Bio


Dr. Kwo is currently Professor of Medicine and Director of Hepatology at the Stanford University where he joined the faculty in November 2016. Prior to joining the faculty at Stanford, he was at Indiana University for 21 years where he served as the Medical Director of Liver Transplantation. He has distinguished himself in the field of Hepatitis C therapeutics and has been the principal investigator on multiple international trials. He recently authored the ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries.

Clinical Focus


  • Hepatology
  • Liver Transplant
  • Gastroenterology

Academic Appointments


Administrative Appointments


  • Director of Hepatology, Stanford University (2016 - Present)

Honors & Awards


  • Best Doctors Gastroenterology/Hepatology, Best Doctors in America (2003-2015)
  • Outstanding Young Clinician, Department of Medicine, Indiana University School of Medicine (2003)
  • America’s Top Doctors Gastroenterology/Hepatology, Consumers Research Council of America (2002-2014)
  • America's Best Doctors: Gastroenterology/Hepatology, Best Doctors in America (2003-2015)
  • America’s Top Doctors, Gastroenterology/Hepatology, Castle Connelly Publishing, (2002-2016)

Boards, Advisory Committees, Professional Organizations


  • Development Committee, American Association for the Study of Liver Diseases (2015 - Present)
  • Editorial Board, Journal of Clinical Gastroenterology (2013 - Present)
  • Nominating Committee, American Association for the Study of Liver Disease (2016 - Present)
  • Board of Trustees, American College of Gastroenterology (2015 - Present)

Professional Education


  • Residency:University of Maryland Medical Center GME Training Verifications (1991) MD
  • Board Certification: Transplant Hepatology, American Board of Internal Medicine (2006)
  • Board Certification: Gastroenterology, American Board of Internal Medicine (1995)
  • Fellowship:Mayo Clinic Graduate Medical Education (1995) MN
  • Medical Education:Wayne State University School of Medicine (1988) MI

Clinical Trials


  • A 5-year Longitudinal Observational Study of Patients With Nonalcoholic Fatty Liver (NAFL) or Nonalcoholic Steatohepatitis (NASH) Recruiting

    TARGET-NASH is a longitudinal observational cohort study of patients being managed for NAFL or NASH in usual clinical practice. TARGET-NASH will create a research registry of patients with NAFL or NASH within academic and community real-world practices in order to assess the safety and effectiveness of current and future therapies.

    View full details

  • A 5-year Longitudinal Observational Study of the Natural History and Management of Patients With HCC Recruiting

    TARGET-HCC is a longitudinal, observational study of patients being managed for HCC in usual clinical practice. TARGET-HCC will create a research registry of participants with HCC within academic and community real-world practices in order to assess the safety and effectiveness of the entire spectrum of current and future therapies across diverse populations.

    View full details

  • AURORA: Phase 3 Study for the Efficacy and Safety of CVC for the Treatment of Liver Fibrosis in Adults With NASH Recruiting

    The AURORA study will be conducted to confirm the efficacy and safety of cenicriviroc (CVC) for the treatment of liver fibrosis in adult subjects with NASH.

    View full details

  • Direct Acting Antiviral-Post Authorization Safety Study Recruiting

    This is an independent optional sub-study parallel to TARGET-HCC (NCT02954094). The purpose of Direct-Acting Antiviral-Post Authorization Safety Study (DAA-PASS) is to investigate the impact of exposure to direct-acting antivirals (DAAs) on early recurrence of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients following successful HCC treatment interventions.

    View full details

  • Study of the Efficacy and Safety of Lonafarnib / Ritonavir With and Without Pegylated Interferon -Alfa-2a Not Recruiting

    Two LNF-containing regimens will be evaluated in the D-LIVR Phase 3 study: (1) LNF/RTV/PEG IFN-alfa-2a and (2) LNF/RTV. Each of these arms will have efficacy endpoints that measure clinical benefit with regard to viral suppression and alanine aminotransferase (ALT) normalization. For each LNF-containing regimen, a composite endpoint of EOT (48 weeks) virologic response and ALT normalization will be used. Virologic response will be defined as a 2 log10 IU/mL reduction from baseline.

    Stanford is currently not accepting patients for this trial. For more information, please contact Angela Fuller, 650-721-4288.

    View full details

All Publications


  • Toward Elimination of Hepatitis C Infection: How Bestto Address Gaps in the Cascade of Care? Hepatology communications Prabhakar, V., Kwo, P. Y. 2019; 3 (9): 1174–76

    Abstract

    Because of the changing demographics of hepatitis C, screening for viral hepatitis should be done routinely in all pregnant woman. This process should include linkage to care. The best elimination strategy would incorporate universal screening for hepatitis C in all individuals over the age of 18.

    View details for DOI 10.1002/hep4.1403

    View details for PubMedID 31497738

  • iLFT: A big assist in the recognition of liver disease in general practice. Journal of hepatology Cheung, A. C., Kwo, P. Y. 2019

    View details for DOI 10.1016/j.jhep.2019.08.002

    View details for PubMedID 31447223

  • Suboptimal Use of Inpatient Palliative Care Consultation May Lead to Higher Readmissions and Costs in End-Stage Liver Disease. Journal of palliative medicine Adejumo, A. C., Kim, D., Iqbal, U., Yoo, E. R., Boursiquot, B. C., Cholankeril, G., Wong, R. J., Kwo, P. Y., Ahmed, A. 2019

    Abstract

    Background/Aims: Patients with end-stage liver disease (ESLD) have a high risk for readmission. We studied the role of palliative care consultation (PCC) in ESLD-related readmissions with a focus on health care resource utilization in the United States. Methods: We performed a retrospective longitudinal analysis on patients surviving hospitalizations with ESLD from January 2010 to September 2014 utilizing the Nationwide Readmissions Database with a 90-day follow-up after discharge. We analyzed annual trends in PCC among patients with ESLD. We matched PCC to no-PCC (1:1) using propensity scores to create a pseudorandomized clinical study. We estimated the impact of PCC on readmission rates (30- and 90-day), and length of stay (LOS) and cost during subsequent readmissions. Results: Of the 67,480 hospitalizations with ESLD, 3485 (5.3%) received PCC, with an annual increase from 3.6% to 6.7% (p for trend <0.01). The average 30- and 90-day annual readmission rates were 36.2% and 54.6%, respectively. PCC resulted in a lower risk for 30- and 90-day readmissions (hazard ratio: 0.42, 95% confidence interval [CI]: 0.38-0.47 and 0.38, 95% CI: 0.34-0.42, respectively). On subsequent 30- and 90-day readmissions, PCC was associated with decreased LOS (5.6- vs. 7.4 days and 5.7- vs. 6.9 days, p<0.01) and cost (US $48,752 vs. US $75,810 and US $48,582 vs. US $69,035, p<0.01). Conclusion: Inpatient utilization of PCC for ESLD is increasing annually, yet still remains low in the United States. More importantly, PCC was associated with a decline in readmission rates resulting in a lower burden on health care resource utilization and improvement in cost savings during subsequent readmissions.

    View details for DOI 10.1089/jpm.2019.0100

    View details for PubMedID 31397615

  • y Integrated analysis of 8-week glecaprevir/pibrentasvir in Japanese and overseas patients without cirrhosis and with hepatitis C virus genotype 1 or 2 infection JOURNAL OF GASTROENTEROLOGY Naganuma, A., Chayama, K., Notsumata, K., Gane, E., Foster, G. R., Wyles, D., Kwo, P., Crown, E., Bhagat, A., Mensa, F. J., Otani, T., Larsen, L., Burroughs, M., Kumada, H. 2019; 54 (8): 752–61
  • EFFICACY AND SAFETY OF GLECAPREVIR/PIBRENTASVIR IN PATIENTS WITH HCV GENOTYPE 5 OR 6 INFECTION: AN INTEGRATED ANALYSIS OF PHASE 2 AND 3 STUDIES Yao, B. B., Asselah, T., Frederick, L., Schnell, G., Kowdley, K., Kwo, P. Y., Poordad, F., Kinh Nguyen, Lee, S. S. BMJ PUBLISHING GROUP. 2019: A146–A147
  • Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors AMERICAN JOURNAL OF TRANSPLANTATION Kwong, A. J., Wall, A., Melcher, M., Wang, U., Ahmed, A., Subramanian, A., Kwo, P. Y. 2019; 19 (5): 1380–87

    View details for DOI 10.1111/ajt.15162

    View details for Web of Science ID 000471342300016

  • Efficacy and safety of glecaprevir/pibrentasvir in patients with HCV genotype 5 or 6 infection: An integrated analysis of phase 2 and 3 studies Yao, B., Asselah, T., Fredrick, L., Schnell, G., Kowdley, K. V., Kwo, P., Poordad, F., Kinh Nguyen, Lee, S., Mensa, F. ELSEVIER SCIENCE BV. 2019: E248
  • Effectiveness and safety with tenofovir alafenamide (TAF) for hepatitis B in US clinical practice Curry, M., Bae, H., Dieterich, D., Ankoma-Sey, V., Reddy, R., Pan, C., Hann, H., Tong, M., Kim, W., Kwo, P., Frazier, L., Milligan, S., Spitz, K., Afdhal, N. ELSEVIER SCIENCE BV. 2019: E462
  • A combination of the ACC inhibitor GS-0976 and the nonsteroidal FXR agonist GS-9674 improves hepatic steatosis, biochemistry, and stiffness in patients with non-alcoholic steatohepatitis Lawitz, E., Gane, E., Ruane, P., Herring, J., Younes, Z. H., Kwo, P., Zhang, J., Jia, C., Chuang, J., Mccolgan, B., Chung, C., Subramanian, M., Myers, R., Middleton, M., Li, K., Hellerstein, M., Noureddin, M., Harrison, S., Loomba, R. ELSEVIER SCIENCE BV. 2019: E794
  • Interim safety and efficacy results of the ABI-H0731 phase 2a program exploring the combination of ABI-H0731 with Nuc therapy in treatment-naive and treatment-suppressed chronic hepatitis B patients Ma, X., Lalezari, J., Tuan Nguyen, Bae, H., Schiff, E. R., Fung, S., Yuen, M., Hassanein, T., Hann, H., Elkhashab, M., Dieterich, D., Sulkowski, M., Kwo, P., Nahass, R., Agarwal, K., Ramji, A., Park, J., Ravendhran, N., Chan, S., Weilert, F., Han, S., Ayoub, W., Gane, E., Jacobson, I., Bennett, M., Huang, Q., Yan, R., Huey, V., Ruby, E., Liaw, S., Colonno, R., Lopatin, U. ELSEVIER SCIENCE BV. 2019: E130
  • Integrated analysis of 8-week glecaprevir/pibrentasvir in Japanese and overseas patients without cirrhosis and with hepatitis C virus genotype 1 or 2 infection. Journal of gastroenterology Naganuma, A., Chayama, K., Notsumata, K., Gane, E., Foster, G. R., Wyles, D., Kwo, P., Crown, E., Bhagat, A., Mensa, F. J., Otani, T., Larsen, L., Burroughs, M., Kumada, H. 2019

