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April 2014 HCV Advocate

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In This Issue:

CROI: 2014
Alan Franciscus, Editor-in-Chief

HEALTHWISE: Hepatitis C; Harm Reduction; and Health
Lucinda K. Porter, RN


Snapshots
Lucinda K. Porter, RN


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CROI: 2014
—Alan Franciscus, Editor-in-Chief

The Conference on Retroviruses and Opportunistic Infections (CROI) was recently held in Boston, MA. This year there were quite a few presentations about hepatitis C (HCV) and HIV/HCV coinfection. In this month’s HCV Advocate newsletter I will discuss data on HCV inhibitor therapy (direct-acting antivirals (DAAs)) to treat HCV. 

AbbVie
The results of a study from Abbvie were released at CROI that included a combination of different HCV inhibitors (with and without ribavirin) for the treatment of HCV genotype 1b treatment-naïve patients.  The treatment duration was 12 weeks.   Three HCV inhibitors –ABT-450/r (boosted with ritonavir), ABT-267 and ABT-333–with ribavirin (210 patients) and without ribavirin (209 patients) were given.  

The stage of liver damage of patients in the study included those with F0-F1 (68-72%), F2 (18-23%) or F3 (21%).  There were no patients with cirrhosis.  The average age was about 48 yo.  Most were white race and the gender was about equal between females and males. 

The cure rates were 99.5% in the group that received ribavirin and 99% in the group that did not receive ribavirin.  One patient had virologic breakthrough at week 10 and 2 patients were lost to follow-up. 

The most common side effects were mild—headache, fatigue, pruritus (itching), nausea, and weakness.  Itching, anemia and rash were higher in the ribavirin containing groups.  There were no treatment discontinuations. 

Dr. Reddy, an author and a presenter, concluded that “For treatment-naïve GT1b patients without cirrhosis, ABT-450/r, ABT-267 and ABT-333 is well tolerated and highly efficacious with or without ribavirin.”

Comment: Abbvie’s combination of HCV inhibitors continues to impress with cure rates exceeding 90% with and without ribavirin for a treatment period of 12 weeks in both genotype 1a and 1b.  Abbvie has noted that they expect to apply for marketing approval to the Food and Drug Administration (FDA) this year so these drugs could hit the market within the year.  Great news for patients especially since it appears that ribavirin can be dropped from this therapy for genotype 1.

BMS
Another interferon- and ribavirin-free study presented at CROI was on three HCV inhibitors that have been developed by Bristol-Myers Squibb. In the current study a total of 168 treatment naïve HCV genotype 1a and 1b patients were treated with a three drug combination of daclatasvir, asunaprevir, and BMS-791325. There were two arms in the study—the drugs in the two arms were the same except the dose of BMS-791325 was 75mg (80 patients) in one arm and 150mg (86 patients) in the other arm.  The treatment duration was 12 weeks.  The demographics of the people in the study were: average 54 yo; men (67%); white race (83%); HCV genotype 1a (82%); F0-F1(46%), F2 (13%), F3 (20%), F4 (18% with biopsy confirmed cirrhosis); unknown grade (2%). 

The overall cure rates were 92% and the cure rates were similar cure between the arms and by patient demographics.  There were 8 treatment discontinuations, due mainly to lack of efficacy (3 patients) and adverse event (2 patients). The most common side effects reported were headache, diarrhea, fatigue, and nausea. 

Dr. Hawkins commented “The 12-week, interferon- and ribavirin-free, all oral 3-DAA regime achieved SVR12 in >90% of patients despite high prevalence of genotype 1a, advanced fibrosis/cirrhosis, and IL28B non-CC genotypes.”

Comments:  The results in this early trial are very encouraging for interferon- and ribavirin-free therapy for 12 weeks of treatment.  This combination has also been designated as a ‘Breakthrough Therapy” by the FDA which means the FDA will help guide BMS through the clinical trial process and the designation will help to accelerate the approval process.

BMS/Janssen
The combination of BMS’s daclatasvir and Janssen’s simeprevir with and without ribavirin to treat HCV genotypes 1a and 1b was presented.  In the study, the subtypes (1a and 1b) were divided into different arms. 

The first data presented was on subtype 1b—147 (104 treatment naive; 43 prior null responders).  The patient characteristics were age 53-59 yo; male (42-52%); white race (85-100%); liver histology F0-F2 (39-77%), F3 (10-22%); F4 (11-39%).

The patients were randomized to receive 12 weeks (76 patients) of daclatasvir plus simeprevir either without ribavirin (76 patients) or with ribavirin (71 patients). At the end of the 12 weeks the patients were again randomized to receive either no additional treatment or an additional 12 weeks of daclatasvir, simeprevir with and without ribavirin. 

