Safety and efficacy of continuous terlipressin infusion in HRS-AKI in a transplant population.

BACKGROUND AND AIMS: Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and as such was assessed in a population comprised of liver transplant (LT) candidates. METHODS AND RESULTS: Fifty hospitalized, LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. ACLF grade 3, serum creatinine (SCr)>5.0 mg/dL, or MELD≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide (M&O) or norepinephrine (NorEpi) for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as ≥30% decrease in SCr with EOT SCr≤1.5, partial response (PR) as ≥30% decrease in SCr with EOT SCr>1.5, and non-response (NR) as <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p<0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. CONCLUSIONS: With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical M&O/NorEpi cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Hepatic Encephalopathy-A Guide to Laboratory Testing.

Hepatic encephalopathy (HE) remains both a clinical diagnosis and one of exclusion. Laboratory testing is largely focused on identifying precipitating factors. Ammonia levels in the blood can be helpful for the diagnosis of HE but are not required for confirmation. More recent literature is lending support to the prognostic capabilities of ammonia in cirrhosis, both in predicting future HE events and in determining outcomes in hospitalized patients. Accurate ammonia testing requires strict protocols to avoid common pitfalls in the measurement of this labile analyte. Future studies investigating the utility of other laboratory testing to diagnose, stage, or predict HE are encouraged.

INFUSE: Rationale and design of a multi-center, open label, collaborative study to treat HRS-AKI with continuous terlipressin infusion.

Background: Hepatorenal syndrome-acute kidney injury (HRS-AKI) carries significant morbidity and mortality among those with end-stage liver disease. Bolus terlipressin for treatment of HRS-AKI received FDA approval in September 2022. US implementation of terlipressin, however, is hindered by the paucity of local data on the optimal patient population and administration mode, as well as the effect on transplant priority. The INFUSE study is designed to evaluate the use of continuous terlipressin infusion among transplant candidates with advanced liver disease and HRS-AKI. Methods: Fifty prospective patients with HRS-AKI will receive a single bolus of terlipressin 0.5 mg followed by continuous infusions of terlipressin from 2 to 8 mg/day for up to 14 days. The cohort will be enriched with those listed, in evaluation, or eligible for liver transplantation, while those with ACLF grade 3, MELD ≥35, and serum creatinine >5.0 mg/dL will be excluded. Fifty patients who received midodrine plus octreotide or norepinephrine for HRS-AKI will serve as a retrospective comparator cohort. Conclusion: The INFUSE study aims to assess the safety and efficacy of continuous terlipressin infusion among largely transplant-eligible patients with HRS-AKI, and to provide US-based data on transplant outcomes. This novel study design simultaneously mitigates terlipressin adverse events while providing renal benefits to patients, thus addressing the unmet medical need of those with HRS-AKI who have limited treatment options and are awaiting liver transplantation in the US.

Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome.

BACKGROUND: The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe. METHODS: We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons. RESULTS: A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group. CONCLUSIONS: In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.).

Feasibility and Procedural Safety of alfapump System Implantation by IR: Experience from the MOSAIC Study, a Multicenter, Open-Label Prospective Study in Cirrhotic Patients with Refractory Ascites.

PURPOSE: To evaluate feasibility, procedural outcomes, and safety aspects of implantation of the alfapump system for management of refractory ascites by interventional radiology (IR) methods. MATERIALS AND METHODS: The multicenter open-label prospective MOSAIC study included 29 patients (mean age 60.0 y ± 9.9; range, 32-72 y, 17 [56.7%] male) with cirrhotic refractory ascites who received an alfapump system implanted by IR. The fully subcutaneous alfapump system consists of a pump and 2 silicone catheters, whose distal ends are inserted in the peritoneum and the bladder, respectively. The device moves ascites from the peritoneum to the bladder, reducing the requirement of paracentesis. Pumped volume and speed can be customized as required. The implant procedure was performed under general or local anesthesia. Both catheters were placed under ultrasound guidance. The pump was inserted in a subcutaneous pocket on the upper abdomen. Incidence and severity of procedure-related serious adverse events up to 3 months after implantation were recorded. RESULTS: Technical success was achieved in 29 (100%) IR implant procedures. The pump was usually implanted on the right abdomen (76.7%). In 5 patients, deviation from the Instructions for Use was required. Adverse events (requirement of additional incisions, postoperative bleed) occurred in 3 patients. At 3 months after implantation, 3 possibly procedure-related serious adverse events (ascites leakage, bacterial peritonitis, postoperative bleeding) had occurred. Two explantations (2/29; 6.8%) (cellulitis, pump pocket infection) and 4 reinterventions (pump or catheter replacement) were required, corresponding to an adverse event incidence rate of 9/29 (31.0%). CONCLUSIONS: Placement of the alfapump using IR methods is both feasible and technically successful.

Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo.

BACKGROUND & AIMS: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). METHODS: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. RESULTS: Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child-Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child-Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK-18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. CONCLUSIONS: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.

Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal Syndrome Type 1.

BACKGROUND & AIMS: Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (<2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1. METHODS: Adult patients with cirrhosis, ascites, and HRS-1 (based on the 2007 International Club of Ascites criteria of rapidly deteriorating renal function) were assigned randomly to groups given intravenous terlipressin (1 mg, n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through day 14 unless the following occurred: confirmed HRS reversal (CHRSR, defined as 2 serum creatinine [SCr] values ≤1.5 mg/dL, at least 40 hours apart, on treatment without renal replacement therapy or liver transplantation) or SCr at or above baseline on day 4. The primary end point was the percentage of patients with confirmed CHRSR. Secondary end points included the incidence of HRS reversal (defined as at least 1 SCr value ≤1.5 mg/dL while on treatment), transplant-free survival, and overall survival. The study was performed at 50 investigational sites in the United States and 2 in Canada, from October 2010 through February 2013. RESULTS: Baseline demographic/clinical characteristics were similar between groups. CHRSR was observed in 19 of 97 patients (19.6%) receiving terlipressin vs 13 of 99 patients (13.1%) receiving placebo (P = .22). HRS reversal was achieved in 23 of 97 (23.7%) patients receiving terlipressin vs 15 of 99 (15.2%) receiving placebo (P = .13). SCr decreased by 1.1 mg/dL in patients receiving terlipressin and by only 0.6 mg/dL in patients receiving placebo (P < .001). Decreases in SCr and survival were correlated (r(2) = .882; P < .001). Transplant-free and overall survival were similar between groups. A significantly greater proportion of patients with CHRSR who received terlipressin survived until day 90 than patients who did not have CHRSR after receiving terlipressin (P < .001); this difference was not observed in patients who did vs did not have CHRSR after receiving placebo (P = .28). There were similar numbers of adverse events in each group, but patients in the terlipressin group had more ischemic events. CONCLUSIONS: Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.

Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy.

BACKGROUND & AIMS: Rifaximin is a gut-selective, oral antimicrobial agent shown to reduce the recurrence of overt hepatic encephalopathy (HE) and HE-related hospitalizations in a 6-month, randomized, controlled trial (RCT). We performed a phase 3, open-label maintenance study to assess the safety and rate of hospitalization with long-term rifaximin use. METHODS: We conducted a 24-month, open-label maintenance study of rifaximin (550 mg, twice daily) in patients with HE who participated in the previous RCT of rifaximin or new patients enrolled from March 2007 to December 2010. Safety was assessed (adverse events, clinical laboratory parameters) for the integrated population of all patients, who were given rifaximin 550 mg twice daily (all-rifaximin population, N = 392). Safety and hospitalization data were compared between the group given placebo in the original RCT (n = 159) and those given rifaximin (n = 140). RESULTS: In the all-rifaximin population, the median exposure to rifaximin was 427.0 days (range, 2-1427 d), with 510.5 person-years of exposure. The profile and rate of adverse events with long-term rifaximin treatment were similar to those of the original RCT. There was no increase in the rate of infections, including with Clostridium difficile, or development of bacterial antibiotic resistance. Rates of hospitalizations with long-term rifaximin administration remained low: the HE-related hospitalization rate, normalized for exposure (0.21; all-rifaximin population), was similar to that of the rifaximin group in the original RCT (0.30), and lower than that for the placebo group (0.72). CONCLUSIONS: Long-term treatment (≥24 mo) with rifaximin (550 mg, twice daily) appears to provide a continued reduction in the rate of HE-related and all-cause hospitalization, without an increased rate of adverse events. ClinicalTrials.gov number: NCT00686920.

A Rare Case of Icteric Acute Hepatitis C Infection Acquired Through Intranasal Methamphetamine Use.

Most patients with acute hepatitis C (HCV) infections are asymptomatic, while 15% present with jaundice. Intranasal drug use can uncommonly transmit HCV via contaminated instruments and nasal epithelial breakdown. Given a 15% prevalence of HCV infection in chronic methamphetamine users, recognition of potential transmission routes is important to target prevention and screening efforts in this population.

