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Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic Diseases: A Community-Based Long-Term Prospective Study - (R.E.V.E.A.L.)-HCV study
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from Jules: this study found if a person had HCV with detectable viral load which almost everryone does, risk for death due to liver related disease increased a lot, risk for extrahepatic disease (kidney, cancers, heart disease, circulatory diseases increased. THIS notion is something that clnicians often in the past never told their patients, patients were told 'you can delay therapy, in fact maybe you don't ever have to be treated. But its clear, always has been to me & to some others that there is a real risk for developing extrahepatic diseases & this study found this increases risk for death!!!! Very important, the message is to get cured.
"In this community-based cohort study, HCV infection was found to be associated with deaths from hepatic and extrahepatic diseases, particularly for those with detectable serum HCV RNA" .......increased risk for those with detectable HCV viral load all causes of death; 12.48, for hepatic diseases; 1.35 (1.15-1.57), for extrahepatic diseases; 1.50 (1.10-2.03), for circulatory diseases; 2.77 (1.49-5.15) for nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38-12.08) for esophageal cancer; 4.19 (1.18-14.94) for prostate cancer; and 8.22 (1.36-49.66) for thyroid cancer- pdf attached
J Infect Dis. (July 2012)
"Our findings indicate that anti-HCV seropositives with detectable serum HCV RNA had an elevated mortality from several extrahepatic diseases, whereas the risk for anti-HCV seropositives with undetectable HCV RNA had mortality rates much similar to those seronegative for anti-HCV."
"Anti-HCV seropositives, particularly those with detectable serum HCV RNA, should be encouraged to modify health behaviors, including weight reduction, tobacco cessation, or eating a balanced diet, in order to decrease the risk of cancers, circulatory diseases, and renal diseases."
"We found that anti-HCV seropositives with detectable serum HCV RNA had an increased risk of dying from all causes of death, whereas the risk for anti-HCV seropositives with negative HCV RNA was similar to the risk for anti-HCV seronegatives. The results implied that chronic hepatitis C patients with active virus infection may benefit from antiviral treatment to reduce their overall mortality....In this study, the cumulative hepatic disease mortality 18 years after enrollment was as high as 9.3% for anti-HCV seropositives......Our previous report also documented an elevated incidence of hepatocellular carcinoma in anti-HCV seropositives when detectable serum HCV RNA levels were compared to those with undetectable levels [9]......In this prospective study, HCV infection was associated with an increased mortality from extrahepatic diseases, including circulatory diseases and renal diseases. Chronic HCV infection was associated with an increased (1.4-fold) mortality from circulatory diseases......We have reported that HCV infection was associated with cerebrovascular death after considering for conventional risk factors. The dose-response relationship between serum HCV RNA level and the risk of cerebrovascular death further strengthened the causal association of HCV infection and atherosclerosis [21]. HCV infection may play as a stimulus for atherothrombosis by triggering a cascade of immune and inflammatory responses, either locally within vascular tissue or systematically through inflammatory mediators [22]......Anti-HCV seropositives, particularly anti-HCV seropositives with positive HCV RNA, had an increased risk of dying from renal diseases compared with anti-HCV seronegatives......In addition to hepatocellular carcinoma, this study found significant associations between HCV infection and increased mortality from cancers of the esophagus, prostate, and thyroid."
"Participants seropositive for anti-HCV had an increased risk of dying from hepatic diseases with a multivariate-adjusted HR (95% CI) of 12.48 (9.34-16.66).."