The cure rates in the genotype 1b treatment patients was 85% in the group that received daclatasvir plus simeprevir and 75% in the group that received the triple combination of daclatasvir, simeprevir plus ribavirin.  There was little difference in cure rates between the groups that were treated for 12 or 24 weeks.   However, higher rates were seen in the ribavirin arms especially in the patients who were prior null responders. 

Twenty-two people discontinued mainly due to lack of efficacy. 

In the group of patients with genotype 1a the results were disappointing.  There were only 21 patients in the two genotype 1a arms (12 treatment naïve; 9 null responders). Most were white males aged 49 to 55yo, liver histology
—F0-F2 (9 patients); F3 (6 patients); F4 (6 patients). 

The cure rate was 67% in the treatment-naïve patients.  None of the null responders achieved a cure. 

There were two treatment discontinuations in each group due to adverse events. 

Dr. Hézode commented that the low dose of daclatasvir (30 mg) might have been a factor in the low response rates in prior null responders, and going forward BMS would use the daclatasvir at the 60 mg dose.

Comments:  The cure rates in the study were good for genotype 1b but dismal for genotype 1a. However, the study of HCV genotype 1a was small, so it’s hard to draw solid conclusions.  Still, there have been higher cure rates with other combinations of HCV medications, including BMS DAA combinations and other all-DAA combinations with and without interferon or ribavirin.      

Gilead
A study conducted in Washington D.C. by the National Institutes of Allergy and Infectious Diseases is shedding some light on interferon- and ribavirin-free DAA therapy in a real world setting to treat people with HCV genotype 1.  The clinical trial was conducted in Washington D.C., and the trial participants were mostly low-income HCV genotype 1 patients.   Many of the patients in the study had negative predictors of treatment response—65-80% male, 80-95% African Americans, 55-85% genotype 1a.  The study was interferon-free and ribavirin-free.  About a quarter of the patients in the study had severe fibrosis or cirrhosis.  All of the patients with cirrhosis were treated for 12 weeks (arm 1).  The three treatment arms (20 patients each) and the cure rates are listed below: 

  • Sovaldi, ledipasvir – 12 weeks –100% cure rates

  • Sovaldi,  ledipasvir, GS-9669 –6 weeks
    —95% cure rate

  • Sovaldi, ledipasvir, GS-9451 –6 weeks—100% cure rate

The most common side effects were headache and fatigue, but they occurred in only the minority of patients.  There were no serious side effects and no treatment discontinuations.  The study was designed as an 8 arm study.  The other arms will include triple therapy combinations for people with cirrhosis. 

In conclusion, Dr. Kohli stated, “Hepatitis C can be successfully and safely treated in six weeks using three direct acting agents with different mechanisms of action.”

Dr. Kohli also stated that they are currently enrolling patients in a 4-week treatment arm.  

Comments:  This study is a valuable piece of the treatment response puzzle with only DAA therapy.  Unlike other studies that usually have a higher percentage of the easier to treat HCV population—the  population in this study are more typical of the HCV population and are also the more difficult to cure.  It is also an indication that the results can be replicated out in the real world of hepatitis C.      

The table below lists HCV inhibitors currently in interferon-free studies to treat HCV.

 

Polymerase inhibitor-
Nucleosides (NI)
Polymerase Inhibitor-
Non-Nucleosides (NNI)
Protease Inhibitor
(PI)
NS5A
Abbvie   ABT-333 ABT-450/ritonavir ABT-267
Achillion     ACH-2684 ACH-3102
Boehringer Ingelheim   deleobuvir faldaprevir  
Bristol-Myers Squibb   BMS791325 asunaprevir daclatasvir
GSK       GSK2336805
Genentech RG7128 setrobuvir Danoprevir
/ritonavir
 
Gilead sofosbuvir GS-9669 GS-9451 ledipasvir
Janssen   TMC647055 simeprevir  
Merck     MK-5172 MK-8742
Presidio       PPI-668
Vertex VX-135      

*Adapted from Pawlotsky JM. Gastroenterology 2012:  in press

Generic names of HCV inhibitors are given a suffix to identify the mechanism of action or what enzyme of the hepatitis C virus that drug inhibits:

  • HCV protease inhibitors suffix “previr”

  • HCV polymerase inhibitors suffix “buvir”

  • HCV NS5A inhibitors suffix “asvir”



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HEALTHWISE: Hepatitis C, Harm Reduction, and Health
—Lucinda K. Porter, RN

World Health Day is April 7, 2014. Health is not just a global concern—it is a personal one. Most of us value our health more than material wealth. The loss of health is deeply painful, a loss that those with hepatitis C need to confront in a monumental way. Chronic hepatitis C has the potential to interrupt the course of one’s life, and may change it forever.

