Treatment with direct-acting antivirals (DAAs) reduced the risk of
death, liver cancer and death from liver-related causes in French people with
hepatitis C, according to results of one of the largest studies to date of the
impact of the drugs.
The findings are published in advance online by The Lancet this week.
DAA treatment for hepatitis C was introduced
from 2012, and the most effective regimens deliver almost universal cure rates.
Many countries are now moving to implement testing and treatment programmes designed
to eliminate hepatitis C as a significant cause of illness and death by 2030,
by seeking to diagnose and treat everyone with the infection.
- 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’.
- sustained virological response (SVR)
Undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 24 weeks (six months) after ending treatment and is considered to be a cure. SVR4 and SVR12 refer to RNA remaining undetectable for 4 and 12 weeks respectively.
systematic review by the Cochrane Collaboration concluded that trials of DAAs did not provide enough evidence to conclude that curing hepatitis C
reduced risks of death or clinical illness.
The review was strongly criticised by liver experts, including
the American Association for the Study of Liver Diseases, for the short
follow-up period of the studies selected and the lack of statistical power to
detect differences in death rates in relatively small studies.
French researchers set out to assess the impact of treatment
on mortality and morbidity in a large cohort followed over several years.
ANRS Co22 Hepather is a large cohort of French patients
followed prospectively to evaluate the impact of DAAs in
people with chronic hepatitis C. The cohort began to follow patients after the
introduction of the first generation of DAAs in August
The study excluded cohort participants with hepatitis B,
with a history of hepatocellular carcinoma or decompensated cirrhosis, liver
transplant recipients, and people who received pegylated interferon as part of
their hepatitis C treatment after cohort entry. A total of 10,166 people were eligible for
inclusion in the analysis, of which 3045 had cirrhosis at the time of
The study compared the mortality and health of people
treated with DAAs (7344 people) and people who remained
untreated in the cohort between 2012 and 2015 (2551 people).
There were no significant differences in current alcohol
use, route of hepatitis C virus (HCV) acquisition, or degree of cirrhosis as measured by MELD
score, between treated and untreated people, but treated participants were
significantly older (57 vs 54 years), were more likely to be over weight or
obese, more likely to have a history of previous treatment (57% vs 39%), more
likely to have genotypes 1 or 3, more likely to have cirrhosis (42% vs 10%)
and to have poorer liver function and more advanced fibrosis as measured by
median APRI and FIB-4 scores (all p < 0.001).
Treated participants were also more likely to have diabetes,
hypertension, low platelet count, elevated ALT and AST, and elevated
alpha-fetoprotein (p < 0.001).
The median follow-up time was 33.4 months. During this
period, 129 people in the treatment group died (48 of liver-related causes), an
incidence of 0.95 per 100 person-years. The incidence of death in the untreated
participants was 0.70 per 100 person-years, but after adjustment for cirrhosis
and other demographic and HCV-related variables, treated people had a lower
risk of death.
Treatment reduced the risk of death by 52% (HR 0.48, 95% CI
0.33-0.70) and reduced the risk of liver-related death by 61% (HR 0.39, 95% CI
Treatment also reduced the risk of hepatocellular carcinoma
by 34% (HR 0.66, 0.40-0.93).
The effect of treatment on mortality was only evident in
people with cirrhosis and did not affect mortality or rates of liver cancer in
people with less advanced disease, in part because the number of reported deaths
and cases of liver cancer or liver-related death were so low in people without
When the researchers looked at the relationship between
sustained virological response (SVR) and mortality as opposed to exposure to treatment,
they found that SVR was associated with a reduced risk of all outcomes apart
from decompensated cirrhosis. Seventy-six per cent of participants who
received treatment achieved SVR. Lack of SVR more
than doubled the risk of developing hepatocellular carcinoma (aHR .2.23,
The study investigators note that cirrhosis was not confirmed
by biopsy in all cases and people with decompensated cirrhosis were excluded
from the study, potentially leading to an underestimation of the effect of
treatment on mortality.
In an accompanying Comment article, Jacinta Holmes,
Stephanie Rutledge and Raymond Chung say “these findings firmly counter those
of a Cochrane review of direct-acting antiviral treatment trials that could
neither confirm or reject if direct-acting antivirals had an effect on
long-term HCV-related morbidity and mortality. They also provide the best
evidence to date to support guidance documents that recommend direct-acting
antiviral treatment for all patients with chronic HCV infection.”