Terry D. Box

ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV

BACKGROUND The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. RESULTS The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).

Perforation during colonoscopy in endoscopic ambulatory surgical centers

BACKGROUND Perforation as a complication of colonoscopy is estimated to occur in 0.01% to 0.3% of procedures, but the frequency in ambulatory settings is unknown. This study determined the number of perforations occurring within a network of endoscopic ambulatory surgery centers. METHODS A total of 116,000 colonoscopies were performed within one network of 45 endoscopic ambulatory surgery centers in the United States during 1999. All identified perforations were reported to the network clinical director and reviewed by a panel of 3 gastroenterologists. RESULTS There were 37 (0.03%) perforations; 27 in women and 10 in men. Median patient age was 75 years (range 39-87 years); 18 patients (49%) had diverticular disease and 20 (54%) had a history of pelvic or colonic surgery. Twenty-four (65%) procedures were diagnostic, and 13 (35%) were therapeutic. The most common site of perforation was the sigmoid colon (62%); followed by the ascending colon (16%); cecum, transverse colon, and splenic flexure (11%); and rectum, anastomotic, or unknown (11%). The time to diagnosis ranged from immediate to 72 hours (29 <1 hour, 8 >1 hour). All patients were hospitalized; 35 (95%) underwent exploratory laparotomy, and 2 (5%) were treated conservatively. No patient died. CONCLUSIONS Reported perforations for procedures performed in endoscopic ambulatory surgery centers occurred most frequently during diagnostic colonoscopy in older woman with a history of surgery or diverticular disease. Reported perforations in endoscopic ambulatory surgery centers were uncommon.

Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death.

Acetaminophen (APAP) is the leading cause of acute liver injury in the developed world. Timely administration of N‐acetylcysteine (N‐Ac) prevents the progression of serious liver injury and disease, whereas failure to administer N‐Ac within a critical time frame allows disease progression and in the most severe cases may result in liver failure or death. In this situation, liver transplantation may be the only life‐saving measure. Thus, the outcome of an APAP overdose depends on the size of the overdose and the time to first administration of N‐Ac. We developed a system of differential equations to describe acute liver injury due to APAP overdose. The Model for Acetaminophen‐induced Liver Damage (MALD) uses a patients aspartate aminotransferase (AST), alanine aminotransferase (ALT), and international normalized ratio (INR) measurements on admission to estimate overdose amount, time elapsed since overdose, and outcome. The mathematical model was then tested on 53 patients from the University of Utah. With the addition of serum creatinine, eventual death was predicted with 100% sensitivity, 91% specificity, 67% positive predictive value (PPV), and 100% negative predictive value (NPV) in this retrospective study. Using only initial AST, ALT, and INR measurements, the model accurately predicted subsequent laboratory values for the majority of individual patients. This is the first dynamical rather than statistical approach to determine poor prognosis in patients with life‐threatening liver disease due to APAP overdose. Conclusion: MALD provides a method to estimate overdose amount, time elapsed since overdose, and outcome from patient laboratory values commonly available on admission in cases of acute liver failure due to APAP overdose and should be validated in multicenter prospective evaluation. (HEPATOLOGY 2012)

Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection.

BACKGROUND & AIMS The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients. METHODS Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA <15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment). RESULTS Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study. CONCLUSIONS The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885.

Liver transplantation in septuagenarians receiving model for end-stage liver disease exception points for hepatocellular carcinoma: the national experience.

