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HCV Advocate Newsletter

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July 2014 HCV Advocate

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In This Issue:

HCV Drugs
Alan Franciscus, Editor-in-Chief

Snapshots
Lucinda K. Porter, RN

HEALTHWISE: Hepatitis C: A Global Pandemic
Lucinda K. Porter, RN


Patients First: The Right to Be Treated and Cured
Alan Franciscus, Editor-in-Chief


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HCV Drugs
—Alan Franciscus, Editor-in-Chief

In this month’s column I will discuss many news stories related to HCV drugs in development, including a study from Japan on Gilead’s combination of sofosbuvir/ledipasvir to treat HCV genotype 1, and, also from Japan, BMS’s combination of daclatasvir plus asunaprevir to treat HCV genotype 1b. There is more information from AbbVie: The 3-D combination to treat HCV genotype 1, the FDA priority review and AbbVie’s collaboration with OraSure Technologies.  Also in the news was Merck’s acquisition of Idenix and Achillion’s resurrection of one of their HCV drugs that was on clinical hold and on another Achillion drug that is about to begin a proof of concept study.   

Hepatitis C is a disease with a largely unmet need for drugs to treat it.  But in Japan this need is even more pressing since the HCV epidemic began earlier there and, as a result, the impact of hepatitis C on the health system is much worse in Japan than in the United States and Europe.  The newer interferon and ribavirin-free therapies can slow the expected severe health-care crisis and prevent deaths related to hepatitis C in Japan.   The results from two studies on interferon and ribavirin-free treatments conducted in Japan were recently released: Gilead’s ledipasvir plus sofosbuvir and BMS’s daclatasvir plus asunaprevir. 

 

Gilead

Ledipasvir/Sofosbuvir:
Gilead reported on a Phase 3 study using a once-a-day fixed-dose combination of ledipasvir (NS5A inhibitor – 90 mg) plus sofosbuvir (polymerase inhibitor – 400 mg) with and without ribavirin.  The treatment period was 12 weeks for all groups treated.  All of the patients in the study were genotype 1; 166 treatment- naïve; 175 treatment-experienced; 76 had compensated cirrhosis.  The cure rates (SVR12) are listed below.

The most common side effects in the non-ribavirin containing arms were nasopharyngitis (inflammation of the nasal passages), headache and malaise.  In the groups that received ribavirin the additional side effects included anemia, pruritus (itching) and rash.

 

HCV Medications

Cure Rates

Treatment Naïve

LDV/SOF

100% (83 of 83 pts)

Treatment Naïve

LDV/SOF/RBV

96% (80 of 83 pts)

Treatment Experienced

LDV/SOF

100% (88 of 88 pts)

Treatment Experienced

LDV/SOF/RBV

100% (87 of 87 pts)

ledipasvir (LDV); sofosbuvir (SOF); ribavirin (RBV)

Comments:  The results with and without ribavirin are excellent.  Gilead indicated in their press release that they plan to submit a New Drug Application to the Japanese Pharmaceutical and Medical Devices Agency (PMDA) by the end of 2014.

 

BMS

Daclatasvir/Asunaprevir:
Bristol-Myers Squibb (BMS) has multiple HCV drug regimes in clinical development for the treatment of HCV.  This article will discuss the data from a recent article published in Hepatology on a Phase 3 trial for the treatment of HCV genotype 1b with the combination of daclatasvir (NS5A inhibitor – 60 mg dosed once-a-day) plus asunaprevir (HCV protease inhibitor – dosed twice a day).  A journal article provides the best type of information since it is peer-reviewed and, in this case, has been published in a prestigious medical journal.

BMS has submitted the Phase 3 data to the Food and Drug Administration (FDA) for approval.  The treatment period was 24 weeks. 

There were two groups in the study:

Group 1: 135 patients who were either interferon-ineligible or intolerant: 100 medically ineligible for interferon, and 35 intolerant to interferon. The median age was 64 yo, male (28%), IL28B cc genotype (70%), cirrhosis (8%), interferon intolerant (26%).

Group 2:  87 patients who were non-responders: 48 null responders, 36 partial responders, and 3 who were previously treated but their treatment status was undetermined. The median age was 60 yo, male (45%), IL28B cc genotype (18%), cirrhosis (13%), prior null response (55%).

The sustained virological response rates (SVR 24) or cure rates were 80.5% to 87.4% (see table).

Comments:  The results are encouraging and relatively high for people with HCV genotype 1b, a patient population that is typically difficult to treat.  It is important to know that this is a relatively small population of patients so once this combination is approved and given to a larger population of people we will get a better picture of the effectiveness and safety of the combination of these two medications.

