People with HIV and hepatitis C co-infection 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 – indicating that treatment should
not be deferred until advanced disease, according to a presentation at the Conference on Retroviruses and Opportunistic Infections (CROI 2015) last week in
Seattle, USA. Treating only after progression to cirrhosis increased the risk of
liver-related death by more than five-fold and the duration of infectiousness
by four-fold.
Over years or decades, chronic hepatitis C virus (HCV) infection can lead
to advanced liver disease including cirrhosis (scarring), hepatocellular
carcinoma (HCC; a type of primary liver cancer) and end-stage liver failure.
People with HIV and HCV co-infection experience faster disease progression, on
average, than those with HCV alone. Successful hepatitis C treatment reduces –
but does not eliminate – the risk.
When the standard of care for chronic hepatitis C was interferon-based
therapy – which was poorly tolerated, lasted up to a year and only cured about
half of people with HCV genotype 1 – experts generally recommended that
patients put off treatment until they experienced liver disease progression.
Now that highly effective and well-tolerated direct-acting antiviral (DAA) regimens
are available, many providers and advocates believe that everyone living with
hepatitis C should be eligible for treatment. But the high cost of the new
drugs has led to restrictions on their use, with some insurers and public
payers only covering treatment for the sickest patients.
Glossary
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
Cindy Zahnd from the University of Bern and
fellow investigators with the Swiss HIV and Swiss Hepatitis C Cohort Studies used
a mathematical model to predict the impact of different HCV treatment strategies on
liver fibrosis progression among people with HIV and HCV co-infection.
The researchers fed the model data on new HCV infections among gay and
bisexual men in the Swiss HIV Cohort Study, who are screened annually for HCV
antibodies and ALT liver enzyme levels. The model simulated patients from the
time of acute HCV infection through all stages of liver disease: absent
fibrosis (Metavir stage F0), mild fibrosis (F1), moderate fibrosis (F2), severe
or advanced fibrosis (F3) and liver cirrhosis (F4), as well as decompensated liver
disease (liver failure), liver cancer and death. They assumed that age at the
time of HCV infection and alcohol consumption influenced liver disease
progression.
In the initial scenario, before the advent of DAAs, the researchers
assumed that 60% of patients were treated with pegylated interferon plus
ribavirin, with about a 40% sustained response rate. They then ran a scenario based
on interferon-free DAA regimens, assuming 100% of patients were treated with an
efficacy of about 90%.
The researchers then looked at the model's predictions about occurrence of liver-related
events and death, as well as the duration of infectiousness (i.e. having detectable
HCV RNA), comparing the strategies of treating all patients one month after HCV
diagnosis (not necessarily one month after actual time of HCV infection), one
year after diagnosis or as they reached liver disease stages F2, F3 or F4. They
did not take into account the potential for HCV re-infection after successful
treatment, which can be substantial in some high-risk groups.
In the initial scenario, about 10% of patients experienced liver decompensation,
more than 15% developed HCC and more than 25% died of liver-related complications.
Using new DAA regimens, treatment started at one month or one year after
diagnosis dramatically reduced the proportions of people with decompensation
(around 1%), HCC (around 2%) and liver-related death (around 3%), with almost
no difference between one month and one year.
Starting treatment at liver disease stages F2 or F3 gradually increased
the risk of liver-related events and death, with a steeper jump if treatment
was deferred until stage F4. For those starting treatment at stage F3, the rate
of decompensation was about 3%, the rate of HCC about 8% and the rate of
liver-related death about 10%.
For those starting at stage F4, the corresponding rates were about 5%,
20% and 25%, respectively. If treatment was deferred from stage F2 to F3, the
rate of liver-related death doubled from 5% to 10%. If deferred from stage 2 to
stage F4, the death rate increased by nearly five-fold to 25%.
People treated at one month or one year after diagnosis remained
infectious, or able to transmit HCV, for about five years, compared to about 12
years if treated at stage F2, more than 15 years if treated at stage F3 and
nearly 20 years if treated at stage F4.
Starting treating after one month versus one year "did not really
make a difference," Zahnd explained, but whether treatment is started at
stage F2, F3 or F4 "really matters".
Importantly, the risk of progression to decompensation, liver cancer or
liver-related death did not fall to zero even after successful treatment. Some of
these events occurred after HCV clearance, with post-clearance proportions
increasing as treatment was further delayed. In fact, if therapy was deferred
to stages F3 or F4, a majority of liver-related deaths occurred after being
cured.
The remaining risk of liver complications and liver-related death after
successful treatment indicates that people with HIV/HCV co-infection often
"have other factors that keep them at risk of liver disease even after HCV
clearance," Zahnd suggested. These may include antiretroviral drug
toxicity, other coinfections or metabolic liver disease.
"Our model suggests that timely treatment of HCV infection is
important," the researchers concluded. "Patients can progress to
end-stage liver disease after HCV clearance if treatment is delayed until later
stages of liver disease due to imperfect treatment responses and residual
fibrosis progression in HIV-infected patients."
These findings provide support for a "different mental model"
of when to treat HCV, David Thomas of Johns Hopkins said at a CROI press conference
at which Zahnd and others described their hepatitis C studies. "We used to
wait until [stage] F3 or F4 before treating. But that is changing."
After Zahnd's presentation, her colleague Hans-Jakob Furrer from the Swiss
HIV Cohort Study team noted that providing evidence for earlier treatment is
why they did this study. "We're using this data for discussions with
governments," he said. "It is making negotiations easier – the data
clearly support earlier [treatment] rollout."