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Transformative Therapies for Hepatitis C at Penn Medicine

Clinicians and investigators at Penn Gastroenterology and 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 (or 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.

 

Depiction of HCV life cycle

 

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 more than 100 reports co-authored by Dr. Reddy since the approval of Harvoni® in 2014.

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 received one of the three combination regimens to determine whether they work equally well under real-world conditions. In Phase 2, (now active, but not recruiting) patients received 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 for this trial.

References

1. US Burden of Disease Collaborators. JAMA 2010;310:591-608.
2. N Engl J Med. 2014 Apr 17;370(16):1483-93.

About this Blog

The Penn Physician Blog is a resource for health care professionals featuring Penn Medicine physicians and their research, innovations, programs and events. 

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