 

Group 1
Interferon-Ineligible
/ Intolerant
(Daclatasvir / Asunaprevir)

Group 2
Non-responders
(Daclatasvir / Asunaprevir)

Cure Rates

87.4%
(118 of 135 patients)

80.5%
(70 of 87)
patients

The most common side effects were nasal congestion, elevated liver enzymes, headache, diarrhea and fever.

 

AbbVie

In June AbbVie announced that their New Drug Application (NDA) had been accepted by the Food and Drug Administration (FDA) and that it had been granted priority review.  In addition, it was noted earlier that AbbVie submitted marketing authorization applications (MAAs) for regulatory approval in the European Union and that these applications and priority review had been accepted.  AbbVie is seeking marketing approval for their 3D combination of HCV medications to treat HCV genotype 1 patients. 

In a related story, OraSure Technologies announced that it had reached an agreement with AbbVie on a co-promotion agreement for an OraQuick HCV Rapid Antibody test.  The agreement will provide OraSure  $75 million in payments for the exclusive use of its HCV tests through December 31, 2019.  This means that AbbVie will be sponsoring mass testing to identify the other 50% to 75% of people with hepatitis C who don’t know they are infected.  It is definitely going to be a very interesting coming decade. 

 

Merck/Idenix

Acquisitions seem to be a permanent part of the HCV treatment landscape.  In June, Merck announced that they had offered 3.85 billion dollars in a bid to acquire Idenix Pharmaceuticals Inc.  The offer goes to Idenix stockholders, but I can’t imagine that any sane stockholder would turn this down!  In the news, however, there have been stories about the bid being undervalued and overvalued.  Who knows! 

Idenix has three HCV inhibitors in Phase 1 and Phase 2 clinical development—IDX21437 and IDX21459 (polymerase inhibitors) and samatasvir (NS5A inhibitor).  Merck has its own MK-5172 plus MK-8742 with and without ribavirin in Phase 3 clinical development.  If and when these drugs come to market it will be interesting to see how they are priced since the acquisition price tag is a bit hefty for the Idenix pipeline.

 

Achillion

In June, Achillion announced that the FDA removed a clinical hold on their HCV protease inhibitor—sovaprevir—at doses of 200 mg once daily and that they have completed Phase 2 clinical trials of this drug.  Additionally, Achillion announced that they have begun a proof of concept study in people with HCV genotype 1 on a new drug candidate—ACH-3422—an HCV polymerase inhibitor.


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Think You Know the Basics?

Check out our new
“Basics” blog where you can find easy to
understand information for those who want to learn the basics about hepatitis – and then take the Quiz at the end to see how you did!!
http://blog.hcvadvocate.org/

 



Snapshots
—Lucinda K. Porter, RN

Article: Probiotics Prevent Hepatic Encephalopathy in Patients With Cirrhosis:  A Randomized Controlled Trial—Manish Kumar Lunia, et al.
  Source: Clinical Gastroenterology and Hepatology June 2014; Volume 12, Issue 6, Pages 1003–1008

Hepatic encephalopathy (HE) is a condition that may occur with advanced cirrhosis when the liver is unable to metabolize ammonia. This leads to cognitive dysfunction, and at its worst, dementia. HE is associated with a poor prognosis. The treatment for HE is to reduce ammonia in the intestine.  Since probiotics alter the flora in our gut, this prospective, randomized controlled trial investigated the use of probiotics for HE prevention in 160 patients.

The Bottom Line: Three months of probiotic administration significantly reduced measurable signs of HE, and were found to be effective in preventing HE in patients with cirrhosis.

Editorial Comment: Research about the body’s microflora is yielding fascinating findings, so these results don’t surprise me. Talk to your medical provider if you are interested in trying probiotics.  Some foods such as yogurt with live cultures have probiotics in them. Prebiotics feed our own probiotics, and occur in a variety of foods such as garlic, onions, leeks, asparagus, wheat bran, and bananas.

 

Article: Acute Hepatitis C: A 24-Week Course of Pegylated Interferon Alpha-2b versus a 12-Week Course of Pegylated Interferon Alpha-2b Alone or with Ribavirin—Teresa Santantonio, et al.
   Source: Hepatology June 2014; Volume 59, Issue 6, Pages 2101–2109

Treatment of acute hepatitis C (AHC) is not standardized. One major study by Michael Manns in 2001 showed >90% sustained virological response (SVR) of acute hepatitis C in patients treated for 24 weeks with interferon.  Over time, pegylated interferon was used; some clinicians also used ribavirin. As to when to initiate treatment for acute hepatitis C, a June 2013 study in The Lancet (Deterding, et al.) concluded that early treatment has the edge over waiting to see if acute patients clear hepatitis C spontaneously.

