Browsing by Author "Kwo, Paul Y."

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    Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Hepatitis C Virus Genotype 2, 3, 4, or 6 Infections in an Open-Label, Phase 2 Trial
    (Elsevier, 2016-11) Gane, Edward J.; Kowdley, Kris V.; Pound, David; Stedman, Catherine A. M.; Davis, Mitchell; Etzkorn, Kyle; Gordon, Stuart C.; Bernstein, David; Everson, Gregory; Rodriguez-Torres, Maribel; Tsai, Naoky; Khalid, Omer; Yang, Jenny C.; Lu, Sophia; Dvory-Sobol, Hadas; Stamm, Luisa M.; Brainard, Diana M.; McHutchison, John G.; Tong, Myron; Chung, Raymond T.; Beavers, Kimberly; Poulos, John E.; Kwo, Paul Y.; Nguyen, Mindie H.; Department of Medicine, IU School of Medicine
    Background & Aims Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections whose prior course of antiviral therapy has failed, and the feasibility of shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients. Methods We performed a multicenter, open-label trial at 32 sites in the United States and 2 sites in New Zealand from March 3, 2015 to April 27, 2015. Our study included 128 treatment-naïve and treatment-experienced patients (1 with HCV genotype 1b; 33 with HCV genotype 2; 74 with HCV genotype 3; 17 with genotype HCV 4; and 3 with HCV genotype 6), with or without compensated cirrhosis. All patients received sofosbuvir-velpatasvir (400 mg/100 mg fixed-dose combination tablet) and GS-9857 (100 mg) once daily for 6–12 weeks. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). Results After 6 weeks of treatment, SVR12s were achieved by 88% of treatment-naïve patients without cirrhosis (29 of 33; 95% confidence interval, 72%–97%). After 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naïve patients with cirrhosis (28 of 30; 95% CI, 78%–99%). After 12 weeks of treatment, SVR12s were achieved by all treatment-experienced patients without cirrhosis (36 of 36; 95% CI, 90%–100%) and 97% of treatment-experienced patients with cirrhosis (28 of 29; 95% CI, 82%–100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events. Conclusions In a phase 2 open-label trial, we found sofosbuvir-velpatasvir plus GS-9857 (8 weeks in treatment-naïve patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis.
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    Ethical Considerations Surrounding Survival Benefit-Based Liver Allocation
    (Office of the Vice Chancellor for Research, 2013-04-05) Keller, Eric J.; Helft, Paul R.; Kwo, Paul Y.
    The disparity between the demand for and supply of donor livers has continued to grow over the last two decades, placing greater weight on the need for efficient and effective allocation. Although the use of extended criteria donors (ECD) has shown greater potential, it remains unregulated. Schaubel et al. have recently proposed a survival benefit model which balances waitlist survival and potential transplantation benefit for a given quality of donor liver. The OPTN/UNOS Liver and Intestinal Organ Transplantation Committee considered this and other models in a recent report, concluding that the current allocation method does not require modification. In order to further evaluate the survival benefit model, the various ethical concerns shaping organ allocation were discussed and used to identify strengths and shortcomings associated with the proposed model. Compared to the current MELD/PELD system, the survival benefit model incorporates a greater number of ethical principles, uses a sophisticated statistical model to increase efficiency and reduce waste, minimizes bias, and parallels developments in the allocation of other organs. Conversely, the model fails to address quality of life concerns, prioritization for younger patients, its less promising posttransplant prediction accuracy, and potential issues regarding informed consent and economic burdens. To remedy these issues, we suggested incorporating various improvements based on recent literature. Although limitations exist, the survival benefit model now exists as a better means of improving allocation. We support the model proposed by Schaubel et al., with the amendments we suggested, and urge the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee and the transplant community to strongly consider this model as another step toward better liver allocation.
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    HCV/HIV Coinfection: A New Treatment Paradigm
    (2015-06) Kwo, Paul Y.; Agrawal, Saurabh; Department of Medicine, IU School of Medicine
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    Hepatic Arterial Buffer Response: Pathologic Evidence in Non-Cirrhotic Human Liver with Portal Vein Thrombosis
    (Office of the Vice Chancellor for Research, 2016-04-08) Rush, Natalia; Sun, Hongliu; Nakanishi, Yukihiro; Mneimneh, Wadad; Kwo, Paul Y.; Saxena, Romil
    Hepatic arterial buffer response (HABR) is the ability of the hepatic artery (HA) to compensate for changes in portal flow. Experimentally, occlusion of the portal vein leads to compensatory increase in HA flow with minimal parenchymal effects. Wether portal vein thrombosis (PVT) causes similar effects in the human liver is unknown. This study aims to answer this question as well as elucidate any microscopic features that may reliably assist diagnosis of PVT in the non-cirrhotic liver. We studied patients with PVT and no concomitant liver pathology. Age and gender matched livers with normal morphology served as controls. Following parameters were graded as subtle or obvious and focal or diffuse in a blinded fashion: sinusoidal dilatation, central and portal vein (PV) dilatation, PV absence, hepatic plate thinning and thickening. Outer and luminal diameters and wall thickness of HA, and outer diameter of accompanying bile ducts (BD) were measured. There were 16 patients (8 men, 8 women; mean age, 46.5 years) who presented with varices (12), ascites (8) and splenomegaly (11). Subtle and or focal dilatations of CV, PV and sinusoids as well as thinning/thickening of hepatic plates were common findings in both groups but were diffuse and obvious predominantly in cases of PVT. Absence or attenuation of PV was seen only in cases of PVT. The large HA were dilated in resection specimens of patients with PVT, p<0.05. This difference was not seen in biopsy specimens. There was no difference in the small HA in either biopsy or resection specimens or other measurements of HA or BD. In conclusion, septal branches of the HA dilate as a compensatory response to long standing thrombosis. Microscopic features of PVT are subtle but when obvious and/or diffuse in a patient with non-cirrhotic portal hypertension should raise suspicion for this diagnosis.
