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Despite this, the safety profile of <jats:styled-content style=\"fixed-case\">NAs<\/jats:styled-content> is of paramount importance since the majority of patients will require long\u2010term treatment. All <jats:styled-content style=\"fixed-case\">NAs<\/jats:styled-content> can potentially affect human <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> polymerase with decrease in mitochondrial <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>, leading to manifestations of mitochondrial toxicity. As a class effect, therefore, <jats:styled-content style=\"fixed-case\">NAs<\/jats:styled-content> can potentially cause extrahepatic conditions, such as myopathy, nephropathy, neuropathy, and lactic acidosis. Indeed, effects on muscles, including myopathy and creatine kinase elevations, have been described with clevudine and telbivudine use. Both adefovir and tenofovir are associated with dose\u2010dependent nephropathy, predominantly affecting the proximal renal tubules. Neuropathy appears to be rare, and most commonly reported in patients receiving combination therapy with telbivudine and interferon. Increased risk of lactic acidosis has also been described for those with impaired liver and renal function taking entecavir. Loss of bone mineral density and hypophosphatemia have been described with the use of <jats:styled-content style=\"fixed-case\">NAs<\/jats:styled-content>, although the overwhelming studies have been with human immunodeficiency virus\u2010infected patients. However, not all extrahepatic effects are detrimental. Recent evidence has suggested a potential renal beneficial effect with the use of telbivudine. The effect of <jats:styled-content style=\"fixed-case\">NAs<\/jats:styled-content> on pregnancy appears to be minimal for all <jats:styled-content style=\"fixed-case\">NAs<\/jats:styled-content>, with telbivudine and tenofovir having a more favorable category <jats:styled-content style=\"fixed-case\">B<\/jats:styled-content> rating. Ongoing pharmacovigilance is essential to identify new and monitor existing extrahepatic effects associated with <jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content> use.<\/jats:p>","DOI":"10.1111\/jgh.12499","type":"journal-article","created":{"date-parts":[[2013,12,27]],"date-time":"2013-12-27T11:06:44Z","timestamp":1388142404000},"page":"428-434","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Extrahepatic effects of nucleoside and nucleotide analogues in chronic hepatitis <scp>B<\/scp> treatment"],"prefix":"10.1111","volume":"29","author":[{"given":"James","family":"Fung","sequence":"first","affiliation":[{"name":"Department of Medicine The University of Hong Kong  Hong Kong"},{"name":"State Key Laboratory for Liver Research The University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai\u2010Kay","family":"Seto","sequence":"additional","affiliation":[{"name":"Department of Medicine The University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching\u2010Lung","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Medicine The University of Hong Kong  Hong Kong"},{"name":"State Key Laboratory for Liver Research The University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man\u2010Fung","family":"Yuen","sequence":"additional","affiliation":[{"name":"Department of Medicine The University of Hong Kong  Hong Kong"},{"name":"State Key Laboratory for Liver Research The University of Hong Kong  Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,2,19]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020681"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199807093390201"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021812"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa051287"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa051285"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa066422"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0802878"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199510263331702"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.04.019"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22959"},{"key":"e_1_2_9_12_1","first-page":"113","article-title":"Preclinical investigation of L\u2010FMAU as an anti\u2010hepatitis B virus agent","volume":"3","author":"Chu CK","year":"1998","journal-title":"Antivir. 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