This study randomly assigned 130 AHC patients who did not spontaneously clear hepatitis C by week 12 into one of three arms:

  • 24-week course of pegylated IFN (Peg-IFN)
  • 12-week course of Peg-IFN
  • 12-week course of Peg-IFN with ribavirin 

Patients were followed for 48 weeks after therapy ended, and overall SVR rate was 71.5%. Approximately 12% of the patients discontinued the study prematurely, so if you did not use an intent-to-treat analysis, the overall SVR rate was 81%. 

The Bottom Line: Response rates for patients with acute hepatitis C were not influenced by combination therapy or treatment duration.

Editorial Comment: The easiest of the three regimens was a 12-week course of Peg-IFN. Given the SVR rates of 81%, the question that comes up for me is why not let AHC become chronic and then treat with interferon-free regimens?  Personally, I would rather wait for the interferon and ribavirin-free therapies—it seems easier than 12-weeks of interferon, and the response rates are higher. Looks like we need more research on treating acute hepatitis C.

 

Article: Variants of the Inosine Triphosphate Pyrophosphatase Gene Are Associated with Reduced Relapse Risk Following Treatment for HCV Genotype 2/3—Karolina Rembeck, et al.
   Source: Hepatology June 2014; Volume 59, Issue 6, Pages 2131–2139

When treating hepatitis C virus (HCV) with peginterferon, we know a fair amount about genetic factors associated with genotype 1 relapse, but little about genotypes 2 or 3. We also know even less about genetic factors associated with ribavirin, especially in genotypes 2 or 3. This study evaluated the genetic factors associated with anemia and relapse in HCV patients with genotypes 2 and 3.

The Bottom Line: There appears to be an association between polymorphisms at ITPA (part of our own DNA) and relapse risk. The researchers theorize that the addition of ribavirin may help some genotype 2 and 3 patients have reduced relapse risk despite the increased risk of anemia.

Editorial Comment: A genetic test for these polymorphisms would help determine if patients have the features that are associated with relapse risk. However, with ribavirin-free HCV treatments around the corner, this will all be irrelevant, I hope.

 

Article: Patient-Important Benefits of Clearing the Hepatitis C Virus through Treatment: A Simulation Model—Hamish Innes, et al.
   Source: Journal of Hepatology June 2014; Volume 60, Issue 6, Pages 1118–1126

The aim of this study was to evaluate whether the risk of side effects of current HCV therapies was worth the potential benefits. The benefit of SVR was lowest for patients aged 60 or more years and highest for patients with initially compensated cirrhosis aged 30 years and below.

The Bottom Line: Older patients with less advanced liver fibrosis have less chance of achieving an SVR and adding significant life extension. The researchers show the dilemma between recommending immediate treatment with existing therapies (that have multiple side effects) vs. waiting for future treatments with mild-to-moderate side effects, high response rates, and short treatment durations.

Editorial Comment: I believe this dilemma will be short-lived since new HCV therapies are due to be approved in the fall. Some patients are having success with the combination of Olysio and Sovaldi for 12 weeks, which may be a good compromise in this situation.


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HEALTHWISE: Hepatitis C: A Global Pandemic
—Lucinda K. Porter, RN

Hepatitis C is a pandemic. Wikipedia defines a pandemic as “an epidemic of infectious disease that has spread through human populations across a large region; for instance multiple continents, or even worldwide.” The World Health Organization (WHO) estimates that 2.8% of the world’s population has been infected with the hepatitis C virus; 130 to 170 million people in the world are chronically infected. As a result, an estimated 350 to 500 thousand people die every year.

This past May, WHO’s World Health Assembly passed the Hepatitis Resolution, making the global hepatitis pandemic a high priority issue. The resolution is perfectly timed; the new hepatitis C medications have cure rates of above 90% in clinical trials. The treatment lengths are shorter and side effects of these new drugs are milder.

Will the ability to cure hepatitis C make it like small pox, a disease that we can eradicate? I will not attempt to answer this question today, but I do feel it is a question worth asking. When I contracted hepatitis C in 1988, this virus didn’t have a name let alone a cure. We have come such a long way in such a short time, that I feel enormously hopeful about the prospects of wiping out hepatitis C.

Although I am optimistic about eradicating hepatitis C, it won’t be an easy task. In the U.S., we have not diagnosed the majority of those with hepatitis C, let alone treated the patients who have it. Only about 7% to 11% have received hepatitis C treatment. The newest hepatitis C treatments are prohibitively expensive. The price tag of just one drug, Sovaldi, is $84,000. This cost does not include the other drugs combined with Sovaldi, medical visits, lab tests, or drugs to manage the treatment’s side effects.

