11.1.1 Examination of the Scientific Literature
The assessment of the impact of hepatitis C on the risk of death among people who have not advanced to severe liver disease or developed B cell lymphoma (i.e. people identified as having advanced HCV) is challenging. As indicated above, overwhelming evidence, demonstrating the greatly increased risk of death following the development of cirrhosis of the liver (and/or B cell lymphoma) exists; to this should be added renal failure due to Membranoproliferative Glomerulonephritis.
For those without these conditions, however, the analytical problem has been estimating, with confidence, the contribution hepatitis C infection, per se, makes to mortality as opposed to the contributions to mortality made by the conditions so often associated with being infected with hepatitis C; these conditions include, from a behavioural perspective, injecting drug use and excessive alcohol consumption and, from the specific perspective of individuals registered with SIBSS, blood factor disorders and the serious conditions which led to individuals requiring a blood transfusion.
Accordingly, five studies were deemed particularly illuminating - three following up people from known date of infection and two following up people from known time of SVR following therapy.
11.1.2 Analysis of Scottish Death Certificate Data
Health Protection Scotland ( HPS) holds clinical data on all individuals diagnosed with hepatitis C; through the routine linkage of these data with data on hospital discharge diagnoses held at the Information and Statistics division of NHS National Services Scotland and death certificate data held at the National Records of Scotland, a comprehensive understanding of the life course of the hepatitis C infected person can be achieved. Note that all records held in HPS only include partial personal identifiers for anonymity and confidentiality purposes; accordingly, the full name and the address of an individual is not held. Using these data, it was possible to examine the reliability and completeness of the cause of death, with respect to hepatitis C infection, recorded on death certificates.
11.2.1 Examination of the scientific literature
220.127.116.11 Studies: Follow-Up from Known Date of Infection
The first was a report on the follow-up of nearly 1000 individuals infected through blood transfusion in the UK; this unique cohort of individuals had been traced during the UK Hepatitis C Lookback Programme of the 1990s ( 21). For all, the exact date of infection was known and all had been infected through blood transfusion; some were from Scotland. A considerable number of individuals (475), identified in the Lookback, who had been transfused but were not infected by hepatitis C, constituted a control group; accordingly, the study design was robust and highly relevant to the question being asked by the Clinical Review Group.
Over an average of 16 years of follow up following hepatitis C infection from blood transfusion, 28% of 924 individuals infected with HCV and 24% of 475 hepatitis C negative controls had died. Excluding those who died from liver disease, 24% of cases and 23% of controls had died; adjusting for a range of variables including age, age at transfusion, and alcohol consumption, no difference in all-cause mortality was observed between cases and controls over the 16 years of follow up.
A similar study, published just after the discovery of HCV, investigated all-cause mortality among people who had developed non-A, non-B hepatitis following blood transfusion in the United States of America ( US) ( 22 ). Over a follow-up period of
18 years, all-cause mortality rates in both cases and controls were identical at 50%.
The longest follow-up of people for whom time of infection is known relates to people who injected drugs ( PWID) in Norway. All-cause mortality rates over a 33 year period of follow-up among those with chronic hepatitis C and those without (control PWID) were no different ( 23 ).
18.104.22.168 Studies: Follow-Up from Known Date of SVR
For hepatitis C infected people in the US without advanced liver disease, all-cause mortality rates of 39,400 people who cleared their infection and 1,300 who did not following DAA therapies were compared ( 24 ). After adjusting for a number of factors including other clinical conditions (including alcohol and drug use), body mass index, gender, age and ethnicity, the former group had a 50% lower risk of all-cause mortality over a 1-2 year follow up after the completion of therapy. Information about the reported cause of death was unavailable. The authors concluded that getting rid of hepatitis C might decrease the risk of death through reducing a source of chronic inflammation. Another possible reason for the observation is that people with an increased chance of death respond less well to antiviral drugs.
A Scottish study involved the follow-up of 3400 patients, following Interferon-based therapy, for an average of 5.3 years; while there was a significant reduction in all-cause mortality among people with moderate to severe liver disease, there was no significant reduction among those with no/mild disease ( 25 ).
11.2.2 Analysis of Scottish Death Certificate Data
To the end of December 2016,
Of 1,864 individuals known to have i) been infected with hepatitis C through any transmission route, ii) developed liver failure and/or hepatocellular carcinoma and iii) died (almost certainly because of their liver disease), 1,014 (54%) had hepatitis C recorded on their death certificate.
Of 222 individuals known to have i) been infected with hepatitis C through blood transfusion or blood factor and ii) died, 76 (34%) had hepatitis C or viral hepatitis mentioned on their death certificate.
- People who have advanced HCV disease are at considerably greater risk of death than people who are uninfected with Hepatitis C and have similar underlying health characteristics.
- At the population level, HCV infected people without advanced HCV disease have much the same risk of death as people who are uninfected with Hepatitis C and have similar underlying health characteristics. This does not exclude the possibility of Hepatitis C contributing to the death of an infected individual who does not have advanced HCV (e.g. death associated with mental health problems).
- The recording of hepatitis C on the death certificate is unreliable and, when it occurs, cannot be used to differentiate between hepatitis C having made a contribution to death or not in instances where the person has died from non-advanced HCV defining diseases/conditions.