    Abstract

    BACKGROUND: Chronic hepatitis C virus (HCV) infection with genotypes (GT) 1 and 2 accounts for over 50% of HCV infections globally, including over 97% of all HCV infections in Japan. Here, we report an integrated analysis of efficacy and safety of 8-week treatment with the all-oral, fixed-dose combination of the direct acting antivirals (DAA), glecaprevir and pibrentasvir (G/P), in DAA-naive Japanese and overseas patients without cirrhosis and with HCV GT1 or GT2 infection.METHODS: Data from 899 DAA-naive patients without cirrhosis and with HCV GT1 or GT2 infection treated with G/P (300/120mg) for 8weeks in the six Phase 2 or 3 overseas or Japan-only clinical trials were included. All patients who received ≥1 dose of G/P were included in an intent-to-treat (ITT) analysis. The objectives were to evaluate rate of sustained virologic response 12weeks post-treatment (SVR12) and safety of the 8-week regimen in the ITT population.RESULTS: Overall, SVR12 was achieved by 98.9% (889/899) of DAA-naive patients without cirrhosis, including 99.2% (597/602) of GT1-infected and 98.3% (292/297) of GT2-infected patients.Less than1% (2/899) of patients overall and no Japanese patients experienced virologic failure. SVR12 rate was >97% for patients regardless of baseline characteristics, and common comorbidities or co-medications. Overall, <1% (2/899) discontinued G/P due to an adverse event (AE) and 1.6% (14/899) of patients experienced a serious AE.CONCLUSIONS: 8-week G/P treatment is safe and efficacious in DAA-naive patients without cirrhosis and with HCV GT1 or GT2 infection, demonstrating high SVR12 rates regardless of baseline patient and disease characteristics. CLINICALTRIALS.GOV IDENTIFIERS: The trials discussed in this paper were registered with ClinicalTrials.gov as follows: NCT02707952 (CERTAIN-1), NCT02723084 (CERTAIN-2), NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02738138 (EXPEDITION-2).

    View details for PubMedID 30868245

  • Glecaprevir/Pibrentasvir in patients with chronic HCV genotype 3 infection: An integrated phase 2/3 analysis JOURNAL OF VIRAL HEPATITIS Flamm, S., Mutimer, D., Asatryan, A., Wang, S., Rockstroh, J., Horsmans, Y., Kwo, P. Y., Weiland, O., Villa, E., Heo, J., Gane, E., Ryder, S. D., Welzel, T. M., Ruane, P. J., Agarwal, K., Ng, T., Xue, Z., Lovell, S. S., Krishnan, P., Kopecky-Bromberg, S., Trinh, R., Mensa, F. J., Wyles, D. L. 2019; 26 (3): 337–49

    View details for DOI 10.1111/jvh.13038

    View details for Web of Science ID 000458954700004

  • Diagnosis and Management of Primary Biliary Cholangitis AMERICAN JOURNAL OF GASTROENTEROLOGY Younossi, Z. M., Bernstein, D., Shiffman, M. L., Kwo, P., Kim, W., Kowdley, K. V., Jacobson, I. M. 2019; 114 (1): 48–63
  • Potential Benefits of Switching Liver Transplant Recipients to Tenofovir Alafenamide Prophylaxis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Sripongpun, P., Mannalithara, A., Kwo, P. Y., Kim, W. R. 2019

    Abstract

    Tenofovir alafenamide (TAF) is the latest agent approved for chronic hepatitis B virus (HBV) treatment. In its registrations trials, TAF demonstrated better renal safety and improvement in alanine aminotransferase (ALT) activities compared with tenofovir disoproxil fumarate (TDF).1-3 However, data are scarce regarding these outcomes in liver transplantation (LTx) recipients.4 In this study, we determine effects of switching from other antivirals to TAF on ALT and renal function in LTx recipients.

    View details for DOI 10.1016/j.cgh.2019.05.057

    View details for PubMedID 31271737

  • 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 one Kwo, P. Y., Puenpatom, A., Zhang, Z., Hui, S. L., Kelley, A. A., Muschi, D. 2019; 14 (8): e0218759

    Abstract

    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.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.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.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.

    View details for DOI 10.1371/journal.pone.0218759

    View details for PubMedID 31437170

  • Trends in Hospitalizations for Chronic Liver Disease-related Liver Failure in the United States, 2005-2014. Liver international : official journal of the International Association for the Study of the Liver Kim, D., Cholankeril, G., Li, A. A., Kim, W., Tighe, S. P., Hameed, B., Kwo, P. Y., Harrison, S. A., Younossi, Z. M., Ahmed, A. 2019

    Abstract

    Current estimates of the population-based disease burden of liver failure or end-stage liver disease (ESLD) are lacking. We investigated recent trends in hospitalizations and in-hospital mortality among patients with ESLD in the United States (US).A retrospective analysis was performed utilizing the National Inpatient Sample (NIS) from 2005 to 2014. We defined ESLD as either decompensated cirrhosis or hepatocellular carcinoma (HCC), criteria obtained from the International Classification of Diseases, Ninth Revision. Nationwide rates of hospitalization and in-hospital mortality were analyzed from 2005 to 2014.Hospitalization rates for decompensated cirrhosis during this period increased from 105.3/100,000 persons to 159.9/100,000 persons. In terms of HCC, hospitalization rates increased from 13.6/100,000 to 22.1/100,000. In patients with nonalcoholic fatty liver disease (NAFLD)-related decompensated cirrhosis, the hospitalization rate increased from 13.4/100,000 to 32.1/100,000 with an annual incremental increase of 10.6%, a magnitude two-fold higher than other etiologies. The proportion of NAFLD among hospitalizations with ESLD steadily increased from 12.7% to 20.1% for decompensated cirrhosis while the proportion of chronic hepatitis C (HCV) and alcoholic liver disease (ALD) declined (29.3% to 27.6% for HCV; 39.0% to 37.4% for ALD). Although the overall in-hospital mortality rates for ESLD declined during the study, mortality rates for NAFLD-related decompensated cirrhosis showed no significant change.Among etiologies of chronic liver disease, NAFLD demonstrated the fastest growing rate of hospitalizations in non-HCC patients with ESLD in the US. Our study highlights the need for a focus on NAFLD-related hospitalizations and its impact on resource utilization. This article is protected by copyright. All rights reserved.

    View details for PubMedID 31081997

  • The effects of a transjugular intrahepatic portosystemic shunt on the diagnosis of hepatocellular cancer PLOS ONE Wong, K., Ozeki, K., Kwong, A., Patel, B. N., Kwo, P. 2018; 13 (12)
  • Diagnosis and Management of Primary Biliary Cholangitis. The American journal of gastroenterology Younossi, Z. M., Bernstein, D., Shiffman, M. L., Kwo, P., Kim, W. R., Kowdley, K. V., Jacobson, I. M. 2018

    Abstract

    Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease with a variable progressive course. PBC can cause debilitating symptoms including fatigue and pruritus and, if left untreated, is associated with a high risk of cirrhosis and related complications, liver failure, and death. Recent changes to the PBC landscape include a name change, updated guidelines for diagnosis and treatment as well as new treatment options that have recently become available. Practicing clinicians face many unanswered questions when managing PBC. To assist these healthcare providers in managing patients with PBC, the American College of Gastroenterology (ACG) Institute for Clinical Research & Education, in collaboration with the Chronic Liver Disease Foundation (CLDF), organized a panel of experts to evaluate and summarize the most current and relevant peer-reviewed literature regarding PBC. This, combined with the extensive experience and clinical expertise of this expert panel, led to the formation of this clinical guidance on the diagnosis and management of PBC.

    View details for PubMedID 30429590

  • Glecaprevir/Pibrentasvir in Patients with Chronic HCV Genotype 3 Infection: An Integrated Phase 2/3 Analysis. Journal of viral hepatitis Flamm, S., Mutimer, D., Asatryan, A., Wang, S., Rockstroh, J., Horsmans, Y., Kwo, P. Y., Weiland, O., Villa, E., Heo, J., Gane, E., Ryder, S. D., Welzel, T. M., Ruane, P. J., Agarwal, K., Ng, T. I., Xue, Z., Lovell, S. S., Krishnan, P., Kopecky-Bromberg, S., Trinh, R., Mensa, F. J., Wyles, D. L. 2018

    Abstract

    Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression, and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12-, and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment-naive or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naive patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naive patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, non-cirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naive patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30421537

  • Liver Transplantation for HCV Non-Viremic Recipients with HCV Viremic Donors. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A. J., Wall, A., Melcher, M., Wang, U., Ahmed, A., Subramanian, A., Kwo, P. Y. 2018

    Abstract

    In the context of organ shortage, the opioid epidemic, and effective direct-acting antiviral (DAA) therapy for hepatitis C (HCV), more HCV-infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor-derived HCV in previously non-viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor-derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing (NAT). Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non-viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12 weeks post-treatment (SVR-12) with DAA-based regimens, with a median time from transplant to treatment initiation of 43 days (IQR 20-59). There have been no instances of graft loss or death, with median follow-up of 380 days (IQR 263-434) post-transplant. Transplantation of HCV-viremic livers into non-viremic recipients results in acceptable short-term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30378723

  • Treatment of Hepatitis B in the Us; Real-World Evidence from the Trio Network Bae, H., Curry, M. P., Dieterich, D. T., Ankoma-Sey, V., Reddy, K., Pan, C. Q., Hann, H. L., Tong, M. J., Kim, W., Kwo, P., Reau, N., Frazier, L., Milligan, S., Afdhal, N. H. WILEY. 2018: 264A–265A
  • Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection HEPATOLOGY Reau, N., Kwo, P. Y., Rhee, S., Brown, R. S., Agarwal, K., Angus, P., Gane, E., Kao, J., Mantry, P. S., Mutimer, D., Reddy, K., Tran, T. T., Hu, Y. B., Gulati, A., Krishnan, P., Dumas, E. O., Porcalla, A., Shulman, N. S., Liu, W., Samanta, S., Trinh, R., Forns, X. 2018; 68 (4): 1298–1307

    Abstract

    Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent.Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).

