The ongoing impacts of hepatitis c - a systematic narrative review of the literature

Transmission of Hepatitis C

We identified 42 cohort studies investigating the transmission of hepatitis C in various community and hospital based populations. Eighteen of these followed up community-based injecting drug users (IDU) and two studies also included non-injecting participants (see Additional file 1: Table S1). In thirteen, the IDU cohort was seronegative for hepatitis C at baseline, with rates of new infection ranging from 8.1 to 45.8 per 100 person-years. While all reported incidence rates were significantly higher than in non-IDU, rates appeared to be unrelated to the period of follow up. This may be due to infection of susceptible populations relatively early in their injecting careers. Roy et al. [16] noted that around 50% of a cohort of IDU in Canada had seroconvert within the first four years of injecting, and Maher et al. [17] found that being within the first year of injecting independently predicted hepatitis C seroconversion after adjusting for a range of demographic factors and risk behaviours. Re-infection rates among IDU previously achieving viral clearance tended to be lower than new infection rates – suggesting a role for host related factors.

Twenty four studies investigated incidence rates in the general population and its subpopulations (see Additional file 1: Table S2). Studies undertaken in general population samples in Chile, Italy and Japan indicate tha the incidence of hepatitis C general populations overall was low compared to IDU populations – ranging from 0.01 to 0.4 per 100 person years in four identified studies. A higher general population rate was reported by Grebely et al. [18] – 7.4 per 100 person years – who sampled an inner city population that included a high proportion of IDU. Reported rates were higher in renal patients undergoing long term hemodialysis in some countries, although reductions were observed in Italy and Germany in line with improving infection control practices.

There is evidence that perinatal transmission is associated with maternal hepatitis C viraemia, and is significantly more frequent in maternal HIV co-infection. While up to 31 percent of babies born to mothers with hepatitis C were reported to be seropositive shortly after birth, Sbebl et al. [19] found that only 2.4% remain so by three years of age. Hepatitis C transmission in people already infected with HIV, and in HIV negative men who have sex with men, was relatively low – and occurred mainly through injecting drug use. Four studies in the UK and Australia demonstrated an elevated transmission rate in prisoner populations – particularly in prisoners reporting injection drug use whilst incarcerated. Dolan et al. [20] estimated a rate of 21.3 per 100 person years in imprisoned heroin users, while a rate of 4.6 per 100 person years was observed in the South Australian prison population [21] – although community exposure couldn’t be ruled out in the latter study.

Natural history of chronic hepatitis C infection

We identified 69 cohort studies investigating the natural history of chronic hepatitis C infection (see Additional file 1: Table S3). Of these, 42 studies focused on health outcomes for people mono-infected with hepatitis C, while the remainder (27 studies) compared outcomes in hepatitis C, hepatitis B or HIV mono- and co-infection. Mortality, disease progression and development of hepatocellular carcinoma (HCC) were outcomes investigated by the majority of all studies, and a small number focused on viral clearance. Two studies investigated behavioral outcomes – one looking at clinical factors associated with treatment uptake and the other looking at general practitioner (GP) patterns of management and referral to specialists in hepatitis C.

The studies in people with untreated chronic hepatitis C monoinfection had follow up periods ranging from one to 35 years in samples of clinical groups as small as 17 to sample sizes approaching half a million from large clinical data bases. The evidence for fibrotic changes and development of liver cirrhosis, development of HCC and increased liver-specific mortality in chronic hepatitis C over time was relatively consistent. Several studies found that the more serious complications of chronic infection were predicted by the presence of persistent viraemia, moderate to high alcohol consumption and increasing age. Age was not as important in a study in elderly Italians with chronic hepatitis C, which found deaths to non-liver related causes occurred more frequently than liver-specific deaths over ten years of follow up. Studies investigating health outcomes for people with persistently normal alanine amino transferase (ALT) levels suggest that liver cirrhosis and HCC do occur, but the frequency and rate of disease progression tends to be low relative to those with consistently high ALT levels. Despite the apparent importance of this indicator, Yawn et al. [22] found that less than half of primary care physicians monitored ALT in their patients with hepatitis C. While unlikely to have direct impact on the experience of living with hepatitis C, a lack of ongoing ALT monitoring might eventually have implications for health outcome in their patients. Yawn et al. also found there was only limited and inconsistent management and referral with respect to potential accelerators of progression such as excessive alcohol consumption and viral co-infections.

