan="1">115 (74.7)</td><td align="left" rowspan="1" colspan="1">80 (74.1)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t004fn001"><p>Data is presented as n (%). ALP = Alkaline Phosphatase; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma-glutamyltransferase. P values indicate comparisons between HIV-ART males and HIV-Control males as well as between HIV-ART females and HIV-Control females. P value < 0.05 was considered significant.</p></fn><fn id="t004fn002"><p>* Indicate comparisons between males and females of HIV-ART).</p></fn><fn id="t004fn003"><p><sup>†</sup> Indicate comparisons between males and females of HIV-Controls).</p></fn><fn id="t004fn004"><p>***/††† is significant at the < 0.0001 level.</p></fn></table-wrap-foot></table-wrap><p>From Tables <xref rid="pone.0134449.t005" ref-type="table">5</xref> and <xref rid="pone.0134449.t006" ref-type="table">6</xref>, there was a significant positive correlation between all hepatic enzymes (ALP, ALT, AST and GGT) for both the HIV-ART and HIV-Control groups (<italic>P</italic> < 0.01 each). Conversely, each of the enzymes is likely to rise concurrently with the rise of another. Duration of ART positively correlated with ALT (<italic>P</italic> < 0.05) but not with ALP, AST and GGT.</p><table-wrap id="pone.0134449.t005" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0134449.t005</object-id><label>Table 5</label><caption><title>Pearson’s correlation matrix showing the relationship between hepatic enzymes and duration of ART amongst HIV—ART participants.</title></caption><alternatives><graphic id="pone.0134449.t005g" xlink:href="pone.0134449.t005"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Parameters</th><th align="left" rowspan="1" colspan="1">GGT</th><th align="left" rowspan="1" colspan="1">ALP</th><th align="left" rowspan="1" colspan="1">ALT</th><th align="left" rowspan="1" colspan="1">AST</th><th align="left" rowspan="1" colspan="1">ART duration</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>GGT</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.46</bold><xref rid="t005fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.31</bold><xref rid="t005fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.42</bold><xref rid="t005fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.11</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ALP</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.44</bold><xref rid="t005fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.48</bold><xref rid="t005fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.01</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ALT</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.76</bold><xref rid="t005fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.15</bold><xref rid="t005fn002" ref-type="table-fn">*</xref></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>AST</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.13</bold></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t005fn001"><p>Correlation is significant at</p></fn><fn id="t005fn002"><p>* P < 0.05 and</p></fn><fn id="t005fn003"><p>** P < 0.01 (2-tailed).</p></fn><fn id="t005fn004"><p>ART = Antiretroviral Therapy; ALP = Alkaline Phosphatase; ALT = Alanine Transaminase; AST = Aspartate Transaminase; GGT = Gamma-glutamyltransferase.</p></fn></table-wrap-foot></table-wrap><table-wrap id="pone.0134449.t006" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0134449.t006</object-id><label>Table 6</label><caption><title>Pearson’s correlation matrix of hepatic enzymes amongst the HIV—Control group.</title></caption><alternatives><graphic id="pone.0134449.t006g" xlink:href="pone.0134449.t006"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Parameters</th><th align="left" rowspan="1" colspan="1">GGT</th><th align="left" rowspan="1" colspan="1">ALP</th><th align="left" rowspan="1" colspan="1">ALT</th><th align="left" rowspan="1" colspan="1">AST</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>GGT</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.41</bold><xref rid="t006fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.40</bold><xref rid="t006fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.86</bold><xref rid="t006fn003" ref-type="table-fn">**</xref></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ALP</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.45</bold><xref rid="t006fn003" ref-type="table-fn">**</xref></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.51</bold><xref rid="t006fn003" ref-type="table-fn">**</xref></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ALT</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="char" char="." rowspan="1" colspan="1"><bold>0.53</bold><xref rid="t006fn003" ref-type="table-fn">**</xref></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>AST</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t006fn001"><p>Correlation is significant at</p></fn><fn id="t006fn002"><p>* P < 0.05 and</p></fn><fn id="t006fn003"><p>** P < 0.01 (2-tailed).</p></fn><fn id="t006fn004"><p>ART = Antiretroviral Therapy; ALP = Alkaline Phosphatase; ALT = Alanine Transaminase; AST = Aspartate Transaminase; GGT = Gamma-glutamyltransferase.</p></fn></table-wrap-foot></table-wrap><p><xref rid="pone.0134449.t007" ref-type="table">Table 7</xref> presents the relationship between disease progression, as indicated by the CD4 lymphocyte counts and ART-related hepatic injury. The effect size of disease progression on hepatic enzymes for the HIV-ART group was small, as indicated by eta squared for the hepatic enzymes. This was similar for the HIV-Control group.