A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis.

BACKGROUND AND AIMS: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population. APPROACH AND RESULTS: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n = 7), 1 mg (n = 42), 3 mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was -0.5 (95% CI, -0.7 to -0.2; p = 0.0003) between the 3 mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1 mg, and 3 mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1 mg, and 3 mg group, respectively, discontinued due to treatment-related adverse events. CONCLUSIONS: Aldafermin 3 mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.

Sofosbuvir with peginterferon-ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis.

UNLABELLED: Sofosbuvir (SOF) in combination with ribavirin (RBV) for 12 or 24 weeks is the current standard of care for patients infected with hepatitis C virus (HCV) genotypes 2 and 3, respectively. However, in clinical trials treatment-experienced patients, particularly those with cirrhosis, had suboptimal sustained virological response (SVR) rates. We assessed the efficacy and safety of sofosbuvir plus peginterferon and ribavirin (SOF+Peg-IFN+RBV) administered for 12 weeks to treatment-experienced patients with HCV genotypes 2 and 3, with and without cirrhosis. We enrolled 47 patients in this open-label, nonrandomized, uncontrolled phase 2 study. The primary endpoint was the proportion of patients with SVR at 12 weeks after cessation of study treatment (SVR12). The overall rate of SVR12 was 89% (95% confidence interval [CI]: 77-97). Rates of SVR12 were higher in patients with genotype 2 than in those with genotype 3, 96% (95% CI: 78-100) and 83% (95% CI: 62-95), respectively. Rates of SVR12 were similar in patients with and without cirrhosis: for genotype 2, 93% of patients with cirrhosis and 100% of patients without cirrhosis achieved SVR12, and for genotype 3, the SVR12 rate was 83% in patients both with and without cirrhosis. One patient discontinued study treatment because of an adverse event and four patients experienced serious adverse events. The most common adverse events were influenza-like illness, fatigue, anemia, and neutropenia. CONCLUSION: In treatment-experienced patients with HCV genotypes 2 and 3, 12-week administration of SOF+Peg-IFN+RBV provided high SVR rates, irrespective of cirrhosis status. No safety concerns were identified.

Response-guided therapy in patients with genotype 1 hepatitis C virus: current status and future prospects.

On-treatment responses to antiviral therapy are used to determine duration of therapy in patients being treated for genotype 1 hepatitis C virus infection. Such use of response-guided therapy has successfully reduced exposure of patients to the side-effects of pegylated interferon and ribavirin without jeopardizing overall treatment success. Response-guided therapy is an integral part of treatment using the current standard treatments involving the direct-acting antiviral (DAA) agents--boceprevir or telaprevir--combined with pegylated interferon/ribavirin. Improvements in our understanding of the kinetics of viral load during antiviral therapy have shown us that more potent suppression of viral replication increases the rate of viral eradication, providing impetus for the development of more potent DAAs. Emerging results from clinical trials of these agents--including trials of interferon-free DAA combinations--suggest that very high rates of viral eradication are achievable, even in patients who failed to respond to previous courses of interferon-based therapy. Furthermore, because of these high rates of treatment success, on-treatment assessment of viral response may become unnecessary. The field of hepatitis C virus therapy is evolving rapidly and current trends indicate that the era of simple treatment regimens with high rates of success and good tolerability are near.

Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial.

BACKGROUND: Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen--a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin--in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen. METHODS: For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329978. FINDINGS: In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75-100) in group 1, by 21 (100%) of 21 patients (84-100) in group 2, and by 18 (95%) of 19 patients (74-100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74-100) in group 4 and by all 21 (100%) of 21 patients (84-100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment. INTERPRETATION: These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin. FUNDING: Gilead Sciences.

Cyclophilin inhibitors for hepatitis C therapy.

This article highlights a unique time in the history of hepatitis C therapy. In the last few years new families of direct-acting antivirals have emerged, that block different viral proteins to interrupt viral replication, such as protease, NS5A inhibitors, and NS5B inhibitors. There are few host-targeted agents in development; currently cyclophilin inhibitors are the only host-targeted agents in advanced development. One of these new agents has now progressed to phase 3 clinical trials; in this review article their potential role as a future therapy to cure hepatitis C is discussed.

The HCV NS5B nucleoside and non-nucleoside inhibitors.