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    Initial uptake, time to treatment, and real-world effectiveness of all-oral direct-acting antivirals for hepatitis C virus infection in the United States: A retrospective cohort analysis
    (PLOS, 2019-08-22) Kwo, Paul Y.; Puenpatom, Amy; Zhang, Zuoyi; Hui, Siu L.; Kelley, Andrea A.; Muschi, David; Biostatistics, School of Public Health
    BACKGROUND: Data on initiation and utilization of direct-acting antiviral therapies for hepatitis C virus infection in the United States are limited. This study evaluated treatment initiation, time to treatment, and real-world effectiveness of direct-acting antiviral therapy in individuals with hepatitis C virus infection treated during the first 2 years of availability of all-oral direct-acting antiviral therapies. METHODS: A retrospective cohort analysis was undertaken using electronic medical records and chart review abstraction of hepatitis C virus-infected individuals aged >18 years diagnosed with chronic hepatitis C virus infection between January 1, 2014, and December 31, 2015 from the Indiana University Health database. RESULTS: Eight hundred thirty people initiated direct-acting antiviral therapy during the 2-year observation window. The estimated incidence of treatment initiation was 8.8%±0.34% at the end of year 1 and 15.0%±0.5% at the end of year 2. Median time to initiating therapy was 300 days. Using a Cox regression analysis, positive predictors of treatment initiation included age (hazard ratio, 1.008), prior hepatitis C virus treatment (1.74), cirrhosis (2.64), and history of liver transplant (1.5). History of drug abuse (0.43), high baseline alanine aminotransferase levels (0.79), hepatitis B virus infection (0.41), and self-pay (0.39) were negatively associated with treatment initiation. In the evaluable population (n = 423), 83.9% (95% confidence interval, 80.1-87.3%) of people achieved sustained virologic response. CONCLUSION: In the early years of the direct-acting antiviral era, <10% of people diagnosed with chronic hepatitis C virus infection received direct-acting antiviral treatment; median time to treatment initiation was 300 days. Future analyses should evaluate time to treatment initiation among those with less advanced fibrosis.
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    Narrow-band imaging versus white light for the detection of proximal colon serrated lesions: a randomized, controlled trial
    (Elsevier, 2016-01) Rex, Douglas K.; Clodfelter, Ryan; Rahmani, Farrah; Fatima, Hala; James-Stevenson, Toyia N.; Tang, John C.; Kim, Hak Nam; McHenry, Lee; Kahi, Charles J.; Rogers, Nicholas A.; Helper, Debra J.; Sagi, Sashidhar V.; Kessler, William R.; Wo, John M.; Fischer, Monika; Kwo, Paul Y.; Department of Medicine, School of Medicine
    Background The value of narrow-band imaging (NBI) for detecting serrated lesions is unknown. Objective To assess NBI for the detection of proximal colon serrated lesions. Design Randomized, controlled trial. Setting Two academic hospital outpatient units. Patients Eight hundred outpatients 50 years of age and older with intact colons undergoing routine screening, surveillance, or diagnostic examinations. Interventions Randomization to colon inspection in NBI versus white-light colonoscopy. Main Outcome Measurements The number of serrated lesions (sessile serrated polyps plus hyperplastic polyps) proximal to the sigmoid colon. Results The mean inspection times for the whole colon and proximal colon were the same for the NBI and white-light groups. There were 204 proximal colon lesions in the NBI group and 158 in the white light group (P = .085). Detection of conventional adenomas was comparable in the 2 groups. Limitations Lack of blinding, endoscopic estimation of polyp location. Conclusion NBI may increase the detection of proximal colon serrated lesions, but the result in this trial did not reach significance. Additional study of this issue is warranted. (Clinical trial registration number: NCT01572428.)
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    The new standard of HCV therapy: Treatment in therapy-naive patients
    (Wiley, 2012-03-06) Agrawal, Saurabh; Kwo, Paul Y.; Medicine, School of Medicine
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    Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis
    (Elsevier, 2017-05) Jacobsen, Ira M.; Lawitz, Eric; Kwo, Paul Y.; Hézode, Christophe; Peng, Cheng-Yuan; Howe, Anita Y. M.; Hwang, Peggy; Wahl, Janice; Robertson, Michael; Barr, Eliav; Haber, Barbara A.; Medicine, School of Medicine
    Background & Aims Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. Methods We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12−18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA <15 IU/mL. Results Among treatment-naïve and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naïve patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event. Conclusions In an analysis of data from 6 clinical trials, rates of SVR12 ranged from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on the proportion of treatment-naïve or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RASs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and the need for ribavirin in patients with HCV genotype 1a infection.