The results from this population-based cohort study indicated that HCV infection was associated with all-cause and liver-related mortality, highlighting the favourable role of prevention and treatment of HCV infection. We found that individuals positive to antibodies against HCV, and in particular those with chronic infection were at higher risk of all-cause and liver-related deaths than those who were anti-HCV negative, suggesting that approximately 34% of all-cause deaths and 85% of liver-related deaths may be attributable to chronic HCV infection. On the contrary, no increased risk emerged among those with cleared the infection.
Several studies have sought to quantify the burden of mortality from HCV [24,25,26,27,28,29,30,31]. Most of them -although remarkably different in design, in the number of patients, and in length of follow-up- revealed elevated mortality associated with HCV infection, as measured by anti-HCV seropositivity alone [25,26,27,28, 31]. In line with other studies [29, 32], we observed that only anti-HCV positive individuals with circulating HCV RNA had an increased risk of dying from all causes of death, whereas the risk for anti-HCV seropositive people with negative HCV RNA was similar to that for anti-HCV seronegative ones. These results implied that patients with active viral infection may consistently benefit from antiviral treatment to reduce their overall mortality.
The assessment of mortality among people with HCV should comprise the characterization of cause-specific mortality. It is well recognized that HCV may cause fatal liver diseases, including liver cirrhosis and HCC. Our results are in agreement with several studies that showed a strong association between HCV infection and liver-related mortality [24,25,26,27, 29, 30], this association was evident only in individuals with chronic infection who had a significantly higher risk of dying from liver-related diseases than anti-HCV-negative ones. To this regard, our previous study also documented an elevated incidence of HCC in individuals with chronic HCV infection as compared to uninfected ones [15], emphasizing the importance of active infection in predicting also long-term mortality risks from liver conditions. Indeed, it has been shown that patients with cleared HCV infection presented a lower risk of liver fibrosis and, therefore, a presumably lower risk of death [33, 34].
The association between HCV infection and the risk of death from any cause other than liver disease has been frequently reported with conflicting results. Our findings of no increased risk are consistent with those of a large US study using data from the Third National Health and Nutrition Examination Surveys [24]. Similarly, a cohort study from Denmark reported no substantial association between chronic HCV-infection and an increase in non-liver related mortality overall after adjustment for potential confounders [34]. On the other hand, few investigations have shown an increased risk of non-liver-related deaths in patients infected with HCV, probably explained by the presence of comorbidities, alcohol abuse, and injecting drug use in the HCV-infected population [35].
In the present study, most of the deaths from non-liver-related causes were ascribed to circulatory system diseases (238/550, 43%), malignant neoplasms excluding liver cancer (171/550, 31%), respiratory system diseases (42/550, 8%), and diabetes (40/550, 7%) (see Supplementary Table 2), even though they were not significantly associated with HCV (data not shown). In contrast, other investigations have demonstrated significant associations between HCV and mortality from a series of extra-hepatic conditions, including renal and cardiovascular diseases [27, 29, 36]. Previous clinical studies reported an elevated prevalence of metabolic disorders in HCV patients compared to uninfected controls [37]. However, other factors, including high-risk behaviours, lower socioeconomic status, and genetic predisposition, may have also played a role in non-liver-related mortality [24].
A significant burden of comorbidities in patients with HCV and, in particular, elevated risk of death in presence of diabetes, chronic renal diseases, or cardiovascular diseases have been previously found in other studies [17, 38]. Our analysis conducted in the subgroup of people infected with HCV found that non-liver-related mortality -particularly mortality from circulatory system diseases- was increased among individuals with reduced kidney function, while no association emerged in people with hyperglycaemia. Furthermore, the risk of liver-related deaths was elevated in the presence of both disorders, but results should be interpreted with caution since they were based on a low number of events (n = 2).
We also observed that high FIB-4 index score was associated with both all-cause and liver-related mortality among anti-HCV-positive people. In line with our results, a recent investigation of HCV patients showed that the risk of liver-related deaths increased significantly with elevated FIB-4 scores, suggesting that the FIB-4 index could be an important tool to evaluate liver disease risk profile and treatment prioritization [39]. Moreover, in a cohort of HIV-infected patients, the FIB-4 was found to be a risk factor for liver-related deaths, regardless of infection with HCV [40].
