RESUMO
OBJECTIVES: Results from two Phase 3 studies, through 2 years, in chronic hepatitis B infection (CHB) showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. Here, we report updated results through 5 years. METHODS: Patients with HBeAg-negative or -positive CHB with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses. RESULTS: Of 1298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDFâTAF3y) or year 3 (n = 202; TDFâTAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA < 29 IU/mL (missing = failure) in the TAF, TDFâTAF3y, and TDFâTAF2y groups, respectively; no patient developed TAF or TDF resistance. Median eGFR (by Cockcroft-Gault) declined < 2.5 mL/min, and mean declines of < 1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDFâTAF groups had improvements in these parameters at year 5 after switching to OL TAF. CONCLUSIONS: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety.
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Butyrate, a histone deacetylase inhibitor, has several therapeutic applications, including cancer. However, the effect of butyrate in HBV replication is not known so far. It was hypothesized that butyrate might inhibit HBV replication and host cell proliferation via SIRT-1. It was found that the increased expression of SIRT-1 in Hep G2.2.15 cells (HBV expressing cells) than Hep G2 cells. Next the expression of SIRT-1 and Acetylated p53 (Ac-p53) were measured in the liver biopsy samples of chronic hepatitis B (CHB) patients with high viral load and compared to CHB patients with low viral load and found that there was a high SIRT-1 expression and a low Ac-p53 levels in CHB patients with high viral load compared to CHB patients with low viral load. Incubation of butyrate inhibited SIRT-1 expression and cell proliferation. Inhibition of SIRT-1 by butyrate or SIRT-1 siRNA increased the levels of Ac-p53. The elevated Ac-p53 decreased p-akt, cyclin D1, and thereby inhibited cell proliferation. Incubation of butyrate with Hep G2.2.15 cells also inhibited HBx protein expression, HBV-DNA and hepatitis B surface antigen (HBsAg). Taken together, the data showed that butyrate inhibited HBV replication and cell proliferation by inhibiting SIRT-1 expression in hepatoma cells.
Assuntos
Butiratos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Hepatite B Crônica/complicações , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Replicação Viral/efeitos dos fármacos , Acetilação , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Sirtuína 1/genética , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND & AIMS: Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double-blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials. METHODS: In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25â¯mg TAF or 300â¯mg TDF in a double-blinded fashion. One study enrolled HBeAg-positive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population. RESULTS: At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference -2.2% (95% CI -8.3 to 3.9%; pâ¯=â¯0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference -0.6% (95% CI -7.0 to 5.8%; pâ¯=â¯0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change -0.33% vs. -2.51%; pâ¯<0.001) and lumbar spine (mean % change -0.75% vs. -2.57%; pâ¯<0.001), as well as a significantly smaller median change in estimated glomerular filtration rate by Cockcroft-Gault method (-1.2 vs. -4.8â¯mg/dl; pâ¯<0.001). CONCLUSION: In patients with HBV infection, TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341. LAY SUMMARY: At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued improved renal and bone safety. Registration: Clinicaltrials.gov number: NCT01940471 and NCT01940341.
Assuntos
Adenina/análogos & derivados , Hepatite B/tratamento farmacológico , Tenofovir/uso terapêutico , Adenina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina , Alanina Transaminase/sangue , Densidade Óssea/efeitos dos fármacos , DNA Viral/análise , Método Duplo-Cego , Farmacorresistência Viral , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hepatite B/virologia , Antígenos E da Hepatite B/análise , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: There is limited data on the safety and efficacy of metabolic and bariatric (MBS) surgery in patients with advanced liver fibrosis. METHODS: This is a retrospective analysis of data of patients with advanced liver fibrosis undergoing MBS at a tertiary care centre. Weight loss and complications were analysed. Transient elastography and liver biopsy findings 1 year after surgery were compared with baseline. RESULTS: Twenty-two patients had cirrhosis and 16 had stage 3 fibrosis; all were Child Pugh A. Majority (76%) underwent sleeve gastrectomy. Mean excess BMI loss was 65.8 ± 18.9%. There were no leaks or 30-day mortality. One patient with cirrhosis had late mortality due to liver decompensation. Preoperative and postoperative median LSM were 15.5 kPa (interquartile range IQR = 24.4-11.6) and 10.9 kPa (IQR 19.3-7.6), respectively. Preoperative and postoperative median CAP were 352.5 dB/m (IQR = 372-315.5) and 303 dB/m (IQR 331-269.5), respectively. On follow-up biopsy, nine of twelve patients had improvement in fibrosis, while three had no change. Four out of five patients in the cirrhotic cohort had improvement in fibrosis stage and LSM improved in all of them. Five out of seven patients with stage 3 fibrosis had an improvement in fibrosis stage and none progressed to cirrhosis. LSM improved in three of these five patients. CONCLUSION: MBS has the potential to ameliorate advanced liver fibrosis, including cirrhosis. Transient elastography can be used as an effective tool for screening and follow-up of liver disease in patients undergoing MBS.