Current liver allocation policy in the United States grants liver transplant candidates with stage T2 hepatocellular carcinoma (HCC) a priority Model for End‐Stage Liver Disease (MELD) score of 22, regardless of age. Because advanced age may portend an increase in all‐cause mortality after transplantation for any diagnosis, the aim of this study was to examine overall posttransplant survival in elderly patients with HCC versus younger cohorts. Based on Organ Procurement and Transplantation Network data, Kaplan‐Meier 5‐year survival rates were compared. Recipients undergoing primary liver transplantation were stratified into cohorts based on age (<70 or ≥70 years) and the receipt of MELD exception points for HCC. Log‐rank and Wilcoxon tests were used for statistical comparisons. In 2009, 143 transplants were performed for patients who were 70 years old or older. Forty‐two percent of these patients received a MELD exception for HCC. Regardless of the diagnosis, the overall survival rate was significantly attenuated for the septuagenarians versus the younger cohort. After 5 years of follow‐up, this disparity exceeded 10% to 15% depending on the populations being compared. The 1‐, 2‐, 3‐, 4‐, and 5‐year actuarial survival rates were 88.4%, 83.2%, 79.6%, 76.1%, and 72.7%, respectively, for the patients who were younger than 70 years and 81.1%, 73.8%, 67.1%, 61.9%, and 55.2%, respectively, for the patients who were 70 years old or older. Five‐year survival was negatively affected for patients with HCC who were younger than 70 years; this disparity was not observed for patients with HCC who were 70 years old or older. In conclusion, although patients who are 70 years old or older compose a small fraction of transplant recipients in the United States, patients in this group undergoing transplantation for HCC form an even smaller subset. Overall, transplantation in this age group yields outcomes inferior to those for younger cohorts. However, unlike patients who are less than 70 years old and receive MELD exception points, overall liver transplant survival is not affected by HCC at an advanced age. Liver Transpl 18:423–433, 2012.

Racial differences in response rates to consensus interferon in HCV infected patients naive to previous therapy.

Background: Despite a rapid evolution in the treatment of Hepatitis C (HCV), response to therapy among different racial and ethnic groups is poorly characterized. Study: Three hundred and thirty HCV infected patients naive to previous therapy received induction therapy followed by every other day dosing with consensus interferon. Greater than 30% of treated patients were not white, allowing comparison of response among different races/ethnicities and genotypes. Results: An overall sustained virologic response (SVR) was achieved in 24% of white, 12% of Hispanic, and 4% of AA patients (P = 0.003 white vs. non-white). 15% of white and 13% of Hispanic Genotype 1 patients achieved an SVR; 2% of AA patients achieved an SVR (P = 0.001 AA vs. non AA). Surprisingly, an SVR of 50% and 40% was achieved by AA and White Genotype 2 patients, compared with 10% in Hispanic patients (P = 0.001). Conclusion: Significant differences in response rates to induction therapy followed by every other day dosing with consensus Interferon was observed when comparing white to non-white patients, particularly when comparing response rates by genotype. These observations reinforce the requirement that prospective studies that enroll a significant percentage of non-whites are needed to adequately characterize response rates to anti-HCV directed therapy.

Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection

ABSTRACT ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance in vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10 IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.)

Recurrent liver failure in a 25-year-old female

Acute liver failure (ALF) is defined as severe and sudden liver dysfunction leading to coagulopathy and encephalopathy in a previously healthy person without preexisting liver disease. Almost half of adult cases of ALF are due to acetaminophen toxicity, with 21% labeled indeterminate or other. We present a patient with a second episode of ALF, both episodes being initiated by catabolic stress. Elevated aminotransferases, jaundice, an elevated international normalized ratio, and confusion were typical of idiopathic ALF, and a low serum ceruloplasmin level initially led to a misdiagnosis of acute Wilson disease. Citrullinemia type I, a urea cycle defect caused by a deficiency of argininosuccinate synthetase, was diagnosed on the basis of plasma amino acids and was confirmed by molecular testing. Urea cycle defects are not generally considered causes of ALF in adults and are described rarely in children beyond the neonatal period. Our case illustrates the importance of screening patients with idiopathic ALF for a metabolic disorder. A prompt diagnosis and timely treatment enabled her to recover fully without the need for liver transplantation. Liver Transpl 16:1049–1053, 2010.

On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3–infected patients treated with daclatasvir and sofosbuvir

Many currently available direct‐acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all‐oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3–infected treatment‐naive and ‐experienced patients (ALLY‐3) who achieved rates of sustained virological response at post‐treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on‐treatment responses to daclatasvir + sofosbuvir in genotype 3–infected patients could predict treatment outcome.

Minimally invasive aortic valve replacement with orthotopic liver transplantation: report of a case

Cardiac surgery and liver transplantation (LT) are rarely performed at the same time, because of the potential risks of coupling two such complex surgical procedures [1–3]. This combined surgery is typically reserved for patients with structural heart disease, including multivessel obstructive coronary artery disease and severe valvular disease with heart failure and end-stage liver disease, in whom the untreated organ may decompensate if only one organ is addressed [4]. Combined aortic valve replacement (AVR) and LT is the rarest of such combined surgery, with only ten cases published previously. We present the first reported case of combined minimally invasive AVR and LT and review the literature on similar combined surgery.