When I contracted hepatitis C in 1988, it was an incurable disease. However, the lack of a cure did not mean that I was helpless. I could do little about having hepatitis C, but there was a lot I could do about my health. At that point, I was living an unhealthy lifestyle, so there was room for much improvement. I was a potato chip-eating couch potato. I believed in better living through chemistry, tobacco and alcohol. It was not pretty.

Before I had hepatitis C, I had tried to improve my health by aiming for total perfection. That approach inevitably failed, and I’d throw in the towel and go back to my previous ways. It never occurred to me to make small changes. However, hepatitis C changed everything; I needed to find a successful approach to a healthier lifestyle.  

Rather than change everything, I changed one thing. I didn’t know it at the time, but basically I was using a harm reduction concept on myself. In HCV and Harm Reduction, Heather Lusk describes harm reduction as “a philosophy and set of practical policies, programs and practices for working with potentially harmful behaviors…any positive change is harm reduction.” 

Since the all-or-nothing approach wasn’t working, I decided to change one behavior that had the potential to kill me the quickest—drinking alcohol. I knew that alcohol was like fertilizer for hepatitis C, so I figured that giving up drinking might improve my chances of living with hepatitis C. Desperate to succeed, I got help for this.

One of the benefits of changing a behavior is that success builds confidence. If I could change one thing, then I could change something else. However, change is hard, and just because I could stop drinking didn’t mean that I could stop smoking. That required a different plan. I tried nicotine gum in order to reduce the harm tobacco was doing. Eventually I quit smoking.

Changing my diet was more difficult. Unlike alcohol and tobacco, food is a necessity. Eating is also a great pleasure. Improving my diet has been a two-steps forward, one-step back process. Although I have made great gains in my nutritional health, there is still room for improvement. However, my imperfection is not an opportunity to scold myself. According to Lusk, harm reduction is about respect and empowerment. Shame and guilt disrespect the self and lead to powerlessness. Shame and guilt are more likely to cause me to dive into a jumbo bag of M&Ms than to eat a crisp apple.

WHD

In observance of World Health Day, I invite you to reflect on ways you can reduce harm to your health. Pick just one thing to change. It may be something big, it may be something small—the important thing is that it is your choice and one you are ready to change. There are countless ways to reduce harm and gain health, and the HCV Advocate website provides factsheets and guides on a variety of health subjects. For information about harm reduction and diet, see last month’s Healthwise.  Here are some ideas to get you started:

  • Reduce the amount of alcohol you drink; try not drinking one day a week, or give up alcohol just for today. Perhaps you can limit the amount of alcohol you drink to one or two glasses.

  • If you use drugs, learn safer drug use practices. Whether injected, inhaled, skin-popped, or smoked, there are ways you can reduce potential harm to yourself and others. For instance, there are multiple delivery systems for cannabis that are less harmful than smoking it.

  • Try to get enough sleep on most nights, aiming for 7 to 8 hours. Set a goal of going to bed fifteen minutes earlier. If insomnia is an issue, try listening to soothing music while trying to fall asleep.

  • If you need to start or increase your exercise, start with 5 minutes. If that is too long, start with a minute. If you are a TV watcher, walk in place, stretch, or lift hand weights during the commercials. Add in activity by parking the car at the other end of the parking lot.

  • Learn about nutrition and hepatitis C. Eat smaller portions of less healthy foods. Reserve the least healthy foods for special occasions. Pick one food to skip for today, such as fried food or sugar.  

  • Reduce stress. Like so many of these suggestions, reducing stress is easier said than done. It takes knowledge and commitment. Dedicate five minutes of your day to meditation or relaxation, and that is a good health investment. Spend time outdoors, appreciating nature.  

  • Wash your hands more frequently, or for longer periods of time (aim for 20 seconds).

  • Increase daily water intake. Begin your day with a full glass of water. Buy a bigger water bottle and try to finish the contents. Drink a glass of water before every meal.

  • Add humor to your life. Laughter has a positive effect on health, and while it can’t fix everything, it makes life more pleasurable. You can start this now, by clicking here.

Virgil said, “The greatest wealth is health.” Health is a process—not an endpoint. We can always strive for a bit more. It starts with changing just one thing. What are you willing to change today in exchange for a better tomorrow? 

Lucinda K. Porter, RN, is a long-time contributor to the HCV Advocate and author of Free from Hepatitis C and Hepatitis C One Step at a Time. Her blog is www.LucindaPorterRN.com

Further Information



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Snapshots
—Lucinda K. Porter, RN

Article: Chronic Hepatitis C Virus Infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010.
  Source: Annals of Internal Medicine March 4, 2014; Volume 160, Number 5

This study used data collected from 30,074 participants in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2010. The researchers estimate that approximately 2.7 million persons* in the U.S. have chronic hepatitis C virus (HCV) infection. Less than half of those with HCV have been tested, which means they lack vital information that accompanies an HCV diagnosis.  Those with HCV are frequently poor and less educated, and many do not receive medical care. Baby Boomers, those born between 1945 and 1965, are six times more likely to have HCV than the general population.

