AustralieFrV1, Pmc, Corpus, bibRecord, 000574

Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

Identifieur interne : 000574 ( Pmc/Corpus ); précédent : 000573; suivant : 000575

Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

Auteurs : Helen Kovari ; Caroline A. Sabin ; Bruno Ledergerber ; Lene Ryom ; Peter Reiss ; Matthew Law ; Christian Pradier ; Francois Dabis ; Antonella D'Arminio Monforte ; Colette Smith ; Stephane De Wit ; Ole Kirk ; Jens D. Lundgren ; Rainer Weber

Source :

Open Forum Infectious Diseases [ 2328-8957 ] ; 2016.

RBID : PMC:4767274

Abstract

Background. Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear.

Methods. Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression.

Results. Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89–6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11–1.49; >2 years RR = 1.26, 95% CI, 1.13–1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26–1.81; >2 years RR = 1.17, 95% CI, 1.03–1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40–1.72; >2 years RR = 1.18, 95% CI, 1.05–1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29–1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03–1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04–1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04–1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE.

Conclusions. Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767274

DOI: 10.1093/ofid/ofw009
PubMed: 26925429
PubMed Central: 4767274

Links to Exploration step

PMC:4767274

Le document en format XML

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<author><name sortKey="Sabin, Caroline A" sort="Sabin, Caroline A" uniqKey="Sabin C" first="Caroline A." last="Sabin">Caroline A. Sabin</name>
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<author><name sortKey="Ledergerber, Bruno" sort="Ledergerber, Bruno" uniqKey="Ledergerber B" first="Bruno" last="Ledergerber">Bruno Ledergerber</name>
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</nlm:aff>
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<author><name sortKey="Ryom, Lene" sort="Ryom, Lene" uniqKey="Ryom L" first="Lene" last="Ryom">Lene Ryom</name>
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<author><name sortKey="Reiss, Peter" sort="Reiss, Peter" uniqKey="Reiss P" first="Peter" last="Reiss">Peter Reiss</name>
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,<country>Netherlands</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Law, Matthew" sort="Law, Matthew" uniqKey="Law M" first="Matthew" last="Law">Matthew Law</name>
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,<institution>University of New South Wales</institution>
,<addr-line>Sydney</addr-line>
,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pradier, Christian" sort="Pradier, Christian" uniqKey="Pradier C" first="Christian" last="Pradier">Christian Pradier</name>
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,<institution>Nice University Hospital</institution>
,<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dabis, Francois" sort="Dabis, Francois" uniqKey="Dabis F" first="Francois" last="Dabis">Francois Dabis</name>
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</nlm:aff>
</affiliation>
</author>
<author><name sortKey="D Arminio Monforte, Antonella" sort="D Arminio Monforte, Antonella" uniqKey="D Arminio Monforte A" first="Antonella" last="D'Arminio Monforte">Antonella D'Arminio Monforte</name>
<affiliation><nlm:aff id="af8"><addr-line>Department of Health Sciences</addr-line>
,<institution>San Paolo University Hospital</institution>
,<addr-line>Milan</addr-line>
,<country>Italy</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Smith, Colette" sort="Smith, Colette" uniqKey="Smith C" first="Colette" last="Smith">Colette Smith</name>
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,<institution>University College London</institution>
,<country>United Kingdom</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="De Wit, Stephane" sort="De Wit, Stephane" uniqKey="De Wit S" first="Stephane" last="De Wit">Stephane De Wit</name>
<affiliation><nlm:aff id="af9"><addr-line>Department of Infectious Diseases</addr-line>
,<institution>St. Pierre University Hospital</institution>
,<addr-line>Brussels</addr-line>
,<country>Belgium</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kirk, Ole" sort="Kirk, Ole" uniqKey="Kirk O" first="Ole" last="Kirk">Ole Kirk</name>
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,<institution>Rigshospitalet, University of Copenhagen</institution>
,<addr-line>København</addr-line>
,<country>Denmark</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lundgren, Jens D" sort="Lundgren, Jens D" uniqKey="Lundgren J" first="Jens D." last="Lundgren">Jens D. Lundgren</name>
<affiliation><nlm:aff id="af3"><addr-line>CHIP, Department of Infectious Diseases</addr-line>
,<institution>Rigshospitalet, University of Copenhagen</institution>
,<addr-line>København</addr-line>
,<country>Denmark</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Weber, Rainer" sort="Weber, Rainer" uniqKey="Weber R" first="Rainer" last="Weber">Rainer Weber</name>
<affiliation><nlm:aff id="af1"><addr-line>Division of Infectious Diseases and Hospital Epidemiology</addr-line>
,<institution>University Hospital Zurich</institution>
,<country>Switzerland</country>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study</title>
<author><name sortKey="Kovari, Helen" sort="Kovari, Helen" uniqKey="Kovari H" first="Helen" last="Kovari">Helen Kovari</name>
<affiliation><nlm:aff id="af1"><addr-line>Division of Infectious Diseases and Hospital Epidemiology</addr-line>
,<institution>University Hospital Zurich</institution>
,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sabin, Caroline A" sort="Sabin, Caroline A" uniqKey="Sabin C" first="Caroline A." last="Sabin">Caroline A. Sabin</name>
<affiliation><nlm:aff id="af2"><addr-line>Research Department of Infection and Population Health</addr-line>
,<institution>University College London</institution>
,<country>United Kingdom</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ledergerber, Bruno" sort="Ledergerber, Bruno" uniqKey="Ledergerber B" first="Bruno" last="Ledergerber">Bruno Ledergerber</name>
<affiliation><nlm:aff id="af1"><addr-line>Division of Infectious Diseases and Hospital Epidemiology</addr-line>
,<institution>University Hospital Zurich</institution>
,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ryom, Lene" sort="Ryom, Lene" uniqKey="Ryom L" first="Lene" last="Ryom">Lene Ryom</name>
<affiliation><nlm:aff id="af3"><addr-line>CHIP, Department of Infectious Diseases</addr-line>
,<institution>Rigshospitalet, University of Copenhagen</institution>
,<addr-line>København</addr-line>
,<country>Denmark</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Reiss, Peter" sort="Reiss, Peter" uniqKey="Reiss P" first="Peter" last="Reiss">Peter Reiss</name>
<affiliation><nlm:aff id="af4"><addr-line>Division of Infectious Diseases and Department of Global Health</addr-line>
,<institution>Academic Medical Center, University of Amsterdam</institution>
,<country>Netherlands</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Law, Matthew" sort="Law, Matthew" uniqKey="Law M" first="Matthew" last="Law">Matthew Law</name>
<affiliation><nlm:aff id="af5"><addr-line>The Kirby Institute for Infection and Immunity in Society</addr-line>
,<institution>University of New South Wales</institution>
,<addr-line>Sydney</addr-line>
,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pradier, Christian" sort="Pradier, Christian" uniqKey="Pradier C" first="Christian" last="Pradier">Christian Pradier</name>
<affiliation><nlm:aff id="af6"><addr-line>Department of Public Health</addr-line>
,<institution>Nice University Hospital</institution>
,<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dabis, Francois" sort="Dabis, Francois" uniqKey="Dabis F" first="Francois" last="Dabis">Francois Dabis</name>
<affiliation><nlm:aff id="af7"><institution>Université Bordeaux, ISPED, Centre INSERM U897-Epidémiologie-Biostatistique France</institution>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="D Arminio Monforte, Antonella" sort="D Arminio Monforte, Antonella" uniqKey="D Arminio Monforte A" first="Antonella" last="D'Arminio Monforte">Antonella D'Arminio Monforte</name>
<affiliation><nlm:aff id="af8"><addr-line>Department of Health Sciences</addr-line>
,<institution>San Paolo University Hospital</institution>
,<addr-line>Milan</addr-line>
,<country>Italy</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Smith, Colette" sort="Smith, Colette" uniqKey="Smith C" first="Colette" last="Smith">Colette Smith</name>
<affiliation><nlm:aff id="af2"><addr-line>Research Department of Infection and Population Health</addr-line>
,<institution>University College London</institution>
,<country>United Kingdom</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="De Wit, Stephane" sort="De Wit, Stephane" uniqKey="De Wit S" first="Stephane" last="De Wit">Stephane De Wit</name>
<affiliation><nlm:aff id="af9"><addr-line>Department of Infectious Diseases</addr-line>
,<institution>St. Pierre University Hospital</institution>
,<addr-line>Brussels</addr-line>
,<country>Belgium</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kirk, Ole" sort="Kirk, Ole" uniqKey="Kirk O" first="Ole" last="Kirk">Ole Kirk</name>
<affiliation><nlm:aff id="af3"><addr-line>CHIP, Department of Infectious Diseases</addr-line>
,<institution>Rigshospitalet, University of Copenhagen</institution>
,<addr-line>København</addr-line>
,<country>Denmark</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lundgren, Jens D" sort="Lundgren, Jens D" uniqKey="Lundgren J" first="Jens D." last="Lundgren">Jens D. Lundgren</name>
<affiliation><nlm:aff id="af3"><addr-line>CHIP, Department of Infectious Diseases</addr-line>
,<institution>Rigshospitalet, University of Copenhagen</institution>
,<addr-line>København</addr-line>
,<country>Denmark</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Weber, Rainer" sort="Weber, Rainer" uniqKey="Weber R" first="Rainer" last="Weber">Rainer Weber</name>
<affiliation><nlm:aff id="af1"><addr-line>Division of Infectious Diseases and Hospital Epidemiology</addr-line>
,<institution>University Hospital Zurich</institution>
,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Open Forum Infectious Diseases</title>
<idno type="eISSN">2328-8957</idno>
<imprint><date when="2016">2016</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><p><bold><italic>Background.</italic>
</bold>
 Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear.</p>
<p><bold><italic>Methods.</italic>
</bold>
 Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression.</p>
<p><bold><italic>Results.</italic>
</bold>
 Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89–6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11–1.49; >2 years RR = 1.26, 95% CI, 1.13–1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26–1.81; >2 years RR = 1.17, 95% CI, 1.03–1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40–1.72; >2 years RR = 1.18, 95% CI, 1.05–1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29–1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03–1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04–1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04–1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE.</p>
<p><bold><italic>Conclusions.</italic>
</bold>
 Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Kovari, H" uniqKey="Kovari H">H Kovari</name>
</author>
<author><name sortKey="Weber, R" uniqKey="Weber R">R Weber</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sterling, Rk" uniqKey="Sterling R">RK Sterling</name>
</author>
<author><name sortKey="Chiu, S" uniqKey="Chiu S">S Chiu</name>
</author>
<author><name sortKey="Snider, K" uniqKey="Snider K">K Snider</name>
</author>
<author><name sortKey="Nixon, D" uniqKey="Nixon D">D Nixon</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kovari, H" uniqKey="Kovari H">H Kovari</name>
</author>
<author><name sortKey="Ledergerber, B" uniqKey="Ledergerber B">B Ledergerber</name>
</author>
<author><name sortKey="Battegay, M" uniqKey="Battegay M">M Battegay</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Crum Cianflone, N" uniqKey="Crum Cianflone N">N Crum-Cianflone</name>
</author>
<author><name sortKey="Collins, G" uniqKey="Collins G">G Collins</name>
</author>
<author><name sortKey="Medina, S" uniqKey="Medina S">S Medina</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bansi, L" uniqKey="Bansi L">L Bansi</name>
</author>
<author><name sortKey="Gazzard, B" uniqKey="Gazzard B">B Gazzard</name>
</author>
<author><name sortKey="Post, F" uniqKey="Post F">F Post</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Blanco, F" uniqKey="Blanco F">F Blanco</name>
</author>
<author><name sortKey="Barreiro, P" uniqKey="Barreiro P">P Barreiro</name>
</author>
<author><name sortKey="Ryan, P" uniqKey="Ryan P">P Ryan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sulkowski, Ms" uniqKey="Sulkowski M">MS Sulkowski</name>
</author>
<author><name sortKey="Mehta, Sh" uniqKey="Mehta S">SH Mehta</name>
</author>
<author><name sortKey="Torbenson, M" uniqKey="Torbenson M">M Torbenson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mcgovern, Bh" uniqKey="Mcgovern B">BH McGovern</name>
</author>
<author><name sortKey="Ditelberg, Js" uniqKey="Ditelberg J">JS Ditelberg</name>
</author>
<author><name sortKey="Taylor, Le" uniqKey="Taylor L">LE Taylor</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Merchante, N" uniqKey="Merchante N">N Merchante</name>
</author>
<author><name sortKey="Perez Camacho, I" uniqKey="Perez Camacho I">I Perez-Camacho</name>
</author>
<author><name sortKey="Mira, Ja" uniqKey="Mira J">JA Mira</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ryom, L" uniqKey="Ryom L">L Ryom</name>
</author>
<author><name sortKey="Lundgren, Jd" uniqKey="Lundgren J">JD Lundgren</name>
</author>
<author><name sortKey="De Wit, S" uniqKey="De Wit S">S De Wit</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kovari, H" uniqKey="Kovari H">H Kovari</name>
</author>
<author><name sortKey="Ledergerber, B" uniqKey="Ledergerber B">B Ledergerber</name>
</author>
<author><name sortKey="Peter, U" uniqKey="Peter U">U Peter</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sabin, Ca" uniqKey="Sabin C">CA Sabin</name>
</author>
<author><name sortKey="Ryom, L" uniqKey="Ryom L">L Ryom</name>
</author>
<author><name sortKey="Kovari, H" uniqKey="Kovari H">H Kovari</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ingiliz, P" uniqKey="Ingiliz P">P Ingiliz</name>
</author>
<author><name sortKey="Valantin, Ma" uniqKey="Valantin M">MA Valantin</name>
</author>
<author><name sortKey="Duvivier, C" uniqKey="Duvivier C">C Duvivier</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Morse, Cg" uniqKey="Morse C">CG Morse</name>
</author>
<author><name sortKey="Mclaughlin, M" uniqKey="Mclaughlin M">M McLaughlin</name>
</author>
<author><name sortKey="Matthews, L" uniqKey="Matthews L">L Matthews</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Friis Moller, N" uniqKey="Friis Moller N">N Friis-Moller</name>
</author>
<author><name sortKey="Sabin, Ca" uniqKey="Sabin C">CA Sabin</name>
</author>
<author><name sortKey="Weber, R" uniqKey="Weber R">R Weber</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kowalska, Jd" uniqKey="Kowalska J">JD Kowalska</name>
</author>
<author><name sortKey="Friis Moller, N" uniqKey="Friis Moller N">N Friis-Moller</name>
</author>
<author><name sortKey="Kirk, O" uniqKey="Kirk O">O Kirk</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sterling, Rk" uniqKey="Sterling R">RK Sterling</name>