"The mortality rate of extrahepatic diseases per 100 000 person-years was 671.6 for anti-HCV seronegatives and 1054.8 for anti-HCV seropositives. Among the extrahepatic causes of death, 1383 (68.5%) and 124 (69.3%) were noncancer deaths for participants seronegative and seropositive for anti-HCV, respectively. The mortality rates per 100 000 person-years for extrahepatic noncancer causes were 459.8 for anti-HCV seronegatives and 730.7 for anti-HCV seropositives with an multivariate-adjusted HR (95% CI) of 1.38 (1.15-1.16). Participants seropositive for anti-HCV had a higher risk of dying from circulatory diseases and renal diseases with a multivariate-adjusted HR (95% CI) of 1.50 (1.10-2.03) and 2.77 (1.49-5.15), respectively, compared with anti-HCV-seronegative participants."
Abstract
Background. The study aimed to evaluate the risk of hepatitis C virus (HCV) infection on hepatic and extrahepatic deaths.
Methods. A cohort of 23 820 adults aged 30-65 years old were enrolled during 1991-1992. The seromarkers hepatitis B surface antigen (HBsAg), anti-HCV, and serum HCV RNA levels at study entry were tested. The vital status was ascertained through computerized linkage with national death certification profiles from 1991 to 2008.
Results. There were 19 636 HBsAg-seronegatives, including 18 541 anti-HCV seronegatives and 1095 anti-HCV seropositives. Among anti-HCV seropositives, 69.4% had detectable serum HCV RNA levels. There were 2394 deaths that occurred during an average follow-up period of 16.2 years. Compared with anti-HCV seronegatives, anti-HCV seropositives had higher mortality from both hepatic and extrahepatic diseases, showing multivariate-adjusted hazard ratio (95% confidence interval) of 1.89 (1.66-2.15) for all causes of death; 12.48 (9.34-16.66) for hepatic diseases; 1.35 (1.15-1.57) for extrahepatic diseases; 1.50 (1.10-2.03) for circulatory diseases; 2.77 (1.49-5.15) for nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38-12.08) for esophageal cancer; 4.19 (1.18-14.94) for prostate cancer; and 8.22 (1.36-49.66) for thyroid cancer. Anti-HCV seropositives with detectable HCV RNA levels had significantly higher mortality from hepatic and extrahepatic diseases than anti-HCV seropositives with undetectable HCV RNA.
Conclusions. Monitoring HCV RNA in anti-HCV seropositives is essential for the prediction of mortality associated with hepatitis C.
Hepatitis C virus (HCV) infects more than 170 millions people worldwide [1]. There is a considerable geographical variation in seroprevalence of antibodies against HCV (anti-HCV) throughout the world, with approximately 1.3% in developed countries and 2.6% in developing countries [2]. HCV is well recognized to cause fatal liver diseases, including liver cirrhosis and hepatocellular carcinoma. Individuals infected with HCV are often asymptomatic and not aware of their illness until severe and irreversible liver diseases occur. Several long-term follow-up studies examined the sequelae associated with HCV infection were often limited to specific populations [3-5]. The impacts of HCV infections, particularly among those with viremia persistently, on the mortality of liver diseases have been less evaluated for the general population in the community.
In addition to hepatic diseases, HCV infection has also been found to be involved in a variety of extrahepatic diseases. Several clinical manifestations have been reported to be linked with HCV infection [6]. Negative-strand HCV RNA by strand-specific reverse transcriptase polymerase reaction, an evidence for viral replication, has been detected in extrahepatic tissues [7]. Antiviral therapy has been documented to decrease the rate of fibrosis progression in patients with chronic HCV infection [8], suggesting extrahepatic diseases may become an important health burden in HCV-infected patients. However, the HCV-associated mortality from extrahepatic diseases has seldom been assessed in long-term follow-up studies on community-based cohorts. The associations between the seropositivity of HCV RNA and the mortality from extrahepatic diseases have never been evaluated.
The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (R.E.V.E.A.L.)-HCV study is a prospective community-based cohort study in Taiwan, which provides a large number of participants for investigations of natural history and long-term disease burden of chronic hepatitis C [9]. In this analysis, we compared both hepatic and extrahepatic mortality rates predicted by seromarkers of HCV infection, including anti-HCV and HCV RNA at study entry.
