Laboratories of Epidemiology and Biostatistics,
a Experimental Pathophysiology
b and Biochemistry;
d Department of Medicine,
c Medical Research Institute IRCCS Saverio De Bellis Castellana Grotte, Italy.
Reprint requests to: Alberto R Osella, Laboratory of Epidemiology and Biostatistics, Via F Valente 4, 70013 Castellana G (BA), Italy. E-mail: osellar{at}libero.it
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Abstract |
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Methods A population random sample of 2472 subjects aged 30 years was enrolled and followed up from 1985 to 1996. At enrolment, a structured interview and a clinical evaluation were performed. Serum samples were tested using HCV ELISA and RIBA HCV. Outcomes were overall and liver-related mortality and tracing procedures included review of office and hospital records, death certificates, and interviews with general practitioners, attending hospital and next of kin. Statistical analysis was performed using Poisson and binomial prospective data regression.
Results Crude overall and liver-related mortality rates were 7.66 (95% CI : 6.688.79) and 0.9 (95% CI : 0.32.2) per 103 person-years, respectively. For HCV infection effect, incidence rate ratio and difference (per 103 person-year), risk ratio and difference were 27.5 (95% CI : 6.5115.6), 4 (95% CI : 37), 33.1 (95% CI : 7.8 139.3) and 0.06 (95% CI : 0.040.08), respectively; all measures were adjusted for age at death, sex and daily alcohol intake.
Conclusions The results show a strong relative but weak absolute effect of HCV infection on liver-related mortality in the 10-year period considered. Poisson and binomial models are virtually equivalent, but the choice of the summarizing measure of effect may have a different impact on health policy.
Keywords Binomial models, cohort study, HCV infection, liver-related mortality, Poisson models
Accepted 17 March 2000
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Introduction |
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In different studies liver-related mortality rates ranging from <1% to 11.7% have been reported.8,9 Most of these studies were conducted in tertiary care centres and used different designs to assess the impact of HCV on mortality. Estimates of the HCV effect may therefore be biased as a result of a form of selection bias operating toward the less favourable prognostic segment of the HCV-related liver disease spectrum. Two carefully controlled studies by Seef et al.4,11 showed a small statistical significant difference in liver-related deaths between post-transfusional hepatitis C patients and controls after 18 years of follow-up and, that a proportion of them had mild disease. In these studies, most patients who died from liver-related disease were identified as heavy drinkers.
On the other hand, in a few population-based studies, albeit with strong geographical variability, a high prevalence of HCV infection has been shown in older subjects; the great majority being viraemic and without clinically obvious disease.12,13 As previously reported,14 HCV infection is highly prevalent in Castellana G (small town in southern Italy) with more than 40% of subjects aged 50 years being anti-HCV positive. The longitudinal phase of this study showed a moderate incidence rate of HCV infection. However, the impact of HCV infection on mortality in this population remains unknown.
Antiviral therapy15 is now available and certain responders' characteristics have also been identified. However, as antiviral therapy has significant side effects, estimation of the magnitude of liver-related death associated with HCV exposure outside the clinical setting is an issue of public health concern, as is identification of groups of patients at risk who could benefit from therapy.
Analysis of epidemiological data is generally based on multiplicative models which are useful in aetiological research, but others such as additive ones are more useful from the point of view of public health.1618
To evaluate the potential impact of different models on health policy, we conducted a prospective, population-based study. The aim of this study was to estimate the absolute and relative effects of HCV infection on liver-related mortality rate and risk.
