Welcome to HCV Advocate’s hepatitis blog. The intent of this blog is to keep our website audience up-to-date on information about hepatitis and to answer some of our web site and training audience questions. People are encouraged to submit questions and post comments.

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Alan Franciscus
HCV Advocate

Friday, October 9, 2015

What the Heck are RAVs? —Alan Franciscus, Editor-in-Chief

RAVs are resistance associated variants.  RAVs occur during (viral breakthrough) and after treatment (relapse) with direct acting antiviral medications (inhibitors—protease, polymerase, NS5A).  In other words, someone is treated and not cured.
This can lead to a particular class of drugs (protease, polymerase, NS5A inhibitors) not working as well because a person has developed drug resistance.
In clinical trials of the direct acting antiviral medications, approximately 1% to 7% of the trial participants were not cured.  In real world settings it is likely higher because of many issues such as missed doses, LIFE, and various health and other issues not addressed in clinical trials.  
In this month’s Snapshots, I wrote about a couple of studies that addressed re-treatment.  To overcome the RAVs and other negative predictors of treatment response (previous treatment non-response, cirrhosis, etc.,) ribavirin was added to both re-treatment groups.  As a result, 75%-100% of the patients were cured.  There are drugs being developed that have a high barrier to resistance that will replace ribavirin.  Thankfully we have ribavirin now to help people in need of re-treatment and cure and, importantly, to prevent further hepatitis C disease progression.
The approach to retreatment of RAVs is rapidly evolving.  Some physicians are beginning to test for RAVs, but it is far from being a routine test.  Talk with your medical provider if you have questions.

If you are being re-treated with a direct acting antiviral medication, it is important to find an expert to consult with about the best HCV treatment regime for you.  

HealthWise - Hepatitis C Treatment Is Finished, so Now What? - Lucinda K. Porter, RN

Hepatitis C Treatment Is Finished, so Now What? 
A post-hepatitis C treatment discussion, including how long it takes medications to leave the body.

Dear Lucinda,
I just finished hepatitis C treatment with ribavirin. Now that I have taken the last pill, I’d like to detox and speed the clearing of these drugs from my body. My body feels so toxic; I just want to flush this poison out as quickly as possible. I am wondering if it is better to let the ribavirin linger around for as long as possible post-treatment. On the other hand, if it hasn’t done the job by now, will leaving it in my system longer make any difference? Are there supplements I can take to hasten the detox and build up my immune system?
—A Reader

I loved this question, and pondered it awhile, particularly since I was on ribavirin twice (once for a year). Here’s my reply:

Dear Reader,
It is unlikely that you can flush ribavirin out of your system any faster than it will leave on its own, since the metabolic pathway is complex. I provided a list of drug elimination times at the end of this article, so you can estimate how long it will take the medications to leave your body.

As for using supplements to help with this, the short answer is, no one knows for sure since there isn’t any research on this. I rarely use supplements because the potential burden these place on the liver and kidneys don’t seem worth it, especially since food provides better sources of vitamins and minerals. My thinking was that after finally getting off all the hep C drugs, I didn’t want to add any more burden to my liver. It is like cleaning out a storage shed and then buying more stuff and filling it back up.  Plus, if I failed treatment, I didn’t want to always wonder if it was from the supplements. I did make an exception with vitamins, especially B-12. I was quite anemic and research supports the use of B-12 and ribavirin and favorable treatment outcomes.

Despite this, I was not content to sit back, so I focused on rebuilding health. There is much more to recovering from treatment (especially if ribavirin and/or peginterferon is used), than waiting for the medications to leave the body. If there was a reduction in physical activity, then it may be necessary to become active again.  

Because you took ribavirin, I am guessing that you lost a few red blood cells (RBCs) during treatment. It will take time for ribavirin to be eliminated and for RBC production to be completely restored. It typically takes about four weeks before the body notices the change, with significant improvements in two to three months. The time varies, especially since some people are genetically inclined towards ribavirin-induced hemolytic anemia.

After completing hepatitis C treatment, my health-rebuilding plan included keeping track of water intake, eating well, sleeping a lot, not jumping back into a high stress life, increasing my activity (walking, aerobics class, etc), and building back my muscle strength. I started slowly, but chipped away at it, and was surprised at how quickly I noticed improvement.

