Browsing by Author "Kwo, Paul"

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    Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis
    (2015-05) Muir, Andrew J.; Poordad, Fred; Lalezari, Jacob; Everson, Gregory; Dore, Gregory J.; Herring, Robert; Sheikh, Aasim; Kwo, Paul; Hézode, Christophe; Pockros, Paul J.; Tran, Albert; Yozviak, Joseph; Reau, Nancy; Ramji, Alnoor; Stuart, Katherine; Thompson, Alexander J.; Vierling, John; Freilich, Bradley; Cooper, James; Ghesquiere, Wayne; Yang, Rong; McPhee, Fiona; Hughes, Eric A.; Swenson, E. Scott; Yin, Philip D.; Department of Medicine, IU School of Medicine
    Importance Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis. Objective All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis. Design, Setting, and Participants The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls. Interventions All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo. Main Outcomes and Measures Sustained virologic response at posttreatment week 12 (SVR12). Results One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5% CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.4%-100.0%) for patients in the treatment-naive group and 87% (97.5% CI, 75.3%-98.0%) for those in the treatment-experienced group. Three serious adverse events were considered to be treatment related and there were 4 adverse event–related discontinuations. Treatment-emergent grade 3 or 4 alanine aminotransferase elevations were observed in 4 patients, of which 1 had concomitant total bilirubin elevation. Conclusions and Relevance In this open-label uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR12.
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    De Novo Malignancy Post Liver Transplantation: A Single Center, Population Controlled Study
    (Wiley, 2013) Chatrath, Hemant; Berman, Kenneth; Vuppalanchi, Raj; Slaven, James; Kwo, Paul; Tector, A. Joseph; Chalasani, Naga; Ghabril, Marwan; Medicine, School of Medicine
    Background: With the growing numbers of liver transplant recipients, it is increasingly important to understand the risks of de novo malignancy after liver transplantation. Aim: To characterize the incidence of de novo malignancy after liver transplantation compared with a control non-transplant population. Methods: We studied 534 Indiana state residents undergoing liver transplantation at our center between 1997 and 2004, followed through August 2010. The incidence and predictors of malignancy were determined. The standardized incidence ratio (SIR) of cancer in our cohort was compared with age-, gender-, and period-matched state population using the Indiana State Cancer Registry. Results: After a mean follow-up of 5.7 ± 3.2 yr, 73 patients (13.7%) developed 80 cancers, with five- and 10-yr incidence rates of 11.7% and 24.8%, respectively. These included 24 (30%) skin, 16 (20%) hematologic, and 40 (50%) solid tumors. The most common solid cancers were aerodigestive. Compared with matched state population, liver transplant recipients had significantly higher incidence of all cancers (SIR: 3.1, 95% CI [Confidence interval]: 2.9-3.2), skin (melanoma) (SIR: 5.8, 95% CI: 4.7-7.0), hematologic (SIR: 7.1, 95% CI: 6.3-8.0), and solid (SIR: 2.7, 95% CI: 2.5-2.8) tumors. Conclusion: There is a significantly increased risk of de novo malignancies after liver transplantation, highlighting the need for surveillance strategies in this population.
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    Fatigue as Reported at 12 Time Points during the First Year Post-Liver Transplant
    (2013) Scott, Patricia J.; Krause, Audrey; Tector, A. Joseph; Kwo, Paul
    BACKGROUND: Although liver transplantation has evolved as an effective procedure, fatigue remains a post-transplant complaint [1]. As yet, there are no published accounts of the experience of fatigue at temporal intervals during the first post-transplant year, and this information would benefit LT candidates in recovery planning. Van Ginneken [2] found that time since transplant was not associated with physical fatigue and reduced activity, but was associated with albumin levels less than 25g/l and with lower GFR. METHODS: Data used in this study were collected through an ongoing, longitudinal, prospective design. Results presented here are for fatigue and biometric data at 12 data points starting one week post hospital discharge, continued weekly for the first 8 weeks, then monthly at 3, 6, 9, and 12 months. RESULTS: We sampled 30 subjects: 19 (70.4%) male and 8 (29.6%) female, age 55.4 ± 9.8 years. A mixed models analysis of variance was done to investigate a change in FACIT over time. The initial model included age, MELD, sex, week, albumin, ALT, BILI T, and CREAT. The final model included age, BILI T, and week. Increasing age and BILI T were associated with greater fatigue (p=0.0376 and p=0.0005, respectively). There was significant decrease in fatigue over time (p<0.0001). Pair-wise comparisons were done to determine which weeks significantly differed. Tukey’s adjustment for multiple comparisons was used. Figure 1 indicates which visits significantly differed. DISCUSSION: Our subjects experienced decreased fatigue over time. The data set was rich with prospectively collected longitudinal information helpful for establishing realistic expectations for post-transplant fatigue. Finding include early weeks of recovery (weeks 2-3) differ from weeks 7+ and that there is no significant change after 3 months, up to one year. No association was seen with Albumin levels although total bilirubin and age were associated with greater fatigue.
