Deferring antiviral therapy for hepatitis C until a person progresses to
advanced liver disease has clear drawbacks including lower treatment
effectiveness and an increased risk of clinical events and death, according to a
study of US veterans presented at the European Association for the Study of the
Liver (EASL) 50th International Liver Congress last month, in Vienna,
Over years or decades, chronic hepatitis C virus (HCV) infection can
lead to serious liver disease including cirrhosis, hepatocellular carcinoma (liver
cancer) and need for a liver transplant. When the standard of care for
hepatitis C was interferon-based therapy – with its long course of treatment,
poor tolerability and only modest cure rate – experts generally recommended
delaying treatment until a patient developed advanced disease.
Now that much more effective and well-tolerated interferon-free
direct-acting antiviral therapy is available, a growing number of providers and
advocates think everyone living with hepatitis C should be eligible for
treatment. But treatment is still often limited to the sickest patients due to
the high cost of the new drugs.
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).
Jeffrey McCombs, a health economist at the Schaeffer
Center for Health Policy and Economics in Los Angeles, and colleagues, compared
treatment outcomes for people with hepatitis C treated before or after
development of advanced liver disease.
The aim of the study, McCombs explained, was to
provide information for insurers and other payers about the risks of deferring
treatment. "Can we
eradicate this disease – an opportunity that doesn't come along often in
medicine – without breaking the bank?" he asked. To date, many providers
and payers have employed a 'watchful waiting' approach, monitoring patients and
starting therapy only when they show signs of disease progression. This study,
McCombs said, tried to answer "what do you watch and how long can you
This retrospective analysis looked at data from US
Veterans Administration electronic records collected from 1999 through to 2010
– prior to the interferon-free treatment era. Hepatitis C prevalence in this
population is estimated to be around 5%.
A previous study found that HCV viral suppression
reduced the risk of liver disease events by 27% and deaths by 45%. Compared to people
with HCV genotype 1, those with genotype 2 had a lower risk of progression and
death, while those with genotype 3 did worse. Treatment effectiveness decreased
if patients started therapy only after they developed abnormal laboratory
values including albumin, platelet count, and ALT and AST liver enzyme levels.
The researchers determined liver disease progression
using FIB-4, a non-invasive index calculated using patient age, platelet count
and ALT and AST levels. This allows estimation of liver fibrosis using
available laboratory tests for patients without liver biopsies. FIB-4 <1.45
indicates absent to mild fibrosis (Metavir F0-F1) while >3.25 indicates
fibrosis or cirrhosis (F3-F4). According to prior research, FIB-4 >1.45
doubles the risk of clinical events and death, while FIB-4 >3.25 quadruples
the risk, McCombs said.
The present analysis included 187,860 veterans (predominantly
men) with chronic hepatitis C who had available FIB-4 data. The main outcome
measures were time to death and time to a composite clinical events outcome
that combined cirrhosis, decompensation, HCV-related
hospitalisation, hepatocellular carcinoma and death.
Over the entire study period – at a time when
hepatitis C treatment was poorly tolerated and not highly effective – 25% of
patients started therapy and only 16% of those treated (or 4% of the study
population overall) achieved undetectable HCV viral load.
The analysis showed that starting treatment with FIB-4
<1.00 was associated with a 41% reduction in clinical events and a 36%
reduction in mortality. People who started therapy with FIB-4 <1.45 saw
reductions of 39% and 40%, respectively, while those who started while FIB-4 was
still <3.25 had a 34% lower risk of clinical events and a 45% lower risk of
Outcomes were not so good for individuals who delayed
treatment until after they had progressed to advanced disease. People who
waited until they reached FIB-4 >3.25 saw only an 11% reduction in clinical
events and a 25% reduction in mortality.
Poorer outcomes are attributable in part to the fact
that the likelihood of achieving viral suppression with interferon-based
therapy is lower once someone develops cirrhosis. (This is also true for
interferon-free treatment, though cure rates even for people with the most
advanced disease are high using the newest direct-acting antivirals.) People
who were treated early and achieved undetectable viral load saw about a 33-35%
reduction in clinical events and 21-24% reduction in mortality, regardless of
whether they started with FIB-4 <1.00, <1.45 or <3.25.
But advanced liver disease may not be fully reversible
even if sustained virological response is achieved. Among people who delayed
treatment until after FIB-4 reached >3.25, reductions in clinical events and
death were only 13% and 24%, respectively, even if they achieved viral
Looking at another measure of treatment effectiveness
– the 'number needed to treat' to achieve a desired outcome – while 180 people
had to be treated with FIB-4 <3.25 in order to prevent a single death, this
rose to 325 people who waited until FIB-4 reached >3.25.
"Delaying treatment until after a patient’s FIB-4
level exceeds 3.25 has a clear detrimental effect on treatment effectiveness,"
the researchers concluded.
The benefits of
treatment are diminished if treatment is delayed," McCombs summarised. "If
you treat too late it is not going to be as effective." This is something
to discuss with payers, he added, since saving money now by delaying treatment
may result in greater costs in the future.
Another recent analysis of people in Switzerland
with HIV and HCV co-infection likewise showed that people who delay hepatitis C
treatment remain at risk for liver failure, hepatocellular carcinoma and
liver-related death even after being cured, with outcomes worsening the longer
it is put off.