Sustained virological response to hepatitis C treatment reduces mortality, liver cancer and liver transplants

Andrew Hill speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com

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

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.

reinfection

In HIV, synonym for superinfection. In hepatitis C, used when someone who has been cured of the virus is infected with hepatitis C again.

antiviral

A drug that acts against a virus or viruses.

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."

References

Hill A et al. Effects of Sustained virological response (SVR) on the risk of liver transplant, hepatocellular carcinoma, death and re-infection: meta-analysis of 129 studies in 23,309 patients with Hepatitis C infection. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract 44, 2014.