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People with HCV attaining SVR continue to have increased mortality risk but this is due to alcohol and drug use

Michael Carter
03 October 2016

Mortality rates among people with hepatitis C virus (HCV) who attain a sustained virological response after HCV treatment are approximately twice as high as those expected in the general population, Scottish investigators report in the Journal of Hepatology. Most of the excess mortality was due to drug use or liver cancer. Several modifiable characteristics were associated with subsequent mortality risk, including drug use and heavy alcohol consumption. People without these risk factors – approximately a third of the study population – had survival that matched that of the general population.

“Health risk behaviours exert a strong influence on the extent to which mortality exceeds general population levels,” comment the authors. “Where health risk behaviours are minimal…all-cause mortality rates are equivalent to or even lower than the general population.”

The advent of highly effective direct-acting agents for the treatment of HCV means that the number of people attaining a sustained virological response (SVR) is set to increase dramatically. Attainment of a SVR – eradication of HCV 12-weeks post therapy – is widely regarded as a cure for HCV. But, the researchers point out, it is unclear if achieving SVR also 'cures' the long-term damage to the liver and other organs caused by hepatitis C, so long-term follow-up is needed.


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. 

There are some encouraging data regarding the longer-term health implications of SVR. Two small clinic-based studies of people with advanced fibrosis showed that people who had attained SVR had post-treatment survival rates that matched those in the general population.

Investigators in Scotland wanted to see if this was indeed the case. They therefore identified all patients attaining SVR in Scotland between 1996 and 2011. Therapy was interferon-based and people with hepatitis B virus and/or HIV were excluded.

Data were obtained from central registries regarding all-cause and cause-specific mortality through to the end of 2013. Standardised mortality ratios (SMRs) were calculated so the frequency of mortality among SVR patients could be compared to individuals in the general population. A separate analysis examined whether any modifiable baseline risk factors were associated with mortality risk after SVR.

The authors identified 1824 SVR patients, the mean age was 41 years and 68% were male. Liver cirrhosis was diagnosed in 6% of individuals and 54% had F0-F1 fibrosis. Approximately a fifth had a history of heavy alcohol use (50 or more units per week consumed for more than six months) and 59% reported ever injecting drugs.

The median duration of follow-up was 5.9 years, the patients contributing 10,915 person-years of follow-up. There were 78 deaths. Nine deaths were due to liver cancer (occurring a mean of 4.8 years after SVR) and 18 were drug related.

The estimated ten-year survival rate was 93% overall and 95% for patients without cirrhosis, compared to 96% for the general population.

On the basis of general mortality rates, there should have been 42 deaths in the SVR cohort. The actual number of deaths – 78 – meant that the SMR was 1.86 times higher than seen in the background population.

Analysis of cause-specific SMRs showed significant elevations due to liver cancer (SMR = 23.5) and drug-related causes (SMR = 6.58).

Indeed, drug-related causes were the biggest single contributor to the excess mortality observed in SVR patients (42% overall, 75% for patients without cirrhosis). Liver cancer accounted for approximately a quarter of the excess mortality overall and 13% for patients without cirrhosis. When combined, these two causes were responsible for 66% of all excess deaths in the total cohort and 88% of excess mortality in people without cirrhosis. In the under 50s, drug-related causes accounted for 53% of the excess mortality and liver cancer below 5%, whereas in the over 50s, most of the excess (54%) was attributable to liver cancer, with drug-related causes accounting for 26% of the excess.

Baseline characteristics associated with mortality included older age, male gender, liver cirrhosis, diagnosis with liver cancer, a high number of co-morbidities, past heavy alcohol consumption, a history of injecting drugs and hospitalisation for alcohol intoxication and/or drug intoxication and violence-related injury.

The modifiable risk factors associated with mortality were therefore heavy alcohol consumption, history of injecting drugs, and hospitalisation for alcohol and/or drug abuse and injury from violence. But, it should be noted, these risk factors were recorded at the time of first liver clinic visit, prior to hepatitis C treatment. The investigators could not document health behaviours after SVR, with the exception of documented drug-related deaths.

People with none of these risk factors (36% of the cohort) had SMRs that were modestly lower than those expected for the general population. In contrast the SMR was six times higher for people with three of these risk factors.

Compared to people with no risk factors, individuals with one risk factor had a two-fold increase in their mortality risk (p = 0.035), the risk was increased four-fold for patients with two risk factors (p < 0.01) and by more than seven-fold for individuals with three risk factors (p < 0.001).

The authors say that whereas previous studies of post-SVR outcomes focused on small cohorts of patients with advanced fibrosis, their study represents the outcomes of around 80% of people cured of hepatitis C in Scotland between 1996 and 2010, and shows what might be expected in a population where hepatitis C is predominantly acquired through injecting drugs and alcohol consumption is high.

“Heath risk behaviours emerged as the major modifiable risk factor for mortality in this population underlining the importance of a multidisciplinary approach to HCV that addresses lifestyle risk factors in addition to viral infection,” conclude the authors. “The SVR time-point may be a particularly opportune moment to assess what other services and support the patient may be in need of.”


Innes H et al. Mortality in hepatitis C patients who achieve a sustained viral response compared to the general population. Journal of Hepatology, online edition, (2016).