I have one more comment. I understand that hepatitis C treatment feels toxic, and saying you want “to flush this poison” out makes sense. I went through the same thing. However, it occurred to me that as long as I called it poison rather than medicine, I would be engaged in an emotional battle wtih the drug. Everything changed the day I started calling it medicine and welcomed it in to my body. Perhaps it is too late for you to do this with this particular drug regimen, but in the future should you need to take medication, try calling it medicine rather than poison. Welcome it in, let it do its precious work, and then thank it as the medicine leaves your body. This small shift in thinking lightened my load.

Hepatitis C Medication Elimination Times

Have you ever wondered why women can’t get pregnant for six months after treatment that uses ribavirin? It’s because ribavirin can harm a fetus, and it takes a long time for ribavirin to be eliminated from the body. To determine how quickly a drug will be eliminated, you need to know its half-life. The half-life is how long it takes the body to get rid of half of the dose of a particular drug. If you stopped taking the drug, then it will keep eliminating half until there is nothing left.

Each drug has its own half-life, and the amount of time it takes varies, depending on your age, the efficiency of your kidneys and liver, what other medications or supplements you take, and so on. The general rule of thumb is to multiply the drug’s half-life by 5.5 for a rough estimate of how long it takes to leave the body. Let’s do the math.

Start by finding the drug’s half-life. The median terminal half-life is listed in the manufacturer’s prescribing information in the clinical pharmacology section under the subcategory elimination. You can also find this info on the Web, or use what I’ve provided.

Note that some drugs have metabolites, which is another form of the drug created by the body while it processes the drug. For instance, Sovaldi’s half-life is 0.4 hrs, but its metabolite (GS-331007) is 27 hrs. Sometimes the information will be provided in a range. For instance, the mean plasma elimination half-life of Xanax (alprazolam) is 11.2 hours, but the range is from 6.3 to 26.9 hours in healthy adults.

After you know the half-life, then multiply by 5.5. Here’s the math using ribavirin which has a half-life of 120 to 170 hrs:

  • Best case: 5.5 x 120 hrs = 660 hrs or 27.5 days
  • Worst case: 5.5 x 170 hrs = 935 hrs or around 39 days 

Here are the elimination times for all the major hepatitis C drugs:

  • Daklinza (daclatasvir): half-life 12 to 15 hrs = worst case 82.5 hrs or roughly 3 days
  • Harvoni (ledipasvir/sofosbuvir): Ledipasvir has the longer half-life in this combination at 47 hrs = 258.5 hrs or almost 11 days
  • Olysio (simeprevir): half-life 10 to 13 hrs in those without HCV;41 hrs in those with HCV = worst case 71.5 hrs or 3 days in those without HCV; 225.5 hrs or roughly 9 days for those with HCV
  • Peginterferon alfa 2a (Pegasys): half-life 84 to 353 hrs (average 160 hrs) = worst case 1941.5 hrs or nearly 81 days
  • Peginterferon alfa 2b (PegIntron): half-life 22 to 60 hrs (average 40 hrs) = worst case 330 hrs or nearly 14 days
  • Ribavirin: half-life 120 hrs to 170 hrs = worst case 935 hrs or roughly 39 days 
  • Sovaldi (sofosbuvir): half life 0.4 hrs/GS-331007 half-life 27 hrs = 2.2 hrs for Sovaldi/ 148.5 hrs or roughly 6 days for GS-331007
  • Technivie (ombitasvir, paritaprevir, ritonavir): Ombitasvir has the longest half-life in this combination at 21 to 25 hrs = 115.5 to 137.5 hrs or around 5 to 6 days
  • Viekira Pak (ombitasvir, paritaprevir, ritonavir and dasabuvir): Ombitasvir has the longest half-life in this combination at 21 to 25 hrs = 115.5 to 137.5 hrs or around 5 to 6 days

Knowing the half-life for a drug or supplement can be a valuable tool. For instance, state and private insurance plans are screening for recreational drugs, such as marijuana. If you are trying to get treatment and you indulge in certain substances, it will help you to know the half-life so you can predict if you will be able to pass the tox screen. I’ll leave you with this: if you thought it took a long time for ribavirin to leave your system, wait until you read about the half-life of cannabis.