    View details for PubMedID 29672891

  • Early Adoption of Tenofovir Alafenamide (TAF) for Hepatitis B in US Clinical Practice; Real-World Evidence from the Trio Network Curry, M. P., Bae, H., Dieterich, D. T., Ankoma-Sey, V., Reddy, K., Pan, C. Q., Hann, H. L., Tong, M. J., Kim, W., Kwo, P., Reau, N., Frazier, L., Milligan, S., Afdhal, N. H. WILEY. 2018: 252A
  • PROOF OF CONCEPT STUDY OF AN APOPTOSIS-SIGNAL REGULATING KINASE (ASK1) INHIBITOR (SELONSERTIB) IN COMBINATION WITH AN ACETYL-COA CARBOXYLASE INHIBITOR (GS-0976) OR A FARNESOID X RECEPTOR (FXR) AGONIST (GS-9674) IN NASH Lawitz, E., Herring, R., Younes, Z. H., Gane, E., Ruane, P. J., Aguilar, R., Jia, C., Xu, R., McColgan, B., Oberle, C., Djedjos, C., Subramanian, G., McHutchison, J. G., Myers, R. P., Middleton, M., Li, K., Hellerstein, M., Kwo, P., Noureddin, M., Harrison, S. A. E M H SWISS MEDICAL PUBLISHERS LTD. 2018: 24S
  • DAAs and long-term clinical outcome in hepatitis C: the panacea for all diseases still does not exist Response AMERICAN JOURNAL OF GASTROENTEROLOGY Kwo, P. Y., Shiffman, M. L., Bernstein, D. E. 2018; 113 (8): 1251–52
  • Response to Perrella et al. The American journal of gastroenterology Kwo, P. Y., Shiffman, M. L., Bernstein, D. E. 2018

    View details for PubMedID 29915397

  • Increased Waitlist Mortality and Lower Rate for Liver Transplantation in Hispanic Patients With Primary Biliary Cholangitis CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Cholankeril, G., Gonzalez, H. C., Satapathy, S. K., Gonzalez, S. A., Hu, M., Khan, M., Yoo, E. R., Li, A. A., Kim, D., Nair, S., Wong, R. J., Kwo, P. Y., Harrison, S. A., Younossi, Z. M., Lindor, K. D., Ahmed, A. 2018; 16 (6): 965-+
  • Daclatasvir and Sofosbuvir Treatment of Decompensated Liver Disease or Post-Liver Transplant Hepatitis C Virus Recurrence in Patients With Advanced Liver Disease/Cirrhosis in a Real-World Cohort HEPATOLOGY COMMUNICATIONS Kwo, P., Fried, M. W., Reddy, K., Soldevila-Pico, C., Khemichian, S., Darling, J., Zamor, P. J., Napoli, A. A., Anduze-Faris, B., Brown, R. S. 2018; 2 (4): 354–63

    Abstract

    We report the findings of an early access program providing treatment for chronic hepatitis C virus infection (any genotype) with daclatasvir and sofosbuvir with/without ribavirin to patients with Child-Pugh class C cirrhosis or prior liver transplant recipients with recurrent hepatitis C virus infection and advanced fibrosis/cirrhosis. Patients had <12-month life expectancies per the local investigator. Patients received daclatasvir 60 mg and sofosbuvir 400 mg once daily, with/without ribavirin, for 24 weeks. Sustained virologic response (SVR) at posttreatment week 12 (SVR12) was measured. Assessments adhered to local standards. One patient (prior Child-Pugh class C who improved to class B) enrolled by exemption was included in the overall data but not the class C cohort efficacy/safety data. Of the 77 treated patients, including 62 liver transplant recipients (genotype 1, n = 43, 69%; genotype 3, n = 16, 26%) and 14 patients with Child-Pugh class C cirrhosis (genotype 1, n = 4, 29%; genotype 3, n = 10, 71%), 63 (82%) completed treatment. SVR12 rates by modified intention-to-treat analysis (excluding nonvirologic failures lost to follow-up and withdrawal [consent/no reason]) in the overall, liver transplant, and Child-Pugh class C cohorts were 84% (n = 64/76), 90% (n = 56/62), and 62% (n = 8/13), respectively. Rates increased to 96% (n = 64/67), 97% (n = 56/58), and 89% (n = 8/9), respectively, in patients with available virologic data (including early discontinuations); 22/23 patients with genotype 3 (96%) achieved SVR12. Single cases of virologic nonresponse and relapse (both in liver transplant recipients with genotype 1) and viral breakthrough (Child-Pugh class C; genotype 3) occurred. Six patients died, 10 had adverse events leading to discontinuation, and 30 experienced serious adverse events. Conclusion: Daclatasvir plus sofosbuvir, with/without ribavirin, provided high SVR12 rates and was generally well tolerated in patients with life-threatening disease and high unmet needs. (Hepatology Communications 2018;2:354-363).

    View details for PubMedID 29619415

  • Increased Waitlist Mortality and Lower Rate for Liver Transplantation in Hispanic Patients With Primary Biliary Cholangitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Cholankeril, G., Gonzalez, H. C., Satapathy, S., Gonzalez, S. A., Hu, M., Khan, M. A., Yoo, E. R., Li, A. A., Kim, D., Nair, S., Wong, R. J., Kwo, P. Y., Harrison, S. A., Younossi, Z. M., Lindor, K. D., Ahmed, A. 2018

    Abstract

    BACKGROUND & AIMS: Data on the differences in ethnicity and race among patients with primary biliary cholangitis (PBC) awaiting liver transplantation (LT) are limited. We evaluated liver transplant waitlist trends and outcomes based on ethnicity and race in patients with PBC in the United States.METHODS: Using the United Network for Organ Sharing (UNOS) registry, we collected data on patients with PBC on the liver transplant waitlist, and performed analysis with a focus on ethnicity and race-based variations clinical manifestations, waitlist mortality and LT rates from 2000 to 2014. Outcomes were adjusted for demographics, complications of portal hypertension, and Model for End-stage Liver Disease score at time of waitlist registration.RESULTS: Although the number of white PBC waitlist registrants and additions decreased from 2000 to 2014, there were no significant changes in the number of Hispanic PBC waitlist registrants and additions each year. The proportion of Hispanic patients with PBC on the liver transplant waitlist increased from 10.7% in 2000 to 19.3% in 2014. Hispanics had the highest percentage of waitlist deaths (20.8%) of any ethnicity or race evaluated. After adjusting for demographic and clinical characteristics, Hispanic patients with PBC had the lowest overall rate for undergoing LT (adjusted hazard ratio, 0.71; 95% CI, 0. 60-0.83; P < .001) and a significantly higher risk of death while on the waitlist, compared to whites (adjusted hazard ratio, 1.41; 95% CI, 1.15-1.74; P < .001). Furthermore, Hispanic patients with PBC had the highest proportion of waitlist removals due to clinical deterioration.CONCLUSIONS: In an analysis of data from UNOS registry focusing on outcomes, we observed differences in rates of LT and liver transplant waitlist mortality of Hispanic patients compared with white patients with PBC. Further studies are needed to improve our understanding of ethnicity and race-based differences in progression of PBC.

    View details for PubMedID 29427734

  • Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial HEPATOLOGY Wyles, D., Poordad, F., Wang, S., Alric, L., Felizarta, F., Kwo, P. Y., Maliakkal, B., Agarwal, K., Hassanein, T., Weilert, F., Lee, S. S., Kort, J., Lovell, S. S., Liu, R., Lin, C., Pilot-Matias, T., Krishnan, P., Mensa, F. J. 2018; 67 (2): 514–23

    View details for DOI 10.1002/hep.29541

    View details for Web of Science ID 000422694900010

  • Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection NEW ENGLAND JOURNAL OF MEDICINE Zeuzem, S., Foster, G. R., Wang, S., Asatryan, A., Gane, E., Feld, J. J., Asselah, T., Bourliere, M., Ruane, P. J., Wedemeyer, H., Pol, S., Flisiak, R., Poordad, F., Chuang, W., Stedman, C. A., Flamm, S., Kwo, P., Dore, G. J., Sepulveda-Arzola, G., Roberts, S. K., Soto-Malave, R., Kaita, K., Puoti, M., Vierling, J., Tam, E., Vargas, H. E., Bruck, R., Fuster, F., Paik, S., Felizarta, F., Kort, J., Fu, B., Liu, R., Ng, T. I., Pilot-Matias, T., Lin, C., Trinh, R., Mensa, F. J. 2018; 378 (4): 354–69

    Abstract

    Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection.We conducted two phase 3, randomized, open-label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once-daily glecaprevir-pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir-pibrentasvir or sofosbuvir-daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir-pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment.In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1-infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group. Genotype 3-infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir-pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir-daclatasvir; 8 weeks of treatment with glecaprevir-pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group.Once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE-1 and ENDURANCE-3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157 .).

    View details for PubMedID 29365309

  • The effects of a transjugular intrahepatic portosystemic shunt on the diagnosis of hepatocellular cancer. PloS one Wong, K., Ozeki, K., Kwong, A., Patel, B. N., Kwo, P. 2018; 13 (12): e0208233

    Abstract

    BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) may be placed to treat complications of portal hypertension by creating a conduit between the hepatic and portal vein. The diagnosis of hepatocellular carcinoma (HCC) is typically made by multiphasic imaging studies demonstrating arterial enhancement with washout on arterial, portal venous, and delayed phase imaging. The aim of our study was to determine how the presence of TIPS would affect the imaging diagnosis of HCC.METHODS: This was a single-center electronic database review of all patients who underwent multiphasic imaging with MRI or CT scan for HCC screening between January 2000 and July 2017 and who were subsequently diagnosed with HCC. Data collected included patient demographics, liver disease characteristics including CPT score, MELD-Na, AFP, type of imaging, tumor stage, and lab values at the time of HCC diagnosis. The diagnosis of HCC was made using LI-RADS criteria on contrast-enhanced CT or MR imaging and confirmed by chart abstraction as documented by the treating clinician. Demographic and imaging characteristics for HCC patients with and without TIPS were compared.RESULTS: A total of 279 patients met eligibility criteria for the study, 37 (13.2%) of whom had TIPS placed prior to diagnosis of HCC. There was no significant difference in demographics or liver disease characteristics between patients with and without TIPS. Compared to cirrhotic patients with no TIPS prior to HCC diagnosis, patients with TIPS had significantly more scans with a longer duration of surveillance until HCC diagnosis. However, LI-RADS criteria and stage of HCC at diagnosis were not significantly different between both groups. There were no differences in outcomes including liver transplant and survival.CONCLUSION: The presence of TIPS does not lead to a delayed diagnosis of HCC. It is associated, however, with greater duration of time from first scan to diagnosis of HCC.

