Review of recent research on hepatitis C therapy for 54th annual meeting of the American association for the study of liver diseases

The latest advances in hepatology were presented in oral and poster presentations. In order to cover the varying subspecialties, the sessions were divided into various sections including 'Acute Liver Failure and Artificial Liver Support', 'Biliary Tract and Immunologic Liver Diseases', 'Cellular and Molecular Biology', 'Clinical and Experimental Hepatobiliary Surgery', 'Hepatotoxicity and Cell Death', 'Transport and Biliary Physiology', 'Viral Hepatitis', 'Evaluation and Treatment of Biliary Disease', 'Necrosis/Apoptosis', 'Portal Hypertension', 'Blood Flow and Vascular Disorders of Cirrhosis', 'Liver Transplantation', 'Fibrogenesis', 'Hepatocellular Carcinoma', 'Metabolism and Genetic Disease', and 'Public Policy, Epidemiology and Decision Analysis'. Drug therapy focused on treatments for viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis, and recurrent viral disease following liver transplant. High dose interferon therapy or various combinations of interferon/ribavirin (ICN Pharmaceuticals Inc) therapy seem to offer the best current therapy for chronic HCV. PEGylated interferon (F Hoffmann-La Roche Ltd) offers hope for treatment and histologic improvement in patients with chronic HCV. Following liver transplantation, combination interferon/ribavirin therapy may also find success, but caution with new potent immunosuppressant monoclonal antibodies is advised. For HBV, intramuscular H-BIG (NABI) appears to be effective and less costly than iv H-BIG administration following liver transplantation. Percutaneous radiofrequency ablation may hold promise over conventional ethanol injection therapy for small hepatocellular carcinoma. Autoimmune hepatitis may respond to tacrolimus therapy whereas budesonide therapy did not provide any advantage to prednisone therapy. For primary biliary cirrhosis, eicosapentate and ursodeoxycholic acid may provide benefit to some patients while silymarin from milk thistle did not provide any additional benefit. In primary sclerosing cholangitis, high dose ursodeoxycholic acid may provide benefit. Ursodeoxycholic acid may also provide benefit for mothers with intrahepatic cholestasis of pregnancy by decreasing pruritus, lowering laboratory values and allowing deliveries to occur closer to term.

Digestive disease week 2000. American Association for the Study of Liver Diseases

Although 13 years have passed since identification of human immunodeficiency virus-1 (HIV-1) as the cause of AIDS, we do not yet know how HIV kills its primary target, the T cell that carries the CD4 antigen. We and others have shown an increase in the percentage of apoptotic cells among circulating CD4+ (and CD8+) T cells of HIV-seropositive individuals and an increase in frequency of apoptosis with disease progression. However, it is not known if this apoptosis occurs in infected or uninfected T cells. We show here, using in situ labelling of lymph nodes from HIV-infected children and SIV-infected macaques, that apoptosis occurs predominantly in bystander cells and not in the productively infected cells themselves. These data have implications for pathogenesis and therapy, namely, arguing that rational drug therapy may involve combination agents targeting viral replication in infected cells and apoptosis of uninfected cells.

Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.

Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs during gestation, intrapartum and postpartum (by breast-feeding), 50-70% of all infected children seem to acquire HIV-1 shortly before or during delivery. Epidemiological evidence indicates that mucosal exposure is an important aspect of intrapartum HIV transmission. A simian immunodeficiency virus (SIV) macaque model has been developed that mimics the mucosal exposure that can occur during intrapartum HIV-1 transmission. To develop immunoprophylaxis against intrapartum HIV-1 transmission, we used SHIV-vpu+ (refs. 5,6), a chimeric simian-human virus that encodes the env gene of HIV-IIIB. Several combinations of human monoclonal antibodies against HIV-1 have been identified that neutralize SHIV-vpu+ completely in vitro through synergistic interaction. Here, we treated four pregnant macaques with a triple combination of the human IgG1 monoclonal antibodies F105, 2G12 and 2F5. All four macaques were protected against intravenous SHIV-vpu+ challenge after delivery. The infants received monoclonal antibodies after birth and were challenged orally with SHIV-vpu+ shortly thereafter. We found no evidence of infection in any infant during 6 months of follow-up. This demonstrates that IgG1 monoclonal antibodies protect against mucosal lentivirus challenge in neonates. We conclude that epitopes recognized by the three monoclonal antibodies are important determinants for achieving substantial protection, thus providing a rational basis for AIDS vaccine development.

Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection.

