Faculty Bibliography

Nonalcoholic steatohepatitis (NASH)-related cirrhosis and cryptogenic cirrhosis (CC) have become leading indications for liver transplantation (LT) in the US. Our aim was to compare the trends, clinical presentation, and outcomes for transplant candidates with NASH and CC.The Scientific Registry of Transplant Recipients (1994-2016) was used to select adult LT candidates and recipients with primary diagnoses of NASH and CC without hepatocellular carcinoma.Two lakh twenty-three thousand three hundred ninety-one LT candidates were listed between 1994 and 2016. Of these, 16,214 (7.3%) were listed for CC and 11,598 (5.2%) for NASH. Before 2004, NASH was seldom coded for an indication for LT, but became more common after 2009. Averaged across the study period, CC candidates compared with NASH candidates were younger and had fewer conditions of metabolic syndrome (MS). CC patients were more likely to have MS components in comparison to candidates with other chronic liver diseases (CLDs) (all P < .0001). For most of the study period, patients with CC or NASH were similarly more likely to be taken off the list due to deterioration or death, with to patients with other CLDs. Post-LT data were available for 14,052 transplant recipients with NASH or CC. With the exception of post-transplant diabetes, the outcomes of patients transplanted for CC and NASH were similar to those of other CLD patients.Number of LT due to CC and NASH cirrhosis is increasing. In the past decade, there is a shift from LT listing diagnosis from CC to NASH potentially related to increased awareness about NASH in transplant centers in the US.

Introduction: Chronic hepatitis C virus (HCV) infection is a systemic disease associated with insulin resistance and other extrahepatic met-abolic manifestations that can accelerate liver disease progression, increasing the risk of fibrosis and hepatocellular carcinoma. Curative treatment of HCV infection with direct-acting antivirals (DAAs) can reduce these risks. The pangenotypic DAA regimen G/P (glecaprevir [NS3/4A inhibitor discovered by AbbVie and Enanta] coformulated with pibrentasvir [NS5A inhibitor]) is approved to treat HCV infection and demonstrated a 98% overall cure rate in clinical trials. We pooled data from 7 phase 3 clinical trials conducted in over 2000 patients and performed an integrated analysis evaluating the safety and efficacy of G/P in patients with baseline metabolic syndrome. Materials-&-Methods: The analysis included patients with HCV genotype 1, 2, 3, 4, 5 or 6 infection and baseline metabolic syndrome de-fined according to the ATP III criteria who received G/P treatment for 8, 12 or 16 weeks. Patients with or without severe renal impairment, and without cirrhosis or with compensated cirrhosis, could be either treatment-naive or experienced with interferon (IFN) or pegIFN with or without ribavirin (RBV) or sofosbuvir and RBV with or without pegIFN. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Adverse events and laboratory abnormalities were recorded in all patients to monitor safety and tolerability Results: The analysis included 349 patients, the majority of whom were male (208; 60%), white (265; 76%), HCV treatment-naive (244; 70%), and without cirrhosis (275; 79%). The most common HCV genotype among enrolled patients was genotype 1 (186/349; 53%), followed by genotype 2 (66/349; 19%) and 3 (62/349; 18%). The median BMI at baseline was 29.8 kg/m² and 54% (189/349) presented with elevated triglycerides. Efficacy is shown in Figure 1; the SVR12 rate was 98% (343/349), with 2 virologic failures. One adverse event led to treatment discontinuation (<1%); no serious adverse events were deemed related to study drug. One patient (<1%) experienced a Grade 3 alanine aminotransferase elevation. Conclusions: G/P is a once-daily DAA therapy with a favorable safety profile that yields high SVR12 rates in patients with comorbid conditions including baseline metabolic syndrome. [Figure Presented]

