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HCV Advocate Newsletter

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June 2011 HCV Advocate

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In This Issue:

FDA Approves Victrelis and Incivek
Alan Franciscus, Editor-in-Chief


HealthWise: Dietary Guidelines for Americans
Lucinda K. Porter, RN


HCV Snapshots
Lucinda K. Porter, RN and Alan Franciscus, Editor-in-Chief


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FDA Approves Victrelis and Incivek
—Alan Franciscus, Editor-in-Chief

May is turning out be to a milestone month for new treatment options for people with HCV genotype 1 with the approval of two new medications to treat hepatitis C—Victrelis and Incivek.  The new drugs are HCV protease inhibitors that work by blocking the replication of the hepatitis C virus.  This article provides a basic overview of Victrelis and Incivek touching on various aspects of the protease inhibitors’ combination therapy, including sustained virological response (SVR) or cure rates, treatment duration, side effects and pricing.  It is important to know that Victrelis and Incivek are only to be taken in combination with pegylated interferon and ribavirin.  The HCV protease inhibitors should never be given as a monotherpay and the dose of Victrelis or Incivek should never be reduced.

An important piece of information is that Victrelis or Incivek should never be stopped without first consulting a medical provider.  Finally, it is important to know that although the newly approved drugs are both HCV protease inhibitors, a comparison of the efficacy of the two drugs cannot be made because the studies were designed differently—different patient populations, lead-in vs. no lead-in, on-treatment response criteria, etc.

VICTRELIS
The first drug that was approved by the Food and Drug Administration (FDA) was Merck’s Victrelis.  Victrelis is a pill (800 mg) taken three times a day (every 7 to 9 hours) with a meal or light snack.

Response-Guided Therapy
Response-guided therapy is recommended for all patients except null responders and patients with compensated cirrhosis.  In null responders and patients with compensated cirrhosis the recommended treatment duration is 48 weeks: A 4-week lead-in phase (pegylated interferon/ribavirin) followed by 44 weeks of triple therapy of Victrelis, pegylated interferon and ribavirin.

Stopping rules 

  • If a patient is HCV RNA (viral load) greater than or equal to 100 IU/mL at treatment week 12—all HCV therapy was stopped.
  • If a patient had a confirmed HCV RNA at treatment week 24—all HCV therapy was stopped.

SVR: The cure rates for all patients and a sub-analysis of the African American (AA) patients in the study who received Victrelis, pegylated interferon and ribavirin include:

  • If HCV RNA or viral load was undetectable at week 8 through week 24,  total treatment duration was 28 weeks:  All patients 63% SVR; AA patients 42% SVR
  • If HCV RNA positive at week 8 but undetectable at week 24, Victrelis was stopped at week 36 and pegylated interferon and ribavirin (without Victrelis) was continued for a total treatment duration of 48 weeks: All patients SVR = 66%; AA patients 53% SVR.

SVR:  “Treatment Failures” 
The patients who were categorized as treatment failures received a 4-week lead-in phase of pegylated interferon plus ribavirin followed by Victrelis, pegylated interferon and ribavirin for 36 or 48 weeks.   

Note:  An important group of people who were not studied in the Victrelis combination studies were those who were considered null responders—that is people who had less than a 2-log10 HCV RNA decline by treatment week 12. Additionally, it was noted in the FDA approved labeling that patients who had less than a 0.5 log10 decrease at the end of the 4-week lead-in phase are predicted to have as poor an interferon response as those who did not have the same log drop at 12 weeks when only given pegylated interferon plus ribavirin.

The SVR rates and duration of treatment periods for all patients are listed below.

  • If HCV RNA negative at week 8 and at week 24 the total treatment duration was 36 weeks: SVR = 59%
  • IF HCV RNA positive at week 8, but undetectable at week 24, Victrelis was stopped at week 36 and the combination of  pegylated interferon/ribavirin was continued for a total treatment duration of 48 weeks: SVR = 66%

Side Effects
The most common side effects (occurred in more than 35% of patients) of Victrelis, pegylated interferon and ribavirin therapy included fatigue, anemia, nausea, headache and dysgeusia (taste change or metal taste). 

