{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T10:37:59Z","timestamp":1777718279242,"version":"3.51.4"},"reference-count":42,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:p>\n                    In a 3-month toxicity study in cynomolgus monkeys at a European contract laboratory, animals were infected with HAV, initially resulting in hepatic injury being incorrectly attributed to the test compound. Elevated serum ALT\/AST\/GLDH (5- to 10-fold) were noted in individual animals from all groups including controls, with no apparent dose, exposure, or time-related relationship. Liver histopathology revealed minimal to slight inflammatory cell accumulation in periportal zones of most animals, and minimal to slight hepatocyte degeneration\/necrosis in 10\/42 animals from all groups. As these findings were more pronounced in 6 drug-treated animals, including 2\/6 in the low dose group, the draft report concluded: \u201c\n                    <jats:italic toggle=\"yes\">treatment-related hepatotoxicity at all dose levels precluded determination of a NOAEL<\/jats:italic>\n                    .\u201d However, the unusual pattern of hepatotoxicity suggested a factor other than drug exposure might have caused the hepatic effects. Therefore, snap-frozen liver samples were tested for hepatitis viruses using a PCR method. Tests for hepatitis B, C, and E virus were negative; however, 20\/42 samples were positive for hepatitis A virus (HAV). Infection was strongly associated with increased serum ALT\/GLDH, and\/or hepatocyte degeneration\/necrosis. Re-evaluation of the study in light of these data concluded that the hepatic injury was not drug-related. A subsequent 6-month toxicology study in HAV-vaccinated cynomolgus monkeys confirmed the absence of hepatotoxicity. Identification of HAV infection supported progression of the drug candidate into later clinical trials. Although rarely investigated, subclinical HAV infection has occasionally been reported in laboratory primates, including those used for toxicology studies and it may be more prevalent than the literature indicates.\n                  <\/jats:p>","DOI":"10.1177\/10915818241237992","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T10:07:26Z","timestamp":1710842846000},"page":"368-376","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate"],"prefix":"10.1177","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3591-3593","authenticated-orcid":false,"given":"Chris J.","family":"Powell","sequence":"first","affiliation":[{"name":"University of Cambridge"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C.","family":"Kapeghian","sequence":"additional","affiliation":[{"name":"Preclinical Safety Associates, LLC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C.","family":"Bernal","sequence":"additional","affiliation":[{"name":"CORES Veterinary Consulting"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John R.","family":"Foster","sequence":"additional","affiliation":[{"name":"ToxPath Sciences Ltd"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.32.7.1799-1804.1994"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-662-25996-2_38"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/9781118924051"},{"issue":"1","key":"e_1_3_5_5_2","first-page":"42","article-title":"Management of a measles outbreak among old world nonhuman primates","volume":"49","author":"Willy ME","year":"1999","unstructured":"Willy ME, Woodward RA, Thornton VB, et al. 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Mice housed at elevated vivarium temperatures display enhanced T-cell response and survival to Francisella Tularensis. Comp Med. 2017;67:491-497.","journal-title":"Comp Med"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/ilar\/ilaa010"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1177\/0192623310388431"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1080\/109158100224962"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/ilar.49.2.191"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1177\/0192623310368981"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1293\/tox.34.1S"},{"key":"e_1_3_5_25_2","unstructured":"ICH M3: International Committee on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. 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