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

“The half-life is how long it takes the body to get rid of half of the dose of a particular drug. If you stopped taking the drug, then it will keep eliminating half until there is nothing left.”  

Thursday, October 8, 2015

Understanding HCV disease progression rates among PWID

The Hepatitis C virus (HCV) infection is a chronic blood-borne viral infection that affects an estimated 160 million people, or 2-3% of the population world-wide. Alarmingly, chronic HCV infection accounts for one-quarter of the cases of cirrhosis and hepatocellular carcinoma (HCC). If HCV is left untreated, chronic liver disease will occur in 60-70% of the cases, cirrhosis in 5-20% of the cases, and 1-5% will die from decompensated cirrhosis or HCC.

In most high-income countries, such as the United States, where drug injection is the primary route of HCV transmission, the disease is concentrated among people who inject drugs (PWID). While it is estimated that 50-80% of PWID are chronically infected, fewer than 5% of PWID have received treatment.

In a new study, "Hepatitis C virus (HCV) disease progression in people who inject drugs (PWID): A systematic review and meta-analysis," published in the International Journal of Drug Policy, a team of researchers from New York University's Center for Drug Use and HIV Research (CDUHR) assessed existing data on the natural history of HCV among PWID. A total of twenty-one studies examined over 8500 PWID, who contributed nearly 120,000 person-years at risk, for the study of four major HCV-related outcomes included in the synthesis.

Read more....

Surge in Youth HCV Presents Hepatologists With Tough Choices

Recently Mark S. Sulkowski, MD, of the John Hopkins University School of Medicine, in Baltimore, saw a teenage patient who had contracted hepatitis C after starting to shoot up as a 12-year-old.

The case is but one in a spike of new infections with the hepatitis C virus (HCV) being driven largely by an epidemic of injection drug use, particularly among adolescents and young adults, according to the Centers for Disease Control and Prevention.

“Sadly, with the heroin epidemic, I’m increasingly seeing teenagers in my practice,” Dr. Sulkowski said earlier this year at the inaugural midyear meeting of the American Association for the Study of Liver Diseases.

See more at: 

Wednesday, October 7, 2015

HCV Drugs - Alan Franciscus

Vol. 18, Issue 10

—Alan Franciscus, Editor-in-Chief

In this month’s column, I will discuss the recently released data from Achillion, and I will touch on various issues related to current treatment—drug-drug interactions, medical providers and insurance companies, and those who are still the most difficult to treat.
On September 17, 2015, Achillion announced the second part of their Phase 2 study (the PROXY study) of odalasvir (ACH-3102) and sofosbuvir to treat genotype 1.  The cure rates were 100% (6 of 6 patients). Earlier, Achillion had announced a 100% cure rate for 12 patients treated for eight weeks, and a 100% cure rate for 12 patients treated for six weeks.  Although there was a small number of patients in the PROXY study, this is encouraging data.
The study used Gilead’s drug—sofosbuvir—as the proxy drug.  A proxy drug is used as a placeholder while another drug is being developed and tested by a pharmaceutical company—in this case Achillion.  Also noteworthy, Achillion and Janssen are collaborating to develop and commercialize HCV drugs worldwide.  Janssen has many drugs in development to treat hepatitis C.  As well, Gilead, AbbVie, and Merck have drugs in the pipeline.  Merck’s new combination of two drugs is expected to be approved by the Food and Drug Administration (FDA) in early 2017.  

Medical Providers
Patients are not the only ones who are having a difficult time with the insurance restrictions.  Medical providers who have to tell their patients are also upset.  Many providers have to spend a lot of time submitting paperwork over and over trying to get their patients’ medications approved.  It takes up an inordinate amount of the medical provider and office staff’s time—many times only to be told that the insurance claim was denied.  As you can imagine it breaks their hearts to tell a patient “there is a cure, but I cannot give you it because insurance will not cover it.”  

There are other issues that are difficult for patients, medical and service providers.  Access to the new medications can be very difficult depending on your insurance carrier.  Many people are being denied access to these life-saving HCV medications unless they have more serious disease progression.  Shame on the insurance companies that are not covering HCV medications!  It doesn’t help that the price of the drugs are so expensive.

The Current State of HCV Therapy
We have certainly come a long way compared to the interferon days.  Additionally, many populations—HIV/HCV coinfection, Latinos, compensated cirrhosis, healthy liver-transplanted—and other groups had very low cure rates.

