Faculty Bibliography

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.

Purpose: Obesity is associated with increased risk of hepatocellular carcinoma (HCC), with higher rates of complications and disease recurrence after liver transplantation and ablation. We studied the impact of obesity on outcomes after transarterial chemoembolization (TACE). Material and Methods: We retrospectively identified 114 TACE (58 HCC patients; 85% due to hepatitis B or C; mean age, 62 years; mean MELD score, 10; mean AFP, 805). Medical charts were assessed for body mass index (BMI), clinical, and procedural data. The 1-2-month follow-up CT or MRI was assessed using mRECIST criteria for residual/ recurrent disease or new lesions. For analysis, patients were grouped by low (<25) and high (>25) BMI. Results: Residual/recurrent disease on 1-2-month imaging was more common after TACE in patients with high BMI than in those with low BMI (63% vs. 31%; X2: 8.3; p=0.004), as were new lesions (42% vs. 19%; X2: 4.9; p=0.02). Mean BMI differed between cases with complete response (mean, 25+/-1), stable disease/partial response (mean, 29; SE, 1), or progressive disease (mean, 29+/-1) by one-way ANOVA (p=0.003). Of 58 patients, 9 had complications. Patients with complications had higher BMI than those without complications (30 vs. 27; p=0.05 by Mann-Whitney U test). Two deaths within 1 month occurred in obese patients (BMI, 33 and 34). Conclusion: High BMI is associated with more residual/recurrent disease, new lesions, and progressive disease after TACE for HCC and possibly with increased complications. Obesity may lead to a more rapidly progressive and difficult to treat HCC

Purpose: Non-occlusive portal vein thrombosis (PVT) develops in patients with cirrhosis due to impaired portal blood flow. Shunting (TIPS) has been proposed as a treatment for PVT due to its ability to restore portal blood flow. In this study, we analyzed outcomes in patients undergoing TIPS, stratified by presence of PVT and MELD score. Material and Methods: A multi-center, retrospective chart review was conducted of 269 patients, consisting of 68 patients with nonocclusive PVT and 201 patients without PVT, who received TIPS from 2005 to 2014. The primary endpoint was 90-day survival. Secondary outcomes included survival at 30 days, change in MELD score, post- TIPS hospitalizations for overt hepatic encephalopathy (HE), and variceal bleeding or persistent ascites. Results: Baseline MELD scores were 14.8 +/- 0.7 and 15.5 +/- 0.4 among groups with and without non-occlusive PVT, respectively (p=0.38). Patients with PVT had significantly improved 90-day survival compared to those without PVT (89.7% vs. 77.1%, p=0.02). Among patients with MELD scores >18, there was an observed trend towards improved 90-day survival for the PVT group compared to the non-PVT group (84.6% vs. 57.4%, p=0.06), though this was accompanied by a higher incidence of hepatic encephalopathy (53.8% vs. 23.5%, p=0.03). Similar reduction in ascites and variceal bleeding was noted in both groups. Conclusion: Survival in patients with non-occlusive PVT was greater than in those without PVT. We speculate that the improved ability of patients with PVT to tolerate TIPS is due to a decreased dependence of the liver on portal blood circulation in these patients

Purpose: TIPS creation fails to control ascites in 40% or more of patients, but the variables predicting outcome are unclear, with prior studies highlighting pre-TIPS portosystemic gradient (PSG) (Nair et al 2004; JVIR 15:1431). We studied which variables predict outcome of TIPS for refractory ascites. Materials and Methods: We retrospectively identified patients who underwent TIPS for refractory ascites between 1/12 and 5/14, yielding 40 patients. We excluded 17 patients due to insufficient peri-procedural documentation or technical failures, leaving 23 patients (16 men, 7 women, mean age 60 +/-2 yrs) for assessment of variables influencing osmotic (albumin and sodium levels) and hydrostatic (pre- and post- TIPS PSG and large varices) pressure. Responders were defined as those requiring fewer or no paracenteses; nonresponders had persistent ascites, with similar pre-TIPS frequency of therapeutic paracentesis. Complications within 1 month requiring hospitalization were noted. Multiple logistic regression, Mann-Whitney U tests, and one-tailed chi² tests assessed group differences. Results: Ten patients (43%: responders) had documented improvement in ascites. Multiple logistic regression including pre- and post-TIPS PSG significantly impacted outcome (p=0.04). Post- but not pre-TIPS PSG predicted outcome (p=0.04 vs. p=0.84). Responders had significantly lower post- TIPS gradient (5.8) compared with non-responders (7.6) (p=0.02). In contrast, responders and non-responders did not differ in albumin (2.7 vs. 2.7) or sodium (136 vs. 134) levels, or pre-TIPS gradient (13.9 vs. 14.7 mmHg) (p>0.05). Similar numbers of responders (50%) had large varices compared to non-responders (61%) (p=0.3). Responders (50%) had significantly more complications compared to non-responders (15%) (p=0.04), mostly encephalopathy (85%) requiring hospitalization. Conclusion: Only post-TIPS PSG predicted which patients had significantly reduced ascites, in contrast to prior studies suggesting importance of pre-TIPS gradient. Findings suggest aggressively lowering the gradient below 6 mmHg may be the most reliable technique to improve outcomes, although with expected higher risk of complications

The detection and management of potential donor-derived infections is challenging, in part due to the complexity of communications between diverse labs, organ procurement organizations (OPOs), and recipient transplant centers. We sought to determine if communication delays or errors occur in the reporting and management of donor-derived infections and if these are associated with preventable adverse events in recipients. All reported potential donor-derived transmission events reviewed by the Organ Procurement and Transplantation Network Ad Hoc Disease Transmission Advisory Committee from January 2008 to June 2010 were evaluated for communication gaps between the donor center, OPO and transplant centers. The impact on recipient outcomes was then determined. Fifty-six infection events (IEs; involving 168 recipients) were evaluated. Eighteen IEs (48 recipients) were associated with communication gaps, of which 12 resulted in adverse effects in 69% of recipients (20/29), including six deaths. When IEs and test results were reported without delay, appropriate interventions were taken, subsequently minimizing or averting recipient infection (23 IEs, 72 recipients). Communication gaps in reported IEs are frequent, occur at multiple levels in the communication process, and contribute to adverse outcomes among affected transplant recipients. Conversely, effective communication minimized or averted infection in transplant recipients.

BACKGROUND & AIMS: Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS: In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS: Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS: Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.