Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis MSc, ELS, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin

O papel da oxigenação hiperbárica na estrutura do fígado e baço após ligadura das veias hepáticas: estudo em ratos The role of hyperbaric oxygenation in the liver and spleen structure after hepatic vein ligation: study in rats

OBJETIVO: Avaliação morfológica do fígado e baço de ratos submetidos à oxigenoterapia hiperbárica após a ligadura das veias hepáticas. MÉTODO: Foram utilizados 30 animais machos adultos da espécie Holtzman, distribuídos aleatoriamente em dois grupos de 15 animais cada, assim designados: grupo 1 - ligadura das veias hepáticas; grupo 2 - ligadura das veias hepáticas associada à oxigenoterapia hiperbárica. Todos os animais foram submetidos à anestesia geral por meio de solução contendo cloridrato de cetamina (40 mg/ml) e cloridrato de meperidina (10 mg/ml) na dose de 50 mg/kg/peso, laparotomia mediana e ligadura das veias hepáticas. A oxigenoterapia hiperbárica foi aplicada nos animais do grupo 2, a partir da oitava hora do pós-operatório, por 120 minutos, sendo 90 minutos sob pressão de 2,5 atmosferas e 15 minutos no início e final da terapêutica, para promover a compressão e descompressão gradativa no período de 20 dias consecutivos. No 21&deg; dia de pós-operatório, os animais foram mortos por inalação de éter e submetidos à laparotomia e extirpação dos fígados e baços para exame histológico. Foram comparados os resultados da histologia hepática e esplênica aplicando-se o teste exato de Fisher, considerando-se a diferença significante de P < 0,05. RESULTADOS: Os exames histológicos dos fígados e baços dos animais dos grupos 1 e 2 mostraram as seguintes alterações: presença de trombose nas veias hepática, porta e centro-lobular em cinco (33,3%) animais do grupo 1 e ausência no grupo 2; presença de necrose dos hepatócitos caracterizada como acentuada em sete animais (46,7%) e leve em oito (53,3%) animais do grupo 1, enquanto que, em todos os animais do grupo 2, esta alteração foi caracterizada como leve; presença de células de Kupffer muito proeminentes e hipertrofiadas em 14 (93,3%) animais do grupo 1 e pouco proeminentes e hipertrofiadas em todos os animais do grupo 2; congestão da polpa vermelha considerada acentuada em seis (40%) e moderada em nove (60%) animais do grupo 1 e em todos os animais do grupo 2; hemossiderose moderada ou acentuada em 14 (93,3%) animais do grupo 1 e leve em todos os animais do grupo 2. As análises estatísticas realizadas entre os dois grupos mostraram diferenças significativas em todas a variáveis estudadas (P < 0,05). CONCLUSÕES: A oxigenoterapia hiperbárica em ratos submetidos à ligadura das veias hepáticas atenuou os efeitos deletérios e precoces sobre o fígado e o baço, analisada pela histologia destes órgãos.<br>OBJECTIVE: Liver and spleen morphologic evaluation of rats submitted to hyperbaric oxygen therapy after hepatic vein ligation. METHOD: Thirty Holtzman adult male rats were used, distributed into two groups of 15 animals: group 1 - hepatic vein ligation; group 2 - hepatic vein ligation associated with hyperbaric oxygen therapy. All animals received general anesthesia by a solution composed of ketamine chloride (40 mg/ml) and meperidine chloride (10 mg/ml) in a dose of 50/mg/weight, and were submitted to median laparotomy and hepatic vein ligation. Group 2 animals were submitted to hyperbaric oxygen therapy, 8 hours after the operation, 90 minutes at 2.5 atmosphere pressure and 15 minutes at the onset and end of the therapy, in a total of 120 minutes, in order to promote the gradual compression and decompression in 20 consecutive days. On the 21st preoperative day, the animals were sacrificed by ether inhalation and submitted to laparotomy and stripping of liver and spleen for histological study. The results of the histological study of livers and spleens were compared using Fisher's exact test. Statistically significant difference was considered when P < 0.05. RESULTS: The histological studies made in the livers and spleens of animals from both groups showed the following alterations: presence of thrombosis of hepatic, portal and central lobular veins in five (33.3%) group 1 animals and absence in group 2 animals; very extensive necrosis of liver cells in seven (46.7%) group 1 animals, and light in eight (53.3%), whereas for all group 2 animals such alteration was considered light; Kupffer cells developed and hypertrophied in 14 (93.3%) group 1 animals and slightly developed and hypertrophied in all group 2 animals; high congestion of the spleen purple in six (40%) and moderate in nine (60%) group 1 animals, whereas all group 2 animals had moderate congestion; moderate or severe hemosiderosis in 14 (93.3%) group 1 animals and mild hemosiderosis in all group 2 animals. The statistical analyses performed between both groups showed significant differences (P < 0.05) for all variables. CONCLUSIONS: The hyperbaric oxygen therapy applied in rats submitted to hepatic vein ligation mitigated its early deleterious effects on the liver and spleen, which was confirmed by the histological study

