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.

Study’s Findings Could Help Expand the Donor Pool for Liver Transplantation

Organ donation after circulatory death (DCD), in which transplant organs are taken from donors after ay period of no blood circulation or oxygenation, is often considered inferior to donation after brain death, in which circulation and oxygenation are maintained until organs are removed for transplantation. Currently, the use of livers from DCD donors remains controversial, particularly with donors with advanced age.

A new study of DCD liver transplantations conducted at the Cleveland Clinic from 2005 to 2014 found no significant correlation between donor age and organ survival, however. The results suggest that stringent donor and recipient selection may ameliorate the negative impact of donor age in DCD liver transplantation.

“Aged DCD organs are generally underutilized by many transplant surgeons because of the higher risk of transplant organ failure; however, by eliminating other risk factors, aged DCD organs can greatly help expand the donor pool for life-saving liver transplantation,” said Dr. Koji Hashimoto, co-author of the Liver Transplantation study.

Source:  http://ca.wiley.com/WileyCDA/PressRelease/pressReleaseId-120486.html

Liver transplants in HIV/HCV co-infection: study underlines importance of hepatitis C treatment

People with HIV and hepatitis C co-infection were significantly more likely to experience organ rejection than people with hepatitis C alone or HIV alone after undergoing a liver transplant, according to a review of 11 years' experience of liver transplantation in people with HIV and with hepatitis C virus (HCV) in the United States, published in advance online in the journal Clinical Infectious Diseases.

The study investigators say that their findings underline the importance of treating hepatitis C either before or immediately after liver transplantation in order to improve outcomes, rather than assuming that people with co-infection will have poorer outcomes based on historical data.

Liver transplantation remains a relatively rare procedure among people living with HIV, due in part to concerns about poorer survival and higher rates of organ rejection in people with HIV. Although a study carried out by the United States National Institutes of Health (NIH) showed a somewhat lower rate of survival three years after transplantation and a higher rate of organ rejection in people with HIV and hepatitis C co-infection compared to people with hepatitis C alone (mono-infection), the majority of transplants in each group was successful. The success of transplantation in people with HIV who are not do not have hepatitis C co-infection has been unclear. Furthermore, data are lacking outside the clinical trial setting regarding the outcomes of transplants in people with co-infection, particularly at transplant centres which did not take part in the NIH trial.

Reference

Sawinski D et al. Beyond the NIH Multicenter HIV Transplant Trial experience: outcomes of HIV+ liver transplant recipients compared to HCV+ or HIV+/HCV+ co-infected recipients in the United States. Clin Infect Dis, advance online publication, 16 June 2015.

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Potential Liver Recipients May Have New Option

Organs harvested after cardiac death appear safe, effective, study says

FRIDAY, June 5, 2015 (HealthDay News) -- Livers from donors who suffered cardiac death can be safely and effectively transplanted into patients dying of liver cancer, a new study suggests.

A liver transplant can cure many liver cancer patients, but many die waiting for a liver because most transplant centers use only livers from brain-dead donors. This study tested livers from both brain-dead donors and donors after cardiac death.

Cardiac death does not mean death from heart attack. Because of damaging oxygen loss, someone who dies from a heart attack is not considered a viable donor of organs for transplantation, the researchers said. Instead, cardiac death is controlled in a patient who will donate organs, they explained.

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HealthWise: Hepatitis C: Giving a Liver, Getting a Liver Lucinda K. Porter, RN

Years of living with chronic hepatitis C virus infection (HCV) destroyed my friend Rick’s liver. Last year, a liver transplant saved his life. A motor vehicle accident killed a 19-year-old man, and now Rick is healthy. Not a day passes, that Rick doesn’t say thank you for the life of the man whose liver restored Rick’s health.

The same year Rick received his liver, I lost three friends who would have lived had hepatitis C been diagnosed earlier and they could have had a chance at liver transplantation. Rick was incredibly fortunate to have received a liver, because there is a major organ shortage in the U.S. According to the American Liver Foundation, approximately 17,000 people are on the liver transplant list. Of these, 6000 people were transplanted; 1500 to 1700 people died before they could receive a liver.