    View details for PubMedID 30592722

  • Resolution of Crizotinib-Associated Fulminant Hepatitis following Cessation of Treatment. Case reports in hepatology Charville, G. W., Padda, S. K., Sibley, R. K., Puthillath, A., Kwo, P. Y. 2018; 2018: 3413592

    Abstract

    Targeted cancer treatments offer the prospect of precise inhibition of tumor growth without the untoward off-target toxicity of traditional chemotherapies. Still, unintended, often idiosyncratic side effects, such as drug-induced liver injury, can occur. We discuss the case of a 26-year-old female with a history of ROS1-rearranged lung adenocarcinoma, undergoing treatment with the tyrosine kinase inhibitor crizotinib, who presented to our hospital with abdominal pain and scleral icterus. Liver chemistries were notable for hyperbilirubinemia (5mg/dL total) and marked transaminasemia (AST 1736 U/L, ALT >3500 U/L); liver biopsy demonstrated acute hepatitis with extensive necrosis. There was no evidence of an infectious or autoimmune etiology. It was discovered that the patient was taking a 500mg once daily dose of crizotinib, in lieu of the intended dose of 250mg twice daily. After immediate cessation of crizotinib therapy upon hospital admission, there was complete biochemical resolution of the hepatitis. This case highlights the potential reversibility of fulminant crizotinib-associated hepatoxicity, possibly related to supratherapeutic dosing, when managed with abrupt stoppage of the drug and initiation of supportive care.

    View details for PubMedID 30155324

  • The Cochrane Review Conclusion for Hepatitis C DAA Therapies is Wrong AMERICAN JOURNAL OF GASTROENTEROLOGY Kwo, P. Y., Shiffman, M. L., Bernstein, D. E. 2018; 113 (1): 2–4

    View details for PubMedID 29134963

  • The Ribavirin Pregnancy Registry: An Interim Analysis of Potential Teratogenicity at the Mid-Point of Enrollment DRUG SAFETY Sinclair, S. M., Jones, J. K., Miller, R. K., Greene, M. F., Kwo, P. Y., Maddrey, W. C. 2017; 40 (12): 1205–18

    Abstract

    Significant teratogenic effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin is prescribed for chronic hepatitis C and is contraindicated in women who are pregnant and in the male sexual partners of women who are pregnant. Both sexes are advised to avoid pregnancy for 6 months after exposure. The Ribavirin Pregnancy Registry was established in 2003 to monitor pregnancy exposures to ribavirin for signals of possible human teratogenicity.This voluntary registry enrolls pregnant women with prenatal exposure to ribavirin. Exposure is classified as direct-women taking ribavirin during pregnancy or the 6 months prior to conception-or indirect-women exposed through sexual contact, 6 months prior to or during pregnancy, with a man who is taking or has taken ribavirin in the past 6 months. Women are followed until delivery and infants for 1 year. When enrollment is complete, birth defect rates will be compared with the Metropolitan Atlanta Congenital Defects Program's published rate of 2.67. Using data collected since inception in 2003 through February 2016, preliminary rates were calculated.The registry has enrolled 272 pregnant women, with 180 live births: there were seven birth defect cases among 85 directly exposed women [7/85 (8.2%) (95% confidence interval (CI) 3.4-16.2)] and four birth defect cases among 95 indirectly exposed women [4/95 (4.2%) (95% CI 1.2-10.4)]. Of the 11 infants, nine had structural defects and two had chromosomal anomalies. Patterns suggesting a common etiology or relationship with ribavirin exposure are not seen.Based on the patterns of birth defects reported, preliminary findings do not suggest a clear signal of human teratogenicity for ribavirin. However, the current sample size is insufficient for definitive conclusions, and ribavirin exposure should be avoided during pregnancy and during the 6 months prior to pregnancy, in accordance with prescribing information.ClinicalTrials.gov identifier: NCT00114712.

    View details for PubMedID 28689333

  • Drug-drug interactions in hepatitis C virus treatment: Do they really matter? Clinical liver disease Ahmed, A., Lutchman, G. A., Kwo, P. Y. 2017; 10 (5): 111–15

    View details for PubMedID 30992768

  • Alcohol Liver Disease is now the most rapidly rising Indication for Liver Transplant Waitlist Registration in the United States Rahim, U., Cholankeril, G., Yoo, E. R., Liu, A., Li, A. A., Kim, D., Kwo, P. Y., Ahmed, A., Goel, A. WILEY. 2017: 708A
  • Initial Uptake and Time to Treatment of all Oral Direct Acting Antivirals for Hepatitis C Kwo, P., Zhang, Z., Knapp, K., Hui, S., Kelley, A., Muschi, D., Puenpatom, A. NATURE PUBLISHING GROUP. 2017: S502
  • Efficacy and Safety of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Treatment-Naive Patients with Chronic HCV Genotype 3: An Integrated Phase 2/3 Analysis Flamm, S. L., Wyles, D. L., Wang, S., Mutimer, D. J., Rockstroh, J. K., Horsmans, Y. J., Kwo, P. Y., Weiland, O., Villa, E., Heo, J., Gane, E. J., Ryder, S. D., Welzel, T. M., Ng, T., Lovell, S. S., Liu, R., Krishnan, P., Kopecky-Bromberg, S., Asatryan, A., Trinh, R., Mensa, F. J. WILEY. 2017: 35A–36A
  • A Prognostic Model for Liver Transplant Candidates with Hepatitis C - A Decision Aid for Antiviral Therapy Lee, H., Mannalithara, A., Asrani, S. K., Biggins, S. W., Heimbach, J., Brandman, D., Abt, P. L., Kwo, P. Y., Kim, W. WILEY. 2017: 548A–549A
  • Real World Effectiveness of 8 vs 12 Weeks of Ledipasvir/Sofosbuvir (LDV/SOF) in Blacks with HCV: A Comparative Analysis of Clinical Trials with Real World Cohorts Wilson, E., Davitkov, P., Kwo, P. Y., Kattakuzhy, S., Qureshi, K., Sundaram, V., Naik, S., Williams, L. A., Wolf, J., Llewellyn, J., Osinusi, A. O., Brainard, D. M., Gordon, S. C., Backus, L. I., Kowdley, K. V. WILEY. 2017: 608A
  • International Liver Transplantation Society Consensus Statement on Hepatitis C Management in Liver Transplant Candidates TRANSPLANTATION Terrault, N. A., McCaughan, G. W., Curry, M. P., Gane, E., Fagiuoli, S., Fung, J. Y., Agarwal, K., Lilly, L., Strasser, S. I., Brown, K. A., gadano, a., Kwo, P. Y., Burra, P., Samuel, D., Charlton, M., Pessoa, M. G., Berenguer, M. 2017; 101 (5): 945-955

    View details for DOI 10.1097/TP.0000000000001708

    View details for Web of Science ID 000400762500021

    View details for PubMedID 28437387

  • International Liver Transplantation Society Consensus Statement on Hepatitis C Management in Liver Transplant Recipients TRANSPLANTATION Terrault, N. A., Berenguer, M., Strasser, S. I., gadano, a., Lilly, L., Samuel, D., Kwo, P. Y., Agarwal, K., Curry, M. P., Fagiuoli, S., Fung, J. Y., Gane, E., Brown, K. A., Burra, P., Charlton, M., Pessoa, M. G., McCaughan, G. W. 2017; 101 (5): 956-967

    View details for DOI 10.1097/TP.0000000000001704

    View details for Web of Science ID 000400762500022

    View details for PubMedID 28437388

  • Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. Journal of hepatology Kwo, P. Y., Poordad, F., Asatryan, A., Wang, S., Wyles, D. L., Hassanein, T., Felizarta, F., Sulkowski, M. S., Gane, E., Maliakkal, B., Overcash, J. S., Gordon, S. C., Muir, A. J., Aguilar, H., Agarwal, K., Dore, G. J., Lin, C., Liu, R., Lovell, S. S., Ng, T. I., Kort, J., Mensa, F. J. 2017

    Abstract

    Hepatitis C virus (HCV) therapy that is highly efficacious, pangenotypic, with a high barrier to resistance and short treatment duration is desirable. The efficacy and safety of 8- and 12-week treatments with glecaprevir (ABT-493; NS3/4A protease inhibitor) and pibrentasvir (ABT-530; NS5A inhibitor) were evaluated in non-cirrhotic patients with chronic HCV genotype 1-6 infection.SURVEYOR-I and SURVEYOR-II were phase II, open-label, multicenter, dose-ranging trials including patients with chronic HCV genotype 1-6 infection who were either previously untreated or treated with pegylated interferon plus ribavirin. Patients received once-daily glecaprevir plus pibrentasvir at varying doses with or without ribavirin for 8 or 12weeks. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at post-treatment week 12 (SVR12).Of the 449 patients who received varying doses of glecaprevir plus pibrentasvir, 25%, 29%, 39%, and 8% had HCV genotype 1, 2, 3, and 4-6 infection, respectively. Twelve-week treatment achieved SVR12 in 97-100%, 96-100%, 83-94%, and 100% in genotypes 1, 2, 3, and 4-6, respectively. Eight-week treatment with 300mg glecaprevir plus 120mg pibrentasvir in genotype 1-, 2-, or 3-infected patients yielded 97-98% SVR12 with no virologic failures. Three (0.7%) patients discontinued treatment due to adverse events; most events were mild (grade 1) in severity. No post-nadir alanine aminotransferase elevations were observed.Glecaprevir plus pibrentasvir was well tolerated and achieved high sustained virologic response rates in HCV genotypes 1-6-infected patients without cirrhosis following 8- or 12-week treatment durations.The combination of direct-acting antivirals glecaprevir and pibrentasvir comprise a once-daily, all-oral, pangenotypic treatment for HCV genotype 1-6 infection. This article describes results from two phase II trials investigating a range of doses at treatment durations of 8 or 12weeks in 449 patients without cirrhosis. Efficacy of the optimal dose, as determined by rates of sustained virologic response at post-treatment week 12, ranged from 92%-100%; treatment was well tolerated and significant laboratory abnormalities were rare.clinicaltrials.gov Identifiers: NCT02243280 and NCT02243293. http://www.clinicaltrials.gov/show/NCT02243280, http://www.clinicaltrials.gov/show/NCT01939197.

