Friday, December 31, 2010

2011: Good News For Hepatitis C Patients

Hepatitis C treatment Eagerly anticipated drug approvals in 2011 include a decision by the US Food and Drug Administration on telaprevir, which could provide relief for the 3% of the world's population infected with the hepatitis C virus. The drug was developed by Vertex Pharmaceuticals in Cambridge, Massachusetts.

In October this year the AASLD annual meeting was held in Boston , MA . The key highlight of this meeting was the release of clinical data for emerging novel direct acting agents (DAAs) for treatment of chronic Hepatitis C virus (HCV) infection.

This year marked an important milestone as Phase III data for two late-stage drug candidates were presented at this meeting.

Other highlights of this meeting were Phase 1 clinical data for new class of drugs and genomic data for IL-28B marker. Based on our attendance at this meeting we have summarized here some of the highlights.

Two promising protease inhibitors for HCV
Telaprevir and boceprevir are peptidomimetic molecules which inhibit NS3-4A protease. They are in late-stages of development for treatment of chronic Hepatitis C. Their Phase III data was released at this AASLD meeting.

The use of these agents in combination with peginterefeon and ribavarin has shown up to 75% SVR in TN, and 30% to 85% SVR in TE genotype 1 patients.
This triple combination could also reduce treatment duration from current 48 weeks to 24 weeks or shorter, depending upon patient’s early viral response.
Based on the history of several drug launches, these two drugs would represent major advancement to the current standard of care.

Personalized medicine in HCV
It seems like that treatment for HCV is setting the stage for one of the best examples of personalized treatment using genomic host data. In the past, patients were tested for genotype of their virus, whether it is 1, 2, 3 or 4. From this year’s presentations it seems like that now patients need to be tested for many other types of genomic data, such as their sub-type (1a versus 1b) and IL-28B alleles. Though in early stages, these data are likely to be used for customizing therapy for individual patients.

Another good news for HCV patients is the possibility of shorter duration of treatment. Clinical studies with novel DAAs are showing that for almost two-third of the patients, their treatment duration can be reduced to 12 or 24 weeks, if they achieve rapid virological response (RVR). Until now, one year treatment with Peg-Interferon and ribavarin has been problematic for several patients, either due to intolerability of interferon, side effects or in-general adherence to one-year regimen. If treatment duration could be reduced to half or one-third time, it would enable many more patients to initiate and complete treatment to achieve SVR.

What factor would drive personalized treatment in HCV?
Testing for sub-types of HCV , IL -28B alleles and customizing based on RVR.
What are the challenges in personalized treatment? One challenge is the need for infrastructure to measure and collect all this data, provide individualized guidance and treatment to patients. It is estimated that ~80% of 3 million chronically infected hepatitis C patients are un-diagnosed. As more patients are diagnosed and initiate treatment it would create need for resources to provide personalized care.

According to one potential treatment algorithm presented at this meeting, treatment naïve patients with IL-28B CC allele and fibrosis stages F3-4, could be treated now with Peg IFN+RBV, whereas patients with IL-28B TC/TT allele and fibrosis stages 0-2, could wait for DAAs.

One common theme at this AASLD: “IL-28B”
There were more than fifty studies focusing on IL-28B. This marker has gained enormous interest since last year’s meeting.

IL-28B is a gene that codes for Interferon lamba and it has been shown that there is strong correlation between its alleles (TT, TC or CC) and SVR with standard of care.
What’s new at this year’s meeting for IL-28B? One is more data from other retrospective studies showing that IL-28B alleles have strong correlation to response. In the future, IL-28B genotype testing can be potentially used to predict outcomes and hence customize regimens for various patients.

Are doctors using it?
Interestingly, answer seems to be yes. In one session three prominent investigators mentioned that they are testing all of their patients for IL-28B genotype. Though its not clear how it will be exactly used in treatment decision making, but doctors admitted that since there is data showing its correlation to response, they have to do testing, for clinical and liability reasons.
From this year’s presentation its looks like IL-28B is going to be important in the future for clinical trial design, patient stratification and clinical decision making

Outstanding challenges in treating Hepatitis C patients
While there are several promising therapies that are on the horizon, there are still several challenges facing treatment for HCV patients.

First challenge is screening and diagnosing these patients before it is too late to treat them. At this meeting, CDC presented their proposal to screen patients based on birth-year cohort (~65% of HCV patients were born during 1945-1965). How soon and effectively we can diagnose these patients during next 2-5 years is an unknown at this stage.

Patient education could be a challenge, as more genomic and response data would be used to customize therapy for patients. For the near term it seems like that with telaprevir and boceprevir, patients will have high pill burden. I think it would be valuable to have patient counselors who can educate and guide HCV patients and keep them adherent on triple combinations. In HIV, patient survivors have been very successful in acting as counselors for newly diagnosed patients. I would recommend state and federal agencies and drug manufacturers to train HCV-survivors as counselors for these baby-boomers who would receive treatment during next 2-5 years.

Cost of treatment: This could be an issue for low-middle income patients, especially if they have to pay 10-20% of cost for triple combination regimen.

Payers: Several investigators raised the issue that in the future payers might play a role in determining whether patients should continue one versus another regimen. This is especially possible for patients who do not achieve RVR and would have only 4-5% chance of achieving SVR with complete regimen.

Lead in or no lead in: Two different strategies were used for Phase III clinical trial design for telaprevir and boceprevir. One used RVR with triple combination, while other used Lead-in with Peg-infereon and ribavarin, followed by triple combination. Which one is better? How do we define better? Is it based on efficacy, safety, cost, patient genotype or patient convenience? I think in this case all of them would be important.

Despite the significantly high efficacy of telaprevir and boceprevir there is still large unmet need for newer therapies in HCV. What are those areas?

Well, immediate ones are:

Treatment options for genotype 1 null-responses
Treatment options for patients who would fail on new triple combinations
New therapies are needed for genotype 4 patients
Strategies to reduce pill burden with triple combination
Interferon free regimens

Top 10 Medical Innovations for 2011

#5 Hepatitis C Protease Inhibiting Drugs
Hepatitis C, a common liver disease that affects an estimated 3.9 million people in the United States, is transmitted through exposure to infected blood (blood was not screened for hepatitis C until 1992) and sexual contact with an infected person. The majority of people with the ailment have no bothersome symptoms, which is why health experts say millions are unaware that they even have it.

Hepatitis C is typically diagnosed when abnormal liver enzymes are identified through a routine blood test or if the infection becomes severe. Seventy percent of patients with hepatitis C develop chronic disease and 30% may develop cirrhosis of the liver within 20 years of exposure to the virus, which causes severe scarring of the liver. An additional 20% of these patients eventually develop liver cancer.

Hepatitis C virus infection is the leading cause of chronic liver disease, the reason for more than 30% of liver transplantations, and a major contributor to as many as 12,000 deaths annually. Total medical costs for people with hepatitis C are approximately $30 billion.

To date, treatments for hepatitis C virus infection have been somewhat disappointing. The best cure rates following a 24-to 48-week course of therapy with the combination of the oral antiviral medicine ribavirin (taken three times a day) and an injectable interferon (once a week) is about 40%. The flulike side effects of these drugs are often debilitating, however, leading many patients to stop treatment. When a second round of treatment is used with this chemotherapy combination, success rates plummet to 10%. There are an estimated 300,000 Americans with hepatitis C who have failed this treatment protocol. When medical care is ineffective and the disease progresses, a liver transplant may be necessary.
Unfortunately, there are no proven medicines for patients who don't respond to traditional hepatitis C therapy—until now, that is.

Two advanced drugs called hepatitis C protease inhibitors now awaiting approval from the Food and Drug Administration (FDA) have the ability to fundamentally change the treatment for hepatitis C for patients who have not responded to previous therapies. Both new drugs have been very successful in curing test subjects in clinical trials, which represents a big step forward in successfully battling this debilitating disease.

The experimental drugs belong to a class of medications called protease inhibitors, which work by blocking a key enzyme that viruses need in order to copy themselves and proliferate. New data from Phase 2 trials report that when the experimental drug telaprevir, developed specifically to target hepatitis C virus, was added to standard treatments for hepatitis C, 72% of the patients achieved sustained viral response (or viral cure) after taking the medication for 24 weeks. This study confirmed that the 24-week course was just as effective as it was for patients taking the drug cocktail for 48 weeks.

Study results with a drug called boceprevir were similar with difficult-to-treat patients with hepatitis C, although cure rates were slightly lower with the three-drug combination. When combined with interferon and ribavirin, boceprevir cured the infections of about 66% of the patients who took the drugs for 48 weeks compared to 38% of those in the control group who received the standard therapy for 48 weeks.
The good news is that cure rates with these new protease inhibitors are higher than those with standard hepatitis C therapy. And so, after decades of research and expected FDA approvals, a new era of antiviral medications developed specifically to target hepatitis C virus is about to begin.

This and That
Our Year in Review series highlights the major medical news stories of 2010. The risks associated with dietary supplements was one of the compelling topics that made headlines during the year and here, again, is the original article, first published on Nov. 17, 2010. In a companion article, you'll find out what's happened since.

Two late additions to BMJ's annual Christmas series of offbeat research articles offered novel perspectives on physicians' parking lot behaviors and the mysteries of "phantom vibration."

Whats Coming Up ?
The 18th International Symposium on Hepatitis C Virus and Related Viruses to be held in Seattle, WA, USA, will cover all aspects of the hepatitis C virus and related viruses

September 8 - 12, 2011.

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