Hepatology : official journal of the American Association for the Study of Liver Diseases
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The extent of provider-to-patient hepatitis C virus (HCV) transmission from diversion, self-injection, and substitution ("tampering") of anesthetic opioids is unknown. To quantify the contribution of opioid tampering to nosocomial HCV outbreaks, data from health care-related HCV outbreaks occurring in developed countries from 1990 to 2012 were collated, grouped, and compared. Tampering was associated with 17% (8 of 46) of outbreaks, but 53% (438 of 833) of cases. Of the tampering outbreaks, six (75%) involved fentanyl, five (63%) occurred in the United States, and one each in Australia, Israel, and Spain. Case counts ranged from 5 to 275 in the tampering outbreaks (mean, 54.8; median, 25), and 1-99 in the nontampering outbreaks (mean, 10.4; median, 5); between them, the difference in mean ranks of counts was significant (P < 0.01). To estimate HCV transmission risks from tampering, risk-assessment models were constructed, and these risks compared with those from surgery. HCV transmission risk from exposure to an opioid preparation tampered by a provider of unknown HCV infection status who is a person who injects drugs (PWID; 0.62%; standard error [SE] = 0.38%) exceeds 16,757 times the risk from surgery by a surgeon of unknown HCV infection status (0.000037%; SE = 0.000029%) and 135 times by an HCV-infected surgeon (0.0046%; SE = 0.0033%). To pose a 50% patient transmission risk, an infected surgeon may take 30 years, compared to <1 year for a PWID tamperer, and weeks or days for a PWID tamperer who intensifies access to opioids. ⋯ Disproportionately, many cases of HCV infection from nosocomial outbreaks were attributable to provider tampering of anesthetic opioids. Transmission risk from tampering is substantially higher than from surgery.
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Randomized Controlled Trial Multicenter Study
Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis.
Patients with hepatitis C virus (HCV) infection and cirrhosis are underrepresented in clinical trials of interferon-free regimens of direct-acting antiviral agents, making it difficult to optimize therapy. We performed a post-hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of the fixed-dose combination of ledipasvir (LDV) and sofosbuvir (SOF), with and without ribavirin (RBV), in 513 treatment-naïve and previously treated patients with genotype 1 HCV and compensated cirrhosis. All patients received LDV-SOF for 12 or 24 weeks with or without RBV. We determined the rates of sustained virological response (SVR) 12 weeks after treatment (SVR12) overall and for subgroups. Of the 513 patients analyzed, 69% were previously treated and 47% had failed previous treatment with a protease-inhibitor regimen. Overall, 493 patients (96%; 95% confidence interval [CI]: 94%-98%) achieved SVR12, 98% of treatment-naïve and 95% of previously treated patients. SVR12 rates did not vary greatly by treatment duration (95% of patients receiving 12 weeks and 98% of patients receiving 24 weeks of treatment), nor by addition of RBV (95% of patients receiving LDV-SOF alone and 97% of those who received LDV-SOF plus RBV), although previously treated patients receiving 12 weeks of LDV-SOF without RBV had an SVR12 rate of 90%. One patient discontinued LDV-SOF because of an adverse event (AE). The most common AEs were headache (23%), fatigue (16%-19%), and asthenia (14%-16%). One patient (<1%) of those receiving LDV-SOF alone, and 4 (2%) of those receiving LDV-SOF plus RBV had treatment-related serious AEs. ⋯ This analysis suggests that 12 weeks of LDV-SOF is safe and effective for treatment-naïve patients with HCV genotype 1 and compensated cirrhosis. The relatively lower SVR in treatment-experienced patients treated with 12 weeks of LDV-SOF raises the question of whether these patients would benefit from adding RBV or extending treatment duration to 24 weeks.
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Comparative Study
Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.
Patients with acute-on-chronic liver failure (ACLF) represent a heterogeneous population. The aim of the study is to identify distinct groups according to the etiologies of precipitating events. A total of 405 ACLF patients were identified from 1,361 patients with cirrhosis with acute decompensation and categorized according to the types of acute insults. Clinical characteristics and prognosis between the hepatic group and extrahepatic group were compared, and the performance of prognostic models was tested in different groups. Two distinct groups (hepatic-ACLF and extrahepatic-ACLF) were identified among the ACLF population. Hepatic-ACLF was precipitated by hepatic insults and had relatively well-compensated cirrhosis with frequent liver and coagulation failure. In contrast, extrahepatic-ACLF was exclusively precipitated by extrahepatic insults, characterized by more severe underlying cirrhosis and high occurrence of extrahepatic organ failures (kidney, cerebral, circulation, and respiratory systems). Both groups had comparably high short-term mortality (28-day transplant-free mortality: 48.3% vs. 50.7%; P = 0.22); however, the extra-hepatic-ACLF group had significantly higher 90-day and 1-year mortality (90-day: 58.9% vs. 68.3%, P = 0.035; 1-year: 63.9% vs. 74.6%, P = 0.019). In hepatic-ACLF group, the integrated Model for End-Stage Liver Disease (iMELD) score had the highest area under the receiver operating characteristic curve (auROC = 0.787) among various prognostic models in predicting 28-day mortality, whereas CLIF-Consortium scores for ACLF patients (CLIF-C-ACLF) had the highest predictive value in the other group (auROC = 0.779). ⋯ ACLF precipitated by hepatic insults is distinct from ACLF precipitated by extrahepatic insults in clinical presentation and prognosis. The iMELD score may be a better predictor for hepatic-ACLF short-term prognosis, whereas CLIF-C-ACLF may be better for extrahepatic-ACLF patients.
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Retreatment of patients who have not achieved sustained virological response (SVR) after treatment with investigational direct-acting antiviral agents (DAAs) has not been extensively studied. We conducted an open-label trial to assess the efficacy and safety of sofosbuvir (SOF) plus pegylated interferon (Peg-IFN) and ribavirin (RBV) in patients with genotype 1 hepatitis C virus (HCV) who participated in previous studies of one or more Gilead investigational DAAs in combination with RBV with or without Peg-IFN. We enrolled 80 patients at 40 sites. All patients received SOF 400 mg once daily plus Peg-IFN-α 180 μg/week and weight-based ribavirin (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 80 patients enrolled, 36 (45%) had received two or more courses of earlier treatment for HCV and 74 (93%) had at least one resistance-associated variant (RAV) at baseline. SVR12 was achieved by 63 of the 80 patients (79%) treated. Rates of SVR12 were similar across patient subgroups. Presence of RAVs at baseline did not appear to be associated with treatment failure. Seventy-one of eighty patients (89%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and nausea. No patients discontinued all treatment because of AEs. ⋯ These findings suggest that SOF plus Peg-IFN and RBV for 12 weeks is effective and safe in patients who have not achieved SVR with earlier regimens of one or more DAAs plus Peg-IFN and RBV.
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Observational Study
Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days. ⋯ Assessment of ACLF patients at 3-7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility.