Clinical review of the impacts of hepatitis C

10. Term of Reference 2

Assess the impact of chronic hepatitis C infection and associated antiviral treatment, on the health, wellbeing and quality of life of people who have not progressed to advanced HCV disease.

Two approaches were adopted – i) the examination of findings of studies published in peer reviewed scientific journals, ii) conversations with beneficiaries of the Scottish Infected Blood Support Scheme ( SIBSS).

10.1 Methods

10.1.2 Examination of the Scientific Literature

The most robust approach to examining large amounts of scientific literature on a particular topic is to undertake a systematic review – a review using a systematic approach which permits the inclusion of studies that meet an agreed high standard – and then, when dealing with large amounts of quantitative data, undertaking a meta-analysis (using sophisticated statistical techniques) which involve pooling results from multiple studies to generate an overall, and far more precise, result than any single one.

For qualitative studies, the systematic review technique is appropriate, but the meta-analysis one is not.

Helpfully, in 2016 and 2017, the following papers were published:

• Extrahepatic Manifestations of Hepatitis C: A Meta-analysis of Prevalence, Quality of Life and Economic Burden. Younossi Z et al. Gastroenterology 2016; 150: 1599-1608 ( 15 ).
• Living with Hepatitis C Virus: A Systematic Review and Narrative Synthesis of Qualitative Literature. Dowsett L et al. Canadian Journal of Gastroenterology and Hepatology 2017; article ID 3268650, 11 pages ( 16 )

Of particular note, is the status of the journal Gastroenterology; it is the most authoritative specialist journal, worldwide, for the topic of Gastroenterology (including Hepatology) and has an extremely high impact factor of 18 (equivalent to that for the British Medical Journal). Also the lead author is a renowned international authority on hepatitis C. The work undertaken by Younossi et al involved examining 600 potentially relevant studies; a total of 102 studies met all of the inclusion criteria and the data from these were included in a range of analyses. Multiple systematic reviews and meta–analyses were undertaken. To address the potential confounding effect of heterogeneity (e.g. age, sex, clinical characteristics such as the presence or absence or cirrhosis, and behaviours such as injecting drug use and alcohol consumption) additional analyses were undertaken; these were limited by data availability.

The Canadian Journal of Gastroenterology and Hepatology is a less prominent journal, but the work undertaken by Dowsett et al is exhaustive and highly impressive. They examined 798 study abstracts, of which 46 met the rigorous inclusion criteria.

On account of i) the high quality of the two reviews, ii) their comprehensiveness and iii) their recency, the Clinical Review Group considered that there was no need to repeat these exercises. Note that these reviews relate to studies of people who have acquired hepatitis C through any route; there is no substantive review literature on extrahepatic manifestations of hepatitis C among individuals who acquired infection through blood factor/transfusion receipt. Indeed very few Hepatitis C outcome studies, with specific reference to people infected through blood factor/transfusion receipt, have been performed.

Accordingly, for Term of Reference 2, the summarised scientific literature findings on the extrahepatic, including psychosocial, manifestations of hepatitis C - manifestations which are particularly applicable to people who have not advanced to severe liver disease – stem from these two published papers.

Anti-Viral Treatment

With respect to adverse impacts of treatment on infected people, the review of the literature was confined to interferon +/- ribavirin regimens - the bedrock of treatment between 1994 and 2014. The Direct Acting Antiviral ( DAA) agents, available from 2014, were not reviewed as these are known to convey minimal side effects.

Three review articles were depended upon because of their high calibre and relevance ( 17, 18, 19 ).

10.1.3 Conversations with beneficiaries of SIBSS

Insufficient time was available to conduct a formal qualitative study of people with chronic HCV; such a study would have involved employing an experienced qualitative researcher and securing ethical committee approval. As an alternative, it was agreed by the Scottish Government and the Clinical Review Group (including patient representatives) that Professor Goldberg, Chair of the Group, should meet a sample of SIBSS beneficiaries to listen to their experiences.

To ensure as representative a sample as possible, 15 SIBSS beneficiaries were identified using a random sampling approach; the approach was refined to ensure that a) the blood factor/transfusion acquired hepatitis C distribution among SIBSS beneficiaries was matched in the sample and b) of the 15, two widows/widowers/partners of infected individuals were included. For those selected through the randomisation process, a telephone invite (incorporating the purpose of the proposed conversation) from a SIBSS administrator was made. The conversations were conducted in the homes, scattered throughout the country, of the SIBSS beneficiaries and lasted up to two hours; patients agreed to their “stories” being used, anonymously, to inform the report, and to quotes being used to illustrate key points.

The conversations between Professor Goldberg and the SIBSS beneficiaries (sometimes accompanied by a relative) were not interviews and the process was not intended to be of a formal qualitative study nature; the initiative was an opportunity for the Chair of the Group to “hear the SIBSS beneficiary voice” – essentially giving the patient the opportunity to tell their story and say whatever they wanted in the context of the Clinical Review, the purpose of which was further explained to them face to face. Accordingly, no questionnaire was used, but notes were taken. Professor Goldberg asked the SIBSS beneficiary to say whatever they wanted; the only questions asked by him related to clarifications of points already made and factual details about e.g. dates of diagnosis/treatment.

Note that the Scottish Infected Blood Forum conducted a similar large-scale exercise, gathering testimonials from infected persons. The findings were published in 2015( 20 ); it was decided not to use these because of the self-selection (and thus the potential for bias) of individuals included in this exercise. However many of the findings of this initiative were consistent with those generated through the random –sample approach used for the Review exercise.

10.2 Results

10.2.1 Examination of the scientific literature: Extrahepatic manifestations of hepatitis C: A meta-analysis of prevalence, quality of life and economic burden. Younossi Z et al. Gastroenterology: 2016.

10.2.1.1 Conditions More Commonly Associated with Hepatitis C

The following conditions were identified as being significantly (statistically) more common among people with, compared to those without, chronic hepatitis C virus infection; the authors did not make any comment on the impact of clinical characteristics (such as liver disease stage or other conditions), behavioural factors (such as injecting drug use or excessive alcohol consumption) or demographic factors, on the findings ( 15 ).

• Mixed Cryoglobulinaemia (symptomatic and asymptomatic): 12 X more common among people with chronic HCV compared to those without.
• Chronic Renal Disease (including end stage): 1.1 X more common
• Diabetes Mellitus (type 2): 1.6 X more common
• B-Cell Lymphoma: 1.6 X more common
• Lichen Planus: 2.3 X more common
• Sjogrens Syndrome: 2.3 X more common
• Porphyria Cutanea Tarda: 8.5 X more common
• Rheumatoid Arthritis: 2.4 X more common
• Depression: 2.3 X more common

Note:

Cryoglobulinaemia is a condition whereby there is an increase in abnormal (mixed) proteins in the blood which can clump together at low body temperature; this may result in inflammation affecting the skin and/or kidneys in particular; renal disease as above is associated with such cryoglobulinaemia.

Sjogrens Syndrome is a disorder of the immune system, sometimes associated with rheumatoid arthritis, causing dry eyes and dry mouth.

B Cell Lymphoma is a type of “blood cancer” in the lymph nodes; it is a life threatening condition with variable response to treatment.

Lichen Planus is an inflammatory condition affecting the skin, hair, nails and mucous membranes.

Porphyria Cutanea Tarda is disorder of metabolism which makes the skin hypersensitive to light.

Publication bias was reported by the authors for both diabetes mellitus and mixed cryoglobulinaemia, but not for other conditions – i.e. the greater likelihood of the publication of studies showing an association between hepatitis C and the disease than the publication of findings not showing an association; accordingly, the increased risks for these conditions should be viewed with caution.

Cardiovascular disease and stroke, respectively, were found to be marginally more common among those with hepatitis C, but, unlike for the associations listed above, were not statistically significant (i.e. there is a reasonable chance that the slightly increased risk finding was a chance one and that if studies were repeated, no increased risk would be detected).

10.2.1.2 The Impact of Hepatitis C on Health-Related Quality of Life

Studies which utilised the SF-36 questionnaire to assess health-related quality of life among hepatitis C infected people were analysed. The SF-36 asks a range of questions (36) about physical and mental health. The questions, generally, apply to recent times; these include, for example:

• Does your health now limit you in these activities – lifting or carrying groceries, or climbing several flights of stairs?
• During the past four weeks have you had any of the following problems with your work or any other daily activities as a result of any emotional problems (such as feeling depressed or anxious)?
  - cut down the amount of time spent on work/other activities.
  - accomplished less than you would have liked.

An overall Mental Component Score ( MCS) and Physical Component Score ( PCS) can be generated by analysing the responses. The overall scores can be compared to the average (mean) score of 50, observed in the general population.

The PCS for hepatitis C infected people, irrespective of their characteristics, was 46 (95% confidence interval 45-47). When the score was further examined for factors such as liver disease severity, anxiety, depression, injecting drug use and alcohol use, a statistically significant association between the proportion of participants with cirrhosis and the PCS was observed - i.e. hepatitis C infected people with cirrhosis were more likely to have a lower score than people without. Accordingly, for people without cirrhosis, the score would be somewhere between 46-50 and for people with cirrhosis the score would be less than 46.

The MCS for hepatitis C infected people was 44 (95% confidence interval 41-46). When further examined for factors, as above, no statistically significant associations were observed - i.e. hepatitis C infected people without advanced liver disease and/or a history of excessive alcohol consumption and/or a history of injecting drug use were just as likely as those with these characteristics to have a 6 point lower MCS than the general population.

The authors of the analysis described the PCS and, particularly, the MCS of hepatitis C infected people as “substantially” lower than the general population average scores. The scores need to be interpreted with caution as they, effectively, represent a snapshot (within a lifetime) of hepatitis C infection. Nevertheless, the findings do indicate that for hepatitis C infected people who have not progressed to cirrhosis, there is evidence of a strong association between having hepatitis C infection and having mental health problems. Further, no evidence of publication bias was reported i.e. there was no greater likelihood of the publication of findings indicating an association between hepatitis C and depression than the publication of findings indicating no association.

10.2.2 Examination of the Scientific Literature: Living with hepatitis C virus: a systematic review and narrative synthesis of qualitative literature. Dowsett L et al. Canadian Journal of Gastroenterology and Hepatology: 2017

The following are key excerpts from the Results section of the paper ( 16 ).

10.2.2.1 Disruption to daily life

“Broadly, studies reported that participants experience considerable disruption to daily living, impaired quality of life and chronic physical and physiological symptoms related to HCV. Study participants reported a variety of physical symptoms such as fatigue (references to 12 studies), weakness (two references), nausea (four references), pain (six references), swelling (one reference), headaches (two references) and sweating (one reference). In addition, a number of studies reported participants experiencing physiological symptoms such as depression (three references), anxiety or panic attacks (one reference), and irritability (two references). Other symptoms such as poor memory (two references) and inability to concentrate (three references) were also reported by participants. Fry and Bates found fatigue and other physical symptoms often made full time work difficult to maintain; many participants switched to working part time, quit their job or changed sectors (one reference).”

10.2.2.2 Impact of diagnosis

“After receiving a positive HCV diagnosis, patients report a range of emotions, including distress (being overwhelmed and frightened and feelings of hopelessness) (twelve references), shame or disgust (five references), denial or doubt (three references) and relief (three references).”

“A diagnosis of HCV impacted individuals’ relationships to varying degrees. Some reported that relationships were strengthened due to the diagnosis (six studies), while others found that HCV negatively impacted relationships (five references).”

“Those who experienced a deterioration in their relationships cited that irrationality and irritability (four references), fatigue (four references), physical pain (two studies), stress and financial burden (one study), fear of transmitting HCV to family and children (two references), and fear of sexual transmission or pregnancy (four references) as the factors contributing to weaker relationships.”

10.2.2.3 Stigma

“Many individuals across these studies describe the stigma associated with HCV. The cause of stigma was consistently found to be based on either the association of HCV with injection drug use or risky behaviours (twelve references) and/or ignorance or misconception about transmission (ten references). Individuals with HCV reported that misinformation made those around them afraid of touching them (four references) and afraid of them using regular utensils and plates (e.g. those with HCV would be offered plastic utensils and paper plates) (five references).”

“Emotional responses to stigma included hurt feeling (two references), shame (four references), embarrassment (two references), low self-worth (one reference), fear (three references), anger (three references), depression (one reference), isolation (one reference), feeling dirty (four references), and feeling rejected (one reference). Action-based responses to stigma included educating others (one reference), blaming others (one reference), and changing relationships (one reference). Due to perceived stigma or fear of stigmatisation, those with HCV were often afraid to disclose their HCV status (ten references), lost friends (one reference), changed their employment to avoid stigmatisation (two references), and isolated themselves to avoid experiencing stigma (five references).”

The authors concluded that there was remarkable consistency of themes across all studies, suggesting that different populations of HCV infected individuals may have similar experiences. They also concluded that even when clinically relevant symptoms are not present, HCV can still substantially impact a patient’s life.

10.2.3 Examination of the Scientific Literature: Impact of treatment

Over the last 25 years, the treatment of hepatitis C has changed dramatically from a regimen which has major side effects and poor effectiveness (standard Interferon therapy) to ones which have few side effects and very high effectiveness (the all-oral Interferon-free Direct-Acting Antiviral ( DAA) agents)( 17,18 ).

The side effects associated with Interferon +/- Ribavirin therapy – usually given over a 24-48 week period – are well recognised; fever, headache, joint pains and muscle pains are encountered in the majority of patients and especially in the early phase of therapy. Neuropsychiatric side effects, such as depression and irritability are also common, as are decreases in white cells, red cells and platelets in the blood.

In 1-6% of instances, Interferon treatment for hepatitis C is associated with the development of an underactive or overactive thyroid gland. Side effects associated with eye sight, hearing, the kidney, the heart and the lungs occur rarely (less than 1% of instances).

The most robust study of the impact of hepatitis C antiviral treatments on physical and mental health of people with mild or no liver disease was published by Younossi et al in 2017 ( 19 ).This study analysed patient-reported outcome data from 16 clinical trials conducted during 2012-17; comparisons were made between the effectiveness and safety of Interferon-containing and Interferon-free treatment regimens. The patient-reported outcome data were collected through the use of several instruments; these included the SF-36 Questionnaire (as described above). The results showed that, generally at the group level, people treated with Interferon experienced very considerable declines in mental health, physical health and work productivity, and that these declines reversed slowly following the completion of therapy; for those achieving viral clearance, the subsequent scores were better than the pre-treatment ones. Note that at an individual level there can be longstanding, sometimes irreversible (e.g. associated with the thyroid gland, as above), effects.

Those treated with Interferon-free regimens showed improvements in mental and physical health during the treatment phase and, for those achieving a sustained viral response (sustained clearance of virus from the blood), these improvements continued after treatment completion; the most prominent improvements related to mental health (including worry and emotional wellbeing).

These findings demonstrate the debilitating effects of Interferon on general mental and physical health during the i) treatment and ii) early post-treatment periods (because of the slow reversal of such effects), and improvements in mental health, in particular, as a consequence of viral clearance.

The robustness and comprehensiveness of the studies, and their purity from a non-liver disease perspective, make the finding especially insightful. The authors concluded that the improvements in mental health among those clearing the virus might be due to the resolution of direct hepatitis C virus-related impact on the brain.

It should also be recognised that, during the Interferon/Ribavirin era in particular, therapeutic failure was common not least because the Group in question were more likely to be infected with the less responsive Genotype 1 strain. The impact of receiving “bad news” after a prolonged course of challenging therapy is not well studied but, intuitively, such an experience will have been a negative one from a mental health perspective.

10.2.4 Conversations with individuals registered with SIBSS

Fifteen beneficiaries were interviewed; of these, 11 were male, four had acquired their hepatitis C through blood factor, nine had become infected through blood transfusion and two were widows/widowers/partners of the deceased. Excluding the two widows/widowers/partners, individuals were aged between 35 and 78. All of the 13 individuals who had been infected indicated that they had cleared their virus.

For a small minority, relatively few past and current health and wellbeing issues were apparent. For most, however, the dominant message conveyed was a strong perception that hepatitis C had seriously compromised their ability to reach their full potential - professionally, socially and financially.

The following themes emerged — issues applicable to at least two, but usually several individuals.

10.2.4.1 Impact of Hepatitis C: Notable Losses/Detriments

Loss of Ambition and Constant Worry

For those diagnosed during the 1990s in particular, the lowering of aspiration and ambition as a consequence of being told, at the time of diagnosis and for years after, that i) treatments were relatively ineffective and ii) knowledge about the impact of the infection on health and survival was poor, but over decades the chances of developing cirrhosis, liver cancer and dying from hepatitis C were high. And the associated worry, with consequent anxiety and distress, often lasting many years.

Testimonials from the Individuals who had been infected

• “...it is narrowing... it changes your horizons, your future...”
• “...saw other people getting on with their lives...”
• “...all I could think about was when my liver was going to stop working...”
• “...had myself dead and buried...”
• “...didn’t apply for promotion as I thought I would be dead...”