DISCUSSION
An increasing HCV-related mortality from 1.09 to 2.40 per 100 000 person-years has been reported in the United States from 1995 to 2004 [14]. The predicted mortality over a 20-year period is expected to continue to rise [15], suggesting the health burden related to HCV infection will be substantially considerable in the foreseeable future.
The detectable serum HCV RNA level is a marker for active replication of HCV, and 52%-80% of serum samples seropositive for anti-HCV were found to have detectable serum levels of HCV RNA in previous reports [16-18]. We found that anti-HCV seropositives with detectable serum HCV RNA had an increased risk of dying from all causes of death, whereas the risk for anti-HCV seropositives with negative HCV RNA was similar to the risk for anti-HCV seronegatives. The results implied that chronic hepatitis C patients with active virus infection may benefit from antiviral treatment to reduce their overall mortality. This finding was in line with another prospective study conducted in Japan, which showed that 28.0% anti-HCV seropositives with HCV viremia (detectable HCV core antigen or HCV RNA in serum) and 17.9% anti-HCV seropositives without HCV viremia died from any cause during an average follow-up period of 8.2 years [19]. However, the cumulative mortality for anti-HCV seropositives without viremia in the Japanese study was 5% higher than that in the R.E.V.E.A.L.-HCV study. This may have resulted from differences in the age and sex composition and clinical characteristics of HCV-infected participants between the 2 studies. Possibly, the different detection limit of the HCV RNA assays might also have contributed to the discrepancy.
In this study, the cumulative hepatic disease mortality 18 years after enrollment was as high as 9.3% for anti-HCV seropositives. It has been reported that the cumulative mortality from hepatic diseases among anti-HCV seropositives was 0.35%-5% after 10-25 years of follow-up [3-5, 20]. However, most previous long-term follow-up studies enrolled relatively young and healthy populations [3, 5]. More notably, anti-HCV seropositives with detectable serum HCV RNA had a significantly higher risk of dying from any hepatic disease than anti-HCV seropositives with undetectable serum HCV RNA. Our previous report also documented an elevated incidence of hepatocellular carcinoma in anti-HCV seropositives when detectable serum HCV RNA levels were compared to those with undetectable levels [9]. The consistent findings suggest active infection (seropositive for HCV RNA) rather than prior infection (seropositive for anti-HCV) is more important in predicting the long-term risk of mortality from liver diseases.
In this prospective study, HCV infection was associated with an increased mortality from extrahepatic diseases, including circulatory diseases and renal diseases. Chronic HCV infection was associated with an increased (1.4-fold) mortality from circulatory diseases, which was consistent with other reports in Western countries [3, 20]. We have reported that HCV infection was associated with cerebrovascular death after considering for conventional risk factors. The dose-response relationship between serum HCV RNA level and the risk of cerebrovascular death further strengthened the causal association of HCV infection and atherosclerosis [21]. HCV infection may play as a stimulus for atherothrombosis by triggering a cascade of immune and inflammatory responses, either locally within vascular tissue or systematically through inflammatory mediators [22].
Anti-HCV seropositives, particularly anti-HCV seropositives with positive HCV RNA, had an increased risk of dying from renal diseases compared with anti-HCV seronegatives. A large cohort of veterans in the United States found that HCV-infected participants had an increased risk of developing end-stage renal diseases treated with dialysis or renal transplantation [23]. The pathogenesis of HCV-associated renal disease might have resulted from the deposition of circulating immune complexes in the mesangium and subendothelium, which activate the complement system with the proliferation and infiltration of mononuclear phagocytes, enabling the release of protease and oxidants to alter the glomerular permeability [24].