</author>
<author><name sortKey="Lissen, E" uniqKey="Lissen E">E Lissen</name>
</author>
<author><name sortKey="Clumeck, N" uniqKey="Clumeck N">N Clumeck</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wai, Ct" uniqKey="Wai C">CT Wai</name>
</author>
<author><name sortKey="Greenson, Jk" uniqKey="Greenson J">JK Greenson</name>
</author>
<author><name sortKey="Fontana, Rj" uniqKey="Fontana R">RJ Fontana</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Nunez, M" uniqKey="Nunez M">M Nunez</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rivero, A" uniqKey="Rivero A">A Rivero</name>
</author>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">Open Forum Infect Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">Open Forum Infect Dis</journal-id>
<journal-id journal-id-type="publisher-id">ofid</journal-id>
<journal-id journal-id-type="hwp">ofids</journal-id>
<journal-title-group><journal-title>Open Forum Infectious Diseases</journal-title>
</journal-title-group>
<issn pub-type="epub">2328-8957</issn>
<publisher><publisher-name>Oxford University Press</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26925429</article-id>
<article-id pub-id-type="pmc">4767274</article-id>
<article-id pub-id-type="doi">10.1093/ofid/ofw009</article-id>
<article-id pub-id-type="publisher-id">ofw009</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Major Articles</subject>
</subj-group>
</article-categories>
<title-group><article-title>Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kovari</surname>
<given-names>Helen</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sabin</surname>
<given-names>Caroline A.</given-names>
</name>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ledergerber</surname>
<given-names>Bruno</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ryom</surname>
<given-names>Lene</given-names>
</name>
<xref ref-type="aff" rid="af3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Reiss</surname>
<given-names>Peter</given-names>
</name>
<xref ref-type="aff" rid="af4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Law</surname>
<given-names>Matthew</given-names>
</name>
<xref ref-type="aff" rid="af5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pradier</surname>
<given-names>Christian</given-names>
</name>
<xref ref-type="aff" rid="af6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dabis</surname>
<given-names>Francois</given-names>
</name>
<xref ref-type="aff" rid="af7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>d'Arminio Monforte</surname>
<given-names>Antonella</given-names>
</name>
<xref ref-type="aff" rid="af8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smith</surname>
<given-names>Colette</given-names>
</name>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>de Wit</surname>
<given-names>Stephane</given-names>
</name>
<xref ref-type="aff" rid="af9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kirk</surname>
<given-names>Ole</given-names>
</name>
<xref ref-type="aff" rid="af3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lundgren</surname>
<given-names>Jens D.</given-names>
</name>
<xref ref-type="aff" rid="af3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Weber</surname>
<given-names>Rainer</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
</contrib>
<on-behalf-of>on behalf of the D:A:D Study Group</on-behalf-of>
<aff id="af1"><label>1</label>
<addr-line>Division of Infectious Diseases and Hospital Epidemiology</addr-line>
,<institution>University Hospital Zurich</institution>
,<country>Switzerland</country>
</aff>
<aff id="af2"><label>2</label>
<addr-line>Research Department of Infection and Population Health</addr-line>
,<institution>University College London</institution>
,<country>United Kingdom</country>
</aff>
<aff id="af3"><label>3</label>
<addr-line>CHIP, Department of Infectious Diseases</addr-line>
,<institution>Rigshospitalet, University of Copenhagen</institution>
,<addr-line>København</addr-line>
,<country>Denmark</country>
</aff>
<aff id="af4"><label>4</label>
<addr-line>Division of Infectious Diseases and Department of Global Health</addr-line>
,<institution>Academic Medical Center, University of Amsterdam</institution>
,<country>Netherlands</country>
</aff>
<aff id="af5"><label>5</label>
<addr-line>The Kirby Institute for Infection and Immunity in Society</addr-line>
,<institution>University of New South Wales</institution>
,<addr-line>Sydney</addr-line>
,<country>Australia</country>
</aff>
<aff id="af6"><label>6</label>
<addr-line>Department of Public Health</addr-line>
,<institution>Nice University Hospital</institution>
,<country>France</country>
</aff>
<aff id="af7"><label>7</label>
<institution>Université Bordeaux, ISPED, Centre INSERM U897-Epidémiologie-Biostatistique France</institution>
</aff>
<aff id="af8"><label>8</label>
<addr-line>Department of Health Sciences</addr-line>
,<institution>San Paolo University Hospital</institution>
,<addr-line>Milan</addr-line>
,<country>Italy</country>
</aff>
<aff id="af9"><label>9</label>
<addr-line>Department of Infectious Diseases</addr-line>
,<institution>St. Pierre University Hospital</institution>
,<addr-line>Brussels</addr-line>
,<country>Belgium</country>
</aff>
</contrib-group>
<contrib-group><contrib contrib-type="collab"><collab>on behalf of the D:A:D Study group</collab>
</contrib>
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<given-names>G.</given-names>
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<contrib contrib-type="collab"><name><surname>Franquet</surname>
<given-names>X.</given-names>
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<contrib contrib-type="collab"><name><surname>Hatleberg</surname>
<given-names>C.I.</given-names>
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</contrib>
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<given-names>L.</given-names>
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<contrib contrib-type="collab"><name><surname>Gras</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Prins</surname>
<given-names>J.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kuijpers</surname>
<given-names>T.W.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Scherpbier</surname>
<given-names>H.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van der Meer</surname>
<given-names>J.T.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wit</surname>
<given-names>F.W.M.N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Godfried</surname>
<given-names>M.H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Reiss</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van der Poll</surname>
<given-names>T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Nellen</surname>
<given-names>F.J.B.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lange</surname>
<given-names>J.M.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Geerlings</surname>
<given-names>S.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Vugt</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pajkrt</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bos</surname>
<given-names>J.C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van der Valk</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Grijsen</surname>
<given-names>M.L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wiersinga</surname>
<given-names>W.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Goorhuis</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hovius</surname>
<given-names>J.W.R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lowe</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lashof</surname>
<given-names>A. Oude</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Posthouwer</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pronk</surname>
<given-names>M.J.H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ammerlaan</surname>
<given-names>H.S.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van der Ende</surname>
<given-names>M.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>de Vries-Sluijs</surname>
<given-names>T.E.M.S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Schurink</surname>
<given-names>C.A.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Nouwen</surname>
<given-names>J.L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Verbon</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Rijnders</surname>
<given-names>B.J.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Gorp</surname>
<given-names>E.C.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van der Feltz</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Driessen</surname>
<given-names>G.J.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Rossum</surname>
<given-names>A.M.C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Branger</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Schippers</surname>
<given-names>E.F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Nieuwkoop</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Elzakker</surname>
<given-names>E.P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Groeneveld</surname>
<given-names>P.H.P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bouwhuis</surname>
<given-names>J.W.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Soetekouw</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>ten Kate</surname>
<given-names>R.W.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kroon</surname>
<given-names>F.P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Dissel</surname>
<given-names>J.T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Arend</surname>
<given-names>S.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>de Boer</surname>
<given-names>M.G.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Jolink</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>ter Vollaard</surname>
<given-names>H.J.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bauer</surname>
<given-names>M.P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>den Hollander</surname>
<given-names>J.G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pogany</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Twillert</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kortmann</surname>
<given-names>W.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cohen Stuart</surname>
<given-names>J.W.T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Diederen</surname>
<given-names>B.M.W.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Leyten</surname>
<given-names>E.M.S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gelinck</surname>
<given-names>L.B.S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kootstra</surname>
<given-names>G.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Delsing</surname>
<given-names>C.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Brinkman</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Blok</surname>
<given-names>W.L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Frissen</surname>
<given-names>P.H.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Schouten</surname>
<given-names>W.E.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van den Berk</surname>
<given-names>G.E.L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Kasteren</surname>
<given-names>M.E.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Brouwer</surname>
<given-names>A.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Veenstra</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lettinga</surname>
<given-names>K.D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mulder</surname>
<given-names>J.W.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vrouenraets</surname>
<given-names>S.M.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lauw</surname>
<given-names>F.N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Eeden</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Verhagen</surname>
<given-names>D.W.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sprenger</surname>
<given-names>H.G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Doedens</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Scholvinck</surname>
<given-names>E.H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Assen</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bierman</surname>
<given-names>W.F.W.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Koopmans</surname>
<given-names>P.P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Keuter</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van der Ven</surname>
<given-names>A.J.A.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>ter Hofstede</surname>
<given-names>H.J.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dofferhoff</surname>
<given-names>A.S.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Warris</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Crevel</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hoepelman</surname>
<given-names>A.I.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mudrikova</surname>
<given-names>T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Schneider</surname>
<given-names>M.M.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ellerbroek</surname>
<given-names>P.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Oosterheert</surname>
<given-names>J.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Arends</surname>
<given-names>J.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wassenberg</surname>
<given-names>M.W.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Barth</surname>
<given-names>R.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Agtmael</surname>
<given-names>M.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Perenboom</surname>
<given-names>R.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Claessen</surname>
<given-names>F.A.P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bomers</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Peters</surname>
<given-names>E.J.G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Geelen</surname>
<given-names>S.P.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wolfs</surname>
<given-names>T.F.W.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bont</surname>
<given-names>L.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Richter</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van der Berg</surname>
<given-names>J.P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gisolf</surname>
<given-names>E.H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van den Berge</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Stegeman</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Vonderen</surname>
<given-names>M.G.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Houte</surname>
<given-names>D.P.F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Weijer</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>el Moussaoui</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Winkel</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Muskiet</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Voigt</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bonnet</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dabis</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bonnet</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bouchet</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Breilh</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Chêne</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dabis</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dupon</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Fleury</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gaborieau</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lacoste</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Malvy</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mercié</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Morlat</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Neau</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pellegrin</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pellegrin</surname>
