Sustained virological response (SVR) improves survival in post‐liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the ...performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post‐SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after‐SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus–infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post‐SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty‐seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%‐85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post‐SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post‐SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). Conclusion: In conclusion, SVR post‐LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683‐1694).
Summary Background Chronic hepatitis C virus (HCV) infection in patients with stage 4–5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and ...chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4–5 chronic kidney disease. Methods In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4–5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov , number NCT02092350. Findings 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up n=2, non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3–100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. Interpretation Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4–5 chronic kidney disease. Funding Merck Sharp & Dohme Corp.
Background and Aims
A variant (p.Arg225Trp) of peroxisomal acyl‐CoA oxidase 2 (ACOX2), involved in bile acid (BA) side‐chain shortening, has been associated with unexplained persistent ...hypertransaminasemia and accumulation of C27‐BAs, mainly 3α,7α,12α‐trihydroxy‐5β‐cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency‐associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration.
Methods and Results
Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27‐BA levels (>50% of total BAs) were identified by high‐performance liquid chromatography‐mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH‐7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1‐S/XBP1‐U ratio), and BAXα expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt‐based cell viability test). THCA‐induced cell toxicity was higher than that of major C24‐BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site‐directed mutagenesis) and expressed in HuH‐7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH.
Conclusions
Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.
Virus‐induced heterologous immunity is considered a barrier to transplantation tolerance. Yet, hepatitis C (HCV)‐infected liver transplant (LT) patients occasionally achieve operational tolerance. We ...investigated the mechanisms through which HCV infection modulates donor‐specific T cell responses following LT and the influence of HCV eradication. We generated T cell lines from HCV‐infected LT and non‐LT patients before and after HCV eradication and quantified alloreactive responses using cell lines expressing single‐HLA class‐I antigens in the presence/absence of PD‐1/CTLA‐4 blockade. HCV‐specific CD8+ T cells cross‐reacted with allogeneic class‐I HLA molecules. HCV‐positive LT recipients exhibited a higher proportion of CD8+ T cells coexpressing inhibitory receptors (PD‐1/CTLA4) than HCV‐negative LT, and their expression correlated with CXCL10 plasma levels. This resulted in decreased antidonor and third‐party proliferative responses, which were significantly reversed by HCV eradication. PD‐1/CTLA‐4 blockade increased the proportion of HCV‐specific CD8+ T cells reacting against donor only before viral clearance. In conclusion, HCV infection results in the generation of HCV‐specific CD8+ T cells capable of reacting against allogeneic HLA molecules. Following LT, this results in a PD‐1/CTLA4‐dependent decrease in alloimmune responses. Our findings challenge the notion that heterologous immunity is necessarily detrimental in LT and provide an explanation for the association between HCV eradication and immune‐mediated allograft damage.
In liver transplant recipients, hepatitis C–specific CD8+ T cells can crossreact with allogeneic HLA molecules, resulting in a PD‐1/CTLA4‐dependent decrease in alloimmune responses.
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•Antiviral therapy with direct-acting antivirals is safe and effective in patients awaiting liver transplantation.•Baseline liver function and the use of two direct-acting antivirals ...were independent predictors of a sustained virological response.•Antiviral therapy improves liver function and allows delisting as a result of clinical improvement in a quarter of treated patients.
Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients.
Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain.
In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma HCC) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p=0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT.
Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted asa result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need.
Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need.
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•After the approval of DAAs, post-liver transplant survival has significantly increased.•The improved survival of LT recipients is exclusive to anti-HCV positive patients.•A high ...access to DAAs before and while on the wait-list and after LT explains these results.•DAAs also result in a significant decrease in anti-HCV patients included on the wait-list.
The efficacy of direct-acting antivirals (DAAs) has dramatically changed the prognosis of patients with chronic hepatitis C. We aimed to evaluate the impact of DAA therapy on the composition of the liver transplant (LT) waiting list and the early post-transplant survival.
We evaluated all patients admitted to the waiting list for a primary LT between 1st January 2008 and 31st of December 2016 in Catalonia, Spain. Time span was divided into two periods according to the availability of different antiviral therapies: 2008–2013 (interferon-based therapies) and 2014–2016 (DAA). Changes in the indications of LT and the aetiology of liver disease, as well as post-LT patient survival, were evaluated according to the year of inclusion and transplantation, respectively.
We included 1,483 patients. Admissions in the waiting list for hepatitis C virus (HCV)-related liver disease decreased significantly, from 47% in 2008–2013 to 35% in 2014–2016 (p <0.001), particularly because of a reduction in patients with decompensated cirrhosis. In contrast, NASH-related inclusions increased from 4% to 7% (p = 0.003). Three-year post-LT patient survival increased significantly in the second period in the whole cohort (82% vs. 91%, p = 0.002), because of better survival in anti-HCV positive patients (76% vs. 91%, p = 0.001), but not in anti-HCV negative patients (88% vs. 91% p = 0.359). Anti-HCV positive serology, the time period of 2008–2013 and higher donor age were independently associated with post-LT mortality in the whole cohort; while time period and donor age were independently associated with post-LT mortality in anti-HCV positive recipients.
The high efficacy of DAAs is associated with significant changes in the composition of the LT waiting list and, more importantly, results in improved post-transplant survival.
The efficacy of the new direct-acting antivirals is associated with a significant improvement in survival of patients undergoing liver transplantation because of hepatitis C virus-related liver disease. In addition, it has decreased the number of patients with hepatitis C that need a liver transplant.
Immune-oncology is a major breakthrough in cancer treatment and has become the standard of care for a wide variety of solid organ malignancies. Unfortunately, manipulation of the immune system with ...checkpoint inhibitors may result in an immune-based attack of normal tissues which can lead to treatment discontinuation. These immune-related adverse events (irAEs) are diverse and affect several organs, constituting a new clinical challenge in the management of cancer patients. The complexity of this scenario requires a multidisciplinary approach that allows the early identification, diagnosis and treatment of specific irAE, ruling out other non-related adverse events. Hospital Clinic has a multidisciplinary team seeking to develop a coordinated strategy to facilitate the access of patients with suspected irAEs to specialised care resulting in harmonised management that guarantees the best patient care. The aim of the manuscript was to describe the current evidence on the management of irAEs reflecting a coordinated multidisciplinary approach to face this clinical challenge regardless of the immunotherapy indication.
Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits.
In this phase 3, ...12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 no itch to 10 worst itch imaginable) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).
Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval CI, 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.
In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).
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