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

A substantial risk in using live attenuated, multiply deleted viruses as vaccines against AIDS is their potential to induce AIDS. A mutant of the simian immunodeficiency virus (SIV) with large deletions in nef and vpr and in the negative regulatory element induced AIDS in six of eight infant macaques vaccinated orally or intravenously. Early signs of immune dysfunction were seen in the remaining two offspring. Prolonged follow-up of sixteen vaccinated adult macaques also showed resurgence of chronic viremia in four animals: two of these developed early signs of disease and one died of AIDS. We conclude that this multiply deleted SIV is pathogenic and that human AIDS vaccines built on similar prototypes may cause AIDS.

Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques

Objective—To determine long-term outcome of dogs with gallbladder mucocele. Design—Retrospective study. Animals—30 dogs with gallbladder mucocele, including 23 that underwent cholecystectomy. Procedure—Medical records were reviewed for signalment, history, and clinical, ultrasonographic, and surgical findings. Follow-up information was obtained for all dogs that survived the perioperative hospitalization period. Results—23 dogs had signs of systemic illness; 7 had no clinical signs. Median values for serum activities of alanine aminotransferase and alkaline phosphatase, serum total bilirubin concentration, and total WBC count were significantly higher among dogs with gallbladder rupture than among dogs without rupture. Sensitivity of sonography for detection of rupture was 85.7%. Overall perioperative mortality rate for dogs that underwent cholecystectomy was 21.7%; mortality rate was not significantly greater for dogs with rupture. Aerobic bacteria were isolated from the bile or gallbladder wall in 8.7% ...

Gallbladder mucocele in dogs: 30 cases (2000-2002).

Contributors vii Preface ix About the CompanionWebsite xi 1. Practical Physical Concepts and Artifacts 1 Marc-Andre d Anjou and Dominique Penninck 2. Eye and Orbit 19 Stefano Pizzirani, Dominique Penninck and Kathy Spaulding 3. Neck 55 Allison Zwingenberger and Olivier Taeymans 4. Thorax 81 Silke Hecht and Dominique Penninck 5. Heart 111 Donald Brown, Hugues Gaillot and Suzanne Cunningham 6. Liver 183 Marc-Andre d Anjou and Dominique Penninck 7. Spleen 239 Silke Hecht andWilfried Mai 8. Gastrointestinal Tract 259 Dominique Penninck and Marc-Andre d Anjou 9. Pancreas 309 Dominique Penninck and Marc-Andre d Anjou 10. Kidneys and Ureters 331 Marc-Andre d Anjou and Dominique Penninck 11. Bladder and Urethra 363 James Sutherland-Smith and Dominique Penninck 12. Adrenal Glands 387 Marc-Andre d Anjou and Dominique Penninck 13. Female Reproductive Tract 403 Rachel Pollard and Silke Hecht 14. Male Reproductive Tract 423 Silke Hecht and Rachel Pollard 15. Abdominal Cavity, Lymph Nodes, and Great Vessels 455 Marc-Andre d Anjou and Eric Norman Carmel 16. Clinical Applications of Contrast Ultrasound 481 Robert O Brien and Gabriela Seiler 17. Musculoskeletal System 495 Marc-Andre d Anjou and Laurent Blond 18. Spine and Peripheral Nerves 545 Judith Hudson and Marc-Andre d Anjou Index 563

Atlas of small animal ultrasonography

The value of ultrasonography was evaluated in 85 dogs and 17 cats presented with a clinically suspected portosystemic shunt (PSS). A PSS was confirmed in 50 dogs and nine cats (single congenital extrahepatic in 42, single congenital intrahepatic in 11, and multiple acquired in six). Six dogs and one cat had hepatic microvascular dysplasia, and 29 dogs and seven cats had a normal portal system. Ultrasonography was 92% sensitive, 98% specific, and had positive and negative predictive values of 98% and 89%, respectively, in identifying PSS, with an overall accuracy of 95%. When a PSS was identified with ultrasonography, extrahepatic, intrahepatic, and multiple acquired PSS could be correctly differentiated in 53/54 patients (98%). The combination of a small liver, large kidneys, and uroliths had positive and negative predictive values of 100% and 51% for the presence of a congenital PSS in dogs. The portal vein/aorta (PV/Ao) and portal vein/caudal vena cava (PV/ CVC) ratios were smaller in animals with extrahepatic PSSs compared with animals with microvascular dysplasia, intrahepatic PSSs and those without portal venous anomalies (P or = 0.8 and > or = 0.75, respectively, did not have an extrahepatic PSS. Reduced or reversed portal flow was seen in four of four patients with multiple acquired PSSs secondary to portal hypertension. The presence of turbulence in the caudal vena cava of dogs had positive and negative predictive values of 91% and 84%, respectively, for the presence of any PSS terminating into that vein.

Ultrasonographic diagnosis of portosystemic shunting in dogs and cats

Objective To evaluate response to chemotherapy in cats with alimentary lymphoma and to determine factors associated with survival time. Design Retrospective case series. Animals 28 cats with alimentary lymphoma that underwent chemotherapy. Results In all cats, the diagnosis had been established by means of cytologic or histologic examination of ultrasound-guided aspirates and biopsy specimens (18 cats), histologic examination of surgically obtained biopsy specimens (7 cats), or examination of specimens obtained endoscopically (3 cats). Clinical signs included anorexia, weight loss, vomiting, and diarrhea. Twenty-seven cats were treated with vincristine sulfate, cyclophosphamide, and prednisone; 1 was treated with chlorambucil and prednisone. Survival time ranged from 2 to 2,120 days (median, 50 days). Nine cats achieved complete remission (remission time ranged from 30 to 1,700 days; median, 213 days), 2 achieved partial remission, and 17 failed to respond to chemotherapy. Sex, FeLV status, hematocrit, serum total protein concentration, site and extent of gastrointestinal involvement, and clinical stage were not found to be associated with survival time. Clinical implications Cats with alimentary lymphoma are poorly responsive to treatment with vincristine, cyclophosphamide, and prednisone; however, a small subset of cats may have long survival times.

Dominique G. Penninck

Papers

Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques

Gallbladder mucocele in dogs: 30 cases (2000-2002).

Atlas of small animal ultrasonography

Ultrasonographic diagnosis of portosystemic shunting in dogs and cats

Alimentary lymphoma in cats: 28 cases (1988-1993).