<given-names>JL.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Reigadas</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Tchamgoué</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bruyand</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Chêne</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dabis</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Fagard</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lawson-Ayayi</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Richert</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Thiébaut</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wittkop</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>André</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bonnet</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bernard</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Caunègre</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cazanave</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ceccaldi</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Chossat</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Courtault</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dauchy</surname>
<given-names>F.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>De Witte</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dondia</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dupon</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dupont</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Duffau</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dutronc</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Farbos</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Faure</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gaborieau</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gerard</surname>
<given-names>Y.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Greib</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hessamfar-Joseph</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Imbert</surname>
<given-names>Y.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lacoste</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lataste</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lazaro</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Malvy</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Marie</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mechain</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Meraud</surname>
<given-names>JP.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mercié</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Monlun</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Morlat</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Neau</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ochoa</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pellegrin</surname>
<given-names>J.L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pillot-Debelleix</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pistone</surname>
<given-names>T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Raymond</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Receveur</surname>
<given-names>M.C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Rispal</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sorin</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Tchamgoué</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Valette</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vandenhende</surname>
<given-names>M.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vareil</surname>
<given-names>MO.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Viallard</surname>
<given-names>J.F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wille</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wirth</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Moreau</surname>
<given-names>J.F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pellegrin</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Fleury</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lafon</surname>
<given-names>M.E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Reigadas</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Trimoulet</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bouchet</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Breilh</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Haramburu</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Miremont-Salamé</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Blaizeau</surname>
<given-names>M.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Crespel</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Decoin</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Delveaux</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Diarra</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>D'Ivernois</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hanappier</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lacoste</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lawson-Ayayi</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Leleux</surname>
<given-names>O.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Le Marec</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lenaud</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mourali</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pernot</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pougetoux</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Uwamaliya-Nziyumvira</surname>
<given-names>B.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Tsaranazy</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Valdes</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Conte</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Louis</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Palmer</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sapparrart</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Touchard</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Law</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Petoumenos</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>McManus</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wright</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bendall</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Moore</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Edwards</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hoy</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Watson</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Roth</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Nicholson</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bloch</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Franic</surname>
<given-names>T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Baker</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vale</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Carr</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cooper</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Chuah</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ngieng</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Nolan</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Skett</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Calvo</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Torres</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mateu</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Domingo</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sambeat</surname>
<given-names>M.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gatell</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Del Cacho</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cadafalch</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Fuster</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Codina</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sirera</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vaqué</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>De Wit</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Clumeck</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Delforge</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Necsoi</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Clumeck</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>De Wit</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gennotte</surname>
<given-names>A.F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gerard</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kabeya</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Konopnicki</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Libois</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Martin</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Payen</surname>
<given-names>M.C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Semaille</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Van Laethem</surname>
<given-names>Y.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Neaton</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bartsch</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>El-Sadr</surname>
<given-names>W.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Krum</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Thompson</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wentworth</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Luskin-Hawk</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Telzak</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>El-Sadr</surname>
<given-names>W.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Abrams</surname>
<given-names>D.I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cohn</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Markowitz</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Arduino</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mushatt</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Friedland</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Perez</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Tedaldi</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Fisher</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gordin</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Crane</surname>
<given-names>L.R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sampson</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Baxter</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lundgren</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kirk</surname>
<given-names>O.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mocroft</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cozzi-Lepri</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Grint</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Podlekareva</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kjær</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Peters</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Reekie</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kowalska</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Tverland</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Fischer</surname>
<given-names>A. H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Nielsen</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Elias</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vetter</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Zangerle</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Karpov</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vassilenko</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mitsura</surname>
<given-names>V.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Suetnov</surname>
<given-names>O.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Clumeck</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>De Wit</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Delforge</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Colebunders</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vandekerckhove</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hadziosmanovic</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kostov</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Begovac</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Machala</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Jilich</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sedlacek</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Nielsen</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kronborg</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Benfield</surname>
<given-names>T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Larsen</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gerstoft</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Katzenstein</surname>
<given-names>T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hansen</surname>
<given-names>A-B. E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Skinhøj</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pedersen</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ostergaard</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Zilmer</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ristola</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Katlama</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Viard</surname>
<given-names>J-P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Girard</surname>
<given-names>P-M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Livrozet</surname>
<given-names>J.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vanhems</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pradier</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Dabis</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Neau</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Rockstroh</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Schmidt</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>van Lunzen</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Degen</surname>
<given-names>O.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Stellbrink</surname>