The current state of HCV treatment is nothing short of amazing.  Current therapy cures up to 90% to 100% of people with HCV genotype 1, 2, and 4.  The medications also have lower side effects and shorter treatment duration.

The improvements in cure rates are impressive especially in certain populations with hepatitis C. In the September 2015 “Mid-Month Edition” of the HCV Advocate newsletter I wrote about 3 different clinical trials using 3 different combinations of direct-acting antivirals to treat HCV in people coinfected with HIV.  The patient populations in these studies included many of the patient characteristics previously considered the most difficult to treat—people with HIV, genotype 1a, cirrhosis, Black patients, previously treated patients—all who had not achieved a cure.  The cure rate in the three trials ranged from 96% to 98%.  Another population that has had dramatic improvements is liver transplanted patients (with moderate liver function and compensated cirrhosis).  The cure rates were 96% - 98%.  
Drug-Drug Interactions
A very important issue with the new direct antiviral medications is the potential for drug-drug interactions (DDIs). This is more of an issue for people of the Baby Boomer generation who may take additional medications for blood pressure, diabetes, cholesterol, etc.  People who are infected with HIV/HCV are also at risk for DDIs.  There is also a risk of DDIs with common over-the-counter medications and herbs. This is why it is so important to tell your medical provider(s) about anything you are taking.

Still Difficult to Treat2
A caveat:  Even though we need better therapies and strategies to treat the most difficult to treat patients listed here, the DAA therapies are still vast improvements from the older therapies in the people and groups below.

People with genotype 3 with cirrhosis and who have not been cured with a previous course of treatment are an unmet medical need.  Current treatments only yield cure rates in the 60 percentile. There is an option of adding pegylated interferon. I wrote about this before and advised people to think about this but I did not get a very positive reaction.

People with decompensated cirrhosis are at risk for severe disease progression, but unfortunately, current treatment does not work as well. Similarly, people with end-stage kidney disease or people who are on dialysis also have a large unmet medical need.  Note:  Merck’s new combination looks very promising for this group of patients.  People who do not respond to a previous course of therapy are another difficult group to treat, but treatment strategies are slowly evolving.

For someone who has relapsed, coming up with a plan to prescribe the right combination of drugs to optimize the chances of re-treatment success is more difficult with the development of RAVs (see a brief overview of RAVs in this issue).

There have been many advances in hepatitis C treatment in a short period of time. Hopefully, many of the treatment issues listed above will be quickly resolved.  In the meantime, we all have to advocate for ourselves and others with hepatitis C and remember to thank those medical providers who are providing such wonderful care.

1 Company Press Release
2 Difficult-to-cure populations with chronic hepatitis c: Vanishing in the direct-acting antiviral era?
Norah Terrault M.D. Hepatology Volume 62, Issue 1, pages 4–7, July 2015

Treating 5 Percent of Hepatitis C Patients with New Drugs Would Reduce Cost, Infections: Study

Treating 5 percent of all hepatitis C patients with the latest drugs would be more effective at reducing infections and health care costs than the current approach, a new study shows.
The cost-benefits analysis by researchers from the USC Schaeffer Center for Health Policy and Economics and other institutions compares three treatment options to the current approach, or "baseline" scenario, which treats patients in the most advanced stages of the disease when they may need a costly liver transplant.
"We made a mistake with HIV by limiting access to treatment to just people who had AIDS, and we ended up with a virus that has been with us for decades," said corresponding author Dana Goldman, the Schaeffer Center director and a professor at the USC School of Pharmacy and the USC Price School of Public Policy. "We didn't initially treat HIV aggressively enough in part because the science wasn't there to justify it. With hepatitis C, we have the science. We just need to find a way to finance it."

Nurse used same syringe on 67 people at N.J. flu clinic, state says

A nurse who administered flu vaccines to employees of a West Windsor company has been reported to health officials because she re-used a single syringe for the shots.
At an employer-sponsored flu clinic at Otsuka Pharmaceuticals last week, the unnamed nurse committed an "infection control breach," according to a spokeswoman for the N.J. Department of Health.
"Full infection control practices that prevent transmission of blood-borne diseases were not used by a contracted health care agency, Total Wellness," said Donna Leusner, the spokeswoman.