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    Improving Survival in Patients with Decompensated Cirrhosis
    (Hindawi, 2011) Amarapurkar, Deepak; Jalan, Rajiv; Guan, Richard; Kwo, Paul; Medicine, School of Medicine
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    Influencing functional outcomes: a look at role performance and satisfaction with life following liver transplant
    (2008-09) Scott, Patricia J.; Misra, Vijay Laxmi; Mangus, Richard S.; Tector, A. Joseph; Lacerda, Marco A.; Vinayek, Rakesh; Munsch, Linda; Musick, Beverly; Kwo, Paul
    Abstract 572 The success of orthotopic liver transplantation (OLT), originally measured as survival, now extends to quality of the life saved. Return to work (RTW) is also a desired outcome. Our AIM was to explore the relationship between 5 pre-OLT factors & 5 post-OLT quality of life (QOL) domains with life satisfaction and primary productive role to better understand how to improve both. METHODS: Patients (pts)1-3 yrs post-OLT filled QOL form during follow-up clinic visits between 7/04 to 6/05. The Liver transplantation Database-Quality of life (LTD-QOL) form yielded data on 5 domains: measure of disease (MOD), psychological distress/well-being (PDW), personal function (PF), social/role function (SRF) & general health perception (GHP). Results: 229 pts were first categorized as satisfied overall with life (79%), or dissatisfied, and then assigned to groups based on primary productive role (51%), no primary productive role, or retired. Pre-OLT variables were age, gender, marital status, education, & etiology of liver disease; HCV (33%), alcohol liver disease (ALD)(11%), HCV+ALD (10%), & others (46%). Marital status & age were not significantly related to the outcome variables. Etiology of liver disease, education, and time since OLT and 5 post-OLT QOL domains were significantly associated with both outcome variables; satisfaction and primary productive role (p<.0001).To understand the differences, the 5 physical & men-tal QOL domains were regressed on primary productive role and satisfaction. Pts (mean age 54 yrs (19-74 yrs), males, 70%) fell into the category of primary productive role rates (51%). Pts transplanted for ALD were significantly (p<.05) more likely to be satisfied with life, whereas individuals with HCV±ALD, had lowest satisfaction and were most likely to be unable/uninterested in work. Stepwise logistical regression analysis of satisfaction demonstrated that GHP and SRF correlated most highly. Although satisfaction was significant in bivariate analysis, regression analysis of the influence of domains of QOL, as well as employment, demonstrated that SRF & GHP correlated most highly with life satisfaction. CONCLUSIONS: SRF and GHP correlate with good QOL post OLT. HCV patients have low levels of satisfaction whereas the highest level of satisfaction is in the ALD group. Further studies should address methods to improve satisfaction in those with HCV.
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    Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease
    (Elsevier, 2015-09) Charlton, Michael; Everson, Gregory T.; Flamm, Steven L.; Kumar, Princy; Landis, Charles; Brown, Robert S., Jr.; Fried, Michael W.; Terrault, Norah A.; O'Leary, Jacqueline G.; Vargas, Hugo E.; Kuo, Alexander; Schiff, Eugene; Sulkowski, Mark S.; Gilroy, Richard; Watt, Kymberly D.; Brown, Kimberly; Kwo, Paul; Pungpapong, Surakit; Korenblat, Kevin M.; Muir, Andrew J.; Teperman, Lewis; Fontana, Robert J.; Denning, Jill; Arterburn, Sarah; Dvory-Sobol, Hadas; Brandt-Sarif, Theo; Pang, Phillip S.; McHutchison, John G.; Reddy, K. Rajender; Afdhal, Nezam; Department of Medicine, IU School of Medicine
    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.