<given-names>H.J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Staszewski</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Fätkenheuer</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kosmidis</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gargalianos</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Xylomenos</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Perdios</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Panos</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Filandras</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Karabatsaki</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sambatakou</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Banhegyi</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mulcahy</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Yust</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Turner</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Burke</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pollack</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hassoun</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Maayan</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vella</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Esposito</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mazeu</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mussini</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Arici</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pristera</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mazzotta</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gabbuti</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Maria</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vullo</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lichtner</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Chirianni</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Montesarchio</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gargiulo</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Antonucci</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Testa</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Narciso</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Vlassi</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Zaccarelli</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lazzarin</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Castagna</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gianotti</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Galli</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ridolfo</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sacco</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Rozentale</surname>
<given-names>B.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Zeltina</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Chaplinskas</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hemmer</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Staub</surname>
<given-names>T.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Reiss</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ormaasen</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Maeland</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bruun</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Knysz</surname>
<given-names>B.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gasiorowski</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Horban</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bakowska</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Grzeszczuk</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Flisiak</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Boron-Kaczmarska</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Pynka</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Parczewski</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Beniowski</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mularska</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Trocha</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Jablonowska</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Malolepsza</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Wojcik</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Antunes</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Doroana</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Caldeira</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mansinho</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Maltez</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Duiculescu</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Rakhmanova</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Zakharova</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Buzunova</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Jevtovic</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mokráš</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Staneková</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Tomazic</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>González-Lahoz</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Soriano</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Labarga</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Medrano</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Moreno</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Rodriguez</surname>
<given-names>J.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Clotet</surname>
<given-names>B.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Jou</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Paredes</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Tural</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Puig</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bravo</surname>
<given-names>I.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gatell</surname>
<given-names>J.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Miró</surname>
<given-names>J.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Domingo</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gutierrez</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mateo</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sambeat</surname>
<given-names>M.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Karlsson</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Flamholc</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ledergerber</surname>
<given-names>B.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Weber</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Francioli</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cavassini</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Hirschel</surname>
<given-names>B.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Boffi</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Furrer</surname>
<given-names>H.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Battegay</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Elzi</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kravchenko</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Chentsova</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Frolov</surname>
<given-names>V.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Kutsyna</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Servitskiy</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Krasnov</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Barton</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Johnson</surname>
<given-names>A.M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mercey</surname>
<given-names>D.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Phillips</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Johnson</surname>
<given-names>M.A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mocroft</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Murphy</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Weber</surname>
<given-names>J.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Scullard</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Fisher</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Leen</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Morfeldt</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Thulin</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Sundström</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Åkerlund</surname>
<given-names>B.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Koppel</surname>
<given-names>K.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Karlsson</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Flamholc</surname>
<given-names>L.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Håkangård</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Moroni</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Angarano</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Antinori</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Armignacco</surname>
<given-names>O.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Castelli</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cauda</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Di Perri</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Galli</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Iardino</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ippolito</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lazzarin</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Perno</surname>
<given-names>C.F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>von Schloesser</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Viale</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Antinori</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Castagna</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ceccherini-Silberstein</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cozzi-Lepri</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Girardi</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lo Caputo</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Mussini</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Puoti</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Andreoni</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ammassari</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Antinori</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Balotta</surname>
<given-names>C.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bonfanti</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Bonora</surname>
<given-names>S.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Borderi</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Capobianchi</surname>
<given-names>R.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Castagna</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Ceccherini-Silberstein</surname>
<given-names>F.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cingolani</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cinque</surname>
<given-names>P.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Cozzi-Lepri</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>De Luca</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Di Biagio</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Girardi</surname>
<given-names>E.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gianotti</surname>
<given-names>N.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Gori</surname>
<given-names>A.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Guaraldi</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lapadula</surname>
<given-names>G.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lichtner</surname>
<given-names>M.</given-names>
</name>
</contrib>
<contrib contrib-type="collab"><name><surname>Lo Caputo</surname>
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<author-notes><fn fn-type="con" id="TN1"><p>Presented in part: CROI 2015, Seattle, WA.</p>
</fn>
<corresp>Correspondence: H. Kovari, Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, CH-8091 Zurich, Switzerland (<email>helen.kovari@usz.ch</email>
).</corresp>
</author-notes>
<pub-date pub-type="collection"><month>1</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub"><day>21</day>
<month>1</month>
<year>2016</year>
</pub-date>
<volume>3</volume>
<issue>1</issue>
<elocation-id>ofw009</elocation-id>
<history><date date-type="received"><day>2</day>
<month>12</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>11</day>
<month>1</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© The Author 2016. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.</copyright-statement>
<copyright-year>2016</copyright-year>
<license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/">http://creativecommons.org/licenses/by-nc-nd/4.0/</ext-link>
), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.</license-p>
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<self-uri content-type="pdf" xlink:href="ofw009.pdf"></self-uri>
<abstract><p><bold><italic>Background.</italic>
</bold>
 Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear.</p>
<p><bold><italic>Methods.</italic>
</bold>
 Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression.</p>
<p><bold><italic>Results.</italic>
</bold>
 Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89–6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11–1.49; >2 years RR = 1.26, 95% CI, 1.13–1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26–1.81; >2 years RR = 1.17, 95% CI, 1.03–1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40–1.72; >2 years RR = 1.18, 95% CI, 1.05–1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29–1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03–1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04–1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04–1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE.</p>
<p><bold><italic>Conclusions.</italic>
</bold>
 Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated.</p>
</abstract>
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<custom-meta-group><custom-meta><meta-name>cover-date</meta-name>
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</front>
<body><p>Human immunodeficiency virus (HIV)-infection has evolved into a chronic disease that requires lifelong antiretroviral therapy (ART). Therefore, drug-related toxicities have emerged as a key issue, including long-term ART-related liver injury [<xref rid="OFW009C1" ref-type="bibr">1</xref>
].</p>
<p>Chronic liver enzyme (alanine aminotransferase [ALT]) elevation, a marker of persistent hepatocyte injury, is frequent among HIV-positive persons, even in the absence of hepatitis C (HCV) and hepatitis B (HBV) coinfection [<xref rid="OFW009C2" ref-type="bibr">2</xref>
–<xref rid="OFW009C4" ref-type="bibr">4</xref>
]. The cause of these elevations, its clinical significance, the need for evaluation, a reasonable diagnostic approach, and its management are often unclear, particularly when the elevation is modest. Most studies on liver disease focused on HCV- or HBV-coinfected persons or on the incidence and prevalence of severely elevated liver enzymes, defined as 3–5 times the upper limit of normal (ULN) or more [<xref rid="OFW009C5" ref-type="bibr">5</xref>
]. Only limited data are available on HIV-monoinfected individuals with ALT values just above normal limits.</p>
<p>In previous studies, metabolic factors, including obesity, dyslipidemia and diabetes mellitus, severe alcohol use, high HIV viral load, and ART were predictive of persistently elevated ALT levels [<xref rid="OFW009C2" ref-type="bibr">2</xref>
–<xref rid="OFW009C4" ref-type="bibr">4</xref>
, <xref rid="OFW009C6" ref-type="bibr">6</xref>
]. Some antiretrovirals, such as the older stavudine (d4T) and didanosine (ddI), have been linked to liver injury [<xref rid="OFW009C3" ref-type="bibr">3</xref>
, <xref rid="OFW009C6" ref-type="bibr">6</xref>
–<xref rid="OFW009C11" ref-type="bibr">11</xref>
]. Data on the association of newer antiretrovirals and chronic liver disease are limited.</p>
<p>Study results on the outcome of liver enzyme elevations are controversial. A previous analysis of the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study suggested that in HIV/HCV-coinfected persons, ALT levels above the normal limit are associated with a higher mortality [<xref rid="OFW009C12" ref-type="bibr">12</xref>