</p><table-wrap id="pone.0134449.t007" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0134449.t007</object-id><label>Table 7</label><caption><title>Relationship between disease progression and ART-related hepatic injury.</title></caption><alternatives><graphic id="pone.0134449.t007g" xlink:href="pone.0134449.t007"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">Parameters</th><th align="left" rowspan="1" colspan="1">Stage 1</th><th align="left" rowspan="1" colspan="1">Stage 2</th><th align="left" rowspan="1" colspan="1">Stage 3</th><th align="left" rowspan="1" colspan="1">Eta Squared</th><th align="left" rowspan="1" colspan="1"><italic>P</italic> for Trend</th></tr></thead><tbody><tr><td rowspan="4" align="left" colspan="1"><bold>HIV-Controls</bold></td><td align="left" rowspan="1" colspan="1"><bold>ALP</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">126.84 ± 7.43</td><td align="left" rowspan="1" colspan="1">138.05 ± 14.07</td><td align="left" rowspan="1" colspan="1">107.67 ± 8.12</td><td align="char" char="." rowspan="1" colspan="1">0.045</td><td align="char" char="." rowspan="1" colspan="1">0.2380</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ALT</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">24.19 ± 1.78</td><td align="left" rowspan="1" colspan="1">27.64 ± 5.67</td><td align="left" rowspan="1" colspan="1">29.27 ± 6.54</td><td align="char" char="." rowspan="1" colspan="1">0.012</td><td align="char" char="." rowspan="1" colspan="1">0.6970</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>AST</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">38.97 ± 6.84</td><td align="left" rowspan="1" colspan="1">33.86 ± 6.17</td><td align="left" rowspan="1" colspan="1">33.08 ± 5.41</td><td align="char" char="." rowspan="1" colspan="1">0.007</td><td align="char" char="." rowspan="1" colspan="1">0.7980</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>GGT</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">101.33 ± 29.35</td><td align="left" rowspan="1" colspan="1">76.96 ± 20.93</td><td align="left" rowspan="1" colspan="1">80.00 ± 21.22</td><td align="char" char="." rowspan="1" colspan="1">0.008</td><td align="char" char="." rowspan="1" colspan="1">0.7730</td></tr><tr><td rowspan="4" align="left" colspan="1"><bold>HIV-ART</bold></td><td align="left" rowspan="1" colspan="1"><bold>ALP</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">123.36 ± 4.58</td><td align="left" rowspan="1" colspan="1">131.84 ± 6.42</td><td align="left" rowspan="1" colspan="1">131.54± 13.98</td><td align="char" char="." rowspan="1" colspan="1">0.008</td><td align="char" char="." rowspan="1" colspan="1">0.5310</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>ALT</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">23.18 ± 1.59</td><td align="left" rowspan="1" colspan="1">25.66 ± 2.34</td><td align="left" rowspan="1" colspan="1">24.69 ± 4.36</td><td align="char" char="." rowspan="1" colspan="1">0.005</td><td align="char" char="." rowspan="1" colspan="1">0.6610</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>AST</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">32.13 ± 1.99</td><td align="left" rowspan="1" colspan="1">33.63 ± 2.64</td><td align="left" rowspan="1" colspan="1">33.54 ± 5.94</td><td align="char" char="." rowspan="1" colspan="1">0.001</td><td align="char" char="." rowspan="1" colspan="1">0.8930</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>GGT</bold> (U/l)</td><td align="left" rowspan="1" colspan="1">60.63 ± 5.09</td><td align="left" rowspan="1" colspan="1">78.64 ± 11.44</td><td align="left" rowspan="1" colspan="1">61.31 ± 12.70</td><td align="char" char="." rowspan="1" colspan="1">0.016</td><td align="char" char="." rowspan="1" colspan="1">0.2700</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t007fn001"><p>Data presented as mean ± SEM. ART = Antiretroviral Therapy; ALP = Alkaline Phosphatase; ALT = Alanine Transaminase; AST = Aspartate Transaminase; GGT = Gamma-glutamyltransferase; Disease progression through categorization of CD4 count: Stage 1 represents ≥ 500/mm<sup>3</sup>, Stage 2 represents 200–499/mm<sup>3</sup> and Stage 3 represents < 200/mm<sup>3</sup>.</p></fn></table-wrap-foot></table-wrap></sec><sec sec-type="conclusions" id="sec013"><title>Discussion</title><p>In spite of the benefits of ART, it may come with adverse effects [<xref rid="pone.0134449.ref003" ref-type="bibr">3</xref>], hence the question of discontinuation or alteration of treatment may come to play [<xref rid="pone.0134449.ref004" ref-type="bibr">4</xref>]. In this study, we sought to determine the effect of ART and disease progression on hepatic enzymes, in a hospital setting in Ghana.</p><p>The results of the present study suggest that in this population, ART has minimal effects on hepatotoxicity. This may be due to the absence of other traditional risk factors such as hepatitis C virus and / or hepatitis B virus (HBV / HCV) co-infection, older age, high alcohol intake and use of illicit drugs that may contribute to the development of hepatic injury in adults [<xref rid="pone.0134449.ref023" ref-type="bibr">23</xref>, <xref rid="pone.0134449.ref024" ref-type="bibr">24</xref>].