Faculty Bibliography
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496
Sofosbuvir and velpatasvir with or without voxilaprevir in direct-acting antiviral-naïve chronic hepatitis C: patient-reported outcomes from POLARIS 2 and 3
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.
PMID: 29181842
ISSN: 1365-2036
CID: 2892932
Liver transplantation (LT) for cryptogenic cirrhosis (CC) and non-alcoholic steatohepatitis (NASH) cirrhosis: Twenty-two years data from the scientific registry of transplant recipients (SRTR) [Meeting Abstract]
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)
EMBASE:618936284
ISSN: 1527-3350
CID: 2778752
Significant and sustained improvement of health-related quality of life (HRQL) scores in patients with hepatitis C (HCV) and sustained virologic response (SVR) [Meeting Abstract]
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)
EMBASE:618935596
ISSN: 1527-3350
CID: 2778852
Grazoprevir, ruzasvir, and uprifosbuvir for hepatitis C virus after NS5A treatment failure
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).
PMID: 28688129
ISSN: 1527-3350
CID: 2758652
Expert review of gastroenterology & hepatology. 2017:11(9):789-795.DOI: 10.1080/17474124.2017.1351295
Sofosbuvir, velpatasvir and voxilaprevir combination for the treatment of hepatitis C
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.
PMID: 28673106
ISSN: 1747-4132
CID: 2758662
Primer on Hepatitis C Virus Resistance to Direct-Acting Antiviral Treatment: A Practical Approach for the Treating Physician
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.
PMID: 28987254
ISSN: 1557-8224
CID: 2758642
Author response to Letters to the Editor LIVint-17-00581 "Cytoplasmic rods and rings in ribavirin treatment" Covini et al and LIVint-17-00867 "Cytoplasmic rods and rings in mycophenolic acid treatment" Chen et al [Letter]
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 .
PMID: 28853201
ISSN: 1478-3231
CID: 2679822
Superiority of Interferon-Free Regimens for Chronic Hepatitis C: The Effect on Health-Related Quality of Life and Work Productivity
Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients.Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy-Fatigue, Chronic Liver Disease Questionnaire- HCV, Work Productivity and Activity-Specific Health Problem) before, during, and after treatment.A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naive, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to -24.4% by treatment week 12, up to -8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to -7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs.IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores.
PMCID:5319496
PMID: 28207507
ISSN: 1536-5964
CID: 2568022
Time to viral suppression is not related to achievement of SVR12 in HCV GT1-infected patients treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin
High rates of sustained virologic response at post-treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co-dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1-infected patients enrolled in six phase 3 studies of 3D +/- RBV. Patients who experienced non-virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT-PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA
PMID: 27935166
ISSN: 1365-2893
CID: 2569302
NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome
BACKGROUND & AIMS: The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. METHODS: NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. RESULTS: Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naive patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naive genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. CONCLUSIONS: Pretreatment ledipasvir-specific RASs that were present in 8-16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. LAY SUMMARY: The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical trials where patients with genotype 1 HCV infection received treatments that included ledipasvir-sofosbuvir to determine how prevalent NS5A RASs are in patients at baseline, and found that ledipasvir-specific RASs were present in 8-16% of patients prior to treatment and had a negative impact on treatment outcome in subset of patient groups, particularly treatment-experienced patients with genotype 1a HCV.
PMID: 28108232
ISSN: 1600-0641
CID: 2568042
