Hepatitis C — Recent Advances in Diagnostics and Therapy
Recent advances in diagnosis and treatment are providing physicians with new options for managing patients with chronic HCV. Dr. Rick Pesano, Medical Director, Infectious Diseases, Quest Diagnostics, discusses how these developments can help physicians predict response to therapy and direct treatment for non-responders.
The hepatitis C virus (HCV) is a serious public health concern, affecting 170 million people worldwide1, and more than 3.2 million people in the United States2, where it is the most widespread chronic blood-borne pathogen. Additionally, HCV is the leading cause of chronic liver disease in the U.S3, and the leading cause of death from liver disease, accounting for over 12,000 deaths annually4.
The standard therapy for those chronically infected with HCV combines peginterferon-α(PegIFN-α) with ribavirin (RBV)5. This is effective in curing some patients, but approximately 50%, do not respond to therapy.
Many have poor tolerance to treatment due to side effects such as fatigue, depression and nausea, and 10-14% discontinue therapy before completion.6. 7.
Genetic variation – New clue to predicting response
Genotyping is the first step to determining potential response to treatment8.
There are 4 major HCV genotypes– 1-4. A person’s genotype predicts their likelihood of response to standard treatment and often helps determine the duration of treatment.6 7.9. Patients with genotypes 2 or 3 respond much better than those with 1 or 4. The majority of patients, 75-80%, are genotype 1.
Even within genotype 1 people respond differently to treatment. As Dr Pesano explains, “Recent studies have looked at something called genome-wide association that examined a variant from a gene called IL28B which encodes interleukin 28, also known as interferon lambda, a cytokine (chemical messenger) with antiviral activity.”10
IL28B – a guide for patient management
Dr Pesano is optimistic that the identification of this gene variant will assist physicians in their treatment decisions. “Identification of that variant really allows a more individualized therapy and will also help physicians consider alternative therapies, which now include HCV protease inhibitors.”
The recent introduction of a test for IL28B enables more effective management of all patients, including those likely to respond to standard therapy, as well as likely non-responders.
Helping compliance for likely responders
For likely responders, says Dr Pesano, the challenge is often to ensure adherence to treatment. “Remember, hepatitis C, unlike many other viral infections, is a curable infection and adherence is a very important factor. If you can tell a patient their chances of a cure are reasonably good, you give them an incentive to complete the regimen.”
Tailoring therapy for non-responders
For a patient who is likely to be a non-responder Dr Pesano would take a different approach:
“For a patient whose genotype makes them less likely to respond to standard therapy, I would probably consider combining a direct-acting agent (DAA) with interferon/ribavirin to give that individual the best possible chance of achieving a sustained virologic response (SVR).” (SVR is defined as the absence of HCV RNA in serum by a sensitive test at the end of treatment and 6 months later.)
Dr. Pesano emphasizes,that while IL28B is an important parameter in determining patient response, it is one of several factors, including viral load, genotype, age of the patient, duration of exposure and lack of fibrosis/cirrhosis.
RVR and EVR - Determining treatment duration
Two other significant parameters to consider are rapid virologic response (RVR) and early virologic response (EVR). Looking at response at specific time points can help a clinician assess the likelihood of response and may guide him/her on the duration of therapy needed to get a sustained virologic response (SVR).
Based on clinical research that is underway, Dr Pesano anticipates a better understanding of whether it is possible to reduce the duration of exposure to standard of care therapeutic agents, while significantly increasing response rates and achieving SVR.
Addressing the challenge of resistance
While therapy with direct acting agents holds considerable promise, it is unlikely to be used as a mono-therapy, particularly due to the risk of resistance. “The HCV viral population is extremely large in vivo, it has a continuous, high replication rate and the potential for genetic change, meaning it really exists in an individual patient as a heterogeneous population of related viruses.” explains Dr Pesano, “With these characteristics there is the possibility of pre-existing resistance to virtually any agent you can give a patient. But the difference between some of the more general immunomodulators, like interferon and ribavirin, and a direct acting antiviral agent (DAA) is the DAA has a known risk of resistance, i.e. genetic changes in the viral genome that confer resistance to a specific direct acting agent. It is vital to drive down HCV viral loads to non-detectable as rapidly as possible to avoid the consequences of such mutations.”
The next challenge is to develop new drugs and, more importantly, new drug classes, to attack the virus at different targets known to be essential for viral replication. This may allow combination direct acting agent therapy without the background of interferon and ribavirin. (Studies are underway to evaluate this approach).
As new drugs become available, with differing resistant profiles, new tests will be needed to understand why a patient doesn’t respond to therapy, or to determine the cause of viral breakthrough. “One way is to genotype their virus and see whether or not they have specific mutations that confer resistance to the drug they're taking. If they do, you can provide the clinician with information to select another drug that has activity against the resistance viral variant .”
Emerging application of IL28B
In looking ahead Dr Pesano anticipates refined treatment approaches based on a further understanding of IL28B. Research into gene regions around IL28B may provide the ability to predict whether or not someone has an increased risk forhemolytic anemia associated with ribavirin therapy. And in the field of transplantation the recipient and donor liver IL28B genotype may help to define the INF-based treatment response in patients after liver transplantation11.
- World Health Organization. Hepatitis C Guide http://www.who.int/csr/disease/hepatitis/Hepc.pdf
- Hepatitis C FAQs for Health Professionals, U.S. Centers for Disease Control and Prevention. www.cdc.gov/hepatitis/HCV/HCVfaq.htm
- Alter, MJ, Kruszon-Moran, D, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556–562.
- Strader et al. Diagnosis, Management, and Treatment of Hepatitis C, Hepatology April 2004; 1147-1171
- Manns MP et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–965.
- Fried MW, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982..
- Simmonds P. Viral heterogeneity of the hepatitis C virus. J Hepatol 1999;31(suppl 1):54–60.
- Hadziyannis SJ, et al. Peginterferon alfa-2a (40 kilodaltons) and ribovirin combination therapy in chronic hepatitis C: randomized study of the effect of treatment duration and ribavirin dose. Ann Intern Med 2004; 140:346–355.
- GeD et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature, 2009;10.1038;1-3.
- Eurich et al. Relationship Between the Interleukin-28b Gene Polymorphism and the Histological.Severity of Hepatitis C Virus–Induced Graft Inflammation and the Response to Antiviral Therapy After Liver TransplantationLiver Transplantation 17:289-298, 2011