Dose Reductions Due to Side Effects
Thirty-nine percent of the people who received Victrelis, pegylated interferon and ribavirin had dose reductions (mainly pegylated interferon/ribavirin) compared to 24% of people who received pegylated interferon and ribavirin (without Victrelis).

Treatment Discontinuation Due to Side Effects:
Thirteen percent of those who received Victrelis, pegylated interferon and ribavirin discontinued treatment due to side effects compared to 12% in the arm that received pegylated interferon and ribavirin (without Victrelis).

Price:
Wholesale Acquisition Cost (WAC) price for Victrelis alone is $1,100 a week; $26,400 for 24 weeks, $35,200 for 32 weeks and $48,400 for 48 weeks.  Pegylated interferon plus ribavirin is approximately $30,000 for 48 weeks.
 
INCIVEK

The next drug that was approved was Vertex’s Incivek.  Incivek is a pill—750 mg  taken three times a day (every 7 to 9 hours) with food (not low fat).

Response-Guided Therapy
Response-guided therapy is recommended for treatment-naïve and prior relapse patients.  It was recommended that prior partial responders and null respsonders should be treated for a total treatment duration of 48 weeks.  Additionally, treatment-naïve people with cirrhosis are recommended a 48-week total treatment duration.  

Stopping Rules for All Patients

  • If HCV RNA positive (greater than 10-100 IU/mL) at week 4 and 12:  Stop Incivek and pegylated interferon/ribavirin at 12 weeks.
  • If HCV RNA positive at week 24:  Stop pegylated interferon/ribavirin.

SVR:  Treatment Naïve
The results for all patients, with a sub-analysis of cirrhotic patients, and African American patients who received Incivek triple therapy include:

  • Study #1: Incivek/pegylated interferon/ribavirin taken for 12 weeks followed by 12 weeks of pegylated interferon/ribavirin (without Incivek).  All patients 79% SVR; cirrhotic 62% SVR; AA 62% SVR.
  • Study #2:  (a) Incivek/pegylated interferon/ribavirin taken for 12 weeks followed by 12 weeks of pegylated interferon (without Incivek) or (b) Incivek/pegylated interferon/ribavirin followed by 36 weeks of pegylated interferon/ribavirin (without Incivek).  All patients (both a and b treatment arms) 74% SVR;  AA 88% SVR; cirrhotics arm (a) 67% SVR and 92% arm (b). 

Note:  Study 2 validated that a 24 week total treatment duration was as effective as 48 weeks.

SVR:  Treatment Experienced
Relapsers, partial responders and null responders were treated with Incivek/pegylated interferon/ribavirin for 12 weeks followed by pegylated interferon/ribavirin (without Incivek) for an additional 12 weeks (relapsers) or 36 weeks for prior partial responders and null responders.

  • Relapsers:  86% SVR
  • Partial Responders 59% SVR
  • Null Responders:  32% SVR

Side Effects:
Rash, anemia, and anorectal events (hemorrhoids, anal itching and burning) were the most serious side effects and were seen more frequently in the groups that received Incivek.  The side effects in the clinical trials were similar across treatment arms except higher rates of rash (56% vs. 34%), anemia (36% vs. 17%) and anorectal (29% vs. 7%) events were seen in the Incivek arms compared to the pegylated interferon plus ribavirin arms. 

Dose Reductions Due to Side Effects / Discontinuation
Ribavirin dose reductions due to anemia occurred in 32% of the patients.  Four percent of patients who received Incivek discontinued treatment and 1% discontinued Incivek combination treatment.  This compares to 12% ribavirin dose modifications due to anemia in the group that received pegylated interferon/ribavirin (without Incivek). 

Price:
 WAC for Incivek alone is $4,100 a week; 12 weeks of Incivek is $49,200.  WAC price for pegylated interferon plus ribavirin is approximately $30,000 for 48 weeks.

Definitions:

Sustained virological response (SVR):  is defined as undetectable HCV RNA (viral load) 24 weeks after the last dose of medicine was taken.

Relapser:  a person who was undetectable at the completion of at least 42 weeks of therapy but who became detectable during the 24 week follow-up period.

Partial responder: a person who achieved at least a 2 log10 reduction in HCV RNA (viral load) at week 12, but who was never HCV RNA undetectable by week 24 of treatment.

Null responder: a person who achieved LESS than a 2 log10 reduction in HCV RNA by week 12.

Example:  2 log drop = 15,000,000 IU/Ml to 150,000 IU/mL; a viral load that starts at 15,000,000 IU/mL and does not decrease to 150,000 IU/mL or lower.

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HEALTHWISE: Dietary Guidelines for Americans
—Lucinda K. Porter, RN

Regular Healthwise readers may notice that I repeat some topics; I think of it more like recycling. Nutrition is one of my favorite recycling projects and there are two reasons why I write about it so frequently. First, our knowledge about it is constantly changing. Second, I need constant reminders of why I need to maintain a healthy diet. It is easy to fall off the vegetable wagon, and I can stay off for a long time, foraging for chocolate and sourdough bread with gobs of butter. I need constant reminding that juicy burgers can clog up my arteries and that if I don’t maintain a healthy diet, I may end up in a stroke unit learning how to use a spoon again. The thought of eating canned peas in a convalescent hospital motivates me to eat better.

There is a massive amount of research about the negative effects of body fat and the liver, especially for those with chronic hepatitis C virus (HCV) infection. A recent Japanese study published in The World Journal of Gastroenterology1 by Takumi Akiyama and colleagues, shows the relationship between body mass index (BMI) and risk for hepatocellular carcinoma (liver cancer) in patients with HCV.

Analyzing ten years of data from 556 HCV patients who have never undergone treatment, researchers discovered that various factors lead to an increased risk of liver cancer. For those under the age of 60, the highest risk for liver cancer is for males, those who use alcohol excessively, and those with increased body mass index (BMI). Smoking and an elevated GGT (a liver enzyme) are also risk factors.

This research, along with thousands of other studies, tells us what we already know—take care of our health and we decrease our risk of diabetes, cancer, heart disease, and stroke. When I get on my soapbox, people reply, “We are all going to die of something. If I am going to die anyway, I might as well live the way I want and enjoy it.”

Unfortunately, life doesn’t usually work that way. Typically lifestyle-related diseases lead to years of suffering before we die. The quality of life for obese or sedentary patients is severely reduced for a long time. Although eating broccoli and oat bran may feel like torture, it really isn’t when compared to by-pass surgery, diabetic-induced neuropathy or living in a wheel chair tethered to oxygen.

So, what are we supposed to eat? With so many books and opinions, it can be hard to know who to trust. For simplicity’s sake, let’s look at the U.S. Department of Health and Human Services and the U.S. Department of Agriculture’s Dietary Guidelines for Americans 2010 (www.dietaryguidelines.gov). This article supplies the “CliffsNotes” version of the Dietary Guidelines.

Strive to maintain a healthy weight throughout your life. If you are overweight, consume less calories than you burn. Plan ahead and track your food intake. Cook at home more often and dine out less. Eat breakfast every day. Consume smaller portions and don’t eat while watching TV.

Choose foods that have high nutritional value. Reduce your intake of fat and sugar. Minimize consumption of foods that have added sugar, such as corn syrup, fructose, dextrose, etc. Although they are natural, honey, molasses, raw sugar, and agave syrup are still just sugar.

Increase your intake of fruits and vegetables. Aim for a colorful variety, particularly of those that are dark green, red, or orange. Fill half of your plate with fruit and vegetables.

Eat lean proteins. Seafood, lean meat, poultry, eggs, beans, peas, nuts, and seeds are good choices. If you eat dairy products, choose nonfat or low-fat versions. Keep dietary cholesterol consumption to less than 300 mg per day.

Minimize sodium and salt intake. About half the U.S. population should keep sodium to less than 1500 mg per day. This includes anyone over age 50, children, African Americans, and those with chronic medical conditions such as diabetes, high blood pressure, and kidney disease. Everyone else should consume less than 2300 mg per day.

Choose foods that are high in fiber rather than refined grains. Half of all grains consumed should be whole. Reduce consumption of refined, processed foods.

Limit saturated fat to less than 10% of total calories. Strive to replace saturated fat (butter and margarine) with monounsaturated or polyunsaturated vegetable oils such as olive and canola. Remember that fats are higher in calories.