], whereas in another investigation of HIV-monoinfected persons ALT elevation was not predictive of an increased death rate, although the observation period in this study was relatively short [<xref rid="OFW009C11" ref-type="bibr">11</xref>
]. Two liver biopsy series demonstrated a high prevalence of liver fibrosis (FIB) and steatosis among HIV-monoinfected adults with chronic elevated liver enzymes [<xref rid="OFW009C13" ref-type="bibr">13</xref>
, <xref rid="OFW009C14" ref-type="bibr">14</xref>
]. Such results emphasize that ALT is an important surrogate marker for relevant liver pathology.</p>
<p>Our study aims were (1) to identify risk factors associated with chronic ALT elevation (cLEE), focusing on the individual antiretroviral drugs and (2) to evaluate the outcome of liver enzyme elevation with regard to liver-related and all-cause mortality, within the frame of the D:A:D Study with its large size and long-term prospective observation.</p>
<sec sec-type="methods" id="s2"><title>METHODS</title>
<sec id="s2a"><title>Study Design</title>
<p>The D:A:D Study, founded in 1999, is a prospective observational study of 11 previously established cohorts as described in detail [<xref rid="OFW009C15" ref-type="bibr">15</xref>
]. Currently, more than 49 000 HIV-positive participants are followed in Europe, the United States, and Australia. The primary study aim was to investigate the associations between exposure to antiretroviral drugs and risk of myocardial infarction, and, subsequently, other major clinical events. Data, including sociodemographic characteristics, acquired immune deficiency syndrome (AIDS), viral hepatitis, deaths, known risk factors for cardiovascular disease, laboratory markers, and ART, are collected prospectively during routine clinical care. Information on causes of death is captured using the Coding of Causes of Death in HIV (CoDe) form [<xref rid="OFW009C16" ref-type="bibr">16</xref>
]. Clinical events are regularly monitored and centrally adjudicated. The present analyses were limited to the participating cohorts that provided data on ALT levels.</p>
</sec>
<sec id="s2b"><title>Definitions</title>
<p>Chronic ALT elevation was defined as ALT levels greater than the ULN (males/females >50/>35 U/L) at ≥2 visits spanning at least 6 months within 2 years. We used the date of the first elevated ALT as the event date. A single normal ALT measurement between 2 elevated values was permitted and therefore did not signal the end of a period of cLEE. Hepatitis C virus infection was defined by HCV seropositivity or detectable HCV RNA. Hepatitis B virus infection was defined by a positive HBV surface antigen, HBV e antigen, HBV core antibodies, or detectable HBV DNA. Participants with unknown HBV or HCV status were excluded. Fibrosis-4 and aspartate aminotransferase (AST)-to-platelet index (APRI), 2 noninvasive biomarkers of liver FIB, were calculated as follows: FIB-4: (age × AST)/[platelet count (10<sup>9</sup>
 cells/L) × sqrt(ALT)], and APRI: [(AST/ULN)/platelet count] × 100. A FIB-4 value >3.25 or an APRI score >1.5 is considered indicative of cirrhosis, whereas with a FIB-4 ≤ 1.45 and an APRI score ≤0.5, respectively, significant FIB is unlikely [<xref rid="OFW009C17" ref-type="bibr">17</xref>
, <xref rid="OFW009C18" ref-type="bibr">18</xref>
].</p>
</sec>
<sec id="s2c"><title>Statistical Analyses</title>
<p>Cohort-specific baseline dates were chosen according to the introduction of routine ALT monitoring in the individual cohorts. All D:A:D participants without HBV and HCV infection, with ≥3 ALT measurements, ≥6 months of follow-up, and normal ALT at baseline, were followed from baseline to the earliest of cLEE, death, 6 months prior to a date of a first positive HCV/HBV test, 6 months after last visit, or February 1, 2014. The incidence of cLEE was defined as the number of first events divided by the total person years of follow-up (PYFU).</p>
<p>We used Poisson regression models to assess the incidence of cLEE and its association with ART and other risk factors. Models were manually built using a standard structured approach including variables into a multivariable model in groups. At each stage, factors that were not significantly associated with cLEE were removed before moving to the next set of variables. Fixed covariables were sex, ethnicity, and participating cohort. Time-updated covariables were age, calendar year, hypercholesterolemia, hypertriglyceridemia, use of lipid-lowering drugs, lipodystrophy, body mass index (BMI), arterial hypertension, smoking status, and exposure to the individual antiretrovirals. Antiretroviral therapy exposure was categorized as follows for each individual drug: no exposure, ongoing short- and long-term exposure (<2 or ≥2 years) after initiation; and discontinuation for <2 or ≥2 years. We do not present risk estimates for drugs after discontinuation because interpretation is difficult without considering the subsequent drugs persons were switched to. Use of ritonavir (RTV) includes both full and boosting doses.</p>
<p>We also investigated the association between the total number and duration of cLEE episodes with all-cause mortality using Poisson regression models. For these analyses, individuals were followed to the earliest of death, 6 months prior to a date of a first positive HCV/HBV test, 6 months after last visit, or February 1, 2014, and all periods of cLEE, including any subsequent episodes, were included. Analyses were adjusted for age, sex, ethnicity, mode of HIV acquisition, calendar year, cohort, smoking status, BMI, and in a subsequent model additionally for time-updated CD4 cell counts and HIV viral loads. Note that these models did not include adjustment for the ART drugs received, because it was anticipated that any impact of ART on mortality would be largely driven by changes in CD4 counts and HIV viral loads. Multivariable analyses were not feasible for liver-related deaths because of small numbers. All analyses were performed using SAS version 9.3.</p>
</sec>
</sec>
<sec sec-type="results" id="s3"><title>RESULTS</title>
<sec id="s3a"><title>Patient Characteristics</title>
<p>Of 49 711 participants included in D:A:D until the cutoff date for the study of February 1, 2014, 29 291 (58.9%) were HCV and HBV negative and had available ALT results. We further excluded 3986 (8%) with <3 visits with ALT determinations or <6 months of follow-up and 3820 participants (7.7%) because of preexisting elevated ALT levels at time of baseline visit. Excluded participants were similarly compared with those who were included in terms of sex, age, ethnicity, mode of HIV acquisition, previous AIDS, and date of D:A:D enrollment, except that the group with incomplete follow-up contained more intravenous drug users (IDU) and persons of unknown ethnicity, and the group with increased ALT levels at baseline were more often IDUs and participants with previous AIDS. The present study is thus based on 21 485 HIV-positive individuals with normal ALT values at baseline (Figure <xref ref-type="fig" rid="OFW009F1">1</xref>).
<fig id="OFW009F1" orientation="portrait" position="float"><label>Figure 1.</label>
<caption><p>Patient flowchart. ALT, alanine aminotransferase; HBV, hepatitis B virus; HCV, hepatitis C virus.</p>
</caption>
<graphic xlink:href="ofw00901"></graphic>
</fig>
</p>
<p>The study population consisted of 72.9% men with a median age of 40 years. Of the participants, 51.9% were white, and 51.2% had acquired HIV through sex between men. At study entry, the median CD4 lymphocyte count was 470 cells/µL and 72.1% of participants were on ART. In total, 77.2% had ever been exposed to ART for a median duration of 3.9 years. Aspartate aminotransferase-to-platelet score was >1.5 in 523 (2.4%) and FIB-4 score was >3.25 in 647 (3.0%) of 12 857 (60%) persons with available scores (Table <xref ref-type="table" rid="OFW009TB1">1</xref>). Participants contributed a median of 13 (interquartile range [IQR], 6–23) ALT measurements to the analyses. Overall, the median baseline ALT level was 22 (IQR, 16–30) U/L.
<table-wrap id="OFW009TB1" orientation="portrait" position="float"><label>Table 1.</label>
<caption><p>Baseline Characteristics of 21 485 D:A:D Study Participants Without HCV or HBV Coinfection</p>
</caption>
<table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col>
<col align="left" span="1"></col>
<col align="char" char="(" span="1"></col>
</colgroup>
<tbody><tr><td rowspan="1" colspan="1">Total of participants, no. (%)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">21 485 (100)</td>
</tr>
<tr><td rowspan="1" colspan="1">Sex, no (%)</td>
<td rowspan="1" colspan="1">Male</td>
<td rowspan="1" colspan="1">15 661 (72.9)</td>
</tr>
<tr><td rowspan="1" colspan="1">Age, years</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">40 (33, 49)</td>
</tr>
<tr><td rowspan="1" colspan="1">Ethnicity, no. (%)</td>
<td rowspan="1" colspan="1">White</td>
<td rowspan="1" colspan="1">11 159 (51.9)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Black</td>
<td rowspan="1" colspan="1">2110 (9.8)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Other</td>
<td rowspan="1" colspan="1">580 (2.7)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Unknown</td>
<td rowspan="1" colspan="1">7636 (35.5)</td>
</tr>
<tr><td rowspan="1" colspan="1">Mode of HIV acquisition, no. (%)</td>
<td rowspan="1" colspan="1">Heterosexual</td>
<td rowspan="1" colspan="1">8916 (41.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Homosexual</td>
<td rowspan="1" colspan="1">10 990 (51.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Injection drug use</td>
<td rowspan="1" colspan="1">243 (1.1)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Other/unknown</td>
<td rowspan="1" colspan="1">1336 (6.2)</td>
</tr>
<tr><td rowspan="1" colspan="1">Duration of D:A:D cohort follow-up</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">6.6 (2.1, 10.8)</td>
</tr>
<tr><td rowspan="1" colspan="1">Previous clinical AIDS</td>
<td rowspan="1" colspan="1">No. (%)</td>
<td rowspan="1" colspan="1">5090 (23.7)</td>
</tr>
<tr><td rowspan="1" colspan="1">CD4 cells/µL</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">470 (318, 656)</td>
</tr>
<tr><td rowspan="1" colspan="1">Ever received antiretroviral therapy</td>
<td rowspan="1" colspan="1">No. (%)</td>
<td rowspan="1" colspan="1">16 578 (77.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Cumulative ART exposure (years)</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">3.9 (1.8, 7.0)</td>
</tr>
<tr><td rowspan="1" colspan="1">Ever received NRTIs</td>
<td rowspan="1" colspan="1">No. (%)</td>
<td rowspan="1" colspan="1">16 360 (76.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Cumulative ART exposure (years)</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">3.7 (1.7, 6.7)</td>
</tr>
<tr><td rowspan="1" colspan="1">Ever received PIs</td>
<td rowspan="1" colspan="1">No. (%)</td>
<td rowspan="1" colspan="1">11 922 (55.9)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Cumulative ART exposure (years)</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">2.5 (1.1, 4.2)</td>
</tr>
<tr><td rowspan="1" colspan="1">Ever received NNRTIs</td>
<td rowspan="1" colspan="1">No. (%)</td>
<td rowspan="1" colspan="1">10 094 (47.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Cumulative ART exposure (years)</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">1.9 (0.7, 4.4)</td>
</tr>
<tr><td rowspan="1" colspan="1">Body mass index, kg/m<sup>2</sup>
, no. (%)</td>
<td rowspan="1" colspan="1"><18</td>
<td rowspan="1" colspan="1">545 (2.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">≥18, ≤26</td>
<td rowspan="1" colspan="1">14 232 (66.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">>26, ≤30</td>
<td rowspan="1" colspan="1">3129 (14.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">>30</td>
<td rowspan="1" colspan="1">1154 (5.4)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Unknown</td>
<td rowspan="1" colspan="1">2425 (11.3)</td>
</tr>
<tr><td rowspan="1" colspan="1">Diabetes mellitus</td>
<td rowspan="1" colspan="1">No. (%)</td>
<td rowspan="1" colspan="1">704 (3.3)</td>
</tr>
<tr><td rowspan="1" colspan="1">Total cholesterol, mmol/L</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">5.0 (4.2–5.8)</td>
</tr>
<tr><td rowspan="1" colspan="1">HDL cholesterol, mmol/L</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">1.2 (1.0–1.5)</td>
</tr>
<tr><td rowspan="1" colspan="1">Triglycerides, mmol/L</td>
<td rowspan="1" colspan="1">Median (IQR)</td>
<td rowspan="1" colspan="1">1.5 (1.0–2.4)</td>
</tr>
<tr><td rowspan="1" colspan="1">Use of lipid-lowering drugs</td>
<td rowspan="1" colspan="1">No. (%)</td>
<td rowspan="1" colspan="1">1855 (8.6)</td>
</tr>
<tr><td rowspan="1" colspan="1">Lipodystrophy</td>
<td rowspan="1" colspan="1">No. (%)</td>
<td rowspan="1" colspan="1">4260 (19.8)</td>
</tr>
<tr><td rowspan="1" colspan="1">Smoking status, n (%)</td>
<td rowspan="1" colspan="1">Current</td>
<td rowspan="1" colspan="1">7144 (33.3)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Former</td>
<td rowspan="1" colspan="1">4735 (22.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Never</td>
<td rowspan="1" colspan="1">7459 (34.7)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Unknown</td>
<td rowspan="1" colspan="1">2147 (10.0)</td>
</tr>
<tr><td rowspan="1" colspan="1">FIB-4 score</td>
<td rowspan="1" colspan="1">≤1.45</td>
<td rowspan="1" colspan="1">10 352 (48.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">>1.45, ≤3.25</td>
<td rowspan="1" colspan="1">1858 (8.7)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">>3.25</td>
<td rowspan="1" colspan="1">647 (3.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Unknown</td>
<td rowspan="1" colspan="1">8628 (40.2)</td>
</tr>
<tr><td rowspan="1" colspan="1">APRI score</td>
<td rowspan="1" colspan="1">≤0.5</td>
<td rowspan="1" colspan="1">11 385 (53.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">>0.5, ≤1.5</td>
<td rowspan="1" colspan="1">949 (4.4)</td>
</tr>
<tr><td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">>1.5</td>
<td rowspan="1" colspan="1">523 (2.4)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="tblfn1"><p>Abbreviations: AIDS, acquired immune deficiency syndrome; ALT, alanine aminotransferase; APRI, aspartate aminotransferase-to-platelet ratio; ART, antiretroviral therapy; D:A:D, Data Collection on Adverse Events of Anti-HIV Drugs; FIB, fibrosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HDL, high-density lipoprotein; HIV, human immunodeficiency virus; IQR, interquartile range; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
<sec id="s3b"><title>Predictors for Chronic Alanine Aminotransferase Elevation</title>
<p>During a median follow-up of 6.6 years (IQR, 2.1–10.8) and 105 413 PYFU, 6368 (29.6%) participants experienced episodes of cLEE, resulting in an incidence of 6.04 per 100 PYFU (95% CI, 5.89–6.19). Increased BMI (>26 kg/m<sup>2</sup>
), dyslipidemia, use of lipid-lowering drugs, arterial hypertension, high HIV levels (≥5 log<sub>10</sub>
 copies/mL), and earlier calendar years were associated with cLEE. Older age (≥50 years), black ethnicity, male gender, and current smoking were inversely correlated (<ext-link ext-link-type="uri" xlink:href="http://ofid.oxfordjournals.org/lookup/suppl/doi:10.1093/ofid/ofw009/-/DC1">Supplementary Figure 1</ext-link>
).</p>