BACKGROUND:Chronic hepatitis C infection leads to impairment of patient-reported outcomes (PROs). Treatment with direct-acting antiviral regimens results in short- and long-term improvement of these outcomes. AIM/OBJECTIVE:To assess PROs in patients treated with a newly developed direct-acting antiviral, a fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) with/without voxilaprevir (VOX). METHODS:The PRO data were collected from participants of POLARIS-2 and POLARIS-3 clinical trials (DAA-naïve, all HCV genotypes). Participants self-administered SF-36v2, FACIT-F, CLDQ-HCV and WPAI:SHP instruments at baseline, during treatment, and in follow-up. RESULTS:Of 1160 patients, 611 received SOF/VEL/VOX and 549 received SOF/VEL (52.8 ± 11.0 years, 55.9% male, 75.4% treatment-naïve, 33.9% cirrhotic). The sustained viral response at 12 weeks (SVR12) rates were 95%-98%. During treatment, improvements in most PRO scores were significant (all but one P < .01) and ranged from, on average, +2.3 to +15.0 points (on a 0-100 scale) by the end of treatment. These improvements were similar between SOF/VEL/VOX and SOF/VEL arms (all P > .05). After treatment discontinuation, patients treated with both regimens achieved significant and clinically meaningful PRO gains (+2.7 to +16.7 by post-treatment week 12, +3.9 to +20.1 by post-treatment week 24; all but one P < .001). Multivariate analysis showed that depression, anxiety and cirrhosis were the most consistent independent predictors of PRO impairment while no association of PROs with the treatment regimen choice was found (all P > .05). CONCLUSIONS:The pan-genotypic regimens with SOF/VEL with or without VOX not only have excellent efficacy and safety, but also significantly positively impact patients' experience both during treatment and after achieving sustained virologic response in DAA-naïve patients with HCV.

Type 2 diabetes mellitus (T2DM) has been identified as an extrahepatic manifestation of chronic HCV infection. Conversely, in the context of chronic HCV infection, T2DM can accelerate the course of HCV-induced liver disease leading to increased risk of fibrosis, cirrhosis and hepatocellular carcinoma. The presence of T2DM negatively impacts the efficacy of interferon-based antiviral therapy, but real-world data with high-efficacy direct-acting antiviral therapies suggest high viral clearance rates in T2DM patients. In HCV-infected individuals, viral eradication is associated with a reduced risk of de novo T2DM in non-diabetic patients and beneficial metabolic changes in patients with T2DM, highlighting the importance of antiviral treatment and physician awareness of this association.

People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. CONCLUSION: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017).

We would like to thank Covini and colleagues as well as Chen and colleagues for their interesting comments regarding a recently proposed mechanism for the action of ribavirin. Both groups refer to recent work from Covini and colleagues demonstrating that exposure of cells to ribavirin leads to a rearrangement of the IMPDH enzyme to form rod-like structures termed RR1 . These RRs have been demonstrated to form in lymphocytes and antibodies targeting them have been noted in patients treated with peginterferon and ribavirin. Covini and colleagues hypothesize that inhibition of RRs by autoantibodies may lead to IMPDH inhibition and GTP depletion as a possible mechanism for the action of ribavirin2 .

Treatment of hepatitis C virus has been vastly transformed by the arrival of all-oral, interferon-free, direct-acting antiviral regimens. Despite the high rate of success with these agents, a small portion of treated patients fail therapy and the emergence of viral resistance is the most common cause of treatment failure. Given the error-prone hepatitis C virus polymerase, baseline resistance-associated substitutions (RASs) may be present before direct-acting antiviral exposure. Clinicians need to understand the role of baseline RAS testing and the settings and manner in which the treatment regimens need to be customized based on the presence of RASs.