A proposal of multiplace hyperbaric chamber for animal experimentation and veterinary use

To develop a project of hyperbaric chamber that allows its safe and reliable use in veterinary and animal experimentation. Methods: Based on the technical specifications for the construction of hyperbaric chambers for human beings, it has been developed a design of a chamber with dimensions and characteristics for the use of a midsize animal, (dog or pig), as well as a multiple chamber for the use in small animals (mice, rats, hamsters, rabbits or cats). The technical specifications allowed that the chamber could be used both for veterinary use and for use in experiments on Health Sciences. Results: A chamber with the following characteristics was built: ASTM A36 steel for the manufacture of the master cylinder and rear cover; front door built in 5052 aluminum; internal diameter of 50.5 cm and 83.0 cm in length; weight 160Kg and internal area of 150cm3; internal space to accommodate 2 acrylic baskets; 150mm high, 280mm wide and 690mm in length. It was capable of supporting a maximum of hydrostatic pressure test of 3.0 to 4.0 BAR ACT and maximum working pressure of 2.0 BAR or 3.0 ACT; equipped with security devices and valves that triggers with load of 2.2 BAR or 3.2 ACT. Tests for engineering and biological use on animals showed the effectiveness of the device. Conclusion: The development of the project enabled the construction of a hyperbaric chamber with security features and reliability comparable to those required by the legal and technical specifications of a hyperbaric chamber human use.Desenvolver um projeto de câmara hiperbárica que permita o seu uso seguro e confiável em veterinária e em animais de experimentação de pequeno e médio porte. Métodos: Baseados em especificações técnicas de construção de câmaras hiperbáricas de seres humanos, foi desenvolvido uma adaptação de projeto de uma câmara com dimensões e características para uso em animal de médio porte (cão ou porco), assim como câmara múltipla para animais de pequeno porte (camundongos, ratos, hamsters, coelhos ou gatos). O atendimento às especificações técnicas deve permitir a sua utilização tanto para uso veterinário quanto para uso em experimentação em Ciências da Saúde. Resultados: Uma câmara com as seguintes características foi construída: aço ASTM A36 para a confecção do cilindro principal e tampo traseiro, tampo frontal (porta) construído em alumínio 5052, diâmetro interno de 50,5cm e 83,0cm de comprimento; peso de 160Kg e espaço interno de 150cm3; espaço para acomodar 2 cestas de acrílico de 150mm de altura, 280mm de largura e 690mm de comprimento; capacidade para suportar um máximo de pressão hidrostática teste de 3,0BAR ou 4,0 ACT e uma pressão máxima de trabalho de 2,0 BAR ou 3,0 ACT; equipado com dispositivos e válvulas de segurança que disparam com carga de 2,2 BAR ou 3,2 ACT. Os testes de engenharia e de uso biológico com animais mostraram a efetividade do equipamento. Conclusão: O desenvolvimento do projeto permitiu a confecção de uma câmara hiperbárica com características de segurança e confiabilidade comparável às exigidas pelas especificações técnicas e legais de uma câmara para tratamento hiperbárico