<p>Among the nucleoside reverse-transcriptase inhibitors, cLEE was associated with ongoing exposure to regimens containing ddI, d4T, tenofovir disoproxil fumarate (TDF), and with exposure to emtricitabine (FTC) during the first 2 years. Exposure to lamivudine (3TC) was inversely correlated with cLEE. Among the nonnucleoside reverse-transcriptase inhibitors, the first 2 years of exposure to nevirapine (NVP) and efavirenz (EFV) were only associated with cLEE. The only protease inhibitor (PI) to demonstrate an association with cLEE was atazanavir (ATV) during the first 2 years of exposure. There was no evidence for an association with increased risk for the other PIs. Exposure to darunavir, RTV, and ATV for periods in excess of ≥2 years appeared to be protective for cLEE (Figure <xref ref-type="fig" rid="OFW009F2">2</xref>
, <ext-link ext-link-type="uri" xlink:href="http://ofid.oxfordjournals.org/lookup/suppl/doi:10.1093/ofid/ofw009/-/DC1">Supplementary Table 1</ext-link>).
<fig id="OFW009F2" orientation="portrait" position="float"><label>Figure 2.</label>
<caption><p>Incidence rate ratios and 95% confidence intervals (CIs) for the development of chronic liver enzyme elevation as a function of duration of antiretroviral drug exposure. Results are from Poisson regression based on 6368 events among 21 485 participants with 105 413 person years of follow-up. Models were adjusted for exposure to the other antiretrovirals, sex, age, ethnicity, body mass index, lipids, use of lipid-lowering drugs, lipodystrophy, arterial hypertension, smoking status, calendar year, and participating cohort, and for each drug discontinued for <2 years and ≥2 years. Abbreviations: ABC, abacavir; APV, amprenavir; AZT, zidovudine; AZV, atazanavir; D4T, stavudine; DDI, didanosine; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; LPV, lopinavir; NVP, nevirapine; RTV, ritonavir; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine.</p>
</caption>
<graphic xlink:href="ofw00902"></graphic>
</fig>
</p>
<p>Because the association of TDF with cLEE was unexpected, we further analyzed commonly used TDF-containing regimens. The association was found to be more pronounced when TDF was used in combination with FTC and/or EFV (Figure <xref ref-type="fig" rid="OFW009F3">3</xref>).
<fig id="OFW009F3" orientation="portrait" position="float"><label>Figure 3.</label>
<caption><p>Incidence rate ratios and 95% confidence intervals (CIs) for the development of chronic liver enzyme elevation as a function of duration of antiretroviral drug exposure. Analyses are based on 6368 events among 21 485 participants with 105 413 person years of follow-up. Poisson regression models were adjusted for exposure to all other antiretrovirals (excluding lamivudine [3TC], emtricitabine [FTC], efavirenz [EFV], and tenofovir disoproxil fumarate [TDF]), sex, age, ethnicity, body mass index, lipids, use of lipid lowering drugs, lipodystrophy, arterial hypertension, smoking status, calendar year, and participating cohort.</p>
</caption>
<graphic xlink:href="ofw00903"></graphic>
</fig>
</p>
</sec>
<sec id="s3c"><title>Sensitivity Analyses</title>
<p>To substantiate the positive association between TDF and cLEE, we performed several sensitivity analyses. First, we excluded all participants who acquired HBV/HCV during follow-up, or who ultimately developed end-stage liver disease (ESLD), who might have received TDF for an unreported HBV infection or because of its perceived good liver safety profile. Second, we limited the analyses to ART-naive persons initiating TDF to rule out hepatotoxicity caused by a previous drug exposure. Third, we used a modified LEE definition of a single ALT value of ≥100 U/L. Results of all sensitivity analyses were consistent with our main analyses.</p>
</sec>
<sec id="s3d"><title>Clinical Outcome</title>
<p>Of the 6368 participants with ≥1 episode of cLEE, 1758 (27.6%) had at least 1 subsequent additional episode of cLEE. In total, the participants experienced a median of 1 (IQR, 1–6) episodes of cLEE with a median total duration of 1.5 (IQR, 0.5–13.7) years.</p>
<p>Overall, 924 persons died over a total of 151 191 PYFU (rate 0.61/100 PYFU; IQR, 0.57–0.65). All-cause mortality was slightly higher in those who ever had an episode of cLEE compared with participants without cLEE (0.66/100 PYFU versus 0.60/100 PYFU), but this was not significant, either when unadjusted (rate ratio [RR] = 1.10; IQR, 0.95–1.28; <italic>P</italic>
 = .19), adjusted for basic demographic variables (RR = 1.13; IQR, 0.97–1.32; <italic>P</italic>
 = .11), or adjusted additionally for the latest CD4 cell count and HIV viral load (RR = 1.15; IQR, 0.99–1.34; <italic>P</italic>
 = .08). Neither number of episodes of cLEE nor total duration of cLEE was associated with an increased risk of mortality in unadjusted or adjusted analyses (Table <xref ref-type="table" rid="OFW009TB2">2</xref>). The total number of liver-related deaths was 15 with 5 events among persons with cLEE and 10 events among those without any cLEE.
<table-wrap id="OFW009TB2" orientation="portrait" position="float"><label>Table 2.</label>
<caption><p>Associations between cLEE, number of Episodes of cLEE, Total Duration of cLEE, and All-Cause Mortality<sup>a</sup>
</p>
</caption>
<table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col>
<col align="char" char="/" span="1"></col>
<col align="char" char="(" span="1"></col>
<col align="left" span="1"></col>
<col align="char" span="1"></col>
<col align="char" span="1"></col>
<col align="char" span="1"></col>
<col align="left" span="1"></col>
<col align="char" span="1"></col>
</colgroup>
<thead><tr><th align="left" rowspan="2" colspan="1">Events</th>
<th align="center" colspan="2" rowspan="1">All-Cause Mortality<hr></hr>
</th>
<th align="center" colspan="2" rowspan="1">Unadjusted<hr></hr>
</th>
<th align="center" colspan="2" rowspan="1">Adjusted (1)<hr></hr>
</th>
<th align="center" colspan="2" rowspan="1">Adjusted (2)<hr></hr>
</th>
</tr>
<tr><th align="center" rowspan="1" colspan="1">Deaths/PY</th>
<th align="center" rowspan="1" colspan="1">Rate (95% CI)/100 PY</th>
<th align="center" rowspan="1" colspan="1">RR (95% CI)</th>
<th align="center" rowspan="1" colspan="1"><italic>P</italic>
 Value</th>
<th align="center" rowspan="1" colspan="1">RR (95% CI)</th>
<th align="center" rowspan="1" colspan="1"><italic>P</italic>
 Value</th>
<th align="center" rowspan="1" colspan="1">RR (95% CI)</th>
<th align="center" rowspan="1" colspan="1"><italic>P</italic>
 Value</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1">Overall</td>
<td rowspan="1" colspan="1">924/151191</td>
<td rowspan="1" colspan="1">0.61 (.57, .65)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td colspan="9" rowspan="1">Any cLEE</td>
</tr>
<tr><td rowspan="1" colspan="1"> No</td>
<td rowspan="1" colspan="1">682/114389</td>
<td rowspan="1" colspan="1">0.60 (.55, .64)</td>
<td rowspan="1" colspan="1">Ref.</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Ref.</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Ref.</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Yes</td>
<td rowspan="1" colspan="1">242/36802</td>
<td rowspan="1" colspan="1">0.66 (.57, .74)</td>
<td rowspan="1" colspan="1">1.10 (.95, 1.28)</td>
<td rowspan="1" colspan="1">.19</td>
<td rowspan="1" colspan="1">1.13 (.97, 1.32)</td>
<td rowspan="1" colspan="1">.11</td>
<td rowspan="1" colspan="1">1.15 (.99, 1.34)</td>
<td rowspan="1" colspan="1">.08</td>
</tr>
<tr><td colspan="9" rowspan="1">No. of episodes of cLEE</td>
</tr>
<tr><td rowspan="1" colspan="1"> None</td>
<td rowspan="1" colspan="1">682/114389</td>
<td rowspan="1" colspan="1">0.60 (.55, .64)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">  1</td>
<td rowspan="1" colspan="1">192/28835</td>
<td rowspan="1" colspan="1">0.67 (.57, .76)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">  2</td>
<td rowspan="1" colspan="1">41/6539</td>
<td rowspan="1" colspan="1">0.62 (.43, .82)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">  3</td>
<td rowspan="1" colspan="1">9/1168</td>
<td rowspan="1" colspan="1">0.77 (.35, 1.46)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">  ≥4</td>
<td rowspan="1" colspan="1">0/230</td>
<td rowspan="1" colspan="1">0 (, 1.60)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Per cLEE</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">1.05 (.95, 1.17)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">.35</td>
<td rowspan="1" colspan="1">1.06 (.96, 1.18)</td>
<td rowspan="1" colspan="1">.25</td>
<td rowspan="1" colspan="1">1.07 (.96, 1.19)</td>
<td rowspan="1" colspan="1">.20</td>
</tr>
<tr><td colspan="9" rowspan="1">Total duration of cLEE, years</td>
</tr>
<tr><td rowspan="1" colspan="1"> ≤0.5</td>
<td rowspan="1" colspan="1">685/117583</td>
<td rowspan="1" colspan="1">0.58 (.54, .63)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> >0.5–1</td>
<td rowspan="1" colspan="1">90/13227</td>
<td rowspan="1" colspan="1">0.68 (.54, .82)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> >1–1.5</td>
<td rowspan="1" colspan="1">40/5745</td>
<td rowspan="1" colspan="1">0.70 (.48, .91)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> >1.5–2</td>
<td rowspan="1" colspan="1">30/3935</td>
<td rowspan="1" colspan="1">0.76 (.49, 1.04)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> >2–3</td>
<td rowspan="1" colspan="1">51/4566</td>
<td rowspan="1" colspan="1">1.12 (.81, 1.42)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> >3–4</td>
<td rowspan="1" colspan="1">18/2527</td>
<td rowspan="1" colspan="1">0.71 (.42, 1.13)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> >4</td>
<td rowspan="1" colspan="1">10/3609</td>
<td rowspan="1" colspan="1">0.28 (.13, .51)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Per year</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">1.02 (.96, 1.07)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">.61</td>
<td rowspan="1" colspan="1">1.01 (.95, 1.07)</td>
<td rowspan="1" colspan="1">.76</td>
<td rowspan="1" colspan="1">1.01 (.96, 1.07)</td>
<td rowspan="1" colspan="1">.67</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="tblfn2"><p>Abbreviations: CI, confidence interval; cLEE, chronic liver enzyme elevation; HIV, human immunodeficiency virus; PY, patient years; Ref., reference; RR, rate ratio.</p>
</fn>
<fn id="tblfn3"><p><sup>a</sup>
 Adjusted for (1) sex, age, ethnicity, mode of HIV acquisition, body mass index, smoking status, calendar year, and participating cohort, and (2) additionally for the latest CD4 cell count and HIV RNA value.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
</sec>
<sec sec-type="discussion" id="s4"><title>DISCUSSION</title>
<p>In this large longitudinal cohort analysis, the incidence of cLEE among HIV-positive individuals without viral hepatitis was high. In adjusted analyses, cLEE was associated with ongoing exposure to regimens containing ddI, d4T, and TDF and short-term exposure to NVP, EFV, FTC, and ATV. However, mortality did not appear to be increased in HIV-monoinfected participants with cLEE.</p>
<p>The potential for drug-induced liver toxicity of d4T, ddI, NVP, and EFV has previously been described [<xref rid="OFW009C19" ref-type="bibr">19</xref>
]. In HIV-monoinfected and HCV-coinfected individuals, d4T and ddI have been associated with transaminase elevation, FIB, steatosis, and ESLD, most likely related to mitochondrial toxicity [<xref rid="OFW009C3" ref-type="bibr">3</xref>
, <xref rid="OFW009C6" ref-type="bibr">6</xref>
–<xref rid="OFW009C10" ref-type="bibr">10</xref>
]. In our study, NVP and EFV, known to cause early acute hepatitis driven by an immune-mediated hypersensitivity reaction, were associated with elevated ALT in the first 2 years of exposure [<xref rid="OFW009C19" ref-type="bibr">19</xref>
, <xref rid="OFW009C20" ref-type="bibr">20</xref>
].</p>
<p>We were surprised to find a strong relationship between TDF and the development of cLEE emerging within the first 2 years after drug initiation. We confirmed this association using different sensitivity analyses. In another recent D:A:D Study of HIV-monoinfected and HCV/HBV-coinfected participants, TDF was also found to be associated with ESLD/hepatocellular carcinoma, supporting our observation [<xref rid="OFW009C10" ref-type="bibr">10</xref>
]. In addition, our results are consistent with small case studies [<xref rid="OFW009C21" ref-type="bibr">21</xref>
–<xref rid="OFW009C24" ref-type="bibr">24</xref>
]. There are a few reports of liver injury and hepatic failure, including 1 person requiring liver transplantation, developing a few months after starting treatment with TDF/FTC/EFV in persons without preexisting liver disease [<xref rid="OFW009C22" ref-type="bibr">22</xref>
–<xref rid="OFW009C24" ref-type="bibr">24</xref>
]. Lattuada et al [<xref rid="OFW009C21" ref-type="bibr">21</xref>
] reported on 3 individuals with liver enzyme elevation after the addition of TDF to an EFV-containing regimen. The drug registration trials did not identify a link between TDF and hepatotoxicity [<xref rid="OFW009C25" ref-type="bibr">25</xref>
, <xref rid="OFW009C26" ref-type="bibr">26</xref>
]. The STEAL study, a randomized trial comparing abacavir/3TC versus TDF/FTC, showed a small but statistically significant increase in mean ALT levels on TDF/FTC [<xref rid="OFW009C27" ref-type="bibr">27</xref>
], whereas the AIDS Clinical Trials Group A5202, a similar study, showed inconsistent results regarding elevated ALT values [<xref rid="OFW009C28" ref-type="bibr">28</xref>
]. Randomized trials usually enroll participants who are healthier and younger and may therefore not be representative of the general population. Moreover, these trials with viral primary outcomes often lack statistical power to detect rare adverse drug effects due to their limited sample size.</p>
<p>The mechanisms of a possible TDF-related liver injury are unclear. In vitro data showed that TDF is not associated with mitochondrial toxicity [<xref rid="OFW009C29" ref-type="bibr">29</xref>
]. In an animal study, it was found that TDF induced marked oxidative stress in renal and hepatic tissues of Wistar rats [<xref rid="OFW009C30" ref-type="bibr">30</xref>
]. Our finding of the enhanced TDF signal when used in combination with EFV could reflect drug-drug interactions of TDF, which have been described with other antiretrovirals including ddI and ATV [<xref rid="OFW009C31" ref-type="bibr">31</xref>
, <xref rid="OFW009C32" ref-type="bibr">32</xref>
]. It is interesting to note that in slow EFV metabolizers, such as those with CYP2B6 loss/diminished-function alleles, EFV plasma area-under-the-curve values were highest among patients receiving TDF [<xref rid="OFW009C33" ref-type="bibr">33</xref>
].</p>
<p>In line with other recent reports, most PIs were not associated with liver toxicity [<xref rid="OFW009C34" ref-type="bibr">34</xref>
]. We found that ATV during the first 2 years of exposure was predictive, but with ≥2 years of exposure ATV was protective for cLEE. In a previous study, ATV was associated with grade 3 LEE in HIV/HCV-seropositive individuals [<xref rid="OFW009C34" ref-type="bibr">34</xref>
], whereas other investigations suggested that liver tolerability of ATV was good [<xref rid="OFW009C35" ref-type="bibr">35</xref>
, <xref rid="OFW009C36" ref-type="bibr">36</xref>
]. Continuing surveillance for possible ATV-related hepatotoxicity is warranted.</p>
<p>Our data confirm that metabolic features, including dyslipidemia and a high BMI, are one of the main causes of liver disease in HIV-positive persons without chronic hepatitis B and C coinfection, similar to the general population. Our finding of black ethnicity as a negative predictor for ALT elevation is in agreement with other investigations, which found an inverse association of black ethnicity and hepatic steatosis in the general population and among HIV-infected patients [<xref rid="OFW009C37" ref-type="bibr">37</xref>
, <xref rid="OFW009C38" ref-type="bibr">38</xref>
