Doctors need to have “full and frank” discussions with
patients about the potential risks and benefits of using direct-acting
antivirals (DAAs) to treat hepatitis C in late-stage liver disease, especially among
those waiting for a liver transplant, liver specialists said at the 2016
International Liver Congress
in Barcelona on Thursday.

Direct-acting antiviral treatment may not eliminate the need for a liver transplant or significantly prolong life in cases where a transplant is not available.

Experts were commenting on a large Spanish study of people
with advanced liver disease who have received DAAs since
2013.

Although DAAs have produced high cure
rates in people with hepatitis C who have advanced fibrosis and cirrhosis,
there is still caution regarding their use in people with decompensated
cirrhosis who are candidates for liver transplant. Use of ribavirin alongside DAAs in these patients is considered risky, and the extent
to which DAAs can improve liver function in advanced liver disease in people
awaiting a liver transplant is unclear.

Spanish researchers presented findings from patients
enrolled in the Hepa-C registry, governed by the Spanish Association for the Study of
the Liver and the Networked Biomedical Research Centre for the Study of the
Liver and Digestive Diseases, Spain. The registry recorded treatment outcomes
in 843 people who
demonstrated clinical symptoms of advanced liver disease, had liver
cirrhosis and had not received a liver transplant during or within 12 weeks
after treatment.

The study
cohort consisted of people with Child-Pugh A (compensated) cirrhosis and 175
people with Child-Pugh B or C
(decompensated) cirrhosis. Those with Child-Pugh A had a median MELD
score of 8; those with Child-Pugh B or C cirrhosis had a median MELD score of
15. MELD score predicts the risk of liver disease in patients with
end-stage liver disease and helps to prioritise allocation of livers for
transplant. The score ranges from 6, for those with less severe disease, to 40,
for those who are critically ill. The score determines how urgently someone
requires a transplant within three months and takes into consideration results
from three routine lab tests. 

Participants
in the cohort received a variety of interferon-free regimens. Forty-five per cent received
sofosbuvir and simeprevir, 22% sofosbuvir and daclatasvir, 16% sofosbuvir and
ledipasvir, 10% ombitasvir, paritaprevir/ritonavir and dasabuvir, and the
remainder received other DAA regimens. The majority of patients also received ribavirin.

Sustained
virologic response data 12 weeks after completion of treatment were available
for 595 cohort participants, and showed that people with Child-Pugh A cirrhosis
were significantly more likely to be cured when analysed by intention to treat
(i.e. the cure rate among all those who began treatment, regardless of whether
they completed treatment or not). 94% of those with Child-Pugh A cirrhosis were
cured (402/428), compared with 78% of those with Child-Pugh B or C cirrhosis
(102/131). The difference was due to a higher rate of virologic relapse after
treatment and a higher frequency of deaths in those with Child Pugh B and C
cirrhosis.

People
with Child-Pugh B or C cirrhosis were also more likely to experience severe
adverse events during treatment, including the development of liver
decompensation, anaemia requiring transfusion or other adverse events. Severe
adverse events during treatment and post-treatment mortality were predicted by
a MELD score of 18 or above, such that only 68% of those with a MELD score of
18 or above were alive 36 weeks after starting treatment, compared to 97% of
those with MELD scores below 18 (p 0.001). 25% of patients with the most
severe disease died compared to 1.6% of the rest of the patients (p 0.001).

On
average, positive or negative changes in MELD scores after treatment were
modest, and Dr Fernández Carrillo pointed out that for over 90% of patients,
the changes were too small to be clinically meaningful.

However, a smaller multicentre European study of 103 people
with decompensated cirrhosis on the liver transplant waiting list found that 20%
experienced improvements in MELD scores of four points or more after DAA
treatment, allowing them to be taken off the liver transplant waiting list
altogether within a year of beginning
DAA treatment. But, for the remaining 80% a liver transplant continued to be an
urgent necessity despite a high cure rate. Study presenter Luca Belli of the Gastroenterology
and Hepatology Liver Unit, Niguarda Hospital, Milan, Italy, warned that
longer-term follow up is still needed in people taken off the transplant list
to see whether the benefit of treatment persists.

“The results of our study clearly show that those patients suffering
from very advanced liver disease may not obtain benefit from these treatments,”
said Dr Carlos Fernández Carrillo, Liver Unit of Puerta de Hierro-Majadahonda
University Hospital, Spain and lead author of the HEPA-C registry study. “We
believe that in these severe cases, a discussion must take place between the
healthcare professional and the patient, to make an individual decision.
Sometimes it could be better to let the condition run its natural course rather
than intervene and risk severe adverse events or death before curing the hepatitis”,
added Dr José Luis Calleja, the senior study author.

“This
study highlights the risks of using direct-acting antivirals in patients with
severe liver disease. It is important that hepatologists weigh up the risks and
the benefits of treating patients with late-stage disease, and have open and
honest discussions with their patients as to the best course of treatment for
them,” said Professor Laurent Castera, EASL Secretary General.

Another
option is to increase the supply of livers available for transplant to people
with hepatitis C virus (HCV) by transplanting livers from donors with HCV. A review of the
Scientific Registry of Transplant recipients also presented at the
International Liver Congress on Thursday showed no significant difference in post-transplant
mortality or graft rejection between people with hepatitis C who received
livers from HCV-negative or HCV-positive donors in the United States between
1995 and 2013.

The study
compared outcomes in 1930 people with HCV who received organs from HCV-positive
donors and 31,738 who received organs from HCV-negative donors. The study found
that the proportion of people with HCV who received organs from HCV-positive
donors increased from 2.9% in 1995 to 9.4% in 2013.