Tenofovir disoproxil fumarate: in chronic hepatitis B.
ABSTRACT Tenofovir disoproxil fumarate (tenofovir DF) is an orally administered ester prodrug of tenofovir, a nucleotide reverse transcriptase inhibitor that shows potent in vitro activity against both hepatitis B virus (HBV) and HIV-1. As a component of antiretroviral combination therapy regimens, tenofovir DF is well established in the treatment of adults with HIV-1 infection. Tenofovir DF, administered once daily, is also used in the treatment of adults with chronic hepatitis B (CHB) [the main focus of this profile]. In CHB, the efficacy of tenofovir DF against HBV has been evaluated in two large randomized, phase III clinical studies in hepatitis B e antigen (HBeAg)-negative or HBeAg-positive adults, with compensated liver function. The trials (planned duration 8 years) were double-blind for the first 48 weeks; thereafter, patients received open-label tenofovir DF. Results at 48 and 96 weeks are available. In these studies, at week 48, a significantly greater proportion of recipients of tenofovir DF 300 mg once daily than oral adefovir dipivoxil 10 mg once daily achieved a complete response (primary endpoint). A complete response was defined as a reduction from baseline in plasma HBV DNA level to <400 copies/mL and histological improvement (reduction of 2 or more points in Knodell necroinflammatory score without worsening of fibrosis). The efficacy of tenofovir DF in the treatment of CHB was also demonstrated over a 96-week treatment period in both studies. Tenofovir DF was generally well tolerated by adults with CHB in the two phase III trials.
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ABSTRACT: BACKGROUND & AIMS:: Direct-acting anti-viral agents suppress hepatitis B virus (HBV) load but must be given lifelong. Stimulation of the innate immune system could increase its ability to control the virus and have long lasting effects, after a finite regimen. We investigated the effects of immune activation with GS-9620-a potent and selective orally active small molecule agonist of Toll-Like Receptor (TLR)7-in chimpanzees with chronic HBV infection. METHODS:: GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1 week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon (IFN)-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620. RESULTS:: Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of greater than 1 log persisted for months. Serum levels of HB surface antigen and HB e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of IFN-ą and other cytokines and chemokines, and activated ISGs, natural killer cells, and lymphocyte subsets. CONCLUSIONS:: The small molecule GS-9620 activates TLR-7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection.Gastroenterology 02/2013; 144(7). DOI:10.1053/j.gastro.2013.02.003 · 13.93 Impact Factor
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ABSTRACT: Hepatitis B virus (HBV) infections are a major public health problem. It is estimated that there are more than 350 million HBV carriers in the world, of whom one million die annually from HBV-related liver disease . Chronic hepatitis B may cause cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) resulting in significant morbidity and mortality. For this reason the main goals of chronic hepatitis B treatment are a sustained reduction of HBV DNA, biochemical remission, and histological improvement in order to prevent disease progression and long-term complications such as HCC . Tenofovir disoproxil fumarate (tenofovir DF), the oral pro-drug of tenofovir, is a nucleotide reverse transcriptase inhibitor that shows potent in vitro activity against both HBV and immumodeficiency virus (HIV-1) . Tenofovir DF was recently approved by the United States Food and Drug Administration (FDA) for the treatment of chronic HBV infections in adults. Tenofovir has a high genetic barrier and potent viral suppressive effect . Its viral suppression ability in the first weeks after the initial treatment may be important in conditions where urgent viral reduction is necessary. The present study investigated the viral suppression rate sequentially after starting tenofovir treatment. The factors affecting the rapid viral response are also evaluated. This was a prospective trial that recruited patients from the Department of Gastroenterology, School of Medicine, Marmara University between 2008 and 2009. Sixteen patients (Male (n=10), Female (n=6), mean age: 46.9 ± 12.5) with chronic hepatitis B were enrolled in the study and treated with tenofovir (Table I). The median modified histological activity index (HAI) score for the initial liver biopsy was 7.166±5.166. The basal fibrosis stage of the patients was 0 (n=7), 1 (n=7) and 3 (n=2). The patients were diagnosed with chronic hepatitis B using virological, biochemical, and histological parameters. Patients with coexisting hepatitis C, hepatitis D, HIV infection, evidence of hepatocellular carcinoma, decompensated liver disease, or significant renal comorbidity were excluded from the study. Before starting the tenofovir treatment, a detailed physical examination, baseline liver enzyme tests, renal function tests, HBV DNA (TaqMan) measurements, and liver biopsies were carried out, and following the start of tenofovir treatment, weekly outpatient visits included a physical examination, liver enzyme tests, HBV DNA at weeks 2 and 4, followed by monthly follow-up visits testing the same parameters for 12 months. Quantitative HBV DNA levels were measured using the Taqman PCR method. Patients with HBV DNA levels > 6 log were defined as high viral load patients, whereas < 6 log units were defined as low viral load patients. HBeAg status, baseline alanine aminotransferase (ALT) (High ALT 5x upper limit of normal (ULN)), age, gender, and exposure to prior treatment were evaluated for response rates. The statistical analysis was performed by General Linear Models Repeated Measures and Pillar's Trace test. In Pairwase comparisons Bonferroni test was used.Complete treatment response was defined as HBV DNA < 400 copies/ ml. Of the 16 patients enrolled, ten had previously been treated with lamivudine , interferon or/and adefovir , the other six were naive patients . The mean HBV DNA levels at baseline and after 2 weeks, 1, 2, 3, 4, 5, 6, and 12 months were 6.063 ± 1.6 log, 3.438 ± 1.5 log, 2.813 ± 1.6 log, 2.375 ± 1.6 log, 1.688 ± 1.6 log, 1.688 ± 1.6 log, 1.5 ± 1.4 log, 1.25 ± 1.2 log, 0.75 ± 1.055 log respectively (Fig 1). A large and rapid decline (3 log units) was seen in the first 2 weeks, followed by slower rates of decline in the following months. The HBV DNA decline was statistically significant (p <0.001). There was no difference in the rates of decline between patients with either a high or low viral load. However, patients with a low viral load reached one log unit of HBV DNA level more rapidly (in 3 months vs. 6). However, the rate of ALT decline was slower than the rate of HBV DNAMarmara Medical Journal 01/2013; DOI:10.5472/MMJ.2012.02453
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ABSTRACT: Resistance of the reverse transcriptase (RT) of hepatitis B virus (HBV) to the tenofovir nucleotide drug has not been observed since its introduction for treatment of hepatitis B virus (HBV) infection in 2008. In contrast, frequent viral breakthrough and resistance has been documented for adefovir. Our computational study addresses an inventory of the structural differences between these two nucleotide analogues and their binding sites and affinities to wildtype (wt) and mutant RT enzyme structures based on in silico modeling, in comparison with the natural nucleotide substrates.PLoS ONE 09/2014; 9(9):e106324. DOI:10.1371/journal.pone.0106324 · 3.53 Impact Factor