*The researchers noted that these are conservative estimates, because the NHANES did not survey anyone who is homeless, incarcerated, or in the military.

The Bottom Line: At first glance, it appears that the number of chronic HCV cases is the U.S. is shrinking, but the analysis suggests this decrease is because more people are dying from HCV-related conditions. To avoid needless death, the researchers urge implementation of the Centers for Disease Control and Prevention (CDC) recommendation to screen all Baby Boomers for HCV.

Editorial Comment: In June 2013, the U.S. Preventive Services Task Force (USPSTF) echoed the CDC’s advice by issuing recommendations to screen adults born between 1945 and 1965 for hepatitis C. These recommendations have not yet gone into effect, despite the fact that the CDC has been urging this for nearly two years. In the light of this inaction, we can make a difference—urge every Baby Boomer you know to get tested for HCV. 

Article: Fibrosis Progression in Human Immunodeficiency Virus/Hepatitis C Virus Coinfected Adults: Prospective Analysis of 435 Liver Biopsy Pairs – Monica A. Konerma, et al.
  Source: Hepatology March 2014; Volume 59, Issue 3, pages 767–775

Human immunodeficiency virus (HIV) and HCV coinfection (HIV/HCV) is associated with progressive liver disease. The purpose of this research was to examine the incidence of HIV/HCV coinfection and identify risk factors for fibrosis progression. This prospective study enrolled 282 coinfected subjects, and performed 435 liver biopsies.

The Bottom Line: HIV/HCV coinfected patients have an increased risk of rapid liver fibrosis progression. Researchers recommend close monitoring of patients with persistent elevations in liver enzyme levels (ALT/AST) as these may indicate an increased likelihood of disease progression. 

Editorial Comment: Research presented at the March 2014 Conference on Retroviruses and Opportunistic Infections (CROI) revealed that those with HIV/HCV coinfection had significantly shorter 5-year survival rates after liver transplant than people infected only with HCV. This underscores the need for close monitoring of patients along with HCV treatment, especially since treatment has increased success rates in those coinfected with HCV/HCV.

Article: Active At Night, Sleepy All Day – Sleep Disturbances in Patients with Hepatitis C Virus Infection – Meike Heeren, et al.
  Source: Journal of Hepatology December 4, 2013; Epub ahead of print

More than 50% of chronic HCV patients with mild liver disease (no cirrhosis) report chronic fatigue, daytime sleepiness and poor sleep quality. This German study examined sleep patterns of 20 women with mild liver fibrosis who contracted HCV from immunoglobulin in 1978/79.  Those included in the study did not have any other obvious causes of sleep disturbances, such as neuropsychiatric conditions, shift work, medications, etc. When compared to healthy controls, the patients had higher scores for depression, fatigue and sleep disturbances and lower quality of life scores. Fatigue and quality of life scores correlated with poor sleep quality and daytime sleepiness.

The Bottom Line: Chronic fatigue is associated with poor quality sleep and increased nocturnal activity suggesting an alteration of sleep in HCV-infected patients.

Editorial Comment: I believe that sleep disturbances are associated with HCV because I’ve been listening to patients talk about this for decades. It is something I have experienced, and my sleep quality is significantly improved since HCV treatment. However, I have a problem with this study. First, the study is small with only 20 subjects. Second, eight patients were HCV PCR negative, seven spontaneously and one after therapy. This means that 40% of the patients technically did not have HCV. Third, five patients are current smokers and 9 patients reported light to moderate alcohol consumption, and although the control group had a similar composition, alcohol and smoking can affect sleep. In a study using only 20 participants, I would hope for fewer variables.

Article: Hepatitis C Virus (HCV) Viremia and the Risk of Acute Myocardial Infarction at Various Lipid Levels - Butt AA, et al.
  Source: Presentation at the 2014 Conference on Retroviruses and Opportunistic Infections, March 3-6, 2014, Boston; Abstract #685

HCV infection is associated with increased coronary artery disease. Increased lipid levels (cholesterol and triglycerides) are also associated with greater risk of heart attack or myocardial infarction (MI). Lipid levels drop with worsening liver disease, so this study investigated the role of lipids on heart attack risk in HCV-positive veterans.  More than 35,000 HCV antibody-positive men were compared to a similar group of 45,299 antibody-negative veterans.

The Bottom Line: Higher lipid levels increase heart attack risk in HCV RNA-positive male veterans by 22% to 64%, but not in HCV antibody-positive veterans without detectable HCV RNA. The researchers propose managing lipid levels and eliminating HCV as potential strategies for lowering risk of coronary artery disease in HCV-infected persons.

Editorial Comment: Thank goodness easier, more effective treatments are within sight.


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