This article introduces one of the most diverse classes of direct-acting antivirals for hepatitis C, the nucleoside and non-nucleoside NS5B polymerase inhibitors. Through a systematic review of the published literature, we describe their structure, mechanism of action, issues with resistance, and clinical effectiveness shown in the latest clinical trials. Direct-acting antiviral combination trials that have already shown some early promising results even in the setting of interferon-sparing antiviral regimens are discussed.

Liver transplantation for sinusoidal obstructive syndrome (veno-occlusive disease): case report with review of the literature and the UNOS database.

BACKGROUND: Severe sinusoidal obstructive syndrome (SOS) is a life-threatening complication of stem cell transplantation. We report the case of a young man transplanted for SOS. METHOD: A single chart review with query of the United Network of Organ Sharing database and review of the medical literature. CASE: A 23-yr-old male diagnosed with chronic myeloid leukemia underwent a matched unrelated stem cell transplant. The conditioning regimen included high-dose cyclophosphamide and busulfan. Within one month, he developed painful hepatomegaly, jaundice, ascites, and weight gain, and was diagnosed with biopsy-proven SOS. Despite therapy with defibrotide, he continued to deteriorate with the development of progressive renal failure and encephalopathy. The patient underwent orthotopic liver transplantation. After surgery, he developed cytomegalovirus infection and six wk later presented with a bile leak, hepatic artery thrombosis, and a liver abscess. A repeat bone marrow biopsy showed no evidence of recurrent disease. Although the patient was listed for re-transplantation, he succumbed prior to an organ becoming available. CONCLUSION: Severe SOS in the setting of bone marrow transplantation portends a poor prognosis. Careful patient selection, timing, and perhaps less immunosuppression should be considered when performing a liver transplantation in the setting of severe SOS.

Budd-Chiari syndrome: illustrated review of current management.

Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction at any level from the small hepatic veins to the atriocaval junction. BCS is a complex disease with a wide spectrum of aetiologies and presentations. This article reviews the current literature with respect to presentation, management and prognosis of the disease. Medical, interventional and surgical management of BCS is discussed. Particular attention is paid to interventional and surgical aspects of management. The review is augmented by images, which provide a clinical corollary to the text.

Differences in long-term survival after transjugular intrahepatic portosystemic shunt for refractory ascites and variceal bleed.

OBJECTIVE: To compare the survival after transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites and variceal bleed, and to identify the factors predictive of survival. METHODS: Single tertiary center, retrospective-prospective study. Chart review was performed on all patients who underwent TIPS between 1993 and 2000 and prospective follow-up to determine survival. Pre- and post-TIPS clinical parameters were compared and Kaplan-Meier analysis was applied to compare the survival of both groups. Cox regression was used to identify predictors of survival after TIPS. RESULTS: A total of 163 patients were included, 62 with refractory ascites and 101 with variceal bleed. Both groups had similar age (48.2 vs 48.9 year; P = 0.65) and consisted of predominantly Caucasians (51%) and Mexican-Americans (39%). More than 75% had chronic hepatitis C, alcoholic liver disease or both. Overall, the median survival was significantly better for variceal bleed (2 years) compared with refractory ascites (6 months) (P < 0.001). This survival advantage persisted in patients with Mayo risk score greater than 1.17. Transjugular intrahepatic portosystemic shunt improved severe ascites in 45% of patients (P = 0.03). Mayo risk score was highly predictive of survival after TIPS with a hazard ratio of 2.3, followed by Child-Pugh score, creatinine, albumin and ethnicity, with better survival among Mexican-Americans. Shunt dysfunction (31%) and hepatic encephalopathy (27%) were the most common complications of TIPS. CONCLUSIONS: Patients who received TIPS for variceal bleed had significantly longer survival compared with those for refractory ascites. Mexican-Americans had an improved long-term survival compared with Caucasians. The reason for this ethnic difference in survival is unclear and warrants further prospective evaluation.

Antiviral therapy for treatment-naïve hepatitis B virus patients.

Hepatitis B virus infection is a major public health problem worldwide,responsible for considerable morbidity and mortality from chronic liver disease. It is estimated that there are 350 million hepatitis B virus carriers globally. The prevalence of chronic hepatitis B infection varies greatly in different regions of the world. In the United States, approximately 1.5 million people are infected and 50,000 to 100,000 new cases are reported annually despite the availability of effective vaccines. This article reviews various antiviral therapies for treatment naïve hepatitis B virus patients.