Testimonials from the Carers or Spouses of Individuals who had been Infected

• “..we were told that she would probably die from liver failure or heart failure but couldn’t say which would be first....”
• “....every time he is ill ...is it anything to do with hepatitis C....”
• “.....he said “how much longer do I have...do I have months, do I have years?”....”

The Debilitating Consequences of Interferon/Ribavirin

(Note that some of those interviewed had not received such therapy due to contraindications because of other conditions or the relatively recent diagnosis of hepatitis C)

The impact of a course or courses of Interferon +/- ribavirin on health and wellbeing – essentially losing up to a year or years of life, often at a crucial stage, both professional and socially.

• “...treatment was hell... off work for six months...”
• “....very, very tired....and scratching every night....”
• “...very ill with interferon.....”

Restriction on Relationships/Having a Family: Self Imposed to Protect Others

The self-imposed restriction on i) developing relationships (particularly sexual) and ii) having children on the grounds that the knowledge of the time indicated that there was an appreciable chance the virus could be transmitted sexually (now understood to be a rare occurrence but in the 1990s there was considerable uncertainty) and from mother to child. In most instances, such restrictions were “acts of sacrifice” to protect others.

Sexual Relationships

• “...didn’t want a sexual relationship with a lassie...”
• “...it knocked the edge off things (sexual relationship with spouse).....not something I like to talk about....”

General Relationships

• “...couldn’t go out with friends drinking...”
• “...relationships were a no no...”
• “...I felt dirty, I would contaminate people...”

Children

• “...chance the virus could spread to the baby...decided to have a termination...”
• “....decided not to have any more kids....”
• “...when I had that infection I wouldn’t see my grandson....I was feart.....I just wouldn’t take that chance.....”

Restriction on Relationships: Imposed by Others

Restrictions were found to be imposed by family, friends and potential friends/partners on hearing about the individual being infected – thus seriously compromising the development and maintenance of relationships; these restrictions are perceived, and/or definitely known, by the infected individual to be due to other people either being afraid of becoming infected or associating the infection with the stigma of injecting drug using behaviours.

Stigma of Association with Injecting Drug Use

• “...people didn’t visit us again...”
• “...I felt ashamed about having hepatitis C...it just seems such a dirty disease...”
• “.....lost a lot of friends...”

Worries about Becoming Infected

• “......my daughter-in-law wouldn’t allow her to handle the ( grand) children.....she felt dirty...because drug addicts contracted it.....”
• “.... always worried about becoming infected ourselves......”( as told by the carer of an infected person)

Difficulties with Employment

Difficulties in securing or holding down employment as a consequences of having to declare hepatitis C infection to an employer and the inhibitory consequences of those experiences in terms of seeking future employment.

• “...lost my job because of it...”
• “...was suspended for two months...”
• “...less work, less pay, less pension...”
• “...rejected for a few jobs... I cried because I felt so bad...”
• “...lost driving license...and lost my job because of the hepatitis...they thought I was epileptic but it was the hepatitis....”

Difficulties in gaining life insurance or a mortgage

• “...I couldn’t get life insurance even after clearance...”
• “...when you tell them you had hepatitis they load you....”
• “....my son couldn’t get life insurance because he told them his mother had hepatitis C...”

10.2.4.2 Impact of Hepatitis C: Mental Health Problems Affecting Overall Professional and Social Functioning

Lowering of Self-Esteem and the Perception that Hepatitis C has “Held One Back in Life”

The longstanding, suppressing impact on self-esteem of having a stigmatising chronic life threatening infection superimposed on another usually chronic disease (i.e. haemophilia or disease requiring surgery and blood transfusion) – i.e. the double blow.

The perception that episodes of fatigue, depression, anxiety, poor memory, “brain fog”, general non-specific poor health and not reaching one’s full potential were/are due i) entirely, or in part, to hepatitis C and/or ii) long-term post-treatment effects of Interferon/Ribavirin. These perceptions have been reinforced by health care staff indicating (with justification) that their patients’ symptoms were/are possibly related to their hepatitis C; however, because any causal relationship between infection and symptom cannot be proven in most instances, the patient is often distressed because they feel “deep down” that their hepatitis C is not taken seriously.