Avoid trans fatty acids. These are found mostly in margarine, partially hydrogenated oils, and processed food (crackers, cookies, etc.).

Drink lots of water. Unsweetened tea and moderate coffee drinking is fine. A small amount of 100% fruit juice is okay. Avoid soda, fruit drinks, and other high sugar beverages. Sports drinks often have lots of sugar. The guidelines recommend limiting alcohol to one drink a day for women, two for men, but most doctors recommend complete abstinence for those with HCV or other liver diseases.

Increase physical activity and reduce sedentary behavior. Sedentary behavior is the highest risk factor for heart disease and stroke.

Practice safe food handling and storage. Food-related illnesses are rampant and largely preventable.

I encourage everyone to read the Dietary Guidelines. Despite the fact that the document was written by the U.S. government, it is interesting reading—way more compelling than the tax code or latest Congressional budget. The Dietary Guidelines supply practical information, including how to read food labels. One item I found interesting is that with the increased use of bottled water, some Americans are not getting enough fluoride.

Implementing the Guidelines
When I read the Dietary Guidelines, I thought, “This is great. I will just follow them and lose 5 lbs.” However, experience has shown me that making up my mind to do something isn’t enough to make it happen. Dean Ornish pointed out that God’s direct order of “Don’t eat the apple” wasn’t enough to keep Adam and Eve from eating the fruit. If God couldn’t keep them from eating the fruit, then how likely am I to keep away from a bowl of chips and salsa just because I tell myself to?

Goals and plans help me. Eating well is as much about what is going on in my head as what is on my plate. I know what is healthy for my body, but sitting down and doing it is a different matter. I wish I could tell you that I have a perfect diet and that you can too, but that would be a lie. The truth is that sometimes I eat well; sometimes I don’t. However, overall, I keep progressing.

If you are considering making lifestyle improvements, here are a few tips: Make change gradually. Avoid “all or nothing” thinking. If you are the type of person who eats an entire bag of potato chips because you already broke your diet on half a bag, I have news for you—we get to start over at any point. Perhaps you can stop eating the chips and throw the rest away. What’s the difference if you throw them in the trash or trash your body by eating them? Our bodies are not trash cans.

And finally, forgive yourself. The fastest way to sabotage good intentions is when we are hard on ourselves. We are more likely to respond to gentle coaching then with harsh criticism. Remember that this is a process. Taking care of your precious self includes being kind to yourself, regardless of what you eat. 

(Endnotes)
1 Body Mass Index Is Associated with Age-At-Onset of HCV Infected Hepatocellular Carcinoma Patients by T. Akiyama, T. Mizuta, S. Kawazoe, Y. Eguchi, Y. Kawaguchi, H. Takahashi, I. Ozaki, K. Fujimoto  The World Journal of Gastroenterology February 2011.


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HCV Snapshots
—Lucinda K. Porter, RN
Alan Franciscus, Editor-in-Chief

Article: Quality of Life in Patients with Various Liver Diseases - H. L. Tillmann, M. Wiese, Y. Braun, J. Wiegand, S. Tenckhoff, J. Mössner, M. P. Manns1, K. Weissenborn
Source: Journal of Viral Hepatitis April 2011; Volume 18, Issue 4, pages 252–261

People living with chronic hepatitis C virus infection (HCV) have long complained about a mental impairment, which HCV patients call brain fog. In this study, Tillmann and colleagues undertook two cross-sectional studies of 511 and 284 subjects with various liver diseases. After administering a variety of questionnaires, they concluded that those with HCV had worse mental quality of life scores than patients with other types of liver diseases. HCV patients who spontaneously cleared the virus had better mental scores than those who cleared HCV following treatment. Interestingly, patients with Primary Biliary Cirrhosis (PBC) had lower physical quality of life scores but better mental quality of life scores than those with HCV.

The Bottom Line: Patients with HCV have mental impairment, which may not necessarily resolve in all patients after HCV treatment.

Editorial Comment: Depression, sleeping problems, and other medical conditions may cause mental impairment. Those with HCV who have cognitive problems need a complete diagnostic evaluation before assuming that HCV is the cause of their mental impairment.