Chronic liver failure caused by complications from HCV is the most common reason for adult liver transplantation in the United States. Cirrhosis caused by long-term alcohol abuse is the second leading cause. The majority of people living with HCV will never progress to the point where transplantation will be necessary. Liver transplantation is a complicated surgery, requiring lifelong follow-up care. Liver transplant patients have an approximately 86% one-year and 78% three-year survival rate.

Most liver transplants use deceased donors. However, the liver’s remarkable ability to regenerate allows us to use partial livers from living donors. A living donor doesn’t have to be a blood relative, but must have a compatible blood type. About 40% to 60% of the donor’s liver is removed. Within eight weeks, the livers of both the donor and the recipient are usually completely regenerated. The average donor recovers in about two months; recipients recover in roughly six to 12 months.

Although living liver transplantation sounds like the perfect way to address the organ shortage, it isn’t.  The potential risk to the donor is so high that live liver donations are done only when the potential risk to the donor is small and the potential benefit to the recipient is unquestionable. It is difficult to find current data on live liver transplantation, but it appears that there are 250 to 400 liver donor transplants a year. One in 300 donors die and about 30% suffer a complication. Many living donors who die are relatives of the recipients. One can only imagine how difficult it might be to live with the knowledge that you are alive, but your otherwise healthy donor is not. 

Although increasing the donor organ pool is important, a better plan is to reduce the organ demand. Screening, linkage to care, and treating hepatitis C patients will reduce the number of liver transplant procedures needed. When I began working in this field, hepatitis C patients who were transplanted would still have HCV. This meant the transplanted liver was reinfected, and in some cases, it too would progress to cirrhosis. Now we can cure hepatitis C, which greatly cuts down on the stress to the transplanted organ and diverts the need for a second transplant.

Other strategies that will reduce the demand for livers are:

• Immunizing all children against hepatitis B
• Implementing awareness programs to reduce liver-injury risk, such as from alcohol, drug, and dietary supplement use
• Raise awareness of the impact of diet on the liver. Fatty liver disease is on the rise in the U.S., which in turn causes a decrease in the number of viable livers.
• Increase the organ donor pool. For instance, countries that use an “opt-out” strategy have much higher donor rates. “Opt-out” means that everyone is a potential donor unless otherwise indicated. For instance, Germany uses an opt-in system and 12% of its population consents to donate. Neighboring Austria uses an opt-out system, and has a consent rate of nearly 100%. The U.S. uses an “opt-in” strategy.

In some cases, patients whose hepatitis C is cured, may be potential organ donors. This situation is considered if the organ is in good shape, and the recipient would otherwise die. The recipient is given the option to decline the HCV antibody-positive organ. Compared to HCV antibody-negative organs, the long-term survival rate in patients who received an HCV antibody-positive/viral load-negative organ are similar. So, if you are cured of HCV, celebrate by filling out your organ donor card. Ask family and friends to fill theirs out too.

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

Additional Resources

• Donate Life America
  http://donatelife.net
• National Living
  Donor Assistance
  www.livingdonorassistance.org
• OrganDonor.gov
  www.organdonor.gov
• Organ Procurement and Transplant Network
  http://optn.transplant.hrsa.gov
• Transplant Living
  www.transplantliving.org
• United Network for Organ Sharing
  www.unos.org

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A New Liver and the Right Care Make a Rutgers Patient Feel Young Again

The liver transplant center at Rutgers New Jersey Medical School is one of just two such units in the state

 
Mati Muñoz is 65 years old – filled with the enthusiastic energy that comes with a second chance at life. A decade ago, says Muñoz, who lives in Woodbridge Township, N.J., her liver was being destroyed by hepatitis C, a viral disease she believes she contracted as a girl in her native Cuba from a poorly sterilized needle used in a medical procedure.