In addition to hepatocellular carcinoma, this study found significant associations between HCV infection and increased mortality from cancers of the esophagus, prostate, and thyroid. A case-control study found an association between HCV and thyroid cancer with a significant odds ratio of 3.3 [13]. Yet, other large-scale prospective studies failed to find the associations [20, 25]. The associations with HCV infection for prostate and esophagus cancer have never been reported previously and need further studies to confirm. Interestingly, all participants who died from these cancers had detectable serum HCV RNA, suggesting that active HCV infection might play a role. By computerized linkage with national cancer registration profiles, we also found that participants with HCV infection had an increased incidence of esophagus, prostate, and thyroid cancers (data not shown). A large veteran cohort indicated that HCV infection conferred a 20%-30% increased risk of non-Hodgkin lymphoma [25]. In this cohort, only 2 cases died from non-Hodgkin lymphoma and no cases died from Hodgkin's lymphoma among anti-HCV seropositives. It was difficult to evaluate the association between HCV infection and lymphoma in this study.
Our findings indicate that anti-HCV seropositives with detectable serum HCV RNA had an elevated mortality from several extrahepatic diseases, whereas the risk for anti-HCV seropositives with undetectable HCV RNA had mortality rates much similar to those seronegative for anti-HCV. This suggests that not only hepatic deaths but also extrahepatic deaths could be decreased in anti-HCV seropositives by clearing the virus with efficient antiviral therapy. Our results strengthen the importance of including an HCV RNA test for anti-HCV seropositives in clinical practice. Anti-HCV seropositives, particularly those with detectable serum HCV RNA, should be encouraged to modify health behaviors, including weight reduction, tobacco cessation, or eating a balanced diet, in order to decrease the risk of cancers, circulatory diseases, and renal diseases.
The strength of this study is its generalizability for relatively healthy individuals with chronic HCV infection, particularly for those who acquired HCV via iatrogenic exposures in developing countries. Unlike most Western countries, the most important risk factor of HCV infection in our study population was iatrogenic factors [26-28]. The epidemiological characteristics of HCV infection in Taiwan were similar to those in Japan, Korea, Italy, India, and developing countries [16, 19, 29, 30]. People acquired HCV infection when they received medical or dental procedures, blood transfusion, medical injections, hemodialysis, acupuncture, and similar procedures. Although our study population has a limited generalizability to Western countries where most individuals infected with HCV were drug abusers, the findings that active HCV infection (positive for HCV RNA) was associated with an increased risk for either hepatic or extrahepatic diseases are still applicable to Western populations. Drug users should be educated to not share injection equipment to avoid HCV reinfections, and they should be encouraged to receive antiviral treatment. The liver-related mortality reported in this study is considered to be a critical parameter for evaluating the efficacy and effectiveness of chronic hepatitis C management. In addition, the associations between HCV infection and extrahepatic diseases provide insights for future investigations. We classified the risk of hepatic and extrahepatic mortalities for anti-HCV seropositives by including HCV RNA testing, and we also considered other conventional risk factors that have been reported be associated with the diseases. However, some diseases were too rare to derive precise risk estimates associated with HCV infection. A collaborative study with an enlarged sample size is needed to further elucidate the association between HCV infection and rare diseases.
In this community-based cohort study, HCV infection was found to be associated with deaths from hepatic and extrahepatic diseases, particularly for those with detectable serum HCV RNA. It is implied that anti-HCV seropositives should be consulted regarding their elevated risks of both hepatic and extrahepatic diseases. It is also suggested that a serum HCV RNA test with appropriate assay may be helpful to triage HCV-infected patients who need intensive care.
RESULTS
There were 1095 anti-HCV seropositives and 18 541 anti-HCV seronegatives in this study. The mean age in this cohorts was 47.6 years old at study entry (47.4 years in anti-HCV seronegatives and 50.8 years in anti-HCV seropositives; P < .01). There were 9060 (48.9%) males in anti-HCV seronegatives and 465 (42.5%) in anti-HCV seropositives (P < .01).