Article: Suicide Risk in Hepatitis C and during Interferon-Alpha Therapy: A Review and Clinical Update - S. Sockalingam, P. S. Links, S. E. Abbey
Source: Journal of Viral Hepatitis March 2011; Volume 18, Issue 3, pages 153–160

This study examines a serious concern about chronic hepatitis C virus (HCV) treatment—the high incidence of psychiatric side effects associated with the medications; risk of suicide is a particularly huge concern. The researchers conducted a literature review, identifying articles published in English between 1989 and 2010 on suicide for treated and untreated HCV patients. They located 17 articles and the following findings:

The highest risk of suicidal ideation (thoughts about suicide) is during the first 12 weeks of interferon treatment.

Suicidal ideation is associated with neuropsychiatric abnormalities and depletion of serotonin.

Those with high risk neuropsychiatric disorders may be treated with antidepressant medications prior to initiating interferon therapy, which may reduce depression and suicide risk.

The Bottom Line: The researchers recommended further investigation into pharmacological and nonpharmacological interventions on suicide risk during HCV treatment.

Editorial Comment: More than 30% of patients report depression as a side effect of HCV treatment. Although the risk of suicide is very low, even one suicide is too much. This study reinforces the importance of reporting neuropsychiatric history before beginning HCV treatment. Sometimes patients are afraid that if they report a psychiatric history, they will be disqualified from treatment. This is risky because it does not give medical providers enough information to make HCV the best possible experience. A fully informed medical provider can offer pre-treatment antidepressant medications and follow a patient more closely throughout treatment, and make psychiatric referrals if necessary.

Article: Long-Term Outcome after Antiviral Therapy of Patients with Hepatitis C Virus Infection and Decompensated Cirrhosis – A. Iacobellis, F. Perri, M. R. Valvano, N. Caruso, G. A. Niro, A. Andriul
Source: Clinical Gastroenterology and Hepatology March 2011; Volume 9, Issue 3, Pages 249-253

Likely the most difficult HCV patients to treat are those with advanced cirrhosis where the liver is not able to function, known as decompensated cirrhosis. In this study, 75 HCV patients with decompensated cirrhosis were enrolled, each received peginterferon alfa-2b and ribavirin.

Twenty-four subjects achieved sustained virologic responses (SVRs); 7 were genotype 1 or 4, and 17 were genotype 2 or 3. During the study, 2 of the patients who achieved SVR died; 25 without SVRs died. In the follow-up period, 33% of those with SVRs died; 96% of those without SVRs died. The average length of survival was 53 months for patients who did not have an SVR; those with an SVR survived an average of 73 months. Hospital readmission rates were significantly higher for those without an SVR than those with an SVR. In this study, SVR and the risk of hepatocellular carcinoma were not correlated.

The Bottom Line: SVR following HCV treatment predicts a positive outcome. 

Editorial Comment: With new HCV treatments in the pipeline, presumably we will have more to offer patients in the most advanced stages of HCV. Progress is not just ahead of us, it is here. However, we still need better treatments for everyone.

Article: The Association between Lichen Planus and Hepatitis C Virus – Hasnaa A. Abo-Elwafa, Esam-Eldeen A. Nada, Reham, E. El-Sharkawy and Nesreen A. Abdel-Rahman
Source: Journal of American Science, 2011; 7(2)

Hepatitis C virus (HCV) is associated with an increased risk of other medical conditions or extrahepatic manifestations. One of these is lichen planus (LP), an inflammatory disease that affects the skin, nails, hair and mucous membranes. This study enrolled 70 subjects with LP, ages 25 to 80; the control group consisted of 20 subjects with dermatological conditions other than LP, ages 22 to 70.  

The results were that nearly 39% (27 patients) of those with LP had HCV, whereas only 10% (2 patients) of the control group tested positive for HCV. The presence of HCV increased with age, with 50% of those with LP also had HCV.

The Bottom Line: Researchers in this study recommend HCV testing for patients with LP.

 Editorial Comment: Risk-based screening for HCV typically includes history of injection drug use, blood transfusion or organ transplantation prior to 1992, dialysis, etc. However, if screening for HCV included extrahepatic manifestations or diseases that are associated with HCV, perhaps more HCV-positive people would be identified when they are diagnosed with one of these other conditions.


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