“My coworkers said I looked like a ghost,” Muñoz recalls. Her symptoms included insomnia, depression, bloating, nausea – and an especially nasty decline in mental function caused by blood toxins that were degrading her brain.

Muñoz went on a registry to receive a liver transplant and over the next two years her symptoms intensified as she waited for a suitable donor.

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Low Sodium Levels Increases Liver Transplant Survival Benefit in the Sickest Patients

Researchers report that low levels of sodium in the blood, known as hyponatremia, increase the risk of dying for patients on the liver transplant waiting list. The study published in Liver Transplantation, a journal of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, showed an increase in survival benefit for patients with hyponatremia and a Model for End Stage Liver Disease (MELD) score of 12 or more.

The MELD score measures the risk of death on waiting list. It is calculated using patient’s serum bilirubin, creatinine, and prothrombin time and is used by national organ allocation policy to determine the priority for a patient on the transplant waitlist. Patients who are most sick, with a high MELD score, are at the top of the waitlist. Previous research links low serum sodium, in combination with the MELD score, to increased waitlist mortality, prompting Organ and Procurement Transplant Network (OPTN) directors to approve a new policy that gives additional MELD score points (1 to 13 based on serum sodium value) to patients with hyponatremia.

Dr. Pratima Sharma, with University of Michigan Health System in Ann Arbor and lead study author notes, “While the OPTN serum sodium allocation formula may reduce deaths on the waitlist by enhancing access to donor organs, it is not clear if candidates with hyponatremia gain any survival benefit over patients with normal sodium levels. Our study examines if patients with low serum sodium prior to liver transplant have a greater survival benefit than patients without low serum sodium, all other things being equal.”

Using data from the Scientific Registry of Transplant Recipients, researchers identified 69,213 candidates, 18 years of age or older, who were on the waiting list for liver transplant between January 2005 and December 2012. Liver transplant recipients were matched to waitlist candidates with the same MELD score and located in the same donation service area.

Findings indicate that the liver transplant survival benefit increased significantly with decreased serum sodium levels when MELD scores were 12 or more. The survival benefit was not affected by low sodium values for candidates with MELD of 11 or less. Dr. Sharma concludes, “Our results suggest that adjustment based on serum sodium for the purpose of the liver allocation process should be considered for those candidates with low sodium levels and a MELD score of at least 12. Health care providers should also alert liver transplant patients on the waiting list that low sodium levels could increase their mortality risk on the waitlist and may affect the expected survival benefit following liver transplantation."

This research was supported by the National Institutes of Health (NIH, grants DK-088946 and 5R01 DK-70869) along with a research award from the American College of Gastroenterology. 

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Access the full study on the Wiley Press Room here. (To access PDFs and embargoed stories you must be logged in to the Press Room before clicking the link. Request a login here.) Full citation: “Serum Sodium and the Survival Benefit of Liver Transplantation.” Pratima Sharma, Douglas E Schaubel, Nathan P Goodrich and Robert M Merion. Liver Transplantation; (DOI: 10.1002/lt.24063).

URL: http://doi.wiley.com/10.1022/lt.24063
Author Contact: Media wishing to speak with Dr. Sharma may contact Mary F. Masson at University of Michgan at mfmasson@med.umich.edu.

India: Docs get training in liver transplant in Delhi

JAIPUR: There is a ray of hope for the patients who need liver transplant. A team of 14 doctors and 15 nurses from SMS Medical College has returned from Delhi after being trained in liver transplant operation at a private hospital.

According to sources, till now there is no facility for liver transplant in the state. The patients have to go to other states like Delhi and Tamil Nadu for such operations. The Sawai Man Singh Hospital is taking it on a priority basis to introduce the facility as soon as possible in the hospital.

Dr Ashok Jhajharia, who was one of the members of team, said, "It was fruitful 15-day training of liver transplant in Delhi. It will help in introducing the facility of liver transplant in the state."

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