Background: Chronic HCV infection has been associated with adverse clinical outcomes (mortality related to hepatic and extrahepatic manifestations) as well as significant economic burden and impairment of patients' HRQL. Achieving SVR has been associated with clinical benefits and short-term improvement in HRQL scores. However, long-term sustainability of these HRQL improvements is unknown. Aim: To assess long-term changes in HRQL of subjects with chronic HCV infection who have achieved SVR. Methods: We included chronic HCV-infected subjects with complete baseline data who had achieved SVR with sofosbuvir-based regimens and had been enrolled in a follow-up registry. HRQL was assessed every 24 weeks for up to 144 weeks using Short Form-36v2. Results: Baseline data was available for 3,486 subjects with SVR-12 (age 53+/-10, 62.3% male, 15.6% cirrhosis, 10.1% diabetes, 62% employed). Compared to the HRQL scores prior to their initial treatment, patients experienced significant improvements of HRQL in all domains of SF-36 upon achieving SVR and entry into the registry (up to +8.2%, all p<0.0001). By week 144 of follow-up, all gains in HRQL scores were maintained (all p<0.0004) (Figure). Notably, the greatest HRQL gains were consistently observed in the General Health and Vitality domains. Furthermore, upon achieving SVR, all SF-36 domain scores in the study cohort exceeded the general population norms (all p<0.0001). In multivariate regression analysis, history of cirrhosis, depression, anxiety, and clinically overt fatigue were independent predictors of HRQL impairment (p<0.05). Conclusions: Improvement in HRQL after achieving SVR is maintained in long-term follow-up. These data support the comprehensive and sustainable benefit of HCV cure (Figure presented)

BACKGROUND: NASH-related cirrhosis is a leading indication for LT in the U.S. It has generally been assumed that CC is predominantly caused by burnt out NASH. We assessed the prevalence, clinical characteristics, on-list and post-LT outcomes of LT candidates with NASH and CC listed in the U.S. METHODS: SRTR data (1994-2015) was used to select adult LT candidates and recipients with primary diagnoses of NASH and CC. RESULTS: 190,337 adult LT candidates were listed during the study period. Of these, 16,098 (8.4%) were listed for CC and 10,413 (5.5%) for NASH. Compared to CC, NASH was seldom coded as an indication for LT prior to 2004 and became more common after 2009 (Figure). Averaged across the study period, CC candidates were younger (55.9 vs. 59.2 years), less likely Caucasian, and had fewer conditions of metabolic syndrome (MS) [obese 43.1% vs. 65.3%, diabetes 18.6% vs. 52.3%, hypertension 23.8% vs. 41.2%; all p<0.0001]. Nevertheless, CC patients were still more likely to have components of MS in comparison to other chronic liver diseases (CLD) [obese 30.7%, diabetes 10.6%, hypertension 19.5%; all p<0.0001]. Disease severity as measured by MELD (CC-mean 20.6, NASH-21.3) was higher than in other CLD (19.6; p<0.0001). In 1994-2013, in comparison to other LT candidates, patients with CC and NASH were similarly more likely to be taken off the list due to deterioration or death (CC: 27.3%%, NASH: 25.3%, other CLD: 23.8%; p<0.0001). Transplant data was available for 13,034 NASH/CC LT recipients (CC N=8,049, NASH N=4,985). One-, 3-and 5-year post-LT prevalence of obesity and DM as well as post-LT outcomes (mortality and graft failure) were similar amongst CC and NASH LT recipients (all p<0.05). CONCLUSIONS: Although LT recipients with CC are less metabolically deranged than NASH, they still have significantly higher prevalence of metabolic syndrome components than candidates with other CLD, suggesting that most cases of CC are NASH. The outcomes of CC patients are similar to those of NASH. This suggests interchangeable use of the two diagnoses in substantially overlapping populations (Figure presented)

INTRODUCTION: The advent of direct-acting antiviral (DAA) treatments for chronic hepatitis C virus (HCV) infection has dramatically increased rates of cure. However, there remain difficult-to-treat populations, including patients with genotype 3 infection and cirrhosis, and limited salvage treatment options for those that have failed first-line DAA therapy. Areas covered: This is a review of the preclinical and clinical development of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), an interferon-free, oral, once daily, pangenotypic treatment for chronic HCV infection. All relevant literature from 2015 through June of 2017 is included. Expert commentary: Voxilaprevir, a second-generation HCV protease inhibitor, in combination with the already approved combination of sofosbuvir and velpatasvir, was evaluated in the POLARIS trials and found to be a safe and effective regimen. Patients with prior DAA treatment failure, genotype 3, cirrhosis and/or unfavorable resistance profiles all achieved cure rates of 96% or greater. The most distinctive role for this potent regimen may prove to be as a salvage regimen for patients who have failed previous DAA therapy.