    View details for DOI 10.1016/j.jhep.2017.03.039

    View details for PubMedID 28412293

  • International Liver Transplant Society Consensus Statement on HEPATITIS C MANAGEMENT IN LIVER TRANSPLANT CANDIDATES. Transplantation Terrault, N. A., McCaughan, G. W., Curry, M. P., Gane, E., Fagiuoli, S., Fung, J., Agarwal, K., Lilly, L., Strasser, S. I., BROWN, K., Gadano, A., Kwo, P. Y., Burra, P., Samuel, D., Charlton, M., Pessoa, M. G., Berenguer, M. 2017

    View details for DOI 10.1097/TP.0000000000001708

    View details for PubMedID 28252565

  • International Liver Transplant Society Consensus Statement on HEPATITIS C MANAGEMENT IN LIVER TRANSPLANT RECIPIENTS. Transplantation Terrault, N., Berenguer, M., Strasser, S., gadano, a., Lilly, L., Samuel, D., Kwo, P. Y., Agarwal, K., Curry, M., Fagiuoli, S., Fung, J. Y., Gane, E., Brown, K. A., Burra, P., Charlton, M., Pessoa, M., McCaughan, G. W. 2017

    View details for DOI 10.1097/TP.0000000000001704

    View details for PubMedID 28252566

  • Confirming What We Believed: Reducing and Eliminating Vertical Transmission of Hepatitis B. Gastroenterology Kligman, E., Kwo, P. Y. 2017

    View details for DOI 10.1053/j.gastro.2017.02.023

    View details for PubMedID 28257749

  • Ushering in an Era Where No Group Who Wants to Be Treated Should Be Excluded CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Liangpunsakul, S., Kwo, P. Y. 2017; 15 (2): 289-291
  • Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients With Chronic Hepatitis C Infection GASTROENTEROLOGY Kwo, P., Gane, E. J., Peng, C., Pearlman, B., Vierling, J. M., Serfaty, L., Buti, M., Shafran, S., Stryszak, P., Lin, L., Gress, J., Black, S., Dutko, F. J., Robertson, M., Wahl, J., Lupinacci, L., Barr, E., Haber, B. 2017; 152 (1): 164-?

    Abstract

    Patients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population.We analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA <15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was greater than the reference rate (58%).With 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotypes 1 and 4 who relapsed after completing peg-interferon and ribavirin, and 7.5% infected with HCV genotypes 1 and 4, respectively, with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%).The combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov Number: NCT02105701.

    View details for DOI 10.1053/j.gastro.2016.09.045

    View details for Web of Science ID 000390956200039

  • Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial. Hepatology (Baltimore, Md.) Wyles, D., Poordad, F., Wang, S., Alric, L., Felizarta, F., Kwo, P. Y., Maliakkal, B., Agarwal, K., Hassanein, T., Weilert, F., Lee, S. S., Kort, J., Lovell, S. S., Liu, R., Lin, C. W., Pilot-Matias, T., Krishnan, P., Mensa, F. J. 2017

    Abstract

    This study assessed the efficacy and safety of ribavirin-free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. SURVEYOR-II, Part 3 was a partially randomized, open-label, multicenter, phase 3 study. Treatment-experienced (prior interferon or pegylated interferon ± ribavirin or sofosbuvir plus ribavirin ± pegylated interferon therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment-naive or treatment-experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at posttreatment week 12 (SVR12). Safety was evaluated throughout the study. There were 131 patients enrolled and treated. Among treatment-experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; 95% confidence interval [CI], 72-97) and 95% (21/22; 95% CI, 78-99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; 95% CI, 87-99) of treatment-naive patients treated for 12 weeks and 96% (45/47; 95% CI, 86-99) of patients with prior treatment experience treated for 16 weeks. No adverse events led to discontinuation of study drug, and no serious adverse events were related to study drug.Patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. (Hepatology 2017).

    View details for PubMedID 28926120

  • The Liver in Oncology. Clinics in liver disease Dhanasekaran, R., Kwo, P. Y. 2017; 21 (4): 697–707

    Abstract

    Gastroenterologists and hepatologists will encounter oncology patients who develop abnormal liver tests, patients with hepatic malignancies, and patients with acute and chronic liver disease who require chemotherapy or immediate evaluation. Chemotherapy can cause liver injury owing to toxic effects or idiosyncratic reactions. Immune checkpoint inhibitors may be associated with autoimmune-mediated liver toxicities. Venoocclusive disease requires immediate evaluation. Nodular regenerative hyperplasia is a chronic progressive disorder. Screening and prophylaxis for reactivation of hepatitis B is important to minimize complications in patients receiving chemotherapy. Patients with metastatic lesions can undergo resection or ablation. Hepatic injury may occur in those receiving radiation-based therapies.

    View details for PubMedID 28987257

  • All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database ALIMENTARY PHARMACOLOGY & THERAPEUTICS Reddy, K. R., Lim, J. K., Kuo, A., Di Bisceglie, A. M., Galati, J. S., Morelli, G., Everson, G. T., Kwo, P. Y., Brown, R. S., Sulkowski, M. S., Akuschevich, L., Lok, A. S., Pockros, P. J., Vainorius, M., Terrault, N. A., Nelson, D. R., Fried, M. W., Manns, M. P. 2017; 45 (1): 115-126

    View details for DOI 10.1111/apt.13823

    View details for Web of Science ID 000389439600012

  • Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients With Chronic Hepatitis C Infection. Gastroenterology Kwo, P., Gane, E. J., Peng, C., Pearlman, B., Vierling, J. M., Serfaty, L., Buti, M., Shafran, S., Stryszak, P., Lin, L., Gress, J., Black, S., Dutko, F. J., Robertson, M., Wahl, J., Lupinacci, L., Barr, E., Haber, B. 2017; 152 (1): 164-175 e4

    Abstract

    Patients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population.We analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA <15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was greater than the reference rate (58%).With 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotypes 1 and 4 who relapsed after completing peg-interferon and ribavirin, and 7.5% infected with HCV genotypes 1 and 4, respectively, with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%).The combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov Number: NCT02105701.

    View details for DOI 10.1053/j.gastro.2016.09.045

    View details for PubMedID 27720838

  • ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. American journal of gastroenterology Kwo, P. Y., Cohen, S. M., Lim, J. K. 2017; 112 (1): 18-35

    Abstract

    Clinicians are required to assess abnormal liver chemistries on a daily basis. The most common liver chemistries ordered are serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin. These tests should be termed liver chemistries or liver tests. Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels. Cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels. The majority of bilirubin circulates as unconjugated bilirubin and an elevated conjugated bilirubin implies hepatocellular disease or cholestasis. Multiple studies have demonstrated that the presence of an elevated ALT has been associated with increased liver-related mortality. A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females and levels above this should be assessed. The degree of elevation of ALT and or AST in the clinical setting helps guide the evaluation. The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency. In addition, a history of prescribed and over-the-counter medicines should be sought. For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken. Total bilirubin elevation can occur in either cholestatic or hepatocellular diseases. Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings. A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible.

    View details for DOI 10.1038/ajg.2016.517

    View details for PubMedID 27995906

  • ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries AMERICAN JOURNAL OF GASTROENTEROLOGY Kwo, P. Y., Cohen, S. M., Lim, J. K. 2017; 112 (1): 17-36

    Abstract

    Clinicians are required to assess abnormal liver chemistries on a daily basis. The most common liver chemistries ordered are serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin. These tests should be termed liver chemistries or liver tests. Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels. Cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels. The majority of bilirubin circulates as unconjugated bilirubin and an elevated conjugated bilirubin implies hepatocellular disease or cholestasis. Multiple studies have demonstrated that the presence of an elevated ALT has been associated with increased liver-related mortality. A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females and levels above this should be assessed. The degree of elevation of ALT and or AST in the clinical setting helps guide the evaluation. The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency. In addition, a history of prescribed and over-the-counter medicines should be sought. For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken. Total bilirubin elevation can occur in either cholestatic or hepatocellular diseases. Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings. A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible.

    View details for DOI 10.1038/ajg.2016.570

    View details for Web of Science ID 000394131800012

  • High Efficacy of ABT-493 and ABT-530 Treatment in Patients With HCV Genotype 1 or 3 Infection and Compensated Cirrhosis GASTROENTEROLOGY Gane, E., Poordad, F., Wang, S., Asatryan, A., Kwo, P. Y., Lalezari, J., Wyles, D. L., Hassanein, T., Aguilar, H., Maliakkal, B., Liu, R., Lin, C., Ng, T. I., Kort, J., Mensa, F. J. 2016; 151 (4): 651-?

    Abstract

    The combination of ABT-493 (NS3/4A protease inhibitor) plus ABT-530 (NS5A inhibitor) has shown high rates of sustained virologic response at post-treatment week 12 (SVR12) in noncirrhotic patients infected with hepatitis C virus (HCV) genotypes (GTs) 1-6. We describe 2 open-label phase 2 studies investigating the efficacy and safety of ABT-493 plus ABT-530 with or without ribavirin (RBV) in GT1- or GT3-infected patients with compensated cirrhosis.Patients with GT1 infection received 200 mg ABT-493 plus 120 mg ABT-530 for 12 weeks. Patients with GT3 infection were randomized 1:1 to receive 300 mg ABT-493 plus 120 mg ABT-530 with or without once-daily 800 mg RBV for 12 weeks; treatment-experienced patients who were not treated with RBV received 16 weeks of therapy. Efficacy was measured by SVR12, defined as an HCV-RNA level less than 25 IU/mL. Adverse events and laboratory parameters were evaluated throughout the study.Twenty-seven patients with GT1 infection and 55 patients with GT3 infection were enrolled. The majority were treatment-naive (84%) and male (65%). In patients with GT1 infection, SVR12 was achieved by 96% (26 of 27; 95% confidence interval [CI], 82-99) of patients, with 1 relapse. Among GT3-infected patients, SVR12 was achieved in 96% (27 of 28; 95% CI, 82-99) of patients in the RBV-free arm (1 relapse), and in 100% (27 of 27; 95% CI, 88-100) in the RBV-containing arm. The most common adverse events were headache, fatigue, and nausea. Laboratory abnormalities were rare; no patient discontinued treatment.In cirrhotic HCV GT1- or GT3-infected patients, ABT-493 plus ABT-530 with or without RBV achieved SVR12 rates of 96%-100% and was well tolerated. ClinicalTrials.gov identifiers NCT02243280 and NCT02243293.

    View details for DOI 10.1053/j.gastro.2016.07.020

    View details for PubMedID 27456384

  • After the Direct-acting Antivirals Are Gone, There Is Still Work to Be Done in the Liver GASTROENTEROLOGY Kwo, P. Y., Lacerda, M. A. 2016; 151 (4): 582-584

    View details for DOI 10.1053/j.gastro.2016.08.045

    View details for Web of Science ID 000389548500009

    View details for PubMedID 27590790

  • Simeprevir Plus Sofosbuvir (12 and 8 Weeks) in Hepatitis C Virus Genotype 1-Infected Patients Without Cirrhosis: OPTIMIST-1, a Phase 3, Randomized Study HEPATOLOGY Kwo, P., Gitlin, N., Nahass, R., Bernstein, D., Etzkorn, K., Rojter, S., Schiff, E., Davis, M., Ruane, P., Younes, Z., Kalmeijer, R., Sinha, R., Peeters, M., Lenz, O., Fevery, B., De La Rosa, G., Scott, J., Witek, J. 2016; 64 (2): 370-380

    Abstract

    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).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).

