People who achieve
sustained virological response (SVR) when treated with interferon-based therapy
for hepatitis C have a lower risk of death, are less likely to develop liver
cancer and need fewer liver transplants than those who were treated but not cured,
according to results from a meta-analysis of more than 34,000 patients
presented on Sunday at the American Association for the Study of Liver
Diseases (AASLD) Liver Meeting in Boston, USA.
While more research is
needed to confirm these findings, benefits are likely to be even greater for
hepatitis C patients treated with interferon-free direct-acting antivirals (DAAs),
which produce higher cure rates generally above 90%.
Previous studies have
shown that SVR – or continued undetectable HCV viral load after completion of
treatment – reduces the risk of hepatocellular carcinoma (HCC), liver
transplantation, liver-related death and all-cause mortality, but results have
been inconsistent and many of these studies have been small.
Glossary
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or 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.
To learn more about
how SVR affects long-term outcomes, Andrew Hill from the University of
Liverpool and colleagues performed a meta-analysis of data from 34,563 people treated for chronic hepatitis C. Combined
data were used to calculate 5-year risk of all-cause mortality, HCC and liver
transplantation. They also looked at rates of HCV re-infection after treatment.
The cost-effectiveness of hepatitis C treatment depends not on achieving
undetectable HCV RNA per se – although this would reduce the risk of onward
transmission – but rather on reducing the occurrence of liver cancer, need for
liver transplantation and all-cause mortality.
The researchers
searched the MEDLINE and EMBASE databases for studies comparing outcomes among
treated hepatitis C patients with SVR at 24 weeks post-treatment (SVR24) versus
those who were not cured. Typically, the regimen used was pegylated interferon
plus ribavirin – the old standard of care before the advent of direct-acting
antivirals. (SVR12 is now considered to be a cure in studies of DAAs.)
The investigators
looked at people with HCV mono-infection overall, people with HCV mono-infection who had
liver cirrhosis, and people with HIV and HCV co-infection. Although they attempted to
compare results from univariate and multivariate analysis to control for
confounding factors, multivariate data often were not available.
The analysis of
all-cause mortality included 18 studies of people with HCV mono-infection, with a
total of 29,269 participants and an average follow-up period of 4.6 years.
There were nine studies of people with HCV mono-infection who had cirrhosis, with a
total of 2734 participants and an average follow-up of 6.6 years. Finally,
there were five HIV/HCV co-infection studies, with a total of 2560 participants
and an average follow-up of 5.1 years.
Looking at a subset of
studies with multivariate and univariate data, risk of death due to any cause
fell by 71% for people with HCV mono-infection who achieved SVR in univariate
analyses, or 62% in multivariate analyses, relative to those without SVR. Among
people with HCV mono-infection who had cirrhosis, all-cause mortality dropped by 73% in
univariate analyses and by 84% in multivariate analyses. Among people with HIV and HCV
co-infection, risk reductions were 75% and 73%, respectively.
The five-year risk of all-cause death
was 4.5% among people with HCV mono-infection who achieved SVR, compared to 10.5%
among those without SVR. Among people with HCV mono-infection who had cirrhosis,
mortality rates were 3.6% with SVR versus 11.3% without SVR. Among people with HIV and HCV co-infection, mortality rates were 1.3% with SVR versus 10.0% without SVR.
The analysis of liver
cancer included 21 studies of people with HCV mono-infection, with a total of 12,496 participants
and an average follow-up period of 6.1 years. There were 18 studies of people with HCV
mono-infection who had cirrhosis, with a total of 4987 participants and an
average follow-up of 6.6 years. There were three HIV/HCV co-infection studies,
with a total of 2085 participants and an average follow-up of 4.7 years.
The five-year risk of developing
HCC was 2.9% among people with HCV mono-infection who achieved SVR, compared to 9.3%
among those without SVR. Among people with HCV mono-infection who had cirrhosis, HCC rates
were 5.3% with SVR versus 13.9% without SVR. Among people with HCV and HIV co-infection, rates
were 0.9% with SVR versus 10.0% without SVR.
Looking at liver transplants, the analysis included just one study of people with HCV mono-infection, with a
total of 108 participants and an average follow-up period of 4.2 years. There
were two studies of people with HCV mono-infection who had cirrhosis, with a total of 1046 participants
and an average follow-up of 7.7 years. Finally, there were two HIV/HCV
co-infection studies, with a total of 2039 participants and a follow-up of 4.9
years.
Here, 0% of people with HCV mono-infection with SVR needed a liver transplant,
compared with 2.2% of those who were not cured. Among people with HCV mono-infection who had cirrhosis, transplant rates were 0.2% with SVR, rising to 7.3% without SVR.
Among people with HCV and HIV co-infection, transplant rates were 0.6% and 2.7%, respectively.
Turning to re-infection after achieving SVR, Hill said there was a 'marked
difference' across the three populations analysed. Reinfection was rare, at
0.9%, among people considered low-risk (24 studies, 6046 participants, 4.1 years average follow-up). The
re-infection rate rose to 8.2% in a higher-risk group of people in prison settings and people
who inject drugs (16 studies, 1203 participants, 5.0 years
average follow-up). But the re-infection rate was much higher, at 23.6%, among
people with HIV/HCV co-infection (10 studies, 1106 participants, 3.1 years average follow-up).
Hill noted that many of the people with HCV and HIV co-infection were men who have sex
with men. Starting around the year 2000, outbreaks of apparently sexually
transmitted HCV infection have been widely reported among gay and
bisexual men living with HIV in cities in Europe, the US and Australia. He said this analysis
could not provide details about specific risk factors, but the highest
re-infection rate was seen among people with HCV and HIV co-infection who also injected drugs.
With regard to the limitations of this meta-analysis, Hill noted that
people with SVR and those who are not cured may differ in baseline
characteristics, so more multivariate data are needed. He also stressed that
these findings are from studies of interferon-based treatment, and long-term
outcome data are not yet available for people treated with direct-acting
antivirals.
In this analysis of data from 34,563 patients treated for hepatitis C,
achieving SVR was associated with 62-84% reductions in all-cause mortality,
68-79% reductions in the risk of developing HCC and a 90% reduction in liver
transplantation, the researchers summarised.
However, they added, "there was a significant risk of subsequent
re-infection after SVR in some studies, which could reverse these benefits of
treatment."