Adult macaques do not develop disease after infection with a nef deletion mutant of the simian immunodeficiency virus (SIV) and are protected against challenge with pathogenic virus. This finding led to the proposal to use nef-deleted viruses as live, attenuated vaccines to prevent human acquired immunodeficiency syndrome (AIDS). In contrast, neonatal macaques developed persistently high levels of viremia after oral exposure to and SIV nef, vpr, and negative regulatory element (NRE) deletion mutant. Severe hemolytic anemia, thrombocytopenia, and CD4+ T cell depletion were observed, indicating that neither nef nor vpr determine pathogenicity in neonates. Because such constructs have retained their pathogenic potential, they should not be used as candidate live, attenuated virus vaccines against human AIDS.

https://science.sciencemag.org/content/sci/267/5205/1820.full.pdf

Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques

Historical, physical examination, clinicopathologic, radiographic and ultrasonographic findings of 13 dogs with hepatic abscesses were reviewed. Liver abscessation was characterized by number, size, shape, echogenicity and location. Solitary lesions greater than 3 cm were more common than multiple ones. The abscesses were mainly poorly echogenic lesions, often with central cavitation. The shape of the lesion ranged from round to oval or irregular. Enhancement artifact, abdominal effusion, regional lymphadenopathy and hyperechoic perihepatic fat, were identified in several dogs. Ultrasound-guided aspiration was performed in 10 of 13 dogs, and confirmed abscessation with cytologic and microbiologic evaluation. Ultrasound-guided percutaneous drainage of abscesses was performed as an adjunct to medical management in four dogs.

Hepatic abscesses in 13 dogs: a review of the ultrasonographic findings, clinical data and therapeutic options

The rising prevalence of infection with the human immunodeficiency virus type 1 (HIV-1) in young women will increase the number of infected children worldwide. Because HIV-1 seems to be transmitted mostly intrapartum, fetal infection probably occurs mainly via skin or mucous membrane exposure. A model for this route of fetal infection has been established in primates. After injecting the simian immunodeficiency virus (SIV) into amniotic fluid during late gestation, six of seven rhesus monkeys were born infected. All infected neonates were viable and showed signs of disease, such as low birth weights, lymphadenopathy, and rashes. Cytotoxic T-cell responses to SIV were absent in neonates, but present in mothers. The high fetal infection rate allows studies of lentiviral immunopathogenesis during ontogeny and the development of strategies to prevent maternal HIV-1 transmission.

Simian immunodeficiency virus infection via amniotic fluid: a model to study fetal immunopathogenesis and prophylaxis.

Background: Portal vein thrombosis (PVT) in cats is sparsely reported.

Purpose of Study: To evaluate the clinical signs and diseases associated with PVT in cats.

Animals: 6 client-owned cats.

Methods: Medical records for cats with a portal vein thrombus diagnosed on abdominal ultrasound or at necropsy were reviewed. Signalment, historical data, underlying disorders, clinical findings, clinicopathologic and histopathologic data, diagnostic imaging findings, treatment, and outcome were recorded.

Results: All 6 cats identified with PVT also had hepatic disease. Evidence of a congenital portosystemic shunt was present in 3/6 cats. Two cats had primary or metastatic hepatic neoplasia. One cat had acute cholangitis, acute pancreatitis, and locally extensive acute centrilobular hepatic necrosis. Two cats were suspected to have acute thrombi and 4 cats had chronic thrombi.

Conclusion and Clinical Significance: PVT might be an important concurrent finding in cats with hepatic disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1939-1676.2008.0048.x

Portal Vein Thrombosis in Cats: 6 Cases (2001–2006)

Transabdominal ultrasonography is used increasingly for the evaluation of gastrointestinal disorders in small animals, including neoplasms such as lymphosarcoma, carcinoma, and smooth muscle tumors (leiomyoma, leiomyosarcoma). An updated summary of the clinical studies currently investigating the use of ultrasonography to detect and to characterize gastrointestinal neoplasia is presented in this article.

Characterization of gastrointestinal tumors.

The purpose of this study was to evaluate the usefulness of ultrasound-guided fine-needle aspiration biopsy and core biopsy in the diagnosis of infiltrative gastrointestinal diseases. Six dogs and seven cats with clinical signs of gastrointestinal disease underwent ultrasonography and intestinal lesions were identified. One or more ultrasound-guided fine-needle aspiration biopsy and/or core biopsy procedures were performed in each patient. Each patient also underwent one of the following additional procedures for comparison of results: 1) surgery (n=4), 2) endoscopy (n=2), 3) post mortem exam (n=3), and, 4) for lymphoma diagnosed with ultrasound-guided procedures, response to chemotherapy (n=4). Correct diagnoses were obtained in nine of the 13 patients, incorrect diagnoses in two of the 13 patients, and inconclusive diagnoses in two of the thirteen patients. Of the 16 total ultrasound-guided procedures performed, ten were confirmed as correct, three as incorrect, and three were non-diagnostic. Intestinal lesions with bowel wall thickness greater than 2.0 cm had a higher percentage of correct diagnoses than lesions of lesser wall thickness. Gastric lesions had a higher percentage of correct diagnoses than small and large intestinal lesions. Malignant lesions had a higher percentage of correct diagnoses than benign lesions. There were no complications. Ultrasound-guided gastrointestinal fine-needle aspiration biopsy and core biopsy appears to be a safe, accurate, and rapid procedure for use in the diagnosis of infiltrative gastrointestinal disease.

Dominique G. Penninck

Papers

Hepatic abscesses in 13 dogs: a review of the ultrasonographic findings, clinical data and therapeutic options

Simian immunodeficiency virus infection via amniotic fluid: a model to study fetal immunopathogenesis and prophylaxis.

Portal Vein Thrombosis in Cats: 6 Cases (2001–2006)

Characterization of gastrointestinal tumors.

Use of ultrasound-guided fine-needle aspiration biopsy and automated core biopsy for the diagnosis of gastrointestinal diseases in small animals