AT THE INTERNATIONAL LIVER CONGRESS 2016
BARCELONA (FRONTLINE MEDICAL NEWS) – Using direct-acting antiviral therapy and livers from HCV-positive donors are separate approaches that could help reduce waiting lists and ensure that patients with HCV in most need get a liver transplant, according to data from two studies presented at the International Liver Congress.
In a retrospective European cohort study, 33% of HCV-positive patients with decompensated cirrhosis who were awaiting a transplant were no longer considered to be in urgent need and almost 20% could be removed from the list altogether 60 weeks after starting treatment with direct-acting antivirals (DAAs).
Dr. Luca Belli of Niguarda Hospital, Milan, who presented the findings at the meeting, cautioned that while the results were encouraging, it is not clear how long the clinical improvement will last. “It will be critical to assess the long-term risks of death, further redeterioration, and developments of hepatocellular carcinoma more specifically, as all these factors still need to be verified,” he said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).
Meanwhile, data from a large analysis of all solid transplant recipients in the United States showed that using livers from HCV-positive donors in HCV-positive recipients was associated with long-term patient outcomes similar to outcomes of using livers from non–HCV-negative donors in HCV-positive recipients, with no difference in mortality or graft survival.
“Over the past 2 decades, the use of HCV-positive organs for liver transplantation has tripled in the United States,” said Maria Stepanova, Ph.D., a senior biostatistician for Inova Health System in Falls Church, Va., who presented her findings at the meeting.
“Despite this, the medium- to long-term outcomes of HCV-positive liver transplant recipients transplanted from HCV-positive donors were not affected by HCV-positivity of a donor,” added Dr. Stepanova, who also works at the Center for Outcomes Research in Liver Disease in Washington, D.C.
Dr. Zobair Younossi, chairman of the department of medicine at Inova Fairfax (Va.) Hospital, and coauthor of the study, said during a press briefing that this does not mean that livers from HCV-positive donor could be used in HCV-negative recipients. The reason for that is that it would be causing an acute infection regardless of whether or not antiviral treatment is available and “at this point the evidence is not there,” he said.
Dr. Laurent Castera of Hôpital Beaujon in Paris, and Dr. Tom Hemming Karlsen of Oslo University Hospital Rikshospitalet in Norway commented on the significance of these data in press releases issued by the EASL. Both experts, who were not involved in the studies, noted the findings could help take the strain off the liver transplant list in the future.
“Treating patients with direct-acting antiviral therapy could result in those with a more pressing need for a liver transplant receiving the donation they need, potentially reducing the number of deaths that occur on the waiting list,” Dr. Castera said.
“With the number of people waiting for a liver transplant expected to rise, the study results should give hope over the coming years for those on the waiting list,” Dr. Karlsen said. Referring to the U.S. study, he said the results “clearly demonstrate a greater opportunity for use of HCV-positive livers over the coming years due to their comparable outcomes with healthy livers.”
The European study presented by Dr. Belli involved 134 patients with HCV and decompensated cirrhosis but without hepatocellular carcinoma listed for liver transplant between February 2014 and February 2015 at 11 centers in Austria, Italy, and France. Of these patients, 103 had been treated with DAAs while on the transplant list; approximately half had been treated with a single DAA (sofosbuvir plus ribavirin for 24-48 weeks) and half with two DAAs (sofosbuvir with either daclatasvir or ledipasvir for 12-24 weeks).
The primary endpoint was the probability of being “inactivated” and then “delisted.” Inactivated meant that there was clinical improvement resulting in patients being put “on hold,” and “delisted” was defined as patients being taken off the transplant list after a variable period of inactivation.
The median age of patients in the study was 54 years and 68% were male. Just under 50% of patients had a low (less than 16) MELD score, around 37% had a MELD score of 16-20, and 13% had a MELD score of more than 20. Around 45% had Child-Pugh B and 55% had Child-Pugh C cirrhosis. Two-thirds had medically controlled and 26% had medically uncontrolled ascites, and 46% had medically controlled and 1% had medically uncontrolled hepatic encephalopathy.
Good virologic efficacy was seen with both single- and dual-agent DAA therapy, with rapid virologic responses of 61% and 67% and early virologic responses of 98% and 98%. Of the 52 patients given single-agent DAA treatment, 22 had a transplant and one patient had a posttransplant relapse. Of the remaining 30 patients on the transplant list, four relapsed. Nineteen of 51 patients given dual-DAA therapy were transplanted and there was one relapse, with no relapses in the 32 patients who remained on the transplant list.
After about 60 weeks of follow-up, one in three patients were “inactivated” and not considered in urgent need of a transplant, but inactivation occurred as early as 12 weeks after DAA therapy, Dr. Belli observed.
Inactivation was associated with a 3.3 decrease in MELD score, a 2-point reduction in Child-Turcotte-Pugh score, and a 0.5-g/dL increase in serum albumin after 24 weeks. There was also regression or improvement in ascites and hepatic encephalopathy in most patients. The median time of delisting was 48 weeks.
These results suggest that there could be a wider role for DAA therapy even in the sickest of HCV-positive patients who are urgently awaiting a liver transplant. Another approach to increase the number of people receiving a transplant is to use HCV-positive livers. The practice has been increasing over the years, but it is not known if the approach is safe and if the risks outweigh the benefits.
To investigate, Dr. Stepanova and associates obtained data from the Scientific Registry of Transplant Recipients (SRTR) on all liver transplants performed in the United States between 1995 and 2003 involving HCV-positive patients. A total of 37,317 records were found, of which 33,668 had data on the donors’ HCV status and on the recipients’ mortality status. Of these, 1,930 (5.7%) had received a liver from an HCV-positive donor. Dr. Stepanova noted that there had been an increase in the percentage of patients who had received an HCV-positive liver, from less than 3% in 1995 to more than 9% in 2013.
Compared with HCV-negative donors, HCV-positive donors were older, were more likely to have a history of drug abuse, and more likely to be non–heart beating at the time of procurement.
The HCV-positive liver recipients also tended to be older, to be of African-American ethnicity, and to have liver cancer but lower MELD scores than those who received an HCV-negative liver. “So these are patients that cannot wait for a long time so maybe elect to use an HCV-positive donor,” Dr. Younossi said.
Adjusted hazard ratios (aHR) showed no statistically significant difference in posttransplant survival or posttransplant graft loss between HCV-positive and HCV-negative livers; aHR were a respective 1.03 and 0.905, with tight 95% confidence intervals. However, a more recent year of transplant did appear to suggest a possible advantage of using an HCV-positive donor liver in an HCV-positive patient, with lower mortality (aHR = 0.978 per year, P less than .0001) and graft failure (aHR = 0.960 per year, P less than .0001) rates.
While the use of HCV-positive livers in HCV-positive recipients was felt to be “reasonably safe,” these findings “cannot be used in support of indiscriminate use of HCV-positive donors,” Dr. Stepanova observed. Further studies are needed to establish criteria on which to select donors that would provide patients with the best possible risk-to-benefit ratio, she said.
Further avenues for research would also be to see if HCV-positive livers could be given to HCV-negative patients and if genotype matters. It would also need to be seen if posttransplantation antiviral treatment would be necessary.
Dr. Belli has received research support from Gilead, AbbVie and BMS and acted as a consultant to Gilead. Dr. Stepanova did not have conflicts of interest to disclose. Dr. Younossi has acted as a consultant to BMS, AbbVie, Gilead, GlaxoSmithKline, and Intercept. Dr. Castera and Dr. Karlsen had no conflicts of interest to disclose.