Acute liver failure caused by herpes simplex virus in a pregnant patient: is there a potential role for therapeutic plasma exchange?

A young woman presented with a febrile illness in the third trimester of pregnancy. Laboratory investigation revealed severe acute hepatitis with thrombocytopenia and coagulopathy. Liver injury progressed despite emergent caesarian section and delivery of a healthy infant. Therefore, therapeutic plasma exchange (TPE) was performed on three consecutive days post-partum for a presumed diagnosis of acute liver failure (ALF) associated with pregnancy due to hemolysis, elevated liver enzymes, and low platelets (HELLP) or acute fatty liver of pregnancy (AFLP). Treatment with TPE was followed by biochemical and clinical improvement but during her recovery herpes simplex virus type 2 (HSV-2) infection was diagnosed serologically and confirmed histologically. Changes in the immune system during pregnancy make pregnant patients more susceptible to acute HSV hepatitis, HSV-related ALF, and death. The disease is characterized by massive hepatic inflammation with hepatocyte necrosis, mediated by both direct viral cytotoxicity and the innate humoral immune response. TPE may have a therapeutic role in acute inflammatory disorders such as HSV hepatitis by reducing viral load and attenuating systemic inflammation and liver cell injury. Further investigation is needed to clarify this potential effect. The roles of vigilance, clinical suspicion, and currently accepted therapies are emphasized.

Extent of reversibility of hepatic encephalopathy following liver transplantation.

Although hepatic encephalopathy (HE) is prevalent in the cirrhotic population, it has also been considered a potentially reversible condition. Liver transplantation represents the ultimate reversal of the decompensated cirrhotic state and should provide the best option for the reversibility of HE. However, the neurologic compromise associated with HE in the cirrhotic patient may not be completely reversible. Theories regarding fixed structural and reversible metabolic deficits as well as persistence of the hyperdynamic state with continued portosystemic shunting have been proposed to explain this lack of complete reversibility. Whether this remnant neurologic deficit is clinically significant remains unclear.

Current concepts in the pathophysiology and management of hepatic encephalopathy.

Hepatic encephalopathy (HE) represents a broad continuum of neuropsychological dysfunction in patients with acute or chronic liver disease and/or portosystemic shunting of blood flow. The pathophysiology of this disease is quite complex, as it involves overproduction and reduced metabolism of various neurotoxins, particularly ammonia. Recent hypotheses implicate low-grade cerebral edema as a final common pathway for the pathophysiology of HE. Management of this condition is multifaceted and requires several steps: elimination of precipitating factors; removal of toxins, both by reducing them at their source and by augmenting scavenging pathways; modulation of resident fecal flora; proper nutritional support; and downregulation of systemic and gut-derived inflammation.

Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy.

BACKGROUND & AIMS: The immunosuppressive treatment for autoimmune hepatitis (AIH) patients is prednisone and azathioprine. Ten percent to 20% of patients do not respond or are intolerant of standard treatment. The aim of this study was to assess the biochemical, histologic, and hematologic parameters during mycophenolate mofetil (MMF) treatment in AIH patients who did not respond to or were intolerant of prednisone and/or azathioprine. METHODS: A retrospective study was performed of 15 AIH patients who received MMF either as monotherapy or in combination with prednisone after failure or intolerance of the initial regimen. Records were reviewed as to initial therapy, reasons why MMF was initiated, liver enzyme levels, histology on MMF, and complications. RESULTS: The mean age was 60 +/- 15 years. All patients were started on MMF at 1 gram twice a day, 3 on MMF monotherapy, and 12 on prednisone and MMF. The average MMF treatment duration was 41 months. Alanine aminotransferase levels decreased significantly from 91.73 +/- 88.69 to 60.87 +/- 71.2 (P = .03) on MMF treatment. Inflammatory scores (2.59 +/- 0.97 to 1.14 +/- 1.21, P = .02) and Ishak fibrosis scores (4.10 +/- 1.37 to 2.5 +/- 1.51, P = .02) also decreased. No significant hematologic complications were noted during MMF treatment. CONCLUSIONS: Administration of MMF, either as monotherapy or in combination with prednisone, results in biochemical and histologic improvement in AIH patients who are prednisone and/or azathioprine intolerant or resistant without the development of significant complications. MMF should be studied prospectively as an alternative agent in the treatment of autoimmune liver disease.