The average follow-up period was 16.2 years. A total of 2394 deaths occurred during 317 742 person-years follow-up, giving an overall mortality of 753.4 per 100 000 person-years among HBsAg-seronegative participants. Table 1 shows the mortality rates and multivariate-adjusted HRs with 95% CIs of specific causes of death by serostatus of anti-HCV at study entry. Liver cancer and chronic liver diseases and cirrhosis contributed to most of the hepatic diseases. The proportionality assumption (nonchanging HRs over time) of Cox models was examined, and the assumption was not violated. Participants seropositive for anti-HCV had an increased risk of dying from hepatic diseases with a multivariate-adjusted HR (95% CI) of 12.48 (9.34-16.66). The mortality rate of extrahepatic diseases per 100 000 person-years was 671.6 for anti-HCV seronegatives and 1054.8 for anti-HCV seropositives. Among the extrahepatic causes of death, 1383 (68.5%) and 124 (69.3%) were noncancer deaths for participants seronegative and seropositive for anti-HCV, respectively. The mortality rates per 100 000 person-years for extrahepatic noncancer causes were 459.8 for anti-HCV seronegatives and 730.7 for anti-HCV seropositives with an multivariate-adjusted HR (95% CI) of 1.38 (1.15-1.16). Participants seropositive for anti-HCV had a higher risk of dying from circulatory diseases and renal diseases with a multivariate-adjusted HR (95% CI) of 1.50 (1.10-2.03) and 2.77 (1.49-5.15), respectively, compared with anti-HCV-seronegative participants.
In this study, 975 anti-HCV seropositives had retrievable samples for serum HCV RNA test. Among them, there were 298 (30.6%) undetectable and 677 (69.4%) detectable for HCV RNA. Figure 1 shows the cumulative mortality from all causes, hepatic diseases, and extrahepatic diseases by seropositivity of anti-HCV and HCV RNA. Anti-HCV seropositives with detectable serum HCV RNA levels had a significantly higher risk of dying from all causes of death, hepatic diseases, and extrahepatic diseases than anti-HCV seropositives with undetectable serum HCV RNA and anti-HCV seronegatives (P < .001).
Figure 2 shows the cumulative mortality from liver cancer and chronic liver diseases and cirrhosis by seropositivity of anti-HCV and HCV RNA. After 18 years of follow-up, the cumulative liver cancer mortality was 0.3%, 1.6%, and 10.4% for anti-HCV seronegatives, anti-HCV seropositives with undetectable serum HCV RNA levels, and anti-HCV seropositives with detectable serum HCV RNA, respectively (P < .001). There was no case that died from chronic liver diseases and cirrhosis among participants seropositive for anti-HCV with undetectable serum HCV RNA. The cumulative mortality of chronic liver diseases and cirrhosis with detectable serum HCV RNA was 0.3% for anti-HCV seronegatives and 2.8% for anti-HCV seropositives.
Figure 3 shows the cumulative mortality from circulatory and renal diseases by seropositivity of anti-HCV and HCV RNA. The cumulative mortality from circulatory diseases was 2.9%, 3.5%, and 5.0% for anti-HCV seronegatives, anti-HCV seropositives with undetectable serum HCV RNA, and anti-HCV seropositives with detectable serum HCV RNA, respectively (P < .01). The corresponding cumulative mortality from nephritis, nephrotic syndrome, and nephrosis was 0.47%, 0.92%, and 1.48%, respectively (P < .01).
Table 3 shows multivariate-adjusted HRs (95% CIs) of dying from selected causes of death by serostatus of anti-HCV and HCV RNA at study entry. There was a significantly increasing trend in mortality from anti-HCV seronegatives, anti-HCV seronegatives with undetectable serum HCV RNA, to anti-HCV seronegatives with detectable serum HCV RNA for most of the diseases. There was no death from chronic liver disease and cirrhosis, esophagus cancer, prostate cancer, and thyroid cancer among anti-HCV seropositives with undetectable serum HCV RNA at study entry.
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