Treatment of hepatic encephalopathy by on-line hemodiafiltration: a case series study

<p>Abstract</p> <p>Background</p> <p>It is thought that a good survival rate of patients with acute liver failure can be achieved by establishing an artificial liver support system that reliably compensates liver function until the liver regenerates or a patient undergoes transplantation. We introduced a new artificial liver support system, on-line hemodiafiltration, in patients with acute liver failure.</p> <p>Methods</p> <p>This case series study was conducted from May 2001 to October 2008 at the medical intensive care unit of a tertiary care academic medical center. Seventeen consecutive patients who admitted to our hospital presenting with acute liver failure were treated with artificial liver support including daily on-line hemodiafiltration and plasma exchange.</p> <p>Results</p> <p>After 4.9 ± 0.7 (mean ± SD) on-line hemodiafiltration sessions, 16 of 17 (94.1%) patients completely recovered from hepatic encephalopathy and maintained consciousness for 16.4 ± 3.4 (7-55) days until discontinuation of artificial liver support (a total of 14.4 ± 2.6 [6-47] on-line hemodiafiltration sessions). Significant correlation was observed between the degree of encephalopathy and number of sessions of on-line HDF required for recovery of consciousness. Of the 16 patients who recovered consciousness, 7 fully recovered and returned to society with no cognitive sequelae, 3 died of complications of acute liver failure except brain edema, and the remaining 6 were candidates for liver transplantation; 2 of them received living-related liver transplantation but 4 died without transplantation after discontinuation of therapy.</p> <p>Conclusions</p> <p>On-line hemodiafiltration was effective in patients with acute liver failure, and consciousness was maintained for the duration of artificial liver support, even in those in whom it was considered that hepatic function was completely abolished.</p

Sofosbuvir and Ledipasvir/Sofosbuvir for the treatment of patients with Chronic Genotype 6 Hepatitis C Virus Infection: integrated analysis of Phase 2 and Phase 3 studies

This FREE journal suppl. entitled: Special Issue: The 66th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2015Poster Session 2: Hepatitis C: Therapeutics (Approved Agents): no. 1120INTRODUCTION: Chronic HCV infection is endemic in South East Asia with HCV genotype 6 (GT6) accounting for 18-49% of those infected. In the US and Canada, nearly one-third of immigrants from Southeast Asia with HCV are infected with GT6. Few studies have examined the efficacy and safety of direct acting antiviral (DAA) regimens in GT6 infected patients. The aim of this integrated analysis was to characterize the efficacy and safety of sofosbuvir (SOF)-based regimens in patients with chronic GT6 HCV infection. METHODS: GT6 infected subjects were identified in 5 studies (ATOMIC, NEUTRINO, GS-US-334-0115, ELECTRON2, GS-US-337-0131) and are included in this analysis. Treatment-naïve or treatment-experienced patients received SOF+RBV±Peg-IFNα or ledipasvir (LDV)/SOF for 12-24 weeks. The primary efficacy endpoint in all studies was SVR12. RESULTS: A total of 52 subjects with GT6 HCV infection were identified. The majority were treatment-naïve (94%), Asian (81%), male (58%), and had IL28B CC alleles (81%). The mean age was 50 years (range 26-76) and 10% had cirrhosis. GT6 subtypes included 6a, 6a/b, 6c-1, 6e, 6g, 6j, 6l, 6m, 6o, 6p, 6q, and 6r. The table below presents SVR12 by regimen. One subject in ELECTRON2 withdrew consent after receiving 8 weeks of LDV/SOF and relapsed with the emergent NS5B RAV S282T. All remaining 51 patients achieved SVR12, including 100% (3/3) experienced and 100% (5/5) cirrhotics. CONCLUSIONS: SOF+RBV±Peg-IFNα and LDV/SOF regimens are well-tolerated and highly effective in patients with chronic GT6 HCV infection including those who are treatment experienced and have compensated cirrhosis. These regimens provide multiple therapeutic options for consideration when evaluating optimal therapy for individual patients with chronic GT6 HCV infection. (diagram see journal abstracts)link_to_OA_fulltex

Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1–6 without cirrhosis

Background & Aims Hepatitis C virus (HCV) therapy that is highly efficacious, pangenotypic, with a high barrier to resistance and short treatment duration is desirable. The efficacy and safety of 8- and 12-week treatments with glecaprevir (ABT-493; NS3/4 A protease inhibitor) and pibrentasvir (ABT-530; NS5A inhibitor) were evaluated in non-cirrhotic patients with chronic HCV genotype 1–6 infection. Methods SURVEYOR-I and SURVEYOR-II were phase II, open-label, multicenter, dose-ranging trials including patients with chronic HCV genotype 1–6 infection who were either previously untreated or treated with pegylated interferon plus ribavirin. Patients received once-daily glecaprevir plus pibrentasvir at varying doses with or without ribavirin for 8 or 12 weeks. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at post-treatment week 12 (SVR12). Results Of the 449 patients who received varying doses of glecaprevir plus pibrentasvir, 25%, 29%, 39%, and 8% had HCV genotype 1, 2, 3, and 4–6 infection, respectively. Twelve-week treatment achieved SVR12 in 97–100%, 96–100%, 83–94%, and 100% in genotypes 1, 2, 3, and 4–6, respectively. Eight-week treatment with 300 mg glecaprevir plus 120 mg pibrentasvir in genotype 1-, 2-, or 3-infected patients yielded 97–98% SVR12 with no virologic failures. Three (0.7%) patients discontinued treatment due to adverse events; most events were mild (grade 1) in severity. No post-nadir alanine aminotransferase elevations were observed. Conclusions Glecaprevir plus pibrentasvir was well tolerated and achieved high sustained virologic response rates in HCV genotypes 1–6-infected patients without cirrhosis following 8- or 12-week treatment durations. Lay summary The combination of direct-acting antivirals glecaprevir and pibrentasvir comprise a once-daily, all-oral, pangenotypic treatment for HCV genotype 1–6 infection. This article describes results from two phase II trials investigating a range of doses at treatment durations of 8 or 12 weeks in 449 patients without cirrhosis. Efficacy of the optimal dose, as determined by rates of sustained virologic response at post-treatment week 12, ranged from 92%-100%; treatment was well tolerated and significant laboratory abnormalities were rare. Clinical trial registration: clinicaltrials.gov Identifiers: NCT02243280 and NCT02243293. http://www.clinicaltrials.gov/show/NCT02243280, http://www.clinicaltrials.gov/show/NCT01939197

Treatment efficacy and safety of low dose seladelpar, a selective PPAR-δ agonist, in patients with primary biliary cholangitis: Twelve-week interim analysis of an international, randomized, dose ranging, phase 2 study.

Background. In a previous phase 2 study (NCT02609048), Seladelpar, a selective PPAR-δ agonist, demonstrated overt potent anti-cholestatic activity at doses of 50 and 200 mg/day in primary biliary cholangitis (PBC) patients with an inadequate response to ursodeoxycholic acid (UDCA). However, the study was terminated because of transaminase elevation. This study (NCT02955602) evaluates whether the efficacy of lower doses of Seladelpar can be retained without causing transaminase elevation. Methods. This open-label international study enrolls patients with PBC and an inadequate response to UDCA (alkaline phosphatase -AP- ≥1.67 upper limit of normal), or an intolerance of UDCA. Patients are randomized to Seladelpar 5 mg or 10 mg per day for 26 weeks. A pre-specified interim analysis of safety and efficacy was conducted. The primary outcome of efficacy is the % change from baseline in AP. Secondary outcomes include absolute changes in AP, AP responder analyses; changes in other markers of cholestasis (γ-glutamyl-transpeptidase -GGT-, total bilirubin), alanine amino transferase (ALT), LDL-Cholesterol, C-reactive protein (hs-CRP); and pruritus evaluated with a visual analog scale (VAS) and specific questionnaires. Safety analyses include discontinuation for safety, evaluation of adverse events, and routine laboratory markers. Results. There were no serious adverse events and no safety concerns with transaminase elevation. One patient entered the study with intense pruritus and discontinued Seladelpar 10 mg after 5 days for an increase in pruritus, possibly related to PBC, ciprofloxacin, or Seladelpar. In both groups the median VAS decreased between day 1 and week 12 (from 8 to 3 and from 25 to 6, in the 5 and 10 mg groups, respectively). At baseline, mean (SD) AP were 356 (180) and 260 (60) U/L and mean (SD) ALT were 39 (19) and 52 (27) U/L in the 5 and 10 mg groups, respectively. At 12 weeks, AP fell by 39% and 45% respectively at 5 and 10mg, corresponding to a mean (SD) absolute change of -146 (96) and -107 (33) U/L at 5 and 10 mg, respectively, and 18% and 45% of patients had a normal AP on 5 and 10 mg, respectively. The mean or median∗ % change from baseline to 12 weeks for efficacy parameters are tabulated below. Conclusion. In an interim 12-week analysis, at doses of 5 mg and 10 mg/day, Seladelpar appeared well tolerated and safe, was not associated with pruritus, and retained highly potent anti-cholestatic effects