The number of hepatitis C virus (HCV)-related referrals for liver transplant
has declined significantly since the introduction of HCV direct-acting
antivirals (DAAs), according to two US studies presented to the recent 2015 AASLD Liver Meeting
in San Francisco. The approval of the second generation of DAAs was accompanied
by a 23% reduction on the proportion of liver transplant referrals that were
There was a significant 33% reduction in the proportion of referrals related
to HCV that had not yet progressed to non-hepatocellular carcinoma (HCC). The
investigators suggest their findings are early evidence of the clinical impact
However a study of the impact of DAA treatment on liver transplant waiting
list numbers in France found that despite improvements in liver function as a
result of treatment, and a high cure rate, only 16% of candidates with
decompensated cirrhosis due to hepatitis C were taken off the list as a result
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
An accumulation of fluid in the abdomen; may be caused by liver damage, especially cirrhosis.
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
A disease or infection affecting the brain.
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
HCV is the leading cause of referral for liver transplantation in the US;
approximately 45% of people who receive liver transplants in the United States
have hepatitis C. Liver transplantation may be recommended for people with
end-stage liver disease – decompensated cirrhosis – and for people with liver
cancer where the cancer has not spread beyond the liver and tumours are still
Some studies have shown improvements in liver function and clinical symptoms
of liver disease in people with cirrhosis after a sustained virologic response
to treatment of hepatitis C with direct-acting antivirals. Whether this benefit
extends to people in need of liver transplant, and whether treatment can allow
the liver to heal sufficiently for a person to come off the liver transplant
waiting list is unclear.
US investigators designed a retrospective study analysing trends in
referrals for HCV-related liver transplant in the period before (August
2012 to October 2013) and after (January 2014 to March 2015) the approval of simeprevir
and sofosbuvir. Data were obtained from the United Network of Organ Sharing in
Referral trends were also compared between HCV patients with and without
The proportion of all referrals related to HCV declined from 35% in August
2012 to 27% in March 2015, a 23% decline.
In addition, the proportion of referrals involving HCV patients without HCC
fell from 23% in August 2012 to 15% in March 2015, a 33% decline. There was a
significant drop in the number of HCV non-HCC patients referred for transplant
between August 2012 and October 2013 (mean, 188 per month) and January 2014 and March
2015 (mean, 153 per month)(mean difference, 35; p < 0.0001).
Overall, the proportion of HCV non-HCC patients referred for transplant declined by
13% (August 2012 = 66% vs. March 2015 = 58%).
The investigators acknowledge that their study is limited by its
retrospective design. Nevertheless, they conclude there was a significant
decline in new referrals for HCV-related liver transplant after second
generation HCV DAAs became available.
A second analysis, using outcomes from five studies which reported on
post-treatment changes in liver function in people with decompensated cirrhosis
on the transplant waiting list, showed the potential impact of direct-acting
antiviral treatment on liver transplant availability in the United States.
The five studies evaluated various combinations of direct-acting antivirals
in 533 people with decompensated cirrhosis, and recorded information on MELD
(Model For End-Stage Liver Disease) scores before and after treatment. (A MELD score of 15 or above indicates severe
loss of liver function. Patients with scores above 15 are judged to be in need
of a liver transplant.)
The review found that MELD scores improved after treatment in 56% of
participants across the five studies, worsened in 23% and stayed the same in
20%. 47% experienced an improvement of three points or more in MELD score after
Patients with MELD scores close to the threshold tended to experience
improvements in MELD score that reduced the need for a liver transplant more
quickly than those with MELD scores in the range 20 to 25. People with MELD scores
in the range 15 to 19 fell below 15 after an average of 5 months, whereas for
those with MELD scores in the range 20 to 25, a decline in MELD score below 15
took an average of ten months.
Applying these findings to a model of the liver transplant waiting list
population, Santiago Munoz and colleagues estimated that “DAA-induced MELD reduction down to the
threshold of transplant benefit would occur in 592 - 993 listed HCV patients
during the first year.”
between 213 and 515 donated livers could be reallocated to other people on the
waiting list during the first year if between 60% and 90% of people with
decompensated cirrhosis on the waiting list were treated with direct-acting
antivirals and had improvements in MELD score to the degree seen in the five
studies already conducted.
A third study, looking at a
French national cohort of 183 people with hepatitis C awaiting liver
transplantation and treated with direct-acting antivirals between November 2013
and June 2015, found that despite a median baseline MELD score of 9.7, only 18%
were taken off the waiting list after treatment, due in part to the high
proportion of patients with liver cancer on the list (106 patients).
Thirty-six per cent of
patients with decompensated cirrhosis had a complete response to treatment
after an average of 68 weeks follow up, and 57% of those with hepatocellular
carcinoma. In this
study a complete response – as distinct from sustained virological response –
was defined as total bilirubin < 35μmol/L, prothrombin time > 50%, albumin > 35g
L, no ascites, no hepatic encephalopathy. A change in Child Pugh class to less
severe cirrhosis was classified as a partial response; in this cohort 28%
of those with decompensated cirrhosis and 13% of those with hepatocellular
carcinoma had a partial response.
the findings, Audrey Coilly said
that it may be “asking too much in the short term” for liver function to improve
substantially in people with decompensated cirrhosis. She remarked that in the
era of interferon-based treatment, some data suggest that it took up to five
years after successful treatment for the portal pressure gradient to fall in
people with cirrhosis, and that longer-term follow-up is needed of people on
liver transplant waiting lists to assess the effects of treatment.