Twenty seven studies compared the longer term effects of chronic mono-infection with hepatitis C and hepatitis B or HIV, and/or the impact of co-infection with any of these. Fifteen studies investigated the independent or combined effects of hepatitis B and C for between 3.4 and 23 years of follow up. While studies varied in the order of risk for hepatitis B or C monoinfection, co-infection was relatively consistently associated with greater incidence of HCC and lower survival than mono-infection. In their 23 year follow up study, Zampino et al. [23] found that earlier age at infection was associated with a lower disease progression in both mono- and co-infected patients.

Eleven studies were in cohorts infected with either HIV or hepatitis C or both. Most of these compared the independent effects of infection with each virus – with outcomes such as AIDS, liver cirrhosis, and overall and specific mortality. An exception was Grebely et al. [24] who investigated hepatitis C viral clearance (rather than disease outcome) in a community sample in Canada, and found that co-infection with HIV and continuing injecting drug use were associated with hepatitis C viral persistence. In other studies, HIV-hepatitis C co-infection was found to have a synergistic effect in which the progression to AIDS and end stage liver disease and liver-related death (mostly due to HCC) was accelerated. Improvements in survival were calculated for HIV patients in hepatitis C-related end stage liver disease under active anti-retroviral treatment (HAART), although this finding was not supported by other studies in this group (see García-Garcia et al. [25] for example). In their study of antiviral treatment initiation for hepatitis C in Denmark, Hansen et al. [26] found that 33% of patients commenced treatment within five years and this was predicted by higher ALT, HCV genotype 2 or 3 (the most favourable for successful treatment outcome) and HIV negative status.

We identified two cohort studies investigating the combined and/or independent effects of infection with hepatitis B, hepatitis C and HIV. Bonacini et al. [27] found liver-related mortality in HIV patients was increased regardless of the hepatitide with which they were co-infected, and was more common when both were present. In a cohort of haemophilia patients with HIV infection, Melendez-Morales et al. [28] found an 11-fold increase in hepatitis C viral clearance in the presence of hepatitis B. The authors suggest that this may be due to ‘mutual interference in viral replications’ – as is thought to occur in the presence of hepatitis D.

Health related quality of life during the course of antiviral treatment

Eight cohort studies investigated the impact of hepatitis C treatment on health related quality of life (QoL) (see Additional file 1: Table S4). Six of these studies used the 36-item Medical Outcomes Study Short-Form 36 (SF-36) or the 12 item version (SF-12), in wide use around the world to measure health status across eight domains relevant to physical, mental and emotional health. The SF-36 and various measures to establish depression levels and other social and emotional dimensions, uniformly demonstrated reduced health related quality of life during treatment but improving post treatment – particularly when sustained viral responses were achieved. Evon et al. [29] found the prevalence of depression was relatively high in patients prior to treatment (12%) and this predicted early exit from treatment. Depression newly diagnosed during treatment had a lesser impact on early exit.

Health outcomes after antiviral treatment or liver transplant

Twenty eight studies investigated health outcomes following interferon based treatments (generally in combination with Ribavirin) or after liver transplant (see Additional file 1: Table S5). Fifteen studies were in patients with no viral co-infection who were followed up from six months to 14 years after treatment. In most populations, sustained viral responses were attained in between 20% and up to 80% depending on the viral genotype (with genotypes other than 1 and 4 considered the most favourable), and sustained viral responses were associated with a lower incidence of complications such as HCC and lower mortality. Dalgard et al. [30] demonstrated that the comparable outcomes were achievable in people who inject drugs, despite ongoing concerns about compliance with treatment schedules and ongoing drug use.

Four studies investigated treatment-related outcomes in hepatitis C patients co-infected with either hepatitis B or HIV. Ikeda et al. [31] found that any viral response to hepatitis C treatment (transient or sustained) was protective for the development of HCC, but not in the case of co-infection with hepatitis B. Co-infection with HIV appeared to be a barrier to evaluation for, and uptake of, hepatitis C treatment although sustained response rates (per genotype) have been reported to be similar to those seen in hepatitis C mono-infection. Furthermore, hepatitis C disease progression may be slowed with treatment even when sustained response is not achieved.

We identified nine cohort studies investigating health outcomes after liver transplantation. Four of these studies compared health outcomes in organ recipients with and without markers for hepatitis C. In all cases, hepatitis C was associated with lower survival and reduced overall health and function. In their seven-year retrospective study of patients following hepatitis C related liver transplants, Gallegos-Orozco et al. [32] estimated a median survival time of 3.5 years. According to Bizollon et al., [33] sustained response to hepatitis C treatments provided post-transplantation is associated with improved graft survival although not necessarily with improved survival.