Lowering of Self Esteem

• “...all my files still have high risk on them...”
• “...given another name in hospital...made me feel worthless...”

Perception that Hepatitis C has Held One Back: Exhaustion and Memory

• “...always too tired...couldn’t participate...”
• “...in my twenties...always exhausted...”
• “...my memory was shot to bits...”
• “...really, really tired in the last couple of years... maybe it’s the hepatitis C...”

Perception that Hepatitis C has Held One Back: General

• “...over my life I have been held back by hepatitis C – I wonder what I would have been without my hepatitis C...”
• “.... pretty sure hepatitis C kept me off the (renal) transplant list.....”
• “....a difficult life was made even more difficult....” (as told by the spouse of a deceased individual)

The Stress Associated with the Perceived Injustice of Inquiry and Payment Outcomes and “Failure to Get Closure”

For example, stress due to divisions among patients as a consequence of chronic HCV ‘Stage 1’ (and sometimes advanced HCV ‘Stage 2’) individuals believing the award decisions (to date) to be unfair on the grounds that the disparity between chronic and advanced HCV awards is inconsistent with (i.e. much greater than) the disparity in the overall lifetime health and wellbeing impacts of hepatitis C among chronic and advanced HCV individuals.

The ongoing stress associated with the failure to get closure of the issues and put matters behind them. Numerous inquiries, reviews, meetings, personal assessments – all generating cycles of hope and, for many, disappointment.

Inter-Personal Conflict

• “...it turned everyone against each other...”
• “...he (another person with advanced HCV) hates that he is getting this help and I am getting no help at all...I was angry that he no longer had any financial worries...and I felt bad about that...”

Stress Associated with the Process

• “...sick system because if you drank a bottle of whisky (a day) you get rewarded (i.e. one would increase one’s rate of liver disease progression towards advanced disease) ..”
• “...when the Penrose Inquiry came about (i.e. the publication) that really floored me...”
• “...couldn’t take the stress of having to fill in forms and prove it...”

Fear Following Viral Clearance

The fear and the anxiety among those who have cleared their virus, but still have to be monitored because of liver damage (fibrosis but not cirrhosis) and the increased risk of hepatocellular cancer.

• “...scared that it would come back...”
• “...I got fibrosis and it is quite high...worried every time I get a scan...”

Guilt about not Disclosing Hepatitis C Status and the Guilt About Having Possibly Infected Others

The guilt of not having told ex-partners and children about hepatitis C and the nagging suspicion (even though the risk was very low) that they might have become infected and, if so, their infection remains undiagnosed. The guilt of possibly having infected others.

• “...I didn’t know what to say to them...”
• “.....didn’t tell my daughter till last 2 years.....”
• “....I donated blood in the 1980s...somebody else might have it because of me.....”

Anger and Distress about NHS Failures Concerning the Diagnosis of Hepatitis C

Among those diagnosed years after late 1991, when testing was introduced across Scotland, the feeling of anger because the test had not been offered before – generating the perception that damage caused by the virus could have been avoided through the receipt of antiviral treatment and/or advice about the dangers of alcohol consumption; note that a small proportion were diagnosed after 2012.

The feeling of resentment that either a diagnosis of hepatitis C had been made without consent for testing having been obtained and/or an employer knowing about the diagnosis in advance of the patient’s knowledge.

• “...I could have been given a test earlier...”
• “...the work was told in 1992 but I was told in 1994.....”
• “....why was I not asked to have a blood test....anybody with a blood transfusion should have had it (the test) when it came out....”

Distress of Knowing that Hepatitis C Infection/Disease Stemmed from NHS treatment

The ongoing distress associated with having i) a difficult to treat infection which (they were told) would likely cause debilitating illness and shortened life and ii), for some, the distress of experiencing treatment failure and suffering the severe side effects of Interferon-based therapy – all in the context of the infection/disease having resulted from NHS interventions.

• “...if this hadn’t happened I wonder what our lives would have been like...”
• “....and made me feel guilty about the cost of treatment as well...”

Emotional Impact on Close Family Relationships

People described many complex emotional reactions for the whole family in response to the diagnosis of hepatitis C; these included anger, guilt, anxiety and low mood, resulting in a significant strain upon family relationships for some.

