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New Wave in Hepatitis C Treatment

NEW YORK (Jan 4, 2012)

Advances in molecular biology are finally paying off for patients with hepatitis C. In May, the U.S. Food and Drug Administration approved two new drugs to cure patients with the liver infection: boceprevir (Victrelis™) and telaprevir (Incivek™). Both drugs work by targeting a key enzyme that directs the hepatitis C virus to replicate (reproduce). Their development, clinical evaluation, and subsequent approval follow years of painstaking research to identify the molecules driving viral replication and to screen drugs that home in on those therapeutic targets.

And the good news is, there are more new drugs in the pipeline. "Boceprevir and telaprevir represent the first wave of novel therapies for hepatitis C," noted Ira M. Jacobson, M.D. "We expect the field of hepatitis C management to be radically transformed in the next few years, and we hope these drugs are a harbinger of that change."

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More than 3 million people in the United States are infected with hepatitis C. The infection is usually transmitted by blood; in the U.S., the most common mode of transmission is illicit drug use. Some patients contract the virus via sexual activity or as infants born to infected mothers, and in others no route of transmission can be determined. As the liver mounts a chronic immune response in an attempt to clear the virus, persistent inflammation occurs which can lead to liver damage, cirrhosis (scarring), or liver failure. When standard treatment fails, patients with advanced liver scarring may have no other choice but a liver transplant.

Standard therapy includes the drugs ribavirin and pegylated interferon, but less than half of the patients with the most common type of hepatitis C infection – genotype 1 – achieve a sustained virologic response (defined as undetectable hepatitis C viral RNA in the patient's blood 24 weeks after the end of treatment).

Ira M. Jacobson, M.D.
Ira M. Jacobson, M.D.

Telaprevir and boceprevir are both protease inhibitors that are taken in combination with ribavirin/interferon therapy. They exert their antiviral effects by shutting down one of the master enzymes the virus needs to replicate. Both drugs are effective against genotype 1, and are taken orally (by mouth).

NewYork-Presbyterian Hospital has been a leader in the evaluation of both telaprevir and boceprevir. Dr. Jacobson led the international team of investigators who assessed telaprevir in the ADVANCE trial. It showed that 75 percent of patients who received 12 weeks of telaprevir therapy plus standard therapy with ribavirin/interferon (and 69 percent of those who took telaprevir for 8 weeks) achieved a sustained virologic response, compared with only 44 percent of patients who received standard therapy alone. The phase III study was published in the New England Journal of Medicine in June 2011. (N Engl J Med. 2011;364:2405-2416)

Dr. Jacobson was also a co-author of the New England Journal of Medicine study reporting the results of the SPRINT-2 trial, which found similar effectiveness for boceprevir: 67-68 percent of nonblack patients achieved a sustained virologic response with boceprevir. (The response rate in blacks was slightly lower.) (N Engl J Med. 2011;364:1195-1206)

Benjamin Samstein, M.D.
Benjamin Samstein, M.D.

The development of these and other new drugs for hepatitis C will also change the management of liver transplant patients by eliminating the virus from their bodies. "From a surgical perspective, these agents will usher in a new era where the recurrence of hepatitis C infection will be lessened in patients post-transplant," explained Benjamin Samstein, M.D., a surgeon who specializes in liver transplants.

Anemia (low red blood cell count) is the most common side effect associated with both boceprevir and telaprevir, resulting in fatigue and shortness of breath in some patients. It is also associated with ribavirin treatment, so doctors monitor patients and adjust the ribavirin dose accordingly if anemia develops. Some patients may be treated with drugs that boost the red blood cell count. Telaprevir can also cause skin rashes and anorectal discomfort, while boceprevir may slightly alter taste. But it is uncommon for such side effects to cause patients to discontinue treatment.

The length of treatment is based on how well a patient responds, as measured by how quickly the patient's body clears the virus. The total treatment time for telaprevir, for example, may be as little as 24 weeks if the patient responds quickly (28 weeks for boceprevir) – half that of standard ribavirin/interferon therapy.

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Moreover, once the virus is cleared, the patient is considered cured – unlike other viruses treated with protease inhibitors, such as HIV or hepatitis B. The biologic features of the hepatitis C virus make it unable to embed itself inside cells in a dormant form, ready to re-emerge later – as is the case for HIV – so patients do not have to take the drugs for the rest of their lives.

The search for new hepatitis C drugs continues. Both telaprevir and boceprevir must be taken at even intervals three times a day, making patient compliance a challenge. "If the drug concentration is not kept consistent in the bloodstream, the virus can rear its head, so to speak, and develop resistance to the drug," noted Dr. Jacobson. Other drugs in development include similar protease inhibitors designed to be taken just once or twice daily.

Reserchers are developing drug regimens that could possibly eliminate the need for ribavirin and interferon as a "backbone" of therapy, since those drugs have significant side effects (and not all patients can tolerate them). "Nucleoside" drugs are being developed that trick the virus into incorporating fake material into its RNA, halting replication, and the virus is less likely to develop resistance to these agents. "Non-nucleoside" drugs in development interfere with replication by causing the viral "polymerase" enzyme to change its shape. NS5A inhibitors are powerful inhibitors of viral replication which work by blocking a key protein required for viral replication. And other drugs are being developed and assessed which inhibit the proteins that the hepatitis C virus attaches to.

Dr. Jacobson foresees the pace of hepatitis C drug evaluation accelerating with the development of drug combinations that may eliminate the need for ribavirin and interferon. "There are many exciting drugs being evaluated," he concluded. "Our most important goal will be to cure hepatitis C with a cocktail of fast-acting and well-tolerated drugs, which will make treatment accessible to the broadest possible range of patients and save an enormous number of lives."

Contributing faculty for this article:

Ira M. Jacobson, M.D., is Chief of the Division of Gastroenterology and Hepatology at NewYork-Presbyterian/Weill Cornell Medical Center and the Vincent Astor Distinguished Professor of Clinical Medicine at Weill Cornell Medical College.

Benjamin Samstein, M.D., is Surgical Director of the Living Donor Liver Transplant Program at NewYork-Presbyterian/Columbia University Medical Center and an Assistant Professor of Surgery at Columbia University College of Physicians and Surgeons.

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