    View details for DOI 10.1002/hep.28467

    View details for Web of Science ID 000380034500010

    View details for PubMedID 26799692

    View details for PubMedCentralID PMC5412860

  • 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. Gastroenterology Gane, E., Kowdley, K. V., Pound, D., Stedman, C. A., Davis, M., Etzkorn, K., Gordon, S. C., Bernstein, D., Everson, G., Rodriguez-Torres, M., Tsai, N., Khalid, O., Yang, J. C., Lu, S., Dvory-Sobol, H., Stamm, L. M., Brainard, D. M., McHutchison, J. G., Tong, M., Chung, R. T., Beavers, K., Poulos, J. E., Kwo, P. Y., Nguyen, M. H. 2016

    Abstract

    Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections who have failed by a prior course of antiviral therapy, and the feasibility of further 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.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 endpoint was sustained virologic response 12 weeks after treatment (SVR12).Following 6 weeks of treatment, SVR12s were achieved by 88% of treatment-naïve patients without cirrhosis (29/33; 95% CI, 72%-97%). Following 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naïve patients with cirrhosis (28/30; 95% CI, 78%-99%). After 12 weeks of treatment, SVR12s were achieved by all treatment-experienced patients without cirrhosis (36/36; 95% CI, 90%-100%) and 97% of treatment-experienced patients with cirrhosis (28/29; 95% CI, 82%-100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events.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. ClinicalTrials.gov no: NCT02378961.

    View details for DOI 10.1053/j.gastro.2016.07.038

    View details for PubMedID 27486033

  • Hepatic arterial buffer response: pathologic evidence in non-cirrhotic human liver with extrahepatic portal vein thrombosis MODERN PATHOLOGY Rush, N., Sun, H., Nakanishi, Y., Mneimneh, W., Kwo, P. Y., Saxena, R. 2016; 29 (5): 489-499

    Abstract

    Increase in hepatic arterial flow in response to reduced portal flow (hepatic arterial buffer response) has been demonstrated experimentally and surgically. We provide pathologic evidence for hepatic arterial buffer response in non-cirrhotic patients with extrahepatic portal vein thrombosis and elucidate the histopathologic spectrum of non-cirrhotic portal vein thrombosis. Liver biopsies and resections from non-cirrhotic patients with extra-hepatic portal vein thrombosis were retrieved. Morphologic features, extent of CD34 staining, outer diameters, luminal diameters and wall thickness of hepatic arteries cut in cross-section and outer diameters of cross-sectioned paired bile ducts were compared with age- and gender-matched controls. There were 12 male and 9 female patients. Measurements of 280 and 193 arteries from patients and controls, respectively, demonstrated statistically significant (P<0.05) arterial dilatation (increase in percentage of arterial lumen to outer diameter) and arterial wall thinning in resection specimens of non-cirrhotic patients with extra-hepatic portal vein thrombosis. Subtle and/or focal dilatation of central veins, portal veins and sinusoids; focal trabecular thinning/thickening and mild ductular reaction were common findings in both the patient and control groups. Diffuse and obvious changes, and portal vein absence or attenuation were seen only in the patient group. Capillarization of sinusoids was not seen on CD34 stain. Two patients showed significant ductular reaction, one of who developed biliary strictures on follow-up. Hepatic arterial dilatation and wall thinning in non-cirrhotic patients with portal vein thrombosis provide pathologic evidence of hepatic arterial buffer response in the human liver. Obvious and diffuse sinusoidal dilatation and absence or attenuation of portal veins are highly suggestive of extrahepatic portal vein thrombosis in non-cirrhotic patients with portal hypertension. Periportal shunt vessels, hypervascular portal tracts, muscularized portal veins, large thick-walled or dilated arteries aid diagnosis but are rare findings. Normal or near-normal biopsies do not rule out portal vein thrombosis.

    View details for DOI 10.1038/modpathol.2016.43

    View details for Web of Science ID 000375123700006

    View details for PubMedID 26916069

  • Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B) JOURNAL OF HEPATOLOGY Chan, H. L., Ahn, S. H., Chang, T., Peng, C., Wong, D., Coffin, C. S., Lim, S. G., Chen, P., Janssen, H. l., Marcellin, P., Serfaty, L., Zeuzem, S., Cohen, D., Critelli, L., Xu, D., Wind-Rotolo, M., Cooney, E. 2016; 64 (5): 1011-1019

    Abstract

    Peginterferon lambda-1a (lambda) is a Type-III interferon, which, like alfa interferons, has antiviral activity in vitro against hepatitis B virus (HBV) and hepatitis C virus (HCV); however, lambda has a more limited extra-hepatic receptor distribution. This phase 2b study (LIRA-B) evaluated lambda in patients with chronic HBV infection.Adult HBeAg+ interferon-naive patients were randomized (1:1) to weekly lambda (180 μg) or peginterferon alfa-2a (alfa) for 48 weeks. The primary efficacy endpoint was HBeAg seroconversion at week 24 post-treatment; lambda non-inferiority was demonstrated if the 80% confidence interval (80% CI) lower bound was >-15%.Baseline characteristics were balanced across groups (lambda N=80; alfa N=83). Early on-treatment declines in HBV-DNA and qHBsAg through week 24 were greater with lambda. HBeAg seroconversion rates were comparable for lambda and alfa at week 48 (17.5% vs. 16.9%, respectively); however lambda non-inferiority was not met at week 24 post-treatment (13.8% vs. 30.1%, respectively; lambda vs. alfa 80% CI lower bound -24%). Results for other key secondary endpoints (virologic, serologic, biochemical) and post hoc combined endpoints (HBV-DNA <2000 IU/ml plus HBeAg seroconversion or ALT normalization) mostly favored alfa. Overall adverse events (AE), serious AE, and AE-discontinuation rates were comparable between arms but AE-spectra differed (more cytopenias, flu-like, and musculoskeletal symptoms observed with alfa, more ALT flares and bilirubin elevations seen with lambda). Most on-treatment flares occurred early (weeks 4-12), associated with HBV-DNA decline; all post-treatment flares were preceded by HBV-DNA rise.On-treatment, lambda showed greater early effects on HBV-DNA and qHBsAg, and comparable serologic/virologic responses at end-of-treatment. However, post-treatment, alfa-associated HBeAg seroconversion rates were higher, and key secondary results mostly favored alfa. ClinicalTrials.gov number: NCT01204762.

    View details for DOI 10.1016/j.jhep.2015.12.018

    View details for Web of Science ID 000374370300008

    View details for PubMedID 26739688

  • Risk factors for bleeding after liver biopsy ABDOMINAL RADIOLOGY Sandrasegaran, K., Thayalan, N., Thavanesan, R., Kohli, M., Berry, W., Shah, A., Kwo, P. 2016; 41 (4): 643-649

    Abstract

    Determine factors that increase the risk of bleeding after liver biopsy.Retrospective review of radiology and clinical databases from Jan 2008 to Jun 2014 revealed 847 patients with liver biopsy. Of these, 154 (group I) had targeted biopsy of focal lesion and 142 (group 2) had random core biopsy for diffuse liver disease. The rest of the patients were excluded due to insufficient post-biopsy data. Data including pre-biopsy laboratory results, history of transfusion, and biopsy complications were recorded in the study cohort. After review of initial results, a "Risk Score" for bleeding was created using platelet count, INR, estimated glomerular filtration rate (eGFR), and suspicion of malignancy. Zero point was given for normal laboratory results or absence of malignancy. One point was given for mildly abnormal laboratory values or presence of malignancy. Severe biochemical abnormalities, e.g., INR > 2.0, eGFR < 30 mL/min, or platelet count ≤ 50 × 10(9)/L were given two points each. The "Risk Score" was made of adding individual points.Of 847 patients queried by retrospective database search, 296 had adequate records for the period of 2 weeks prior to biopsy to 4 weeks after biopsy. The remaining patients had liver biopsy as outpatients and probably did not have bleeding complications but no electronic records were found to confirm this. 25 (8.4%) of 296 patients had post-biopsy bleeding, with incidences of 11.7% and 4.9% in groups 1 and 2 (p = 0.04). On logistic regression analysis, the only significant predictor of bleeding was the "Risk Score" (p = 0.01, odds ratio 4.6). There was substantial overlap in INR, and platelet count in bleeders vs. non-bleeders. Pre-biopsy fresh frozen plasma or platelet concentrate infusions did not reduce the risk of bleeding.INR and platelet count are not an independent risk factors for post-biopsy bleeding. A "Risk Score" made up of individual risk factors was a better predictor of bleeding.

    View details for DOI 10.1007/s00261-016-0655-5

    View details for Web of Science ID 000374964100009

    View details for PubMedID 26847020

  • Narrow-band imaging versus white light for the detection of proximal colon serrated lesions: a randomized, controlled trial GASTROINTESTINAL ENDOSCOPY Rex, D. K., Clodfelter, R., Rahmani, F., Fatima, H., James-Stevenson, T. N., Tang, J. C., Kim, H. N., McHenry, L., Kahi, C. J., Rogers, N. A., Helper, D. J., Sagi, S. V., Kessler, W. R., Wo, J. M., Fischer, M., Kwo, P. Y. 2016; 83 (1): 166-171

    Abstract

    The value of narrow-band imaging (NBI) for detecting serrated lesions is unknown.To assess NBI for the detection of proximal colon serrated lesions.Randomized, controlled trial.Two academic hospital outpatient units.Eight hundred outpatients 50 years of age and older with intact colons undergoing routine screening, surveillance, or diagnostic examinations.Randomization to colon inspection in NBI versus white-light colonoscopy.The number of serrated lesions (sessile serrated polyps plus hyperplastic polyps) proximal to the sigmoid colon.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.Lack of blinding, endoscopic estimation of polyp location.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. (NCT01572428.).

    View details for DOI 10.1016/j.gie.2015.03.1915

    View details for Web of Science ID 000369230900026

    View details for PubMedID 25952085

  • Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis NEW ENGLAND JOURNAL OF MEDICINE Curry, M. P., O'Leary, J. G., Bzowej, N., Muir, A. J., Korenblat, K. M., Fenkel, J. M., Reddy, K. R., Lawitz, E., Flamm, S. L., Schiano, T., Teperman, L., Fontana, R., Schiff, E., Fried, M., Doehle, B., An, D., McNally, J., Osinusi, A., Brainard, D. M., McHutchison, J. G., Brown, R. S., Charlton, M. 2015; 373 (27): 2618-2628

    Abstract

    As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase.We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin.Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).