• “...mum and dad blamed themselves for my hepatitis C...”
• “...I didn’t tell my daughter for years...I still feel guilty...”
• “...and he (partner) had to deal with my anxiety and mood swings...”
• “....he felt I didn’t understand, I wasn’t sympathetic enough ......and he said “you’re just trying to make me feel worse” when I mentioned Hepatitis C.....I felt he didn’t have the life he should have had, the comfort he should have had .....and it wasn’t easy for me either......”(as told by the spouse of a deceased infected individual)

10.3 Conclusions

• People with hepatitis C, regardless of liver disease status, are at an increased risk of a number of extrahepatic diseases; most of these are relatively uncommon life-affecting but usually not life threatening conditions. Renal disease due to Membranoproliferative Glomerulonephritis ( MPGN) and B-cell Lymphoma (currently a disease which qualifies for advanced HCV payments) are exceptions.

• Key Recommendation
  Accordingly, Renal Disease due to Membranoproliferative Glomerulonephritis ( MPGN) should be added to the advanced HCV eligibility criteria as it is a condition known to cause a considerable negative impact on life expectancy.

• Other conditions such as sporadic porphyria cutanea tarda and rheumatoid arthritis are more common in people with hepatitis C, but any causal link with reduced life expectancy is not clear cut.
• Interferon-based therapies (used between 1994 and 2016 in Scotland) invariably cause adverse effects which are debilitating over long periods; in contrast, the DAA agents, now used for all, are safe (note: long-term follow-up studies of recipients of DAAs will be undertaken for completeness) and very well tolerated.
• Evidence from the scientific literature - indicating that the mental health (particularly depression, anxiety and self-worth), and thus the quality of life, of people with hepatitis C, regardless of liver disease status, is impaired considerably - is compelling; this evidence is strongly supported by testimonials given by SIBSS beneficiaries.
• Evidence from the scientific literature indicates a relatively small reduction in general physical health due to hepatitis C among people without advanced liver disease; the exception applies to people who have relatively uncommon extrahepatic manifestations of hepatitis C.
• While testimonials from SIBSS beneficiaries generally support these findings, individuals often perceived that periods of fatigue and general malaise were due to their hepatitis C in full or in part. It is possible that the physical health impact of hepatitis C is more pronounced in people infected through blood factor/transfusion who often have other chronic disease conditions (e.g. blood factor disorders), but the evidence base associated with this specific group of individuals is insufficient to say.
• There is no appreciable evidence to indicate that the route of acquisition of Hepatitis C or the number/amount of exposure(s) influences health and wellbeing outcomes.
• While hepatitis C in those without advanced liver disease is not life threatening, it is life changing; this is particularly applicable to people who acquired it through blood factor or blood transfusion, not least because of the “additional blow” conveyed to them by NHS interventions.
• Hepatitis C, particularly in the context of the source of infection being an NHS one, changed lives because of its negative effects on family, relationships in general, ambition, employment, finances, self-esteem and general mental wellbeing; these effects stem from a number of factors including the stigma associated with hepatitis C and the recalibrating effects of being diagnosed with an infection that, according to their healthcare attendants, would likely reduce the quality and quantity of one’s life.
• Most individuals with chronic HCV who are registered with SIBSS were aware of their infection for many years, most lived with the uncertainty surrounding its consequences and most attributed, fully or in part, any ill health to it.
• For those diagnosed more recently, there has been less uncertainty due to improved knowledge and better treatment; however, the failure to have been offered a test decades before (and the perceived disadvantages of a later diagnosis) has caused distress.
• While the majority have been treated successfully, the legacy of their infection manifests, commonly, in the reflection – “...if I hadn’t been infected with hepatitis C what would my life have been like...”.
• While some infected people welcome action in the form of Inquiries, Reviews and Reports, most are stressed by them and yearn for closure – a time when they are free from hepatitis C in their bodies, but also free from hepatitis C in their minds.
• In the context of the life changing impacts of hepatitis C on infected individuals, it is critical that the burden on many of their spouses/partners and the widows/widowers/partners of those deceased - a burden which was particularly evident in the conversations with SIBSS beneficiaries - must be recognised.

11. Term of Reference 3

Assess the impact of chronic hepatitis C virus infection, and associated antiviral therapy, on death among people who did not progress to advanced HCV disease and have died (including those whose death
has been attributed (directly or indirectly) on the death certificate to hepatitis C.

Two approaches were adopted; the examination of the scientific literature and the analysis of Scottish data on hepatitis C.