Can Non-Invasive Tests Assess Fibrosis in Hepatitis?

 Percutaneous liver biopsy is a proven way to rate the fibrosis stage both in hepatitis in chronic hepatitis C patients and hepatitis B  patients. But it is uncomfortable for patients, risks complications and is prone to assembling errors.

Reporting at ID Week 2015 in San Diego, CA, Tuma Demirdal, DR, and colleagues at the Katip Celebi University in Izmir, Turkey compared these invasive tests with non-invasive methods.

They looked at 236 patients with chronic hepatitits C and hepatitis B who had ultrasound guided liver biopsy over a seven year period Histological grading of necroinflammation and fibrosis ere performed according to Knodell an ISAK scoring systems. APRI, n-APRI, FIB-4, FI scores were calculated.

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SNAPSHOTS —Alan Franciscus, Editor-in-Chief

This month’s (October 2015) column features a variety of studies, including treatment of people with advanced liver disease, treating people who have not achieved a cure with direct acting antiviral therapy, including people who had developed RAVs.

Article:  Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease—M Charlton et al. 

Source:  Gastroenterology. 2015 Sep;149(3):649-59. doi: 10.1053/j.gastro.2015.05.010. Epub 2015 May 15.

Results and Conclusions

This was a phase 2 study of 337 patients with decompensated cirrhosis with genotype 1 (332 patients) and genotype 4 (5 patients) who received 12 or 24 weeks of Harvoni plus ribavirin twice daily.  None of the patients previously treated developed resistance to sofosbuvir.  People who had been previously treated with an NS5A inhibitor were excluded from the study. 

There were two groups in the study:

•  Group A, who had NOT had a liver transplant: 59 patients with Child-Pugh class B cirrhosis and 49 patients with Child-Pugh class C  cirrhosis*
•  Group B who HAD undergone liver transplantation:  111 patients without cirrhosis, 51 patients with Child-Pugh class A cirrhosis, 52 with Child-Pugh class B cirrhosis, 9 with Child-Pugh class C cirrhosis, and 6 with fibrosing cholestatic hepatitis*

 *Child-Pugh cirrhosis scoring is a system that uses various types of blood markers and liver disease progression such as ascites to evaluate a patient to establish the severity of cirrhosis and long-term patient survival.  The classes are A, B and C with A as the less severe and C as the most severe.  Cholestatic hepatitis is bile duct blockage with fibrosis.

Group A and B had 12- and 24-week treatment arms, but cure rates were similar regardless of treatment duration.

     

 The Bottom Line

In group A (those who had not received a liver transplant), the cure rate was 86% to 89%.  In group B (transplant group) the people who did not have cirrhosis or Class A cirrhosis—the cure rate was 96% to 98%.  Furthermore, in group B with class B cirrhosis (compensated) the cure rate was 85% to 88%, and those with class C cirrhosis (moderate impairment) achieved 60% to 75% cure rates. The people who had fibrosing cholestatic hepatitis achieved 100% cure rates.  There were 13 patients (4%) who discontinued treatment.  Ten patients died in the trial.  The deaths were mainly attributed to complications from hepatic decompensation or end-stage liver disease.

Editorial Comment

In the past, people with these types of severe disease progression have been very difficult to cure or even treat, but now with these ‘miracle’ drugs many people now have a second chance at life.  Now if we could just get these drugs to everyone with hepatitis C before this stage, we would eliminate the need to treat at these stages of disease severity. 

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Article:  Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent—X Forns et al.

Source:  J Hepatol. 2015 Sep;63(3):564-72. doi: 10.1016/j.jhep.2015.04.009. Epub 2015 Apr 18.

Results and Conclusions

There were 79 HCV genotype 1 patients in the study. 

• Sixty-six patients who had been previously treated patients with an NS3/4A protease inhibitor but had not been cured. 
• Of the 13 remaining patients, 12 had discontinued treatment due to side-effect(s). 
• Thirty-four patients had NS3 resistance-associated variants (RAVs), and eight patients had NS5A RAVs. 
• Eight patients treated with the combination of grazoprevir and elbasvir plus ribavirin twice daily.

