Long‐term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95693/1/23566_ftp.pd

Pharmacokinetics of once-daily extended-release tacrolimus tablets versus twice-daily capsules in de novo liver transplant

The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P \u3c .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation

Rifaximin Treatment in Hepatic Encephalopathy

Background Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. Methods In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. Results Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P Conclusions Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430

Impact of Pretransplant Hepatic Encephalopathy on Liver Posttransplantation Outcomes

Patients with cirrhosis commonly experience hepatic encephalopathy (HE), a condition associated with alterations in behavior, cognitive function, consciousness, and neuromuscular function of varying severity. HE occurring before liver transplant can have a substantial negative impact on posttransplant outcomes, and preoperative history of HE may be a predictor of posttransplant neurologic complications. Even with resolution of previous episodes of overt or minimal HE, some patients continue to experience cognitive deficits after transplant. Because HE is one of the most frequent pretransplant complications, improving patient HE status before transplant may improve outcomes. Current pharmacologic therapies for HE, whether for the treatment of minimal or overt HE or for prevention of HE relapse, are primarily directed at reducing cerebral exposure to systemic levels of gut-derived toxins (e.g., ammonia). The current mainstays of HE therapy are nonabsorbable disaccharides and antibiotics. The various impacts of adverse effects (such as diarrhea, abdominal distention, and dehydration) on patient's health and nutritional status should be taken into consideration when deciding the most appropriate HE management strategy in patients awaiting liver transplant. This paper reviews the potential consequences of pretransplant HE on posttransplant outcomes and therapeutic strategies for the pretransplant management of HE

Hyponatremia: A Risk Factor for Early Overt Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation

Hepatic encephalopathy (HE) is a frequent complication in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). Hyponatremia (HN) is a known contributing risk factor for the development of HE. Predictive factors, especially the effect of HN, for the development of overt HE within one week of TIPS placement were assessed. A single-center, retrospective chart review of 71 patients with cirrhosis who underwent TIPS creation from 2006–2011 for non-variceal bleeding indications was conducted. Baseline clinical and laboratory characteristics were collected. Factors associated with overt HE within one week were identified, and a multivariate model was constructed. Seventy one patients who underwent 81 TIPS procedures were evaluated. Fifteen patients developed overt HE within one week. Factors predictive of overt HE within one week included pre-TIPS Na, total bilirubin and Model for End-stage Liver Disease (MELD)-Na. The odds ratio for developing HE with pre-TIPS Na <135 mEq/L was 8.6. Among patients with pre-TIPS Na <125 mEq/L, 125–129.9 mEq/L, 130–134.9 mEq/L and ≥135 mEq/L, the incidence of HE within one week was 37.5%, 25%, 25% and 3.4%, respectively. Lower pre-TIPS Na, higher total bilirubin and higher MELD-Na values were associated with the development of overt HE post-TIPS within one week. TIPS in hyponatremic patients should be undertaken with caution

Hyponatremia: A Risk Factor for Early Overt Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation

Hepatic encephalopathy (HE) is a frequent complication in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). Hyponatremia (HN) is a known contributing risk factor for the development of HE. Predictive factors, especially the effect of HN, for the development of overt HE within one week of TIPS placement were assessed. A single-center, retrospective chart review of 71 patients with cirrhosis who underwent TIPS creation from 2006–2011 for non-variceal bleeding indications was conducted. Baseline clinical and laboratory characteristics were collected. Factors associated with overt HE within one week were identified, and a multivariate model was constructed. Seventy one patients who underwent 81 TIPS procedures were evaluated. Fifteen patients developed overt HE within one week. Factors predictive of overt HE within one week included pre-TIPS Na, total bilirubin and Model for End-stage Liver Disease (MELD)-Na. The odds ratio for developing HE with pre-TIPS Na <135 mEq/L was 8.6. Among patients with pre-TIPS Na <125 mEq/L, 125–129.9 mEq/L, 130–134.9 mEq/L and ≥135 mEq/L, the incidence of HE within one week was 37.5%, 25%, 25% and 3.4%, respectively. Lower pre-TIPS Na, higher total bilirubin and higher MELD-Na values were associated with the development of overt HE post-TIPS within one week. TIPS in hyponatremic patients should be undertaken with caution