Gastroenterology News Update

Transformative Therapies for Hepatitis C at Penn Medicine

Diagram depicts pathogenesis of hepatitis C

In the last decade, clinicians and investigators at Penn Gastroenterology/Hepatology have contributed to advances of historic significance in the management of hepatitis C (HCV) infection.

The Dominion of Hepatitis C

HCV is a highly communicable infection and is the precursor for cirrhosis, end-stage liver disease and hepatocellular carcinoma, and as a result, is the leading cause of liver transplantation in the United States. [1] According to National Health and Nutrition Examination Survey (NHANES) estimates, 1% of the US population (approximately 3.2 million people) has chronic HCV.

In most infected persons, HCV is intractable and covert. On first exposure to HCV and the by-products of its replication, the immune system mounts a type 1 interferon (IFN) reaction, provoking a spectrum of antiviral proteins and immunoactive cytokines. For about 30% of infected persons, this initial response is sufficient to clear the virus, and is tantamount to cure if sustained through 6 months.

Infected persons who do not clear the virus, however, develop chronic HCV infection, presumably because the virus has circumvented the innate immune system response. The mechanisms by which this evasion occurs include interruption of molecular signaling within the IFN pathway and the generation of genetically distinct viral variants, each with its own capacity to elude the control of the host response. Once the symptoms of initial infection subside, patients with chronic HCV infection develop necroinflammatory liver disease, often in the absence of symptoms. For this reason, many infected individuals are unaware of their condition until late in the course of the disease.

The Evolution of HCV Therapy

Injectable interferon-alfa (IRN-a) was approved to treat HCV shortly after the virus was discovered in 1989, and by the mid-1990s was being combined with the anti-viral drug ribavirin to enhance response to therapy. The next major advance in HCV therapy would not appear until 2011 with the FDA approval of boceprevir and telaprevir, the first direct acting antivirals (DAAs). The DAAs, which interfere directly with enzymes in the HCV replication cycle, fall into four major classes: the NS3 protease inhibitors (generics suffixed “…previr”); the NS5A inhibitors (generics suffixed “…asvir”); and the NS5B nucleotide inhibitors and NS5B non-nucleoside inhibitors (both generics suffixed “…buvir”). Some of the current DAAs are effective against all genotypes, while some have restriction to HCV genotype 1, the most common of the known hepatitis C genotypes. Many DAAs are now used in combination regimens.

The Penn Center for Viral Hepatitis was a key participant in several Phase III studies to investigate the safety, tolerability, and antiviral efficacy of a fixed-dose combination (FDC) of sofosbuvir and ledispasvir (Harvoni, Gilead Sciences, Inc.) for the treatment of genotype-1 HCV infection in adults. [2] The drug, the first of its kind to combine two direct-acting antivirals (DAAs) in a single pill for use without IFN or ribavirin, was FDA-approved in 2014.

Established in 2010 under the direction of K. Rajender Reddy, MD, and Kyong-Mi Chang, MD, the Center for Viral Hepatitis leads and contributes to clinical trials for newer, safer and more effective drug therapies for hepatitis. The Center is, as well, a regional nucleus for viral hepatitis care, research and education of medical students, residents, fellows, pharmacy students, and physician extenders, and seeks to enhance public awareness, patient education and patient advocacy of viral hepatitis infections and HIV/viral hepatitis co-infection.

Clinical Research in the Treatment of Cirrhosis, Liver Cancer and Hepatitis

The current environment of care for hepatitis, hepatic cancer, cirrhosis and liver transplantation at Penn Medicine, as well as the breadth and pace of development in hepatitis drug therapy, is reflected in the 82 reports co-authored by Dr. Reddy since the approval of Harvoni in 2014.

Dr. Reddy is the Ruimy Family President’s Distinguished Professor of Medicine, Director of the Viral Hepatitis Center and Medical Director of Liver Transplantation. In addition to sofosbuvir and ledipasvir, the agents Dr. Reddy and his colleagues have investigated in the past three years include asunaprevir, beclabuvir, boceprevir, daclatasvir, dasabuvir, elbasvir, glecaprevir, grazoprevir, ombitasvir, paritaprevir boosted by ritonavir, pibrentasvir, telaprevir, velpatasvir and voxilaprevir. NB - Boceprevir and telaprevir were voluntarily removed from the US market by their manufacturers in 2014-2015, citing competitors' superior efficacy and safety.

Current Research in HCV Therapy at Penn Medicine

At this time, Penn GI is participating in the PRIORITIZE Trial [NCT02786537] to investigate the comparative efficacy of three approved treatment regimens (Harvoni®, Viekira Pak™ and Zepatier™). In Phase 1 of the trial, patients will receive one of the three combination regimens to determine whether they work equally well under real-world conditions. In Phase 2, patients will receive Harvoni® or Zepatier™ to compare their effectiveness. The primary objective of the study, in real world cohorts, will be to ascertain the percentage of patients who achieve undetectable hepatitis C virus RNA 12 Weeks after completing HCV treatment.

Dr Reddy is the principal investigator.

Information about this trial is available from Kelly Borges at 215-615-3755, or kelly.borges@uphs.upenn.edu.

References

1. US Burden of Disease Collaborators. JAMA 2010;310:591-608.

2. N Engl J Med. 2014 Apr 17;370(16):1483-93.


Liver Disease Treatment Program at Penn Medicine

The Gastroenterology and Transplant Surgery divisions, as well as radiology, pathology and other departments at Penn Medicine, work closely together to ensure a seamless experience for patients with liver disease. A highly skilled professional nursing and technical staff further enhances the patient experience and provides the highest standard of care.

Gastroenterology/Hepatology

Rotonya Carr, MD
Assistant Professor of Medicine
The Hospital of the University of Pennsylvania

Kimberly A. Forde, MD, MHS
Assistant Professor of Medicine
The Hospital of the University of Pennsylvania
Assistant Professor of Epidemiology in Biostatistics and Epidemiology

David S. Goldberg, MD, MSCE
Assistant Professor of Medicine
Assistant Professor of Epidemiology in Biostatistics and Epidemiology

Maarouf A. Hoteit, MD
Assistant Professor of Clinical Medicine

Christine Hsu, MD
Assistant Professor of Clinical Medicine

Vandana Khungar, MD, MSc
Assistant Professor of Medicine
The Hospital of the University of Pennsylvania

George A. Makar, MD, MSCE
Associate Professor of Clinical Medicine

Frederick A. Nunes, MD
Clinical Professor of Medicine

Stacey Prenner, MD
Assistant Professor of Clinical Medicine

K. Rajender Reddy, MD
Director, Hepatology
Medical Director, Liver Transplantation
Ruimy Family President's Distinguished Professor Professor of Medicine in Surgery

Marina Serper, MD, MS
Assistant Professor of Medicine

Steven F. Solga, MD
Associate Professor of Clinical Medicine

Robert M. Strauss, MD
Clinical Associate Professor of Medicine

Ethan Weinberg, MD, MS

Xiao Zhao, MD

About this Blog

The Gastroenterology News Update is a biyearly publication that highlights the diagnostic and treatment advances at Penn Gastroenterology, as well as the Division's renowned faculty and clinical research efforts.

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