]. A high HIV viral load was associated with an increased risk of hepatopathy compared with individuals on ART with suppressed viral load, supporting the evidence that HIV itself is contributing to liver injury [<xref rid="OFW009C39" ref-type="bibr">39</xref>
].</p>
<p>We found a low number of liver-related deaths among HIV-monoinfected individuals, in accordance with a previous D:A:D Study [<xref rid="OFW009C40" ref-type="bibr">40</xref>
]. All-cause mortality was not significantly increased among persons with cLEE. Because patients are regularly monitored for their ALT levels, this allows the clinician an early warning and the possibility to switch drugs or introduce risk modification (eg, alcohol reduction, diet), reducing the potential impact from ART-related cLEE on mortality. Another possibility for why we did not see a link between cLEE and mortality may be a relatively short follow-up period. In the large population-based US National Health and Nutrition Examination Survey III study, elevated ALT levels in HCV/HBV-negative persons were associated with a higher risk of liver-related death but not with all-cause death [<xref rid="OFW009C41" ref-type="bibr">41</xref>
]. In contrast, studies including HCV/HBV-positive persons suggested both increased liver-related and all-cause mortality among persons with liver enzyme elevation in the general and HIV-positive population [<xref rid="OFW009C12" ref-type="bibr">12</xref>
, <xref rid="OFW009C42" ref-type="bibr">42</xref>
]. Recent data indicate that cLEE is a marker of serious liver diseases. A large liver biopsy series of HIV-monoinfected individuals with cLEE revealed in two thirds of patients significant histological abnormalities with nonalcoholic steatohepatitis (NASH) in 55% and bridging FIB in 17% [<xref rid="OFW009C14" ref-type="bibr">14</xref>
]. Given the long lag time between asymptomatic liver enzyme elevation and liver-related death, a study with a longer observation period may find an association between the two.</p>
<p>The strength of this study is its large size and the long-term prospective observation of a multinational population-based cohort collaboration. Such large observational studies are crucial to detect infrequent drug-related toxicities on the population level. To assess an individual drug effect might be challenging because antiretrovirals are always used in combination regimens. The large D:A:D Study, however, with extensive follow-up of patients drawn from heterogeneous settings should allow to disentangle individual drug effects because there is generally enough variability in the way an individual drug is used in combination with other drugs. Our study has several limitations. Information on alcohol use was not collected systematically. However, it is unlikely that the observed associations between antiretrovirals and cLEE are confounded by alcohol because alcohol consumption does not modify a physician's choice of ART. Moreover, by excluding HCV/HBV-coinfected persons and therefore most injection drug users with risk for multiple substance-dependence syndromes, including alcohol, many at-risk individuals were excluded. Furthermore, we did not have information on potentially hepatotoxic non-antiretroviral drugs. Finally, as a significant number of antiretrovirals were included in the analysis, we cannot rule out that findings may be a result of multiple testing.</p>
</sec>
<sec sec-type="conclusions" id="s5"><title>CONCLUSIONS</title>
<p>In summary, the long-term observation of HIV-monoinfected individuals in this large cohort revealed a high incidence of cLEE. Besides the antiretrovirals ddI, d4T, NVP, and EFV, previously described to be hepatotoxic, FTC, and ATV restricted to the first 2 years of treatment, we observed an additional strong association between TDF exposure and cLEE emerging within the first 2 years after drug initiation. Although mortality was not increased in our study, other studies found relevant histological abnormalities in HIV-monoinfected persons, with elevated ALT underscoring its link to significant liver morbidity [<xref rid="OFW009C13" ref-type="bibr">13</xref>
, <xref rid="OFW009C14" ref-type="bibr">14</xref>
]. In this context, our results emphasize (1) that ddI and d4T should be avoided if alternative treatment is available and (2) that close monitoring of liver enzymes in persons on NVP and EFV is essential. Finally, the observed novel association between TDF and cLEE calls for further investigations to understand the pathophysiological mechanisms and its clinical implications. Ongoing surveillance of drug-related liver injury in large cohort collaborations is of paramount importance.</p>
</sec>
<sec sec-type="supplementary-material" id="s6"><title>Supplementary Data</title>
<p><ext-link ext-link-type="uri" xlink:href="http://ofid.oxfordjournals.org/lookup/suppl/doi:10.1093/ofid/ofw009/-/DC1">Supplementary material</ext-link>
 is available online at Open Forum Infectious Diseases online (<uri xlink:href="http://OpenForumInfectiousDiseases.oxfordjournals.org/">http://OpenForumInfectiousDiseases.oxfordjournals.org/</uri>
).</p>
</sec>
</body>
<back><ack><title>Acknowledgments</title>
<p>D:A:D Steering Committee: Cohort representatives: F. Dabis (Aquitaine), O. Kirk (EuroSIDA), M. Law (AHOD), A. d'Arminio Monforte (ICONA), C. Pradier (Nice), P. Reiss (ATHENA), R. Weber (SHCS), S. De Wit (Brussels), W. El-Sadr (CPCRA). Central coordination: L. Ryom, J. D Lundgren (chair). Statisticians: C. A Sabin, A. N Phillips. Oversight Committee representatives: B. Powderly, N. Shortman, C. Moecklinghoff, G. Reilly, X. Franquet. Members of the D:A:D Steering Committee From the Oversight Committee: B. Powderly, N. Shortman, C. Moecklinghoff, G. Reilly, and X. Franquet. D:A:D Central Coordination: C. I. Hatleberg, L. Ryom, C. A. Sabin, D. Kamara, C. Smith, A. Phillips, A. Mocroft, A. Bojesen, J. Nielsen, C. Matthews, D. Raben, and J. D. Lundgren (chair). D:A:D Data Managers: R. Salbøl Brandt (coordinator), M. Rickenbach, I. Fanti, E. Krum, M. Hillebregt, S. Geffard, Jaohar Mourabi, A. Sundström, M. Delforge, E. Fontas, F. Torres, H. McManus, S. Wright, J. Kjær, and Dennis Kristensen.</p>
<p>Verification of Endpoints: A. Sjøl (cardiovascular disease primary endpoint), P. Meidahl (oncology, new endpoint), J. Helweg-Larsen (hematology, new endpoint), and J. Schmidt Iversen (nephrology, new endpoint). Kidney Working Group: L. Ryom, A. Mocroft, O. Kirk, P. Reiss, M. Ross, C. A. Fux, P. Morlat, O. Moranne, A. M. Kesselring, D. A. Kamara, C. Smith, and J. D. Lundgren (chair). Mortality Working Group: C. Smith, L. Ryom, A. Phillips, R. Weber , P. Morlat, C. Pradier, P. Reiss, N. Friis-Møller, J. Kowalska, and J. D. Lundgren (chair). Cancer Working Group: C. Sabin, M. Law, A. d'Arminio Monforte, F. Dabis, M. Bruyand, P. Reiss, C. Smith, D. A. Kamara, M. Bower, G. Fätkenheuer, A. Grulich, L. Ryom, and J. D. Lundgren (chair).</p>
<p>The members of the 11 cohorts are as follows.</p>
<p>AIDS Therapy Evaluation Project Netherlands (ATHENA). Central Coordination: P. Reiss, S. Zaheri, M. Hillebregt, and L. Gras.</p>
<p>Participating physicians (site coordinating physicians): Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam: Prof. Dr. J. M. Prins, Prof. Dr. T. W. Kuijpers, Dr. H. J. Scherpbier, Dr. J. T. M. van der Meer, Dr. F. W. M. N. Wit, Dr. M. H. Godfried, Prof. Dr. P. Reiss, Prof. Dr. T. van der Poll, Dr. F. J. B. Nellen, Prof. Dr. J. M. A. Lange, Dr. S. E. Geerlings, Dr. M. van Vugt, Dr. D. Pajkrt, Dr. J. C. Bos, Dr. M. van der Valk, Dr. M. L. Grijsen, Dr. W. J. Wiersinga, Dr. A. Goorhuis, and Dr. J. W. R. Hovius. Academisch Ziekenhuis Maastricht, Maastricht: Dr. S. Lowe, Dr. A. Oude Lashof, and Dr. D. Posthouwer. Catharina-Ziekenhuis, Eindhoven: Dr. M. J. H. Pronk and Dr. H. S. M. Ammerlaan. Erasmus Medisch Centrum, Rotterdam: Dr. M. E. van der Ende, Dr. T. E. M. S. de Vries-Sluijs, Dr. C. A. M. Schurink, Dr. J. L. Nouwen, Dr. A. Verbon, Dr. B. J. A. Rijnders, Dr. E. C. M. van Gorp, and Dr. M. van der Feltz. Erasmus Medisch Centrum–Sophia, Rotterdam: Dr. G. J. A. Driessen, and Dr. A. M. C. van Rossum. Flevoziekenhuis, Almere: Dr. J. Branger. HagaZiekenhuis, Den Haag: Dr. E. F. Schippers, Dr. C. van Nieuwkoop, and Dr. E. P. van Elzakker. Isala Klinieken, Zwolle: Dr. P. H. P. Groeneveld and Dr. J. W. Bouwhuis. Kennemer Gasthuis: Dr. R. Soetekouw and Prof. Dr. R. W. ten Kate. Leids Universitair Medisch Centrum, Leiden: Dr. F. P. Kroon, Prof. Dr. J. T. van Dissel, Dr. S. M. Arend, Dr. M. G. J. de Boer, Dr. H. Jolink, Dr. H. J. M. ter Vollaard, and Dr. M. P. Bauer. Maasstadziekenhuis, Rotterdam: Dr. J. G. den Hollander and Dr. K. Pogany. Medisch Centrum Alkmaar, Alkmaar: Dr. G. van Twillert, Dr. W. Kortmann, Dr. J. W. T. Cohen Stuart, and Dr. B. M. W. Diederen. Medisch Centrum Haaglanden, Den Haag: Dr. E. M. S. Leyten and Dr. L. B. S. Gelinck. Medisch Spectrum Twente, Enschede: Dr. G. J. Kootstra and Dr. C. E. Delsing. Onze Lieve Vrouwe Gasthuis, Amsterdam: Prof. Dr. K. Brinkman, Dr. W. L. Blok, Dr. P. H. J. Frissen, Dr. W. E. M. Schouten, and Dr. G. E. L. van den Berk. Sint Elisabeth Ziekenhuis, Tilburg: Dr. M. E. E. van Kasteren and Dr. A. E. Brouwer. Sint Lucas Andreas Ziekenhuis, Amsterdam: Dr. J. Veenstra and Dr. K. D. Lettinga. Slotervaartziekenhuis, Amsterdam: Dr. J. W. Mulder, Dr. S. M. E. Vrouenraets, and Dr. F. N. Lauw. Stichting Medisch Centrum Jan van Goyen, Amsterdam: Dr. A. van Eeden and Dr. D. W. M. Verhagen. Universitair Medisch Centrum Groningen, Groningen: Dr. H. G. Sprenger, Dr. R. Doedens, Dr. E. H. Scholvinck, Dr. S. van Assen, and Dr. W. F. W. Bierman. Universitair Medisch Centrum Sint Radboud, Nijmegen: Dr. P. P. Koopmans, Dr. M. Keuter, Dr. A. J. A. M. van der Ven, Dr. H. J. M. ter Hofstede, Dr. A. S. M. Dofferhoff, Dr. A Warris, and Dr. R. van Crevel. Universitair Medisch Centrum Utrecht, Utrecht: Prof. Dr A. I. M. Hoepelman, Dr. T. Mudrikova, Dr. M. M. E. Schneider, Dr. P. M. Ellerbroek, Dr. J. J. Oosterheert, Dr. J. E. Arends, Dr. M. W. M. Wassenberg, and Dr. R. E. Barth. Vrije Universiteit Amsterdam, Amsterdam: Dr. M. A. van Agtmael, Dr. R. M. Perenboom, Dr. F. A. P. Claessen, Dr. M. Bomers, and Dr. E. J. G. Peters. Wilhelmina Kinderziekenhuis, Utrecht: Dr. S. P. M. Geelen, Dr. T. F. W. Wolfs, and Dr. L. J. Bont. Ziekenhuis Rijnstate, Arnhem: Dr. C. Richter, Dr. J. P. van der Berg, and Dr. E. H. Gisolf. Admiraal De Ruyter Ziekenhuis, Vlissingen: Dr. M. van den Berge and Dr. A. Stegeman. Medisch Centrum Leeuwarden, Leeuwarden: Dr. M. G. A. van Vonderen and Dr. D. P. F. van Houte. Medisch Centrum Zuiderzee, Lelystad: Dr. S. Weijer and Dr. R. el Moussaoui. Sint Elisabeth Hospitaal, Willemstad - Curaçao: Dr. C. Winkel, Dr. F. Muskiet, Dr. Durand, and Dr. R. Voigt.</p>
<p>The following is a list of the Aquitaine Cohort (France).</p>
<p>Coordination: F. Bonnet, F. Dabis. Scientific Committee: F. Bonnet, S. Bouchet, D. Breilh, G. Chêne, F. Dabis, M. Dupon, H. Fleury, V. Gaborieau, D. Lacoste, D. Malvy, P. Mercié, P. Morlat, D. Neau, I. Pellegrin, J. L. Pellegrin, S. Reigadas, S. Tchamgoué. Epidemiology and Methodology: M. Bruyand, G. Chêne, F. Dabis, C. Fagard, S. Lawson-Ayayi, L. Richert, R. Thiébaut, L. Wittkop. Infectious Diseases and Internal Medicine: K. André, F. Bonnet, N. Bernard, L. Caunègre, C. Cazanave, J. Ceccaldi, I. Chossat, C. Courtault, F. A. Dauchy, S. De Witte, D. Dondia, M. Dupon, A. Dupont, P. Duffau, H. Dutronc, S. Farbos, I. Faure, V. Gaborieau, Y. Gerard, C. Greib, M. Hessamfar-Joseph, Y. Imbert, D. Lacoste, P. Lataste, E. Lazaro, D. Malvy, J. Marie, M. Mechain, J. P. Meraud, P. Mercié, E. Monlun, P. Morlat, D. Neau, A. Ochoa, J. L. Pellegrin, M. Pillot-Debelleix, T. Pistone, I. Raymond, M. C. Receveur, P. Rispal, L. Sorin, S. Tchamgoué, C. Valette, M. A. Vandenhende, M. O. Vareil, J. F. Viallard, H. Wille, G. Wirth. Immunology: J. F. Moreau, I. Pellegrin. Virology: H. Fleury, M. E. Lafon, S. Reigadas, P. Trimoulet. Pharmacology: S. Bouchet, D. Breilh, F. Haramburu, G. Miremont-Salamé. Data Collection, Project Management and Statistical Analyses: M. J. Blaizeau, I. Crespel, M. Decoin, S. Delveaux, F. Diarra, C. D′Ivernois, C. Hanappier, D. Lacoste, S. Lawson-Ayayi, O. Leleux, F. Le Marec, E. Lenaud, J. Mourali, E. Pernot, A. Pougetoux, B. Uwamaliya-Nziyumvira, A. Tsaranazy, A. Valdes. IT Department and eCRF Development: V. Conte, I. Louis, G. Palmer, V. Sapparrart, D. Touchard.</p>
<p>Australian HIV Observational Database, Australia (AHOD):</p>
<p>Central coordination: M. Law, K. Petoumenos, H. McManus, S. Wright, C. Bendall (Sydney, New South Wales);</p>
<p>Participating physicians: R. Moore, S. Edwards, J. Hoy, K. Watson, N. Roth, J. Nicholson (Melbourne, Victoria); M. Bloch, T. Franic, D. Baker, R. Vale, A. Carr, D. Cooper (Sydney, New South Wales); J. Chuah, M. Ngieng (Gold Coast, Queensland), D. Nolan, J. Skett (Perth, Western Australia).</p>
<p>BASS (Spain):</p>
<p>Central coordination: G. Calvo, F. Torres, S. Mateu (Barcelona). Participating physicians: P. Domingo, M. A. Sambeat, J. Gatell, E. Del Cacho, J. Cadafalch, M. Fuster (Barcelona); C. Codina, G. Sirera, A. Vaqué (Badalona).</p>
<p>The Brussels St. Pierre Cohort (Belgium):</p>
<p>Coordination: S. De Wit, N. Clumeck, M. Delforge, C. Necsoi. Participating physicians: N. Clumeck, S. De Wit, A. F. Gennotte, M. Gerard, K. Kabeya, D. Konopnicki, A. Libois, C. Martin, M. C. Payen, P. Semaille, Y. Van Laethem.</p>
<p>Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) (United States):</p>
<p>Central coordination: J. Neaton, G. Bartsch, W. M. El-Sadr, E. Krum, G. Thompson, D. Wentworth. Participating physicians: R. Luskin-Hawk (Chicago, IL); E. Telzak (Bronx, NY); W. M. El-Sadr (Harlem, NY); D. I. Abrams (San Francisco, CA); D. Cohn (Denver, CO); N. Markowitz (Detroit, MI); R. Arduino (Houston, TX); D. Mushatt (New Orleans, LA); G. Friedland (New Haven, CT); G. Perez (Newark, NJ); E. Tedaldi (Philadelphia, PA); E. Fisher (Richmond, VA); F. Gordin (Washington, DC); L. R. Crane (Detroit, MI); J. Sampson (Portland, OR); J. Baxter (Camden, NJ).</p>
<p>EuroSIDA (multinational) Coordinating Centre: J. Lundgren (chair), O. Kirk, A. Mocroft, A. Cozzi-Lepri, D. Grint, D. Podlekareva, J. Kjær, L. Peters, J. Reekie, J. Kowalska, J. Tverland, A. H. Fischer, J. Nielsen. Participating countries and physicians Argentina: M. Losso, C. Elias (Hospital JM Ramos Mejia, Buenos Aires).</p>