Quality of life in untreated hepatitis C

Sixty six studies investigated quality of life (QoL), including eight cohort studies in people undergoing treatment also identified in the biomedical literature. Forty five of these studies measured QoL impacts in untreated chronic infection in community-based and clinic populations, former or current IDU, people with viral co-infections, patients with various stages of disease progression, and patients with co morbidities (see Additional file 1: Table S6). Again, the SF-36 (or SF-12) was the main instrument used to assess health related QoL, and several studies used other validated instruments measuring mental health and psychosocial status. The studies provide relatively consistent evidence of reduced QoL in untreated hepatitis C in most populations. The exception was provided by Bailey et al., [34] who observed moderate to high levels of QoL in US hepatitis patients, upon whom the main negative impact was uncertainty surrounding prognosis. In Australia, Thein et al. [35] found little difference in QoL between HIV and hepatic C mono-infected, co-infected and un-infected patients – although the authors pointed out the numbers in each group may have been too small to demonstrate clear differences.

There was substantial variation among studies about the relative impact of a range of co-factors on QoL. Several studies concluded reduced QoL in hepatitis C was independent of disease activity, liver histology and drug and alcohol use. Gunasekera et al., [36] however, found that QoL was reduced in hepatitis C patients recruited from rural drug and alcohol services when compared to rural primary care or hepatitis C centres. Continued drug use was associated with reduced QoL in two other studies, but not in others analyzing the role of substance use. Two studies led by Kramer [37, 38] both found reduced QoL in hepatitis C which was associated with fatigue, but not with observed slight neuro-cognitive impairment. Fatigue and depression accounted for the majority of reduced QoL in a study of HIV-hepatitis C coinfected patients in France [39].

Several studies proposed an emotional or psychosocial basis for reduced QoL. Dalgard et al. [40] and Shwarzinger et al. [41], for example, found that awareness of hepatitis status explained much of the reduction in QoL. Depression and psychiatric co morbidities were found to be important in some studies, although others found that the co-existence of mental illness failed to fully explain the QoL differentials in those with and without hepatitis C. While several studies found little association between QoL and ALT or liver fibrosis in clinic populations, advanced liver disease did appear to be closely correlated with reduced QoL in hepatitis C.

Quality of life related to hepatitis C treatment

Twenty two studies investigated health related QoL in patients undergoing antiviral treatment or liver transplantation, with the majority using the SF-36 (see Additional file 1: Table S7). The studies were mainly cross-sectional, with seven utilizing a follow up design (as previously described). Most of the eleven studies in patients undergoing interferon-based antiviral treatment noted further reductions in health related QoL during the treatment, with depression playing a significant role. Improvements were noted post treatment in most studies, particularly where sustained virological clearance was achieved. Fontana et al. [42] compared QoL in patients who were accessing treatment and those who were not. They found that emotional distress, which was strongly associated with reduced QoL, was highest in the untreated group – particularly in those who were anticipating a fatal outcome to their chronic hepatitis C infection. One study found no difference in QoL between treated and untreated groups but did find that concurrent treatment had a negative impact on cognitive abilities [43]. Studies of patients post treatment suggest that the benefits of successful treatment can be sustained over time, as can the deleterious effects of less successful treatment. In their study of untreated patients, patients who had relapsed after treatment and patients who did not respond to treatment, Taliani et al. [44] found that non-responders had the lowest QoL. Low quality of life scores were independently associated with co morbidity and non-response to treatment. They suggest that treatment expectations may be important modifiers of QoL.

Three studies investigated QoL following hepatitis C related liver transplantation. Two quantitative studies found significant impairments in QoL in recurrent hepatitis C (occurring in 36% to 62% of the study populations) in the years following transplants, while non-recurrence was associated with improved functional performance and quality of life over time. In a qualitative study involving in-depth interviews with eight post transplant patients, Dudley et al. [45] concluded that stigma and disease uncertainty in hepatitis C continues after liver transplants and may further impact adversely on QoL in hepatitis C patients.