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    Persistence of Virologic Response after Liver Transplant in Hepatitis C Patients Treated with Ledipasvir/Sofosbuvir Plus Ribavirin Pretransplant
    (2017) Yoshida, Eric M.; Kwo, Paul; Agarwal, Kosh; Duvoux, Christophe; Durand, François; Peck-Radosavljevic, Markus; Lilly, Leslie; Willems, Bernard; Vargas, Hugo; Kumar, Princy; Brown, Robert S.; Horsmans, Yves; De-Oertel, Shampa; Arterburn, Sarah; Dvory-Sobol, Hadas; Brainard, Diana M.; McHutchison, John G.; Terrault, Norah; Rizzetto, Mario; Müllhaupt, Beat; Medicine, School of Medicine
    Introduction. Recurrence of HCV infection in patients with chronic hepatitis C virus (HCV) at the time of liver transplantation is nearly universal and reduces the likelihood of graft and patient survival. Materials and methods. We evaluated outcomes of 17 patients (16 with HCV genotype 1 and 1 with genotype 4) who received up to 12 or 24 weeks of ledipasvir/sofosbuvir plus ribavirin prior to or up to the time of liver transplant in the SOLAR-1 and SOLAR-2 trials. In all patients, HCV RNA was < 15 IU/mL prior to transplant. At screening, 6 patients were Child-Pugh-Turcotte (CPT) class B and 11 were CPT class C. Seven patients underwent transplant prior to completing assigned treatment, with 4 treated for < 12 weeks. The primary endpoint was posttransplant virologic response 12 weeks after transplant (pTVR12) in patients with HCV RNA < 15 IU/mL at their last measurement prior to transplant. Results. Overall, 94% (16/17) achieved pTVR12. All who achieved pTVR12 received at least 11 weeks of treatment. The single patient who did not achieve pTVR12 discontinued study drug on day 21 and underwent liver transplant the following day. The patient had HCV RNA < 15 IU/mL at post-transplant week 2 but died 15 days post-transplant because of multi-organ failure and septic shock. Conclusion. Among a small population of HCV patients with decompensated cirrhosis, virologic response to ledipasvir / sofosbuvir plus ribavirin prior to liver transplantation was maintained after transplantation, even if treatment was stopped early. Administration of ledipasvir / sofosbuvir plus ribavirin before liver transplant can prevent post-transplant HCV recurrence.
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    Research methodologies to address clinical unmet needs and challenges in alcohol-associated liver disease
    (Wolters Kluwer, 2022) Singal, Ashwani K.; Kwo, Paul; Kwong, Allison; Liangpunsakul, Suthat; Louvet, Alexandre; Mandrekar, Pranoti; McClain, Craig; Mellinger, Jessica; Szabo, Gyongyi; Terrault, Norah; Thursz, Mark; Winder, Gerald S.; Kim, W. Ray; Shah, Vijay H.; Medicine, School of Medicine
    Alcohol-associated liver disease (ALD) is emerging worldwide as the leading cause of liver-related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital American Association for the Study of Liver Diseases meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused on (a) studying disease burden of ALD using large administrative databases, (b) developing biomarkers for noninvasive diagnosis of alcohol-associated hepatitis (AH) and estimation of disease prognosis, (c) identifying therapeutic targets for ALD and AH, (d) deriving accurate models to predict prognosis or posttransplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient-selection criteria for liver transplantation, and (e) examining qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long-term outcomes in patients with ALD.
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    Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study
    (Wiley, 2016-08) Kwo, Paul; Gitlin, Norman; Nahass, Ronald; Bernstein, David; Etzkorn, Kyle; Rojter, Sergio; Schiff, Eugene; Davis, Mitchell; Ruane, Peter; Younes, Ziad; Kalmeijer, Ronald; Sinha, Rekha; Peeters, Monika; Lenz, Oliver; Fevery, Bart; De La Rosa, Guy; Scott, Jane; Witek, James; Department of Medicine, IU School of Medicine
    Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients. The phase 2 COSMOS study reported high SVR rates in treatment-naive and prior null-responder HCV genotype (GT) 1-infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST-1 (NCT02114177) was a multicenter, randomized, open-label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1-infected treatment-naive and treatment-experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non-CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%-100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76-89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12-week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8-week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12-week arm) and three (2%, 8-week arm) patients experienced a serious adverse event (all unrelated to study treatment). CONCLUSION: Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1-infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370-380).
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