    View details for DOI 10.1056/NEJMoa1512614

    View details for PubMedID 26569658

  • Treatment variables related to liver toxicity in patients with hepatocellular carcinoma, Child-Pugh class A and B enrolled in a phase 1-2 trial of stereotactic body radiation therapy. Practical radiation oncology Lasley, F. D., Mannina, E. M., Johnson, C. S., Perkins, S. M., Althouse, S., Maluccio, M., Kwo, P., Cárdenes, H. 2015; 5 (5): e443-9

    Abstract

    An analysis was performed on patients enrolled in a phase 1-2 trial using stereotactic body radiation therapy for hepatocellular carcinoma evaluating variables influencing liver toxicity.Thirty-eight Child-Pugh class A (CPC-A) (39 lesions) and 21 CPC-B patients (26 lesions) were followed for ≥6 months. Six months local control using modified Response Evaluation Criteria in Solid Tumors criteria, progression-free survival, overall survival, and grade III/IV treatment-related toxicity at 3 months were analyzed.Median follow-up was 33.3 months (2.8-61.1 months) for CPC-A and 46.3 months (3.7-70.4 months) for CPC-B patients. Local control at 6 months was 92% for CPC-A and 93% for CPC-B. Kaplan-Meier estimated 2- and 3-year local control was 91% for CPC-A and 82% for CPC-B (P = .61). Median overall survival was 44.8 months and 17.0 months for CPC-A and CPC-B. Kaplan-Meier estimated 2- and 3-year overall survival was 72% and 61% for CPC-A and 33% and 26% for CPC-B (P = .03). Four (11%) CPC-A patients and 8 CPC-B patients (38%) experienced grade III/IV liver toxicity. Overall, CPC-A patients with ≥grade III liver toxicity had 4.59 (95% confidence interval, 1.19-17.66) times greater risk of death than those without toxicity (P = .0268). No such correlation was seen for CPC-B patients; however, 3 of these CPC-B patients underwent orthotopic liver transplant. CPC-B patients experiencing grade III/IV liver toxicity had significantly higher mean liver dose, higher dose to one-third normal liver, and larger volumes of liver receiving doses <2.5 to 15 Gy in 2.5-Gy increments. For CPC-A patients, there was no critical liver dose or volume constraint correlated with toxicity.In our experience, liver stereotactic body radiation therapy is a safe therapy for patients with hepatocellular carcinoma in the context of liver cirrhosis; however, for CPC-B patients, careful attention should be paid to low-dose volumes that could potentially result in increased liver toxicity.

    View details for DOI 10.1016/j.prro.2015.02.007

    View details for PubMedID 25899219

  • Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease GASTROENTEROLOGY Charlton, M., Everson, G. T., Flamm, S. L., Kumar, P., Landis, C., Brown, R. S., Fried, M. W., Terrault, N. A., O'Leary, J. G., Vargas, H. E., Kuo, A., Schiff, E., Sulkowski, M. S., Gilroy, R., Watt, K. D., Brown, K., Kwo, P., Pungpapong, S., Korenblat, K. M., Muir, A. J., Teperman, L., Fontana, R. J., Denning, J., Arterburn, S., Dvory-Sobol, H., Brandt-Sarif, T., Pang, P. S., McHutchison, J. G., Reddy, K. R., Afdhal, N. 2015; 149 (3): 649-659

    Abstract

    There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease.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).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.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.

    View details for DOI 10.1053/j.gastro.2015.05.010

    View details for PubMedID 25985734

  • Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: Analysis of phase III ION trials HEPATOLOGY Alqahtani, S. A., Afdhal, N., Zeuzem, S., Gordon, S. C., Mangia, A., Kwo, P., Fried, M., Yang, J. C., Ding, X., Pang, P. S., McHutchison, J. G., Pound, D., Reddy, K. R., Marcellin, P., Kowdley, K. V., Sulkowski, M. 2015; 62 (1): 25-30

    Abstract

    In phase III studies, treatment with the once-daily fixed-dose combination tablet of ledipasvir/sofosbuvir (LDV/SOF) with and without ribavirin (RBV) resulted in high rates of sustained virological response (SVR) in patients chronically infected with genotype 1 hepatitis C virus, including those with compensated cirrhosis. We conducted an analysis of data from these trials to compare the safety and tolerability profile of LDV-SOF with and without RBV. We analyzed treatment-emergent adverse events (AEs) and laboratory abnormalities in patients who were randomized to 8, 12, and 24 weeks of LDV/SOF with or without RBV. In total, data from 1,952 patients (of whom 872 received LDV/SOF with RBV and 1,080 received LDV/SOF alone) were analyzed. Overall, 308 patients (16%) were African American, 224 (11%) had compensated cirrhosis, 501 (26%) had a body mass index ≥30 kg/m(2) , and 440 (23%) were treatment experienced. Treatment-related AEs occurred in 71% and 45% of patients treated with and without RBV, respectively, including fatigue, insomnia, irritability, and rash/pruritus. Patients receiving RBV with LDV/SOF were more likely to require dose modification, interruptions of treatment resulting from AEs, or require the use of concomitant medications than those receiving LDV/SOF alone. Rates of treatment-related serious AEs and discontinuations resulting from AEs were similarly low (<1%) in both groups. The rate of SVR in those receiving RBV and those not receiving RBV was the same (97%).LDV/SOF plus RBV was associated with a greater incidence of AEs as well as concomitant medication use than LDV/SOF alone. Use of RBV did not impact the efficacy of LDV/SOF regimens in the ION phase III studies.

    View details for DOI 10.1002/hep.27890

    View details for Web of Science ID 000356864800008

    View details for PubMedID 25963890

  • The Presence of Portal Vein Thrombosis Alters the Classic Enhancement Associated with Diagnosis of Hepatocellular Carcinoma DIGESTIVE DISEASES AND SCIENCES Umar, N. K., Badshah, M. B., Sandrasegaran, K., Ghabril, M., Agarwal, S., Tann, M., Lacerda, M., Kwo, P. Y. 2015; 60 (7): 2196-2200

    Abstract

    To determine whether the presence of portal vein thrombosis (PVT) where venous flow within the liver may be altered may delay the diagnosis of HCC and be associated with more advanced disease. We characterized the incidence and imaging characteristics of patients diagnosed with hepatocellular carcinoma in a cohort of patients with PVT compared with those without PVT.This is a single-center retrospective study of a subset of HCC patients who underwent dynamic imaging for HCC screening and were found to have PVT. Data abstracted included demographic data, TNM stage, number/type of scans, AFP level, MELD score, and time to diagnosis.Eighty-two patients newly diagnosed with HCC on screening were reviewed, of which 37 % (30/82) were found to have portal vein thrombosis. Patients with PVT had higher rates of atypical imaging associated with HCC compared with those without PVT (83 vs 56 %, p = 0.01) and had lower rates of portal venous washout (23 % vs 50 %, p = 0.018). Patients with PVT and HCC were also diagnosed at later TNM stage than those without PVT (70 vs 23 %, p < 0.001) and were significantly less likely to receive orthotopic liver transplant (3.6 vs 42 %, p < 0.001). Fourteen patients had preexisting PV clot without HCC; 16 developed PVT during screening or at diagnosis. Those with preexisting PVT were older (63. vs 55 years) and had higher rates of diagnosis of HCC using MRI (79 vs 21 % with CT, p = 0.01), compared with those without preexisting PVT.The presence of PVT found on dynamic imaging was associated with advanced stage of HCC at the time of diagnosis. Clinicians should have a high suspicion for HCC diagnosis in new liver lesions with atypical enhancement in the setting of PVT. In this setting, MRI was more frequently associated with HCC diagnosis.

    View details for DOI 10.1007/s10620-015-3587-y

    View details for Web of Science ID 000356021500044

    View details for PubMedID 25777258

  • Daclatasvir in Combination With Asunaprevir and Beclabuvir for Hepatitis C Virus Genotype 1 Infection With Compensated Cirrhosis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Muir, A. J., Poordad, F., Lalezari, J., Everson, G., Dore, G. J., Herring, R., Sheikh, A., Kwo, P., Hezode, C., Pockros, P. J., Tran, A., Yozviak, J., Reau, N., Ramji, A., Stuart, K., Thompson, A. J., Vierling, J., Freilich, B., Cooper, J., Ghesquiere, W., Yang, R., McPhee, F., Hughes, E. A., Swenson, E. S., Yin, P. D. 2015; 313 (17): 1736-1744

    Abstract

    Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis.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.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.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.Sustained virologic response at posttreatment week 12 (SVR12).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.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.

    View details for DOI 10.1001/jama.2015.3868

    View details for PubMedID 25942724

  • Fixed-Dose Combination Therapy With Daclatasvir, Asunaprevir, and Beclabuvir for Noncirrhotic Patients With HCV Genotype 1 Infection JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Poordad, F., Sievert, W., Mollison, L., Bennett, M., Tse, E., Braeu, N., Levin, J., Sepe, T., Lee, S. S., Angus, P., Conway, B., Pol, S., Boyer, N., Bronowicki, J., Jacobson, I., Muir, A. J., Reddy, K. R., Tam, E., Ortiz-Lasanta, G., de Ledinghen, V., Sulkowski, M., Boparai, N., McPhee, F., Hughes, E., Swenson, E. S., Yin, P. D. 2015; 313 (17): 1728-1735

    Abstract

    The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection.To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor).This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included.Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg.The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort.Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea.In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir.clinicaltrials.gov Identifier: NCT01979939.

    View details for DOI 10.1001/jama.2015.3860

    View details for PubMedID 25942723

  • An Interferon-free Antiviral Regimen for HCV after Liver Transplantation NEW ENGLAND JOURNAL OF MEDICINE Kwo, P. Y., Mantry, P. S., Coakley, E., Te, H. S., Vargas, H. E., Brown, R., Gordon, F., Levitsky, J., Terrault, N. A., Burton, J. R., Xie, W., Setze, C., Badri, P., Pilot-Matias, T., Vilchez, R. A., Forns, X. 2014; 371 (25): 2375-2382

    Abstract

    Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection.We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigator's discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment.Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study.Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).

    View details for DOI 10.1056/NEJMoa1408921

    View details for Web of Science ID 000346425800006

    View details for PubMedID 25386767

  • Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: Meta-analysis of 5 trials JOURNAL OF HEPATOLOGY Vierling, J. M., Zeuzem, S., Poordad, F., Bronowicki, J., Manns, M. P., Bacon, B. R., Esteban, R., Flamm, S. L., Kwo, P. Y., Pedicone, L. D., Deng, W., Dutko, F. J., DiNubile, M. J., Koury, K. J., Helmond, F. A., Wahl, J., Bruno, S. 2014; 61 (2): 200-209

    Abstract

    HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials.Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring.Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ⩾ 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ⩽ 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with <3 log10 decline and detectable HCV-RNA at TW8 achieved SVR. Anemia and diarrhea occurred more frequently in cirrhotic than non-cirrhotic patients. Serious AEs, discontinuations due to an AE, interventions to manage anemia, infections, and thrombocytopenia occurred more frequently in cirrhotics with BOC/P/R than P/R. Potential hepatic decompensation and/or sepsis were identified in 2 P/R and 3 BOC/P/R recipients.BOC/P/R appears to have a generally favorable benefit-risk profile in compensated cirrhotic patients. SVR rates were particularly high in cirrhotic patients with undetectable HCV-RNA at TW8.