Most insurance plans are paying for the newest treatments. Medicare recently announced that it is easing its restrictions on hepatitis C treatment. However, about one-third of those with hepatitis C are uninsured, according to Health Care Reform and Hepatitis C: A Convergence of Risk and Opportunity (Milliman Report, December 2013). Matters are further complicated because insurers and health policy experts are debating who should be treated. Should those with advanced stages of liver disease have priority over those with minimal liver damage?

I think everyone should be treated, but I am not insensitive to the magnitude of the problem. If we can’t cure 2.7 million Americans how can we eliminate hepatitis C globally? Compare the U.S. to Egypt’s more than 12 million hepatitis C infected people, China’s more than 30 million, or Pakistan’s nine million plus, and our problem seems small. Internationally, the rate of those who have been actually diagnosed with hepatitis C is even smaller than the U.S. rate.  For example, less than 3% of China’s hepatitis C cases have been diagnosed. It is hard to feel hopeful about global eradication of hepatitis C when the U.S., a country that is economically abundant compared to much of the world, can’t set a proactive hepatitis C health policy.

One bright spot in the international realm was news that Sovaldi may be sold at lower prices in other countries. A three-month course of Sovaldi might cost about $900 in Egypt. Although this sounds good, this price may still be prohibitive for many Egyptians. In short, hepatitis C treatment may be out of reach for most developing countries even if the cost is rock bottom. 

Even if we could treat everyone with hepatitis C, we still have the problem of transmission. Most new infections occur among people who inject drugs. Many countries have a punitive approach to dealing with drug users. Instead of seeing drugs as a public health policy issue, drug users are often criminalized or marginalized. WHO’s World Health Assembly endorsed harm reduction (an evidence-based approach to reducing transmission of bloodborne viruses and mortality among people who inject drugs) in the Hepatitis Resolution. Harm reduction includes needle and syringe programs, opioid substitution therapy, access to hepatitis C treatment, and decriminalization of people who inject drugs.

Why should any of this matter? Why should you be concerned about hepatitis C in Pakistan or Egypt or China? Leaving human decency and compassion out of the equation, for me it comes down to something that Diana Sylvestre, MD, wrote in the foreword of my book, “If one of us has hepatitis C, all of us have it.” Hepatitis C spreads. Hepatitis C hurts us. Hepatitis C kills us. If we can eradicate hepatitis C from the world, then why not try?

What can we do? Take part in World Hepatitis Day. For suggestions on how you can raise awareness and bring attention to the global hepatitis C problem, visit the World Hepatitis Alliance’s web site at www.worldhepatitisday.org. Don’t let the size of the problem prevent you from taking action; just do something. Imagine what a difference it would make if everyone did just a little something to raise awareness. We could change the world.

 

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


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Patients First: The Right to Be Treated and Cured
—Alan Franciscus, Editor-in-Chief

Very soon there will be treatments that will cure almost everyone of hepatitis C. These new treatments will have:

  • Minimal side effects, especially compared to the therapies that came before them
  • Cure rates that will be approaching up to 100%
  • Treatment periods that will be limited to  12 weeks—at least for some treatments

Hurray!  Good news for everyone with hepatitis C.

But of course there is a downside – the price of the new medications.  We don’t know yet what the price for the next generation of interferon-free medications will be, but generally once a price has been set there is little chance that medications that come along later will be priced lower—I really, really hope that I am wrong.  But even if they are somewhat lower they are still going to be expensive. 

The problem of the high cost of current medications is already impeding access to treatment.  Insurance companies, government payers (Medicare, Veterans Healthcare, etc.) are trying to come to terms with the expense of the medications when the great number of people who need to be treated is factored into the equation.  There have already been denials of coverage because people are not deemed ‘sick enough’ to qualify for treatment.   Plain and simple: It is unethical to deny people a medication because they are deemed to be ‘not sick enough.’  Another sore point—being ‘sick enough’ is being narrowly defined as having severe liver scarring without any consideration for other (extrahepatic) symptoms and side effects that many people with hepatitis C experience.  

Everyone with hepatitis C should have access to these life-saving medications.  In response the HCV Advocate will be publishing a series of articles, fact sheets and tools to help patients navigate through the medical care maze and help them to self-advocate. 