Psychosocial experience of living with hepatitis C infection

We identified 43 studies investigating the impact of hepatitis C on social functioning, lifestyle, health and well-being (see Additional file 1: Table S8). In a majority of studies, diagnosis with hepatitis C was reported to have profound impacts on social functioning. The perceived stigma associated with infection led to high levels of anxiety, and exaggerated fears of transmission and was the main driver of social isolation and reduced intimacy in relationships [46–48]. Grundy and Beeching [46] found that fear of transmission – particularly in intimate relationships, child birth and child rearing – led to concerns about being able to fulfil gender roles in a group of women with hepatitis C. There is further evidence that the social experience of living with hepatitis C differs between women and men. For instance, Temple-Smith et al. [49] found substantial gender differences in health seeking behaviours and notions of social support.

Fear of transmission, where the perceived risk is often unnecessarily inflated, also appeared to result in unnecessary changes in everyday practices, such as refraining from sharing towels and drinking glasses or not taking part in food preparation [50]. Changes in intimate and/or sexual practices, sometimes exhibiting as sexual dysfunction, have been observed in association with depression and anxiety about transmission [51]. Other lifestyle impacts of hepatitis C include reductions in alcohol consumption, reductions in smoking and modification of dietary intake [52]. In the context of competing priorities including housing, employment and legal implications of injecting, hepatitis C was viewed to be of less consequence by some study participants who injected drugs, but modification of risk behaviours (such as cleaning of syringes and spoons, and less sharing of injecting paraphernalia) was reported [53, 54].

Infection with hepatitis C has been found by a number of studies to have substantial impacts on health and well-being, often in relation to fear and uncertainty about prognosis [55]. One study found that feelings of hopelessness in conjunction with uncertainty were experienced by people with either hepatitis C or HIV, but tended to be heightened in hepatitis C [56]. Perceived stigma and discrimination impeded adaptation to the hepatitis diagnosis and was a common source of anxiety in people with chronic hepatitis C [56, 57]. Hopwood and Treloar [58] found that the psychosocial stress associated with hepatitis C was less in those with a history of IDU, which may arise from greater resilience in coping with hepatitis C stemming from experiences of marginalization for people who inject drugs. A number of studies investigated specific symptoms of hepatitis C infection – with fatigue being the most common, followed by depression and other mental health issues. Bodily pain, particularly in the form of myalgia and a degree of cognitive impairment was also identified by several authors. The majority of studies found symptoms were independent of disease activity or disease severity, but associated with depression, anxiety and other psychosocial factors. The direction of causation might prove difficult to untangle, particularly where specific symptoms are tightly clustered. Golden et al., [59] for instance found that mood disorders were highly prevalent in hepatitis C, and depression was associated with experiences of illness – including stigma, poor adjustment to the diagnosis and physical symptoms. There were three studies that suggested a biological cause for a slight cognitive impairment observed in hepatitis C [60–62].

Responses to diagnosis and management of hepatitis C

Finally, we identified 26 studies investigating experiences related to diagnosis and treatment (see Additional file 1: Table S9). With some degree of overlap, these studies focused on the immediate impact of diagnosis and perceptions of stigma and discrimination in relation to it, accessing health services and making decisions about treatment. Diagnosis with hepatitis C could be a stressful event, characterized by feelings of shock and devastation that transitioned into enduring emotional, psychosocial and even physical effects [63]. For some, the time of diagnosis was an event equivalent to the stress of events such as moving cities, losing a job, marital breakdown and divorce [64]. Some studies, however, described a more dynamic response that was mediated by changes in social context [65]. For instance, the threat of HIV and issues related to substance use was considered a higher priority in some groups [66].

The perception of stigma is generally an internalized phenomenon resulting from individually held understandings and interpretations, or arising in response to actual or perceived discrimination. For instance, study participants described perceptions of stigma resulting from feelings of contamination and fear of disclosure to others, from whom they anticipated rejection, much of which was on the basis of fear of disease transmission [67]. Golden et al. [68] found perceived stigma was associated with decreased acceptance of illness, decreased social adjustment and increased reported symptoms in hepatitis C.

Discrimination can flow from the beliefs and attitudes of others and ultimately shape perceptions of stigma through the differential treatment of people with particular conditions. As Paterson et al. [69] describe, how illnesses are constructed by health providers influences not only the care offered, but also feeds into the self perception of the affected person. Many study participants reporting negative experiences in health care settings in relation to perceived discrimination. In one study of over 500 people with hepatitis C, 65% reported having experienced health care discrimination, which was associated with pessimism about future health and decreased social interaction among other things [70]. Perceived discrimination was also found to be a significant barrier to health treatment access, to the extent that refusal of treatment by providers was reported [71]. Harris [72] found that reports of refusal or withdrawal of health care were common and contributed to a reluctance to disclose to health professionals even in the context of a perceived obligation to do so.