It is worth noting that a general decline in HCV prevalence in the same area of this study has been reported in recent years [41]. This is mostly due to the disappearance of the first and most consistent wave of HCV epidemics in Italy in the 1950s and 1960s at least partly explained by the excess mortality among older persons with HCV which is consistent with our results. Nevertheless, as we have already published, a non-negligible prevalence of undiagnosed HCV infection may still be present among older persons, especially in low socioeconomic areas, and it can be speculated that among them a sizeable population of persons with advanced fibrosis, who should be rapidly treated with the new direct antiviral agents, may exist in southern Italy [42].
Given that treatment with DAAs induces the elimination of HCV in over 98% of cases, and in view of the WHO program to eradicate the infection by 2030, not treating HCV patients is currently considered unethical and illegal. One way to assess the impact of treatment on HCV disease is to evaluate the events that occur before and after treatment with DAAs and the results herein reported could represent a reliable historical assessment useful for the evaluation of the effect of universal DAA provision. Growing literature is providing new insights on the effect of DAAs, showing that a sustained viral response by DAA is able to reduce the risk of developing diabetes [43], renal function [44], and overall cardiovascular events’ risk [45]. Since the extensive introduction of DAAs in several countries, recent evidence has shown a sharp decline in liver disease morbidity and overall mortality, as in the UK [6] and Australia [7], reversing the increasing trend observed before their introduction. Therefore, similar results could be observed also in Italy in the near future; indeed, from 2015 to March 2021, over 220,000 DAA-treatments have been administered according to the National Registry data from the Italian Medicines Agency (AIFA), giving reasons to forecast that Italy could meet WHO targets by 2030 [2]. A recent study on HCV burden and treatment trends in European countries reported that in Italy the number of cured individuals will exceed the number of patients with infection by 2026 [46]; however, despite the availability and the increasing use of DAAs, still a large number of patients remained undiagnosed and untreated in the analysed countries [46].
Some limitations should be taken into account when interpreting study results. First of all, as for most studies involving data derived from population seroprevalence surveys, we could not rule out the possibility of sampling bias, as people who refused to take part in the study may be systematically different from those who participated, and sampling weights were not applied in the analyses. Nevertheless, the impact of non-participation on prevalence estimates of HCV/HBV infection has been already discussed in our previous paper [14].
The lack of information about alcohol consumption -a known risk factor in the progression of liver disease- prevented the evaluation of its potential confounding effect on cause-specific mortality. It is known that people with HCV infection are more likely to drink alcohol than those without HCV [47]. Thus, excessive alcohol consumption could partly explain the poor prognostic outcomes and liver-related deaths in HCV-infected patients [48,49,50]. Nevertheless, in southern Italy, HCV infection has been shown to be the major aetiological factor observed in cirrhotic patients over the last decades [13], a finding widely divergent from that observed in northern Italy and in northern Europe, where excessive alcohol consumption accounted for most cases of liver cirrhosis [13, 51].
Another important limitation is the lack of complete information about antiviral treatment. Indeed, such information was available in less than half (n = 118) of the 246 HCV-RNA positive subjects (i.e., those who were aware of their serostatus at enrolment). Among them, only 42 (35.6%) had received conventional interferon-based treatment at the time of testing. Although the relatively small proportion of individuals being treated makes it unlikely that our results are substantially biased by the lack of data on antiviral treatment, we could not exclude an effect of treatment on liver-related mortality.
In addition, information on FIB-4, eGFR, and presence or absence of hyperglycaemia were collected at enrolment, making it difficult to ascertain their real contribution to mortality. Likewise, the lack of data on the staging of liver fibrosis -which may have altered during the follow-up period- needs to be borne in mind.
Mortality data relied on the underlying cause of death since other contributing causes are not consistently coded or available to the regional mortality database of people residing in the study area. Although accurate evaluation of mortality outcomes was made possible by the local availability of a high-quality, population-based cancer registry validated by IARC, some misclassification on the specific cause of death cannot be totally excluded.
The limited number of observed events did not guarantee sufficient power to detect associations for specific subgroups and to comprehensively investigate the impact of HCV on specific causes of non-liver related mortality, thus potential associations may have been hidden, calling for caution in the interpretation of the results.
Despite these limitations, our study -which involved a large cohort of 4492 people living in an area with a high prevalence of HCV infection- yielded important information on the effect of HCV on cause-specific mortality before the advent of DAAs. The use of population-based data that allowed an accurate evaluation of mortality outcomes, the length of follow-up, and accurate testing for serological detection of HCV (including HCV RNA testing) represent major strengths of our study.