    View details for DOI 10.1016/j.jhep.2014.03.022

    View details for Web of Science ID 000339775700007

    View details for PubMedID 24747798

  • The future of hepatitis C virus therapeutics. Gastroenterology & hepatology Kwo, P. Y. 2014; 10 (7): 433-435

    View details for PubMedID 25904831

    View details for PubMedCentralID PMC4302491

  • Comparison of first- and second-wave DAAs for HCV GT1: efficacy, safety, tolerability, and regimen complexity HEPATOLOGY INTERNATIONAL Burman, B. E., Kwo, P. Y., Kowdley, K. V. 2014; 8 (3): 352-364

    View details for DOI 10.1007/s12072-014-9552-6

    View details for Web of Science ID 000339939700008

    View details for PubMedID 26202638

  • Telaprevir with peginterferon/ribavirin for retreatment of null responders with advanced fibrosis post-orthotopic liver transplant CLINICAL TRANSPLANTATION Kwo, P. Y., Ghabril, M., Lacerda, M. A., Tector, A. J., Fridell, J. A., Vianna, R. 2014; 28 (6): 722-727

    Abstract

    Aggressive recurrence of hepatitis C remains problematic post-orthotopic liver transplant (OLT). There are limited data on treatment of HCV infection with telaprevir/boceprevir therapy with peginterferon/ribavirin (PR) post-OLT.To review our experience with telaprevir addition to peginterferon/ribavirin in treatment of aggressive hepatitis C in null responders to PR post-OLT.Adult patients with recurrent HCV infection post-OLT with null response to peginterferon/ribavirin for 12 wk (<2 log reduction) received four-wk lead-in PEG-IFN alfa-2b (1.0 μg/kg/wk) plus RBV (600-1000 mg/d) followed by addition of telaprevir 750 q8. All patients were converted to cyclosporine from tacrolimus (TAC).Seven patients (3 M, 4 F), mean age 56 yr, were treated. Three were <1 yr post-OLT, six had cirrhosis and one bridging fibrosis. Three of seven achieved sustained virologic response. All patients required RBV dose reduction, 6/7 required erythropoietin, 5/7 required filgrastim, and 2/7 required eltrombopag for platelets <20 000 μL. There were no supratherapeutic/subtherapeutic CYA levels encountered, no episodes of renal insufficiency.Conversion to CYA followed by four-wk peginterferon/ribavirin lead-in with addition of telaprevir can lead to significant clearance rates at week 24 in null responders with advanced fibrosis although high rates of anemia/RBV dose reduction, growth factor, and transfusion requirements were noted.

    View details for DOI 10.1111/ctr.12372

    View details for Web of Science ID 000337690200012

    View details for PubMedID 24708229

  • Role of Cardiac Catheterization and Percutaneous Coronary Intervention in the Preoperative Assessment and Management of Patients Before Orthotopic Liver Transplantation LIVER TRANSPLANTATION Maddur, H., Bourdillon, P. D., Liangpunsakul, S., Tector, A. J., Fridell, J. A., Ghabril, M., Lacerda, M. A., Bourdillon, C., Shen, C., Kwo, P. Y. 2014; 20 (6): 664-672

    View details for DOI 10.1002/lt.23873

    View details for Web of Science ID 000340191200006

  • Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis NEW ENGLAND JOURNAL OF MEDICINE Kowdley, K. V., Gordon, S. C., Reddy, K. R., Rossaro, L., Bernstein, D. E., Lawitz, E., Shiffman, M. L., Schiff, E., Ghalib, R., Ryan, M., Rustgi, V., Chojkier, M., Herring, R., Di Bisceglie, A. M., Pockros, P. J., Subramanian, G. M., An, D., Svarovskaia, E., Hyland, R. H., Pang, P. S., Symonds, W. T., McHutchison, J. G., Muir, A. J., Pound, D., Fried, M. W. 2014; 370 (20): 1879-1888

    Abstract

    High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen.In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy.The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events.Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).

    View details for DOI 10.1056/NEJMoa1402355

    View details for Web of Science ID 000336123600004

    View details for PubMedID 24720702

  • Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection NEW ENGLAND JOURNAL OF MEDICINE Afdhal, N., Zeuzem, S., Kwo, P., Chojkier, M., Gitlin, N., Puoti, M., Romero-Gomez, M., Zarski, J., Agarwal, K., Buggisch, P., Foster, G. R., Braeu, N., Buti, M., Jacobson, I. M., Subramanian, G. M., Ding, X., Mo, H., Yang, J. C., Pang, P. S., Symonds, W. T., McHutchison, J. G., Muir, A. J., Mangia, A., Marcellin, P. 2014; 370 (20): 1889-1898

    Abstract

    In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection.We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea.Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).

    View details for DOI 10.1056/NEJMoa1402454

    View details for Web of Science ID 000336123600005

    View details for PubMedID 24725239

  • Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: a combined analysis of 3 phase 2/3 clinical trials LIVER INTERNATIONAL Manns, M. P., McCone, J., Davis, M. N., Rossaro, L., Schiff, E., Shiffman, M. L., Bacon, B., Bourliere, M., Sulkowski, M. S., Bruno, S., Balart, L., Bronowicki, J., Kwo, P., Poordad, F., Felizarta, F., Reddy, K. R., Helmond, F. A., Sings, H. L., Pedicone, L. D., Burroughs, M., Brass, C. A., Albrecht, J. K., Vierling, J. M. 2014; 34 (5): 707-719

    Abstract

    Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies.SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial.Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts.The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.

    View details for DOI 10.1111/liv.12300

    View details for Web of Science ID 000333828900010

    View details for PubMedID 24118703

  • Ethical Considerations Surrounding Survival Benefit-Based Liver Allocation LIVER TRANSPLANTATION Keller, E. J., Kwo, P. Y., Helft, P. R. 2014; 20 (2): 140-146

    Abstract

    The disparity between the demand for and supply of donor livers has continued to grow over the last 2 decades, and this has placed greater weight on the need for efficient and effective liver allocation. Although the use of extended criteria donors has shown great potential, it remains unregulated. A survival benefit-based model was recently proposed to answer calls to increase efficiency and reduce futile transplants. However, it was previously determined that the current allocation system was not in need of modification and that instead geographic disparities should be addressed. In contrast, we believe that there is a significant need to replace the current allocation system and complement efforts to improve donor liver distribution. We illustrate this need first by identifying major ethical concerns shaping liver allocation and then by using these concerns to identify strengths and shortcomings of the Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease system and a survival benefit-based model. The latter model is a promising means of improving liver allocation: it 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. However, it remains limited in its posttransplant predictive accuracy and may raise potential issues regarding informed consent. In addition, the proposed model fails to include quality-of-life concerns and prioritize younger patients. We feel that it is time to take the next steps toward better liver allocation not only through reductions in geographic disparities but also through the adoption of a model better equipped to balance the many ethical concerns shaping organ allocation. Thus, we support the development of a similar model with suggested amendments.

    View details for DOI 10.1002/lt.23780

    View details for Web of Science ID 000331194500003

    View details for PubMedID 24166860

  • Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1 NEW ENGLAND JOURNAL OF MEDICINE Kowdley, K. V., Lawitz, E., Poordad, F., Cohen, D. E., Nelson, D. R., Zeuzem, S., Everson, G. T., Kwo, P., Foster, G. R., Sulkowski, M. S., Xie, W., Pilot-Matias, T., Liossis, G., Larsen, L., Khatri, A., Podsadecki, T., Bernstein, B. 2014; 370 (3): 222-232

    Abstract

    An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks.Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events.In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.).

    View details for DOI 10.1056/NEJMoa1306227

    View details for Web of Science ID 000330035600008

    View details for PubMedID 24428468

  • Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med N, A., et al 2014; 370 (16): 1483-93.
  • Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: Safety, antiviral activity, resistance, and pharmacokinetics ANTIVIRAL RESEARCH Lawitz, E., Sulkowski, M., Jacobson, I., Kraft, W. K., Maliakkal, B., Al-Ibrahim, M., Gordon, S. C., Kwo, P., Rockstroh, J. K., Panorchan, P., Miller, M., Caro, L., Barnard, R., Hwang, P. M., Gress, J., Quirk, E., Mobashery, N. 2013; 99 (3): 214-220

    Abstract

    Vaniprevir is a competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease that has potent anti-HCV activity in preclinical models. This placebo-controlled dose-ranging study assessed the safety, tolerability, and antiviral efficacy of vaniprevir monotherapy in patients with genotype 1 chronic HCV infection. Treatment-naive and treatment-experienced non-cirrhotic adult patients with baseline HCV RNA >10(6)IU/ml were randomized to receive placebo or vaniprevir at doses of 125 mg qd, 600 mg qd, 25mg bid, 75 mg bid, 250 mg bid, 500 mg bid, and 700 mg bid for 8 days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log₁₀IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg bid. The most commonly reported drug-related adverse events (AEs) were diarrhea (n=5) and nausea (n=5). No pattern of laboratory or ECG abnormalities was observed, all AEs resolved during the study, and there were no discontinuations due to AEs. No serious AEs were reported. Resistance-associated amino acid variants were identified at positions R155 and D168 in patients infected with genotype 1a virus. Vaniprevir monotherapy demonstrated potent antiviral activity in patients with chronic genotype 1 HCV infection, and was generally well tolerated with no serious AEs or discontinuations due to AEs. Further development of vaniprevir, including studies in combination with other anti-HCV agents, is ongoing.

    View details for DOI 10.1016/j.antivira1.2013.05.015

    View details for Web of Science ID 000327108300003

    View details for PubMedID 23747481

  • De novo malignancy post-liver transplantation: a single center, population controlled study CLINICAL TRANSPLANTATION Chatrath, H., Berman, K., Vuppalanchi, R., Slaven, J., Kwo, P., Tector, A. J., Chalasani, N., Ghabril, M. 2013; 27 (4): 582-590

    Abstract

    With the growing numbers of liver transplant recipients, it is increasingly important to understand the risks of de novo malignancy after liver transplantation.To characterize the incidence of de novo malignancy after liver transplantation compared with a control non-transplant population.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.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.There is a significantly increased risk of de novo malignancies after liver transplantation, highlighting the need for surveillance strategies in this population.

    View details for DOI 10.1111/ctr.12171

    View details for Web of Science ID 000322819400043

    View details for PubMedID 23808800

    View details for PubMedCentralID PMC3740024

  • Oral Direct-Acting Antiviral Therapy to Prevent Reinfection of the Liver Graft After Liver Transplantation for Hepatitis C Virus-Related Cirrhosis LIVER TRANSPLANTATION Kwo, P. Y., Tector, A. J. 2013; 19 (7): 780-781

    View details for DOI 10.1002/lt.23662

    View details for Web of Science ID 000330178800013

    View details for PubMedID 23775895