 The Bottom Line

The overall cure rates were 96% (76 of 79 patients)—this included 93% (63 of 66 patients) of the genotype 1a, one hundred percent of the patients (43 of 43 patients) who DID NOT have RAVs achieved a cure.  Ninety-one percent of those who DID have NS3 RAV’s were cured and 75% (6 of 8 patients) of those who had NS5A RAVs were cured.  Of those with cirrhosis 94% were cured with this combination. 

Editorial Comment

The addition of ribavirin to grazoprevir and elbasvir works to help cure resistance-associated variants in people who have been previously treated but who have not been cured.  It is also good strategy to treat other negative predictors to current  medications.

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Article:  Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens—D Wyles et al.  

Source:  Hepatology. 2015 Jun;61(6):1793-7. doi: 10.1002/hep.27814. Epub 2015 Apr 27.

Results and Conclusions

There were 51 genotype 1 patients enrolled in the study (Note: one patient was incorrectly typed as genotype 1, but was subsequently correctly genotyped as genotype 3).  All of the patients in this trial were previously treated with a sofosbuvir containing regimes in Gilead’s phase 1 or phase 2 studies.  The treatment duration in this study was 12 weeks. 

Breaking it down by type of prior type of non-response:

• 25 pts (49%) had previously received sofosbuvir plus pegylated interferon plus ribavirin
• 20 pts (39%) had previously received sofosbuvir plus ribavirin
• 5 pts (10%) received sofosbuvir (sugar pill/placebo) plus pegylated interferon and ribavirin
• 1 pt (2%) received GS-0938 only fourteen patients (27%) had compensated cirrhosis.

 The Bottom Line

The total number of patients who achieved a cure was 98% (50 of 51 patients).  Among those who had received a prior course of sofosbuvir 98% (44 of 45) were cured.  The only patient who did not achieve a cure was the patient who was originally misdiagnosed as a genotype 1. 

The most common side effects were fatigue, headache and diarrhea.  The patients in this trial are considered some the most difficult to treat—those who have not achieved a cure with a previous course of a direct acting antiviral medication, those with cirrhosis, and people with resistant antiviral variants (RAVs). 

Editorial Comment

The addition of ledipasvir and ribavirin to sofosbuvir increased the cure rates to 100% for genotype 1.  Excellent results!  This is a good strategy with another type of direct acting antiviral to stop the virus from replicating and escaping.

Gilead, Merck, AbbVie, Janssen, and Achillion are working on other HCV drugs that have a higher barrier to resistance to avoid the development of resistance and to work for people who are not responding to the current medications.

RIVERSIDE COUNTY: Woman on a mission to get clean needles to drug users

Motivated by friends' deaths, she is setting up a nonprofit group and lobbying local officials -- with some offering resistance and some expressing support.

Growing up, Katie Chamberlain walked the straight and narrow as a “dorky straight-A student.”

The Riverside resident attended a Christian school until ninth grade. The stark reality of drugs hit home the second week of classes, when a classmate died of a heroin overdose.

Over the years, the 27-year-old watched with sadness and despair as too many friends fell victim to illegal narcotics.

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Drug costs a bitter pill

TALLAHASSEE

An estimated 17 percent of America’s prison population could have hepatitis C, a severe viral disease that can lead to cirrhosis, liver failure and cancer if left untreated.

There is a cure. A miracle drug with a 95 percent recovery rate was introduced in 2013. But Sovaldi has an extremely high cost: $84,000 for a standard treatment, although costs can vary with the length of the treatment.

Late last year, Gilead Sciences, which makes Sovaldi, won approval for an even better hepatitis C drug, which doesn’t have to be taken in combination with other drugs that have major side effects. But Harvoni costs about $1,125 per pill, with a standard 12-week treatment priced at $94,500

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Tainted-blood-transfusion-Hepatitis-C - DESPERATE to start a family, Janice Cox and her husband tried for a baby for five long years.

But their dreams were shattered when, earlier this year, fertility investigations revealed that Janice had hepatitis C. She contracted the deadly disease against the odds from her mother who became infected after receiving contaminated blood during a kidney transplant in 1973.

There is just a six in 100 chance of the disease passing from mother to child in the womb. Now Janice fears she is among a new generation of victims, many of whom may not even know they are infected.

Self-employed Janice, 36, who lives in Bedfordshire, said: “I am absolutely horrified that so little has been done to stop the spread of this devastating illness.

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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.
—Lucinda

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

QUOTE:
“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.”