<p>Austria: N. Vetter (Pulmologisches Zentrum der Stadt Wien, Vienna); R. Zangerle (Medical University Innsbruck, Innsbruck). Belarus: I. Karpov, A. Vassilenko (Belarus State Medical University, Minsk); V. M. Mitsura (Gomel State Medical University, Gomel); O. Suetnov (Regional AIDS Centre, Svetlogorsk). Belgium: N. Clumeck, S. De Wit, M. Delforge (Saint-Pierre Hospital, Brussels); R. Colebunders (Institute of Tropical Medicine, Antwerp); L. Vandekerckhove (University Ziekenhuis Gent, Gent). Bosnia-Herzegovina: V. Hadziosmanovic (Klinicki Centar Univerziteta Sarajevo, Sarajevo). Bulgaria: K. Kostov (Infectious Diseases Hospital, Sofia). Croatia: J. Begovac (University Hospital of Infectious Diseases, Zagreb). Czech Republic: L. Machala, D. Jilich (Faculty Hospital Bulovka, Prague); D. Sedlacek (Charles University Hospital, Plzen). Denmark: J. Nielsen, G. Kronborg, T. Benfield, M. Larsen (Hvidovre Hospital, Copenhagen); J. Gerstoft, T. Katzenstein, A.-B. E. Hansen, P. Skinhøj (Rigshospitalet, Copenhagen); C. Pedersen (Odense University Hospital, Odense); L. Ostergaard (Skejby Hospital, Aarhus). Estonia: K. Zilmer (West-Tallinn Central Hospital, Tallinn); Jelena Smidt, Nakkusosakond Siseklinik (Kohtla-Järve). Finland: M. Ristola (Helsinki University Central Hospital, Helsinki). France: C. Katlama (Hôpital de la Pitié-Salpétière, Paris); J.-P. Viard (Hôpital Necker-Enfants Malades, Paris); P.-M. Girard (Hospital Saint-Antoine, Paris); J. M. Livrozet (Hôpital Edouard Herriot, Lyon); P. Vanhems (University Claude Bernard, Lyon); C. Pradier (Hôpital de l'Archet, Nice); F. Dabis, D. Neau (Unité INSERM, Bordeaux). Germany: J. Rockstroh (Universitäts Klinik Bonn); R. Schmidt (Medizinische Hochschule Hannover); J. van Lunzen, O. Degen (University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg); H. J. Stellbrink (IPM Study Center, Hamburg); S. Staszewski, J. W. (Goethe University Hospital, Frankfurt); Markus Bickel (Medizinische Poliklinik, Munich); G. Fätkenheuer (Universität Köln, Cologne). Greece: J. Kosmidis, P. Gargalianos, G. Xylomenos, J. Perdios (Athens General Hospital); G. Panos, A. Filandras, E. Karabatsaki (1st IKA Hospital); H. Sambatakou (Ippokration Genereal Hospital, Athens). Hungary: D. Banhegyi (Szent Lásló Hospital, Budapest). Ireland: F. Mulcahy (St. James's Hospital, Dublin). Israel: I. Yust, D. Turner, M. Burke (Ichilov Hospital, Tel Aviv); S. Pollack, G. Hassoun (Rambam Medical Center, Haifa); S. Maayan (Hadassah University Hospital, Jerusalem). Italy: S. Vella (Istituto Superiore di Sanità, Rome); R. Esposito, I. Mazeu, C. Mussini (Università Modena, Modena); C. Arici (Ospedale Riuniti, Bergamo); R. Pristera (Ospedale Generale Regionale, Bolzano); F. Mazzotta, A. Gabbuti (Ospedale Santa Maria Annunziata, Firenze); V. Vullo, M. Lichtner (University di Roma la Sapienza, Rome); A. Chirianni, E. Montesarchio, M. Gargiulo (Presidio Ospedaliero AD Cotugno, Monaldi Hospital, Napoli); G. Antonucci, A. Testa, P. Narciso, C. Vlassi, M. Zaccarelli (Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome); A. Lazzarin, A. Castagna, N. Gianotti (Ospedale San Raffaele, Milan); M. Galli, A. Ridolfo (Osp. L. Sacco, Milan); A. d′Arminio Monforte (Istituto Di Clinica Malattie Infettive e Tropicale, Milan). Latvia: B. Rozentale, I. Zeltina (Infectology Centre of Latvia, Riga). Lithuania: S. Chaplinskas (Lithuanian AIDS Centre, Vilnius). Luxembourg: R. Hemmer, T. Staub (Centre Hospitalier, Luxembourg). Netherlands: P. Reiss (Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam). Norway: V. Ormaasen, A. Maeland, J. Bruun (Ullevål Hospital, Oslo). Poland: B. Knysz, J. Gasiorowski (Medical University, Wroclaw); A. Horban, E. Bakowska (Centrum Diagnostyki i Terapii AIDS, Warsaw); A. Grzeszczuk, R. Flisiak, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, M. Parczewski (Medical Univesity, Szczecin); M. Beniowski, E. Mularska (Osrodek Diagnostyki i Terapii AIDS, Chorzow); H. Trocha (Medical University, Gdansk); E. Jablonowska, E. Malolepsza, K. Wojcik (Wojewodzki Szpital Specjalistyczny, Lodz). Portugal: F. Antunes, M. Doroana, L. Caldeira (Hospital Santa Maria, Lisbon); K. Mansinho (Hospital de Egas Moniz, Lisbon); F. Maltez (Hospital Curry Cabral, Lisbon). Romania: D. Duiculescu (Spitalul de Boli Infectioase si Tropicale Dr. Victor Babes, Bucarest). Russia: A. Rakhmanova (Medical Academy Botkin Hospital, St. Petersburg); N. Zakharova (St. Petersburg AIDS Centre, St. Peterburg); S. Buzunova (Novgorod Centre for AIDS, Novgorod). Serbia: D. Jevtovic (The Institute for Infectious and Tropical Diseases, Belgrade). Slovakia: M. Mokráš, D. Staneková (Dérer Hospital, Bratislava). Slovenia: J. Tomazic (University Clinical Centre Ljubljana, Ljubljana). Spain: J. González-Lahoz, V. Soriano, P. Labarga, J. Medrano (Hospital Carlos III, Madrid); S. Moreno, J. M. Rodriguez (Hospital Ramon y Cajal, Madrid); B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo (Hospital Germans Trias i Pujol, Badalona); J. M. Gatell, J. M. Miró (Hospital Clinic i Provincial, Barcelona); P. Domingo, M. Gutierrez, G. Mateo, M. A. Sambeat (Hospital Sant Pau, Barcelona). Sweden: A. Karlsson (Venhaelsan-Sodersjukhuset, Stockholm); L. Flamholc (Malmö University Hospital, Malmö). Switzerland: B. Ledergerber, R. Weber (University Hospital, Zürich); P. Francioli, M. Cavassini (Centre Hospitalier Universitaire Vaudois, Lausanne); B. Hirschel, E. Boffi (Hospital Cantonal Universitaire de Geneve, Geneve); H. Furrer (Inselspital Bern, Bern); M. Battegay, L. Elzi (University Hospital Basel). Ukraine: E. Kravchenko, N. Chentsova (Kiev Centre for AIDS, Kiev); V. Frolov, G. Kutsyna (Luhansk State Medical University, Luhansk); S. Servitskiy (Odessa Region AIDS Center, Odessa); M. Krasnov (Kharkov State Medical University, Kharkov). United Kingdom: S. Barton (St. Stephen's Clinic, Chelsea and Westminster Hospital, London); A. M. Johnson, D. Mercey (Royal Free and University College London Medical School, London [University College Campus]); A. Phillips, M. A. Johnson, A. Mocroft (Royal Free and University College Medical School, London [Royal Free Campus]); M. Murphy (Medical College of Saint Bartholomew's Hospital, London); J. Weber, G. Scullard (Imperial College School of Medicine at St. Mary's, London); M. Fisher (Royal Sussex County Hospital, Brighton); C. Leen (Western General Hospital, Edinburgh).</p>
<p>HivBivus (Sweden):</p>
<p>Central coordination: L. Morfeldt, G. Thulin, A. Sundström. Participating physicians: B. Åkerlund (Huddinge); K. Koppel, A. Karlsson (Stockholm); L. Flamholc, C. Håkangård (Malmö).</p>
<p>The ICONA Foundation (Italy):</p>
<p>Board of Directors: M. Moroni (Chair), G. Angarano, A. Antinori, O. Armignacco, A. d′Arminio Monforte, F. Castelli, R. Cauda, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, C. F. Perno, F. von Schloesser, P. Viale. Scientific Secretary: A. d′Arminio Monforte, A. Antinori, A. Castagna, F. Ceccherini-Silberstein, A. Cozzi-Lepri, E. Girardi, S. Lo Caputo, C. Mussini, M. Puoti. ICONA Steering Committee: M. Andreoni, A. Ammassari, A. Antinori, A. d′Arminio Monforte, C. Balotta, P. Bonfanti, S. Bonora, M. Borderi, R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, A. Cingolani, P. Cinque, A. Cozzi-Lepri, A. De Luca, A. Di Biagio, E. Girardi, N. Gianotti, A. Gori, G. Guaraldi, G. Lapadula, M. Lichtner, S. Lo Caputo, G. Madeddu, F. Maggiolo, G. Marchetti, S. Marcotullio, L. Monno, C. Mussini, M. Puoti, E. Quiros Roldan, S. Rusconi. Statistical and Monitoring Team: A. Cozzi-Lepri, P. Cicconi, I. Fanti, T. Formenti, L. Galli, P. Lorenzini. Participating Physicians and Centers: A. Giacometti, A. Costantini (Ancona); G. Angarano, L. Monno, C. Santoro (Bari); F. Maggiolo, C. Suardi (Bergamo); P. Viale, E. Vanino, G. Verucchi (Bologna); F. Castelli, E. Quiros Roldan, C. Minardi (Brescia); T. Quirino, C. Abeli (Busto Arsizio); P. E. Manconi, P. Piano (Cagliari); J. Vecchiet, K. Falasca (Chieti); L. Sighinolfi, D. Segala (Ferrara); F. Mazzotta, S. Lo Caputo (Firenze); G. Cassola, G. Viscoli, A. Alessandrini, R. Piscopo, G. Mazzarello (Genova); C. Mastroianni, V. Belvisi (Latina); P. Bonfanti, I. Caramma (Lecco); A. P. Castelli (Macerata); M. Galli, A. Lazzarin, G. Rizzardini, M. Puoti, A. d′Arminio Monforte, A. L. Ridolfo, R. Piolini, A. Castagna, S. Salpietro, L. Carenzi, M. C. Moioli, P. Cicconi, G. Marchetti (Milano); C. Mussini, C. Puzzolante (Modena); A. Gori, G. Lapadula (Monza); N. Abrescia, A. Chirianni, M. G. Guida, M. Onofrio (Napoli); F. Baldelli, D. Francisci (Perugia); G. Parruti, T. Ursini (Pescara); G. Magnani, M. A. Ursitti (Reggio Emilia); R. Cauda, M. Andreoni, A. Antinori, V. Vullo, A. Cingolani, A. d′Avino, A. Ammassari, L. Gallo, E. Nicastri, R. Acinapura, M. Capozzi, R. Libertone, G. Tebano (Roma); A. Cattelan (Rovigo); M. S. Mura, G. Madeddu (Sassari); P. Caramello, G. Di Perri, G. C. Orofino, S. Bonora, M. Sciandra (Torino); G. Pellizzer, V. Manfrin (Vicenza).</p>
<p>Nice HIV Cohort (France):</p>
<p>Central coordination: C. Pradier, E. Fontas, K. Dollet, C. Caissotti. Participating physicians: P. Dellamonica, E. Bernard, E. Cua, F. De Salvador-Guillouet, J. Durant, S. Ferrando, V. Mondain-Miton, A. Naqvi, I. Perbost, B. Prouvost-Keller, S. Pillet, P. Pugliese, V. Rahelinirina, P. M. Roger.</p>
<p>Swiss HIV Cohort Study, Switzerland (SHCS):</p>
<p>V. Aubert, M. Battegay, E. Bernasconi, J. Böni, H. C. Bucher, C. Burton-Jeangros, A. Calmy, M. Cavassini, G. Dollenmaier, M. Egger, L. Elzi, J. Fehr, J. Fellay, H. Furrer (Chairman of the Clinical and Laboratory Committee), C. A. Fux, M. Gorgievski, H. Günthard (President of the SHCS), D. Haerry (Deputy of “Positive Council”), B. Hasse, H. H. Hirsch, M. Hoffmann, I. Hösli, C. Kahlert, L. Kaiser, O. Keiser, T. Klimkait, R. Kouyos, H. Kovari, B. Ledergerber, G. Martinetti, B. Martinez de Tejada, K. Metzner, N. Müller, D. Nadal, D. Nicca, G. Pantaleo, A. Rauch (Chairman of the Scientific Board), S. Regenass, M. Rickenbach (Head of Data Center), C. Rudin (Chairman of the Mother & Child Substudy), F. Schöni-Affolter, P. Schmid, J. Schüpbach, R. Speck, P. Tarr, A. Telenti, A. Trkola, P. Vernazza, R. Weber, S. Yerly.</p>
<p><bold><italic>Financial support.</italic>
</bold>
 The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study was supported by the <funding-source>Highly Active Antiretroviral Therapy Oversight Committee</funding-source>
, a collaborative committee with representation from academic institutions, the European Agency for the Evaluation of Medicinal Products, the United States Food and Drug Administration, the patient community, and pharmaceutical companies with licensed anti-human immunodeficiency virus (HIV) drugs in the European Union: <funding-source>AbbVie, Bristol-Myers Squibb, Gilead Sciences Inc.</funding-source>
, <funding-source>ViiV Healthcare</funding-source>
, <funding-source>Merck & Co Inc.</funding-source>
, and <funding-source>Janssen Pharmaceuticals</funding-source>
. This work was also funded by a grant from the <funding-source>Danish National Research Foundation</funding-source>
<funding-source>(</funding-source>
CHIP & PERSIMUNE; grant number <award-id>DNRF126</award-id>
); a grant from the <funding-source>Dutch Ministry of Health, Welfare and Spor</funding-source>
t (ATHENA); a grant from the <funding-source>Agence</funding-source>
<funding-source>Nationale de</funding-source>
<funding-source>Recherches sur le</funding-source>
<funding-source>SIDA</funding-source>
<funding-source>et les</funding-source>
<funding-source>Hépatites</funding-source>
<funding-source>Virales</funding-source>
 (Action Coordonnée no. 7, Cohortes; to the Aquitaine Cohort); The Australian HIV Observational Database (AHOD) is funded as part of the Asia Pacific HIV Observational Database, a program of The Foundation for AIDS Research, amfAR, and is supported in part by a grant from the US <funding-source>National Institutes of Health's</funding-source>
<funding-source>National Institute of Allergy and Infectious Diseases</funding-source>
 (grant number <award-id>U01-AI069907</award-id>
) and by unconditional grants from <funding-source>Merck Sharp & Dohme</funding-source>
, <funding-source>Gilead Sciences</funding-source>
, <funding-source>Bristol-Myers Squibb</funding-source>
, <funding-source>Boehringer Ingelheim Roche</funding-source>
, <funding-source>Pfizer</funding-source>
, <funding-source>GlaxoSmithKline</funding-source>
, and <funding-source>Janssen Pharmaceuticals</funding-source>
. The Kirby Institute is funded by The Australian Government Department of Health and Ageing and is affiliated with the Faculty of Medicine, The University of New South Wales. This work was additionally supported by grants from the <funding-source>Fondo de Investigación Sanitaria</funding-source>
 (grant number <award-id>FIS 99/0887</award-id>
) and <funding-source>Fundación para la Investigación y la Prevención del SIDA en Espanã</funding-source>
 (grant number <award-id>FIPSE 3171/00</award-id>
; to the Barcelona Antiretroviral Surveillance Study); the <funding-source>National Institute of Allergy and Infectious Diseases</funding-source>
, <funding-source>National Institutes of Health</funding-source>
 (grants numbers <award-id>5U01AI042170-10</award-id>
 and <award-id>5U01AI046362-03</award-id>
; to the Terry Beirn Community Programs for Clinical Research on AIDS); grants from the <funding-source>BIOMED 1</funding-source>
 (grant number <award-id>CT94-1637</award-id>
) and <funding-source>BIOMED 2</funding-source>
 (grant number <award-id>CT97-2713</award-id>
) programs; the <funding-source>5th Framework Program</funding-source>
 (grant number <award-id>QLK2-2000-00773</award-id>
); the <funding-source>6th Framework</funding-source>
<funding-source>Program</funding-source>
 (grants number <award-id>LSHP-CT-2006-018632</award-id>
), and the <funding-source>7th Framework</funding-source>
 (<award-id>FP7/2007-2013</award-id>
, EuroCoord n° <award-id>260694</award-id>
) programmes of the European Commission and unrestricted grants by <funding-source>Janssen R&D, Merck and Co. Inc., Pfizer Inc., GlaxoSmithKline LLC</funding-source>
 (the participation of centres from Switzerland is supported by <funding-source>The Swiss National Science Foundation</funding-source>
 [grant <award-id>108787</award-id>
]) to the EuroSIDA study; unrestricted educational grants from <funding-source>AbbVie</funding-source>
, <funding-source>Bristol-Myers Squibb</funding-source>
, <funding-source>Gilead Sciences</funding-source>
, <funding-source>GlaxoSmithKline</funding-source>
, <funding-source>Pfizer</funding-source>
, <funding-source>Janssen Pharmaceuticals to the Italian Cohort Naive to Antiretrovirals (The ICONA Foundation);</funding-source>
 and by a grant from the <funding-source>Swiss National Science Foundation</funding-source>
 (grant <award-id>148522</award-id>
) to the Swiss HIV Cohort Study.</p>
<p><bold><italic>Disclaimer.</italic>
</bold>
 The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above.</p>
<p><bold><italic>Potential conflicts of interest.</italic>
</bold>
 H. K. received independent scientific grant support from Gilead Sciences, travel grants from Merck Sharp & Dohme and Gilead Sciences, and attended advisory boards for Gilead Sciences. C. A. S. received funding from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, and MSD for the membership of Data Safety and Monitoring Boards and Advisory Boards, for participation in speaker bureaus, and for the development of educational materials. B. L. received travel grants or honoraria from Bristol-Myers Squibb, Gilead, ViiV, Merck Sharp & Dohme, and Janssen. P. R. received independent scientific grant support from Gilead Sciences, Janssen Pharmaceuticals Inc., Merck & Co., Bristol-Myers Squibb, and ViiV Healthcare; he has served on scientific advisory board for Gilead Sciences; he serves on Data Safety Monitoring Committee for Janssen Pharmaceuticals Inc.; he chaired a scientific symposium by ViiV Healthcare, for which his institution has received remuneration. M. L. received unrestricted research grants from Boehringer Ingelheim, Gilead Sciences, Merck Sharp & Dohme, Bristol-Myers Squibb, Janssen-Cilag, and ViiV HealthCare, and DSMB siting fees from Sirtex Pty Ltd. C. P. received honoraria from Pfizer, Merck Sharp & Dome, Gilead Sciences, and ViiV HealthCare. O. K. received honoraria, consultancy, lecture fees, and travel grants from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Roche, and ViiV Healthcare, and served on Advisory Boards for Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare. R. W. received travel grants from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dome, Pfizer, Roche, TRB Chemedica, and Tibotec, the clinic has received unrestricted educational grants from GlaxoSmithKline, ViiV, and Gilead Sciences.</p>
<p>All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.</p>
</ack>
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Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

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