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Methods |
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Exposure assessment
Serum samples were tested using the HCV ELISA test system (Ortho Diagnostic System, Milan, Italy). The cutoff values for HCV ELISA test ranged from 0.632 to 0.672 nm and a serum sample was considered reactive if its optical density value was twice the cutoff value. All reactive serum were confirmed using RIBA HCV 2.0 SIA (Ortho Diagnostic System, Milan, Italy). Serum HCV RNA was tested by nested RT-PCR using conserved primers in the 5'- non-coding region.21 The HCV genotyping was performed by type-specific primers in the core region according to Okamoto's method and subsequent modifications.21,22
At enrolment, HCV antibody (anti-HCV) serological status was established only in 1969 of 2472 respondents because the serum samples of the 503 remaining subjects had been used in a previous study on the association between endogenous sex hormones and cholesterol gallstones.23 In all 417 of the 503 enrolled subjects whose serum samples were not available (not included in the HCV cohort) were followed-up from 1992 to 1993. To check possible selection bias we established the anti-HCV prevalence in these subjects. It was similar to that of the subjects included in the cohort. Furthermore, the anti-HCV test was repeated for 1699 available paired serum samples. We obtained an overall concordance of 99.5%.
Tracing procedures and outcome assessment
The follow-up of the enrolled subjects ended on 31 December 1996 and their vital status on that date was obtained from the town's Registry. Two outcomes were considered: overall and liver-related mortality (International Classification of Diseases, Ninth Revision, [ICD-9] codes 155.0 and 571). Outcome was assessed by the following means (per cent of dead subjects): (1) interviews with the general practitioner (100%) and attending hospital (11.7%); (2) review of office (22.0%) and hospital records (78%); (3) review of medical history at enrolment (100%); (4) death certificates (81% of anti-HCV positive subjects, 76% of anti-HCV negative and 80% of those with unknown status) and (5) interviews with the next of kin (10%).
Clinical data were evaluated for the presence of cirrhosis and HCC on the basis of established clinical and histological criteria.2426 Subjects with a history of liver disease who did not fulfil the criteria for cirrhosis or HCC were considered to have chronic liver disease on the basis of the presence of biopsy-proven chronic hepatitis27 or when, along with abnormal liver function tests, at least one of the following was present: (1) thrombocytopenia; (2) ultrasonographic or endoscopic signs of portal hypertension; or (3) ascites and either liver or spleen enlargement. Subjects who did not meet any of the above criteria were considered to have no evidence of chronic liver disease. The cause of death for each subject was established after careful evaluation of all data collected, performed always by a single clinician who specialised in hepatology and was unaware of the HCV status of the dead subjects.
Statistical analysis
Differences among continuous variables were evaluated by one-way analysis of variance (ANOVA); multiple comparisons were performed with Scheffeé's method. Categorical variables were analysed by 2 test. Exploratory analysis did not reveal differences between subjects whose sera were not available and the other groups and so further analysis considered only anti-HCV positive and negative subjects.
Absolute and relative effects of HCV exposure on mortality were estimated for two types of measures: rates (incidence rates) and risks (incidence proportion) along with their 95% CI. The general framework of the Poisson regression model for grouped cohort data was used to estimate the incidence rate ratio (IRR) and difference (IRD);28,29 an algorithm was used to allocate person-time exactly.30 Risk ratio (RR) and difference (RD) were estimated as suggested for prospective binomial data.18 In these models, the data were categorized into strata of the covariates (confounding factors) for each of the risk groups. The strata correspond to age at death (<45, 4554,5564 and 65 years), sex (male, female) and daily alcohol intake (<31,
31 g/ethanol). Daily alcohol intake was dichotomized taking into account the regional and national drinking pattern.31,32 From previous analysis,14 it was known that HCV infection was homogeneously distributed in terms of socioeconomic characteristics. The main variability in anti-HCV prevalence was due to age and sex.
Agreement between observed and expected cases, Pearson 2 and deviance statistic were used to evaluate the model's goodness-of-fit. In all analysis, any other cause of death was assumed to operate independently of the cause of death under study.
Computations for rates were performed using the AMFIT33 module in the statistical package Epicure 2.1 whereas the generalized linear interactive modelling (GLIM)34 was used for estimating risks.
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Results |
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The summarizing measures of effects for Poisson models (IRR and IRD) and prospective binomial data (RR and RD), along with the expected and observed number of cases, the deviance associated with each model, and Pearson's 2 are reported in Tables 3 and 4
, respectively. The four models appeared to be roughly equivalent, especