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July 2011 HCV Advocate

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In This Issue:

The New HCV Epidemic?
Alan Franciscus, Editor-in-Chief

Quick Facts about the PI's
Alan Franciscus, Editor-in-Chief

HealthWise: Resisting Resistance
Lucinda K. Porter, RN

HCV Snapshots
Lucinda K. Porter, RN

The Next Wave(s)
Alan Franciscus, Editor-in-Chief

HCV Advocate Eblast
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The New HCV Epidemic?
—Alan Franciscus, Editor-in-Chief

The incidence of new or acute HCV infections has dramatically dropped over the years compared to the 1950’s and 1960’s.  However, because of a poor surveillance system for HCV in the United States we don’t really have an accurate number of past or current infections.  It is estimated that heroin use in the United States increased during 2002 through 2009 from 100,000 to 180,000, and increased drug use—especially heroin use—should have prompted a closer look into the correlation between the increased use of heroin use and the possible increase in new HCV infections. 

One state that did take notice is Massachusetts, in part because a study found that the number of people who self-reported needle use increased from 29% in 2002 to 38% in 2008.  Massachusetts also started increasingly receiving reports of new hepatitis C infections among persons aged 15-24 years who were admitted to state-funded substance abuse programs (for all drug use), which prompted the Massachusetts Department of Public Health and the Centers for Disease Control (CDC) to begin tracking new or acute HCV infections in Massachusetts.    

Based on these trends of injection drug use and new HCV infections, Massachusetts initiated a comprehensive surveillance system and identified 1925 new cases of HCV infections among people aged 15-24 years during 2007 to 2009.   Of these cases, 1026 were confirmed new hepatitis C infections and the remaining cases were classified as probable.  It was also interesting that the new hepatitis C infections were not just confined to the major metropolitan and suburban areas of Boston, but high rates were also found in smaller cities and rural areas.  It was also reported that the incidence of new HCV infections were similar in women and men and were seen mostly among non-Hispanic whites.   In the analysis, 72%  of the people reported current or past injection drug use.  Among the people who self-disclosed that they injected drugs—85% used heroin, 29% cocaine, 1% methamphetamine and 4% had used other drugs. 

What is disturbing is that although we know that there is increased heroin use across the nation and we hear anecdotal information of an increase in acute HCV infections nationally, we don’t have a good handle on the number of new hepatitis C cases or, more importantly, what we can do about it.  In this regard the CDC is working with state and local health departments around the country to determine if similar trends are occurring elsewhere. 

The good news (if there is any) is that the CDC is looking at how to target young injectors with messages that will hopefully take into account the beliefs and lifestyles of the young injectors  in order to develop effective strategies to prevent HCV transmission.  This is important on so many levels with one of the most crucial reasons being to keep our younger generation safe, healthy and free from hepatitis C, hepatitis B and HIV. 

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Quick Facts about the PI's
—Alan Franciscus, Editor-in-Chief

In May 2011 the Food and Drug Administration (FDA) approved the two triple combination HCV protease inhibitor (PI) therapies—Victrelis and Incivek—taken in combination with pegylated interferon and ribavirin. The addition of an HCV protease inhibitor to pegylated interferon and ribavirin therapy has been found to increase the cure rates by 30 to 45% when used as directed in people with chronic hepatitis C—genotype 1.  In last month’s HCV Advocate I wrote about the approval and detailed the efficacy rates, side effects and costs associated with the HCV protease inhibitors and pegylated interferon and ribavirin therapy.  This month I want to concentrate on some of the important information everyone needs to know about the medications to increase the chances of successful treatment and to prevent any possible harm that could result from not taking the medications as prescribed.

For more information on the new therapies, drug resistance and how to avoid it see this month’s Healthwise article.

Brand Names:
• Victrelis (vic-TREL-IS) is the brand name of boceprevir
• Incivek (in-SEE-veck) is the brand name of telaprevir

Instructions on Use:
• When you begin treatment your doctor or nurse will give you instructions about how to take the medications—make sure you completely understand what you are being told—if not, always ask questions.

• Pegylated interferon is a medication taken weekly that is injected right under the skin
• Ribavirin is a pill that is taken twice a day—the dose is based on a person’s body weight
• HCV protease inhibitors are taken every 7 to 9 hours
  ♦ Incivek comes in 375 mg tablets.  A total of 750 mg (2 tablets) is taken every 7 to 9 hours
  ♦ Victrelis comes in 200 mg capsules.  A total of 800 mg (4 capsules) is taken every 7 to 9 hours

Food Requirements:
• HCV protease inhibitors are taken with food: 
  ♦ Incivek is taken with food that is not low fat—your medical provider will give you examples of the types of food you should eat when taking Incivek
  ♦ Victrelis is taken with food—a meal or light snack
• Ribavirin is taken with food.

Drug Interactions:
Some prescribed medications, over-the-counter medications, herbs and supplements may affect how well the medications work or may interfere with how the drugs work.  Always make sure to tell your medical provider about any medications, supplements and/or herbs you are taking.   

Missed Doses:
If you miss a dose of your medications your medical provider will advise you on when to take the next dose.  It is very important to take all three medications, but it is even more important that the protease inhibitor is taken as directed.  Try not to miss a dose because there is a real possibility that drug resistance can emerge, and missing doses will also decrease the chances of a successful outcome.

• The protease inhibitors are only taken with pegylated interferon and ribavirin:
  ♦ Never take the HCV protease inhibitors alone—PI’s are only used in combination with pegylated interferon and ribavirin
  ♦ If pegylated interferon and ribavirin are stopped, the HCV protease inhibitors must also be stopped
• The dose of the HCV protease inhibitor should never be lowered.

Pregnancy Warnings:
• The medications (HCV protease inhibitor, pegylated interferon, ribavirin ) should never be used if you are pregnant.
• Women of child-bearing age must have a negative pregnancy test result before starting treatment and at certain intervals during treatment.  If the test is positive treatment should not be started.    
• Men and women of child bearing age must use 2 forms of effective birth control during treatment and for 6 months after treatment has stopped. 
• If a woman becomes pregnant anytime during treatment, all medications should be stopped. 
• Should you or your female partner become pregnant it should be reported to your medical provider immediately.  You and your medical provider should also contact the Ribavirin Pregnancy Registry at 1-800-593-2214. 

Length of Treatment:
• The length of time the medications are taken depends on the HCV protease inhibitor being taken and will be guided by when a person becomes HCV RNA negative (viral load) early on in treatment:  Rapid virologic response (RVR)=HCV RNA negative at week 4, and a complete virological response (cEVR)=HCV RNA negative at week 12.  eRVR refers to HCV RNA negative at both week 4 and week 12. 

When to Stop
• Your medical provider will tell you when to start taking the various HCV medications and when to stop based on how well you respond to the medications: 
  ♦ Victrelis triple combination therapy should be stopped if the HCV RNA (viral load) is greater than or equal to 100 IU/mL at week 12 or any viral load is detected at week 24.
  ♦ Incivek triple combination therapy should be stopped if the HCV RNA (viral load) is greater than 1,000 IU/mL at week 4 or week 12 or if HCV RNA is detected at week 24.   

Side Effects:
Report all adverse events (side effects) especially if they are serious to your medical provider.  Your medical provider may decide that the side effect needs to be reported to the Food and Drug Administration (FDA), and the specific pharmaceutical company.    You also can report the side effects. 

Treatment Costs:
If you read my article on the approval of the PI’s you read about the high prices. If you are having problems with your insurance covering the medications or if the co-pays are more than you can afford contact the manufacturer of the specific medication (Genentech, Merck & Co., and Vertex Pharmaceuticals, INC) —they may be able to help out with free medications or help with co-pays.   There are also umbrella organizations that can help you out with the process and put you in touch with the specific pharmaceutical company—www.pparx.org (Partnership for Prescription Assistance) and www.needymeds.org (NeedyMeds).  Another avenue to explore is www.clinicaltrials.gov to see if there are any clinical trials you may want to research and enroll in. Please see the article on some clinical trials in this month’s HCV Advocate for an overview of a sample of the ones being conducted. 

The most important thing to remember about taking the new combination therapy is to work closely with your medical provider, report any side effects, and follow your medical provider’s instructions as closely as possible—this is the best strategy to help make treatment as successful as possible. 

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HEALTHWISE: Resisting Resistance
—Lucinda K. Porter, RN

The Food and Drug Administration (FDA) recently approved two new drugs for the treatment of chronic hepatitis C virus (HCV) infection for patients with genotype 1. Victrelis (boceprevir) is manufactured by Merck; Incivek (telaprevir) is manufactured by Vertex. Both drugs are to be used along with peginterferon and ribavirin as part of a triple-therapy regimen.

Victrelis and Incivek are protease inhibitors and are classified as direct-acting antiviral agents (DAAs), also referred to as specifically-targeted antiviral treatment for hepatitis C (STAT-C).  The use of DAAs for HCV treatment is an exciting development as it dramatically improves the odds of reaching the goal of sustained virologic response (SVR) or viral cure for patients with genotype 1. Another benefit may be reduced treatment lengths for those who qualify.

As wonderful as this is, DAAs carry a new risk which was not a problem before with HCV treatment—the development of resistance. This problem is potentially serious but largely preventable. This month’s column discusses viral resistance and how to avoid it.

Basic Theory and the New HCV Drugs
To understand viral resistance let’s review basic evolution, specifically Darwin’s theory of survival of the fittest. Darwin noticed that sometimes the weakest members of a species died off before they could reproduce. Simultaneously, the strongest survived, passing on their genes to future generations.

Here is an example of Darwin’s theory: Imagine that you have a roach infestation. You try stomping on them but the fast ones scurry away. The swiftest roaches survive and have speedy offspring. You try organic pesticides, but that just kills off the weakest roaches; again the strongest roaches reproduce. Finally you resort to the most potent poisons available, but a few of the really tough roaches manage to escape. When they reproduce their babies inherit the resilient genes of their parents and they are resistant to these strong insecticides. All future generations are likely to be resistant to these poisons, leaving you with a new infestation of roaches and no way to kill them.

If you are going to get every roach, you need to apply constant aggressive anti-roach measures and you need to get every single roach. You can’t let up, because if you do, the strongest will reproduce and then you will be fighting the toughest bugs.

DAAs, such as Incivek and Victrelis, apply constant pressure to HCV by directly targeting the virus and interfering with its ability to reproduce. Viruses require healthy cells in order to replicate and DAAs hinder the process. Incivek and Victrelis disable an enzyme (the protease enzyme) necessary for HCV replication. As long as you are taking your medication as directed, HCV is being assaulted.

HCV Treatment with Peginterferon and Ribavirin
You may ask how does this differ from the way peginterferon and ribavirin worked without protease inhibitors.  These two drugs do not work directly on HCV, and thus do not create the potential for resistance. Peginterferon boosts the immune system, which in turn interferes with viral replication. We aren’t sure precisely how ribavirin works, but it also interferes indirectly with viral replication.

To understand this, let’s go back to the roaches. If the critters were in your refrigerator and you decided to blow it up to get rid of them, then any of the roaches that lived managed to do so because of luck. They could be weak or strong and would pass along their regular genetic material. The same is true with viruses that escaped peginterferon and ribavirin—any remaining HCV would likely be similar to its ancestors.

In other words, if you were taking peginterferon and ribavirin and the virus was in the wrong place at the wrong time, the medications would eliminate the HCV. The remaining viral particles would reproduce identical copies. The copies could be strong or weak, just like the roaches in the refrigerator. Alternatively, if you go after the virus with peginterferon, ribavirin and one of the new DAAs, the weakest are killed first, leaving the strongest behind to either make copies or be destroyed by the DAA.

Avoiding Resistance
When you first take a protease inhibitor, it will probably prevent replication of much or all of the HCV. The goal is to apply constant pressure to the virus until every last one is gone.  Your job is to take your medications on time and exactly as prescribed. If you forget to take protease inhibitors, there is a risk that some of the virus will evolve into drug-resistant strains, which are stronger than the type that you had before you began treatment. Later, these viruses may resist the medications you are taking.

You may think that reminding yourself to take your medications on time is unnecessary, because surely you won’t forget something so vital. However, there is a phenomenon that occurs of which you may not be aware. Patients call it “brain fog,” which is a decrease in cognitive function that sometimes interferes with memory. In short, a side effect of the drugs may cause you to forget to take them.

There are tricks to help you remember to take your medication on time. In this electronic age, you can find alarms on your cell phone, computer, and watch. Wallpaper your world with reminders. You can even leave voice mail and email reminders to yourself. There are electronic pill reminders that will remind you to take your medications. Carry extra medication with you in case you don’t make it home on time. If you live with others, ask them to remind you.

Taking the New HCV Medications
Your doctor and pharmacist will discuss how to take your medications. Generally, peginterferon is injected once a week; ribavirin pills are taken twice daily, unless otherwise instructed. Ribavirin should be taken with food.

Here is prescribing information for Incivek (telaprevir):

  • Take three times daily (every 7 to 9 hours).
  • Incivek needs to be taken with high-fat food – aim for 20 grams of fat.
  • If you miss a dose of Incivek but it is more than 4 hours before the next dose, take the missed dose; less than 4 hours before your next dose, skip that dose. Never double up on your medication. If you have questions, call your medical provider.
  • Incivek is an oral drug which should be stored at room temperature of 77°F but can tolerate an exposure range of 59° - 86°F.
  • Incivek interacts with a long list of medications, including St John’s wort, so be sure you report everything you take to your medical provider. 
  • Treatment length is determined by how quickly you respond and if you have been treated before. If this is your first treatment or you were a responder-relapser to prior treatment and have undetectable HCV at weeks 4 and 12, you will be on telaprevir-based triple therapy for 12 weeks, followed by peginterferon and ribavirin for another 12 weeks for a total treatment length of 24 weeks; first-timers and responder-relapsers with detectable virus at weeks 4 and 12 will have 48 weeks of total treatment, with the first 12 weeks of triple-therapy and the other 36 weeks of peginterferon and ribavirin.
  • Previous partial responders and non-responders take telaprevir-based triple therapy the first 12 weeks and then 36 weeks of peginterferon and ribavirin, for a total treatment length of 48 weeks.
  • Treatment-naïve patients with compensated cirrhosis, who have undetectable HCV at weeks 4 and 12, may benefit from an additional 36 weeks of treatment for a total of 48 weeks. Incivek is not recommended for patients with decompensated cirrhosis.

Incivek should never be used alone as an HCV monotherapy.

Here is prescribing information for Victrelis (boceprevir):

  • Take three times daily (every 7 to 9 hours).
  • Victrelis needs to be taken with food, such as a light snack or meal.
  • If you miss a Victrelis dose but it is more than 2 hours before the next dose, take the missed dose; less than 2 hours before your next dose, skip that dose. Never double up on a dose of medication. If you have questions, call your medical provider.
  • Victrelis is an oral drug which should be refrigerated at 36°- 46° F, but may be stored at room temperature up to 77° for 3 months. Store Victrelis away from heat.
  • Victrelis interacts with a long list of medications, including St John’s wort, so be sure you report everything you take to your medical provider.
  • Start off with four weeks of peginterferon and ribavirin without Victrelis. After four weeks, Victrelis is added to the regimen.
  • Treatment length is determined by how quickly you respond and if you have been treated before. If this is your first treatment and have undetectable HCV at week 8, you will be on Victrelis-based triple therapy for a total of 28 weeks; first-timers with detectable virus at week 8 who have undetectable virus at week 24 stay on triple therapy until week 36 and then drop to peginterferon and ribavirin for an additional 12 weeks for a total treatment length of 48 weeks.
  • Previous partial responders and relapsers who have undetectable HCV at weeks 8 and 24, take Victrelis-based triple therapy for a total of 36 weeks; if the virus is detectable at week 8 but undetectable virus at week 24, take triple therapy until week 36 and then drop to peginterferon and ribavirin for an additional 12 weeks for a total treatment length of 48 weeks. 
  • All patients with compensated cirrhosis may benefit from the longer, 48 week regimen. Victrelis is not recommended for patients with decompensated cirrhosis.
  • Patients who don’t respond well to interferon and who were treated with Victrelis had a low response rate and a high likelihood of developing drug-resistant viral strains.

Victrelis should never be used alone as an HCV monotherapy.

Incivek and Victrelis are not recommended for everyone. Before taking either of these drugs, read the product information, as well as the package insert for ribavirin and peginterferon. If you do not meet the criteria for taking these medications, be patient—new drugs are in the pipeline and hopefully something will be available to you soon.

These are exciting times for those with HCV. We don’t need to fear resistance—we need to overcome it. Get clear instructions of how to use these new medications.  Create a system for how to take them and surround yourself with reminders to take your drugs. In the end, the fit survive, and let’s hope that means you.

Disclaimer: No roaches were harmed during the research of this article.

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HCV Snapshots
—Lucinda K. Porter, RN

Article: Second Phase HCV RNA Decline during Telaprevir Based Therapy Increases with Drug Effectiveness: Implications for Treatment Duration – Guedj J and Perelson A
Source: Hepatology June 2011; Volume 53, Issue 6, pages 1801-1808

In this retrospective study, Guedj and Perelson re-analyzed hepatitis C virus (HCV) treatment data collected from two Phase 1 telaprevir studies. Evaluating data from 44 subjects (36 who were treated with telaprevir monotherapy / 8 treated with telaprevir and peginterferon alfa-2a), researchers applied a new viral kinetic model. The researchers observed two stages of viral decline; most notably the second decline was estimated to be four times faster than previously reported. Based on their model, Guedj and Perelson predicted that if drug resistance is avoided (mostly by strict adherence to taking telaprevir as prescribed), HCV treatment length may be dramatically shortened.

The Bottom Line: The authors of this study suggest that there is the potential to use this data in the future. Patients who fully adhere to the prescribed HCV treatment regimen may be able to clear HCV in as few as 10 weeks of treatment, with as much as 95% of patients able to clear infection. Treatment duration would be longer for patients who miss medication doses. 

Editorial Comment: Although this is exciting to think about, DO NOT use this information to make changes in your medically-prescribed treatment length. This is a retrospective study and it is small. The hypothesis needs to be proven in a larger, randomized double-blind, placebo-controlled study. However, what is noteworthy is the critical importance of taking HCV medications on time and as prescribed.

Article:  Combating the Silent Epidemic: Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis – United States Department of Health and Human Services
Source: Released May 12, 2011 by the U.S. Dept. of Health and Human Services www.hhs.gov/ash/initiatives/hepatitis

Although this HCV Snapshot is not referring to a study, this news is important and deserves mention. The HCV community has waited for a long time for the federal government to implement measures to confront the viral hepatitis epidemic in the U.S. This document is a good beginning, considering Congress’s record when it comes to passing health-related measures.

The document has six goals:

  1. Educate providers and communities to reduce health disparities
  2. Improve testing, care, and treatment to prevent liver disease and cancer
  3. Strengthen surveillance to detect viral hepatitis transmission and disease
  4. Eliminate transmission of vaccine-preventable viral hepatitis
  5. Reduce viral hepatitis caused by drug-use behaviors
  6. Protect patients and workers from health-care-associated viral hepatitis

The Bottom Line: The U.S. is facing an even larger health care crisis because of the potential impact that viral hepatitis, particularly HCV, will have in the near future, largely due to an aging Baby Boomer population with a high percentage of HCV. This plan provides the basic fundamentals for reducing this crisis. However, this plan is unfunded and cannot be implemented without money from the Affordable Care Act.

Editorial Comment: It is hard not to be pessimistic about the chances of this plan surviving under the current political climate.  I would be thrilled beyond belief if this plan was funded and implemented.

Article: Genetic Variation in Interleukin 28B with Respect to Vertical Transmission of Hepatitis C Virus and Spontaneous Clearance in HCV-Infected Children - Ruiz-Extremera  A, Muñoz-Gámez J A, Salmerón-Ruiz M A, Muñoz de Rueda P, Quiles-Pérez  R, et al.
Source: Hepatology June 2011; Volume 53, Issue 6, pages 1830-1838

Although vertical transmission rates of HCV (mother with HCV passes virus to fetus) are low (4% - 7%), it is the most common route of pediatric HCV infection. The HCV vertical transmission data are conflicting, and this study sought greater understanding about this risk factor.  

This 18-year study enrolled 145 mothers: 100 were HCV RNA-positive with 128 children; 33 were HCV RNA-negative with positive HCV antibodies and 43 children (I could not account for the remaining 12 subjects and I assume they were HIV-positive since the others were HIV-negative). Particular attention was paid to the role of interleukin 28B (IL28B) in HCV vertical transmission as well as spontaneous clearance among HCV-infected infants.

The Bottom Line: In all, 26 of 128 (20%) infants born to the HCV RNA-positive mothers acquired HCV infection; 7% of these were chronic infections. The higher the mother’s viral load (greater than 600,000 UI/mL), the higher the rate of HCV transmission. Children were also more likely to clear HCV if they did not have genotype-1. The IL28B status of mother or child was not associated with an increased transmission risk; however, genotype-1 children with the genetic variation CC IL28B were more likely to spontaneously clear HCV. Maternal HIV/HCV coinfection continues to be associated with high vertical transmission risk.

Editorial Comment: Vertical transmission is one of the most emotionally-charged issues related to HCV. With new, potentially shorter HCV treatment regimens, coupled with more funding for HCV awareness programs, we may be able to dramatically reduce the number of children who are infected vertically.

Article: Predicting Spontaneous Clearance of Acute Hepatitis C Virus in a Large Cohort Of HIV-1-Infected Men - Thomson E C, Fleming V M, Main J, Klenerman P, Weber J, et al.
Source: Gut June 2011; Volume 60, Issue 6, pages 837-845

The purpose of this research was to examine the factors that predict spontaneous clearance of HCV in HIV-infected men. This prospective study enrolled 112 HIV-positive men with acute HCV in London. Blood samples were taken monthly for 3 months, and then every 3 months after until subjects cleared HCV or were clearly considered chronic.

The Bottom Line: 85% of the participants became chronically-infected with HCV, leaving 15% with spontaneous clearance. Factors that predicted spontaneous clearance in HIV-positive men were rapid drop in HCV RNA (within 100 days), high CD4 count, increased bilirubin and ALT. HCV superinfection (multiple HCV strain infections) is common in HIV-positive MSM (men who have sex with men).

Editorial Comment: Although this is a relatively small study, the data suggest that spontaneous clearance may be predicted by monitoring viral load, CD4 count and liver function tests. Surveillance of patients with acute HCV may enable medical providers to target patients who do not show the markers for spontaneous clearance, and offer early treatment; those who have indicators for potential spontaneous clearance may be able to hold off treatment initially, in the hopes of clearing the virus without expensive treatment and its side effects.

Article: Association of Meat and Fat Intake with Liver Disease and Hepatocellular Carcinoma in the NIH-AARP Cohort - Freedman N D, Cross A D, McGlynn, K A,  Abnet C C ,  Park, Y, et al.
Source: Journal of the National Cancer Institute August 2010

We don’t usually include older research in HCV Snapshots, but this study is worth mentioning.

Researchers followed 495,000 adults for seven years. In this study, those who consumed a high saturated fat diet were 3½ times more likely to die of chronic liver disease and were twice as likely to be diagnosed with liver cancer compared to those who avoided saturated fat. Regular red meat eaters (averaging 4 oz per day) were 2½ times more likely to die of chronic liver disease and were 1¾ times more likely to be diagnosed with liver cancer compared to those who ate 4 oz  of red meat no more than once a week.

Other diet-related risk factors for chronic liver disease were processed meat, nitrate, and nitrite consumption, but these did not seem to increase the liver cancer risk. White meat eaters were at lower risk of chronic liver disease and liver cancer.

The Bottom Line: The researchers concluded that red meat and saturated fat may be associated with increased chronic liver disease and liver cancer risk; white meat consumption is associated with reduced risk.

Editorial Comment: Diet is a key ingredient not just for the liver but for our total health and well-being. The USDA recently replaced the “Pyramid” concept with a new campaign. Check out www.choosemyplate.gov

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The Next Wave(s)
—Alan Franciscus, Editor-in-Chief

Now that the first hepatitis C (HCV) protease inhibitors have been approved and are ready for use, I thought it would be important to look at some of the other drugs in clinical development to treat HCV.  This is even more important because the high cost of triple therapies may mean that some people may not have access to them because of lack of insurance, high co-pays, lower limits of coverage, and some people may not have a medical provider to treat and care for them.  If you do have a medical provider and you are having problems getting the medications because of insurance issues contact the specific pharmaceutical company that makes the drug or one of the umbrella organizations that offer assistance with medications.  Please see the end of this article for a list of resources.

There are a couple of key issues that should be well thought out before entering into a clinical trial.  The list below is just a very brief list of things to consider.  Much more information is available at www.hcvadvocate.org. 

• Clinical trials in humans begin with Phase I, move into Phase II if there are no serious safety issues and the drugs are found to be effective, and then to Phase III studies to further establish the efficacy and safety in certain populations and to compare the new drug to the current standard of care.  Phase III studies are the last leg before FDA approval is sought.  The further along the studies are the more information we know about the safety, tolerability and efficacy of the drug being studied. 

• Research information about the drug(s) from previous study information— www.hcvadvocate.org, www.NATAP.org and www.HIVandHepatitis.com are good places to start to compile information.   

• Remember that clinical trials are conducted to find out how safe and effective the drugs are in certain populations—there is a risk that they could have unknown and undesired side effects, may not be as effective as the current standard of care or that you, the study participant, may not even get the new drug.

• If the study includes getting a placebo (sugar pill) make sure that you are offered the study drug at the end of the study—that is, if the study drug is found to be safe and effective.  Many trials now have “roll-over” studies that enroll people who received the placebo in a study where they will be certain to receive the investigational drug.      

• Make sure you completely understand the potential risks and benefits of the study drugs.  There is a form called Informed Consent that should spell out all the information you need to help you make an informed decision about whether or not to sign up for the study.  If you do not completely understand any of the information—ASK QUESTIONS.  If you still have any doubts don’t sign the consent form until you completely understand it and are comfortable with taking the medications.  No one should rush you into a decision.

There are also clinical trials of drugs that are already approved, such as pegylated interferon, Incivek, and Victrelis.  Do some research to find out if you qualify for these trials.

Searching for Clinical Trials
The best place to start is with www.clinicaltrials.gov.  There are other sites, but I have found this one to be the most comprehensive site on the Internet.  Also talk with your medical provider or local medical centers about any trials in your area.  If you do not have a computer check with your local library or service provider about Internet access.

To find clinical trials listed on www.clinicaltrials.gov:

• In the upper right hand corner there is a search button for the entire www.clinicaltrials.gov site.  Type in “HCV” for a list of all the studies or type in “HCV and {the drug name}” for a list of all the trials for that particular study or studies.  Once a trial is displayed, click on the link and you can read all the information about the drugs being used, the population that is being studied, the inclusion and exclusion criteria, etc.  All of the clinical trials listed below have a placebo arm so you may not get the study drug.  

Phase III Studies
There are two medications that are currently in Phase III clinical studies—TMC435 (Tibotec) and BI 201335 (Boehringer Ingelheim Pharmaceuticals).  These studies also involve pegylated interferon and ribavirin.

HCV Genotype 1: TMC435 is an HCV protease inhibitor that is a once-a-day pill taken in combination with pegylated interferon and ribavirin.  The participants in this trial will receive TMC435 (or placebo) plus pegylated interferon and ribavirin for 12 weeks followed by pegylated interferon and ribavirin for 24 or 48 weeks.  This study is actively recruiting HCV genotype 1 patients who are treatment naïve (never been treated) or relapsers (people who went HCV RNA (viral load) negative during therapy but tested HCV RNA positive again).  There is a study slated for people who failed previous treatment, but it is not actively recruiting yet.  Keep checking back at www.clinicaltrials.gov.  For more information info1@veritasmedicine.com

Comments:  Since this is a Phase III study more safety, tolerability and efficacy is known from the previous Phase I and Phase II trials.  Another advantage is that the HCV protease inhibitor is only taken once-a-day and treatment duration is shorter for some people.

BI 201335
HCV Genotype 1:  BI 201335 is also an HCV protease inhibitor that is a once-a-day pill taken in combination with pegylated interferon and ribavirin.  The trial participants will receive either BI 201335 at 120 mg (or placebo) plus pegylated interferon and ribavirin for 12 or 24 weeks, or BI 201335 240 mg for 12 weeks in combination with pegylated interferon and ribavirin.  Treatment-naïve patient trials are currently recruiting.  There are many trials that are expected to begin soon, but that have not yet started recruitment.  Call center for Boehringer Ingelheim—800-243-0127. 

Comments:  BI 201335 is also a Phase III study and the advantage is that it includes an arm that will use a shorter treatment duration and a protease inhibitor that is only taken once-a-day.  

Phase II Studies
Although these studies are not as far along in clinical development as Phase III studies some are interesting and warrant a look because they may have study arms that do not include interferon and/or ribavirin and may include a shorter treatment duration. 

Some of the studies below are looking at combinations of various DAAs with and without pegylated interferon and ribavirin to help broaden our understanding of who can take the DAAs alone and who will need to include pegylated interferon and/or ribavirin for successful treatment.  In order to eliminate the use of pegylated interferon and/or ribavirin from the HCV treatment regime for at least some people a combination of different types of direct acting antivirals (DAAs) will be needed to completely suppress the virus by interrupting the replication process by way of blocking multiple key enzyme processes that the virus needs to replicate.

BMS Studies
Genotype 1:  189 HCV treatment-naïve patients will be enrolled in various arms that will include: Part A—Pegylated Interferon Lambda with ribavirin plus one direct antiviral (BMS-790052 (NS5A inhibitor) or BMS-650032 (HCV protease inhibitor)) vs. Pegasys and ribavirin.  Part B—Pegylated Interferon Lambda with and without ribavirin plus two DAA’s (BMS-790052 and BMS-0032).  Treatment duration will be 24 or 48 weeks. ClinicalTrials.gov identifier:   NCT01309932

Genotype 1:  420 HCV treatment-experienced patients will be enrolled in 6 arms.  Drugs being studied include danoprevir—an HCV protease inhibitor (boosted with ritonavir), R05024048—an HCV polymerase inhibitor, Pegasys and ribavirin.  All of the arms in the study will receive danoprevir/ritonavir and ribavirin, but some arms will not receive Pegasys.  Study reference number: WV21913.  Call 888-662-6728 for more information.

In another study, 160 HCV treatment-naïve patients will receive R5024048 and danoprevir/ritonavir with and without ribavirin—no interferon will be used in this trial.  Study reference ID number:  PP25213.  Call 888-662-6728,

Comments:   The treatment-experienced study will help answer a lot of questions about various combinations and there will be a large number of patients enrolled, which means the results will be more credible.  The treatment-naïve study is also interesting because interferon is not part of the study and will go a long way to answering some important questions, such as can interferon be eliminated from HCV treatment altogether.

I hope that some of these trials are ones that you will be interested in finding out more about.  Next month’s HCV Advocate will feature more clinical trials with combinations of DAA’s that different companies are working on together to treat HCV.

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