Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate.

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: "treatment-related hepatotoxicity at all dose levels precluded determination of a NOAEL." 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.

Lack of Trypanosoma cruzi Infection in Urban Roof Rats (Rattus rattus) at a Texas Facility Housing Naturally Infected Nonhuman Primates.

The protozoan parasite Trypanosoma cruzi causes Chagas disease, uses kissing bugs as a vector, and is maintained in nature by a variety of wildlife reservoirs. Many natural cases of Chagas disease have been reported in NHP at facilities across the southern United States, where infected vectors and wildlife occur. Infection of NHP with T. cruzi can diminish their value as research models and lead to health problems and death. Identifying the modes of transmission and role of wildlife reservoirs in these facilities is therefore critical to guide interventions to reduce transmission. Here we investigated the role of roof rats (Rattus rattus), the most abundant nuisance species at a primate facility in San Antonio, in the maintenance and transmission of T. cruzi. The hearts and blood from the carcasses of the 145 rats collected underwent 2 independent PCR assays for detection of T. cruzi and other trypanosomes. The 145 hearts and 61 blood samples were all negative for T. cruzi. This population sample of 145 subjects would allow the detection of disease prevalence of 0.020 with a confidence level of 95%. The limited active vector surveillance efforts by our team combined with passive surveillance by facility personnel yielded no kissing bugs during the study period. Our results suggest that roof rats are unlikely to be important local reservoirs of T. cruzi at this facility. Further investigation of transmission dynamics across multiple years and more comprehensive vector surveillance is warranted.