</p><p>Upon HIV infection, it is expected that CD4 lymphocyte counts will drop with ageing of HIV infection, and ART is expected to help increase these numbers. We observed that the median CD4 count of HIV-ART participants was higher than that of HIV-Controls. Findings from other researchers have shown that, after ART, the median CD4 cell counts increase with time [<xref rid="pone.0134449.ref025" ref-type="bibr">25</xref>]. Adherence to therapy may also be a contributing factor to achieving the purpose of therapy in HIV patients [<xref rid="pone.0134449.ref026" ref-type="bibr">26</xref>], thus the finding in the present study. However, since we were unable to assess adherence to therapy, we are unable to ascertain this fact. Recently, Obirikorang <italic>et al</italic>., [<xref rid="pone.0134449.ref027" ref-type="bibr">27</xref>] found a lower CD4 lymphocyte count amongst HIV patients on ART than in those patients who were not. They attributed this to the fact patients who were not on ART had values not so low as to initiate ART, hence causing a possible masked increase in CD4 lymphocyte count amongst patients on ART when compared to ART-naive individuals [<xref rid="pone.0134449.ref027" ref-type="bibr">27</xref>]. Hence, the suggestion of an increase in CD4 lymphocyte count upon ART initiation is still valid.</p><p>Hepatic enzyme elevations are common in HIV-infected patients, especially those treated with ART. Despite such reports, HIV-infected patients may present several risk factors for biochemical abnormalities, and a precise aetiology is rarely defined clearly [<xref rid="pone.0134449.ref028" ref-type="bibr">28</xref>]. Most studies conducted on hepatotoxicity have shown the existence of hepatic injury associated with ART, but in the presence of other co-infections such as HCV [<xref rid="pone.0134449.ref007" ref-type="bibr">7</xref>] and even tuberculosis [<xref rid="pone.0134449.ref011" ref-type="bibr">11</xref>]. In a retrospective study assessing severe hepatic injury during ART, co-infected patients had a 3.99 greater chance of developing severely elevated transaminase levels compared with patients not co-infected with HCV. This risk increased considerably in co-infected patients with identified alcohol abuse [<xref rid="pone.0134449.ref023" ref-type="bibr">23</xref>]. We observed that of all the hepatic enzymes measured (ALT, AST, ALP and GGT), there was no significant difference in mean values between the two groups compared (HIV-ART and HIV-Controls). Thus in the absence of other traditional risk factors that increase the chances or cause hepatotoxicity, injury by ART may be minimal. On the contrary, a study conducted in Cameroon found elevations in both serum AST and ALT in patients on ART [<xref rid="pone.0134449.ref013" ref-type="bibr">13</xref>].</p><p>Reports have shown that slight increases in GGT may be due to contribution from other sources of GGT such as the prostate, pancreas and kidneys [<xref rid="pone.0134449.ref029" ref-type="bibr">29</xref>, <xref rid="pone.0134449.ref030" ref-type="bibr">30</xref>]. In the case of the current study, higher proportion of males with elevated levels of GGT observed could be due in part, to contributions from extra-hepatic sources such as the prostate.</p><p>The observed small effect size of disease progression on hepatic enzymes could indicate that with careful studies, there is indeed an effect of disease progression on hepatic enzymes in HIV but this may not be clinically obvious. Mokondjimobe <italic>et al</italic>., [<xref rid="pone.0134449.ref031" ref-type="bibr">31</xref>] reported that isolated naive HIV infection was associated with higher levels of ALT and GGT before and after adjusting for age and sex. Other researchers have also suggested that in the absence of ART, mild hepatotoxicity is seen in HIV patients [<xref rid="pone.0134449.ref032" ref-type="bibr">32</xref>]. This has been attributed to the fact that HIV infection results from chronic immune system activation and inflammatory cytokine release and studies have shown that ALT and GGT are now considered markers of inflammation with immune dysfunction in HIV [<xref rid="pone.0134449.ref033" ref-type="bibr">33</xref>] and oxidative stress [<xref rid="pone.0134449.ref034" ref-type="bibr">34</xref>]. As disease progresses and chronic inflammation increases, there is a high likelihood of increases in these hepatic enzymes.</p><p>The present study is limited by a number of factors. Our inability to determine the HIV viral RNA in study participants could not enable the determination of the relationship between viral load, ART regimen and liver enzymes, and thus the role of HIV itself on changes in liver enzymes. Furthermore, information on the number of ART regimens used by participants was not available, hence the effects of the number of regimens on liver enzymes was not determined. As this is a case control study, we were unable to determine pre-treatment liver enzyme levels and subsequently follow up with post-treatment levels. The inclusion of higher number of participants, information on antiretroviral exposure, increased observational time, and the use of a more restrictive criterion with regards to antiretroviral exposure is warranted.</p></sec><sec sec-type="conclusions" id="sec014"><title>Conclusion</title><p>Antiretroviral therapy amongst this population has minimal effects on hepatic enzymes and does not suggest modifications in therapy. In the absence of traditional risk factors for hepatotoxicity like alcohol use, viral hepatitis and illicit drug use, hepatic injury may be caused by HIV infection itself. This may however be seen only upon careful studies. 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