Topics will include:

  • Medical appointments: 
    • How to maximize your medical appointments, questions to ask, reporting symptoms, how to dress, being respectful and respected, what to do if you disagree, working with the gatekeeper (the nurse), and many more strategies to make the transition from a passive to an assertive patient.   How to talk to your doctor about treatment.
  • Medical insurance – what, when and how.  How to fight rejection letters.  Open enrollment and what that means for your drug coverage.  Questions you should ask yourself about your coverage.
  • Patient Assistance Programs – getting started before you start treatment.  Knowing your options, and what services are offered. 
  • Finances – what to expect if you are on treatment. 
  • Getting support

We are going to be adding more educational tools as we hear more from people about some of the obstacles they are facing.  But please check out our fact sheets and guides—we already have many resources that can help people access services and treatment. 

Symptoms of Hepatitis C
As I mentioned before, some insurance companies are basing approval of the medications on the degree of liver damage.  People living with chronic hepatitis C have many other symptoms and conditions that are not necessarily related to the scarring of the liver.  This is why it is so important to make sure that all of the conditions and symptoms of hepatitis C are recorded in your medical records. It is also important to record how the symptoms and conditions affect your daily activities. 

The symptoms of hepatitis C range from mild to moderate to severe.  Personally, I believe that everyone with hepatitis C has symptoms, but they come on so gradually and over such a long period of time that most people don’t notice them or believe that they are part of the aging process.  The list below contains some of the more common symptoms reported by people with hepatitis C, but the list is not all inclusive.  If you have symptoms that are not listed here be sure to mention them to your medical provider.

  • Fatigue is the most common symptom reported by people with hepatitis C.  It can range from mild to moderate to severe.  Again, some people may not even realize how fatigued they are if the fatigue falls somewhere within the mild to moderate range.  A good way of measuring it is to talk with friends who are healthy to find out what their fatigue level is. Another good way is to talk to others with hepatitis C and try to gauge how your fatigue measures up with their fatigue.  Finally, try to figure out how fatigue affects your daily life.  How does the fatigue affect your work, recreation and interaction with family and friends. 
  • “Brain Fog” is a common symptom of hepatitis C which is usually defined as low-level cognitive impairment.  Typical symptoms include fuzzy thinking, memory problems, and lack of concentration.
  • Muscle and Joint Pain  – low level aches and pains throughout the body.
  • Insomnia – inability to sleep or sleep that is not restful.
  • Headaches – pain or pressure on one or both sides of the head.
  • Fevers and Night Sweats – generally light fevers and waking up with clothes and/or bedding wet.
  • Depression and anxiety – feeling down and nervous.
  • Loss of Appetite or weight loss.
  • Nausea and vomiting  - feeling sick to your stomach or vomiting.
  • Abdominal Pain or pain in the general area of the stomach and intestines.
  • Liver Pain in the upper right side, right behind the rib cage.

In addition, ask your medical provider to test you for extrahepatic manifestations—these are conditions outside of the liver.  There are many conditions that are either directly caused by hepatitis C or that are more commonly seen in people with hepatitis C.  See our fact sheet on extrahepatic manifestations.  Ask to see a specialist who understands and can diagnose extrahepatic manifestations. 

Symptoms of Cirrhosis
Cirrhosis is a potentially life-threatening condition.  There are two types of cirrhosis—compensated and decompensated.  Compensated cirrhosis is defined as a liver that is heavily scarred but can still perform most of the important chemical functions that keep the body running smoothly.  When the liver is decompensated this means that the liver is severely scarred and damaged and normal function is impaired.  In addition to the symptoms listed above, other symptoms that need to be diagnosed by a medical provider are: 

  • Fluid retention and swelling in the legs and hands
  • Frequent urination
  • Bleeding and excessive bruising
  • Pruritus – excessive itching
  • Jaundice – yellowing of the skin and eyes
  • Menstrual irregularities
  • Nail changes

There are other symptoms that need to be diagnosed and managed by a medical provider including:

  • Encephalopathy – mental confusion, changes in sleep patterns, loss of memory, coma
  • Varices – stretched and bleeding blood vessels of the esophagus and stomach
  • Malnutrition – this happens when the liver isn’t able to process nutrients
  • Portal hypertension – the liver is so scarred that blood can’t get through it
  • Ascites – fluid retention in the abdominal region

Measuring Symptoms
A good way to measure the symptoms is by the 1 to 10 method with 10 being the worst. For example, if you could not get out of bed one day because you were so tired, rate that fatigue as a 10.  If you were tired so that you decided that you would just watch TV that night it might be a 4 or 5.  It might be a good idea to start a symptom log or journal.  A copy could be inserted into your medical chart.  Don’t be afraid to tell your doctor or nurse what symptoms you are having—most doctors and nurses welcome patient involvement in their medical care.

Remember everyone has the right to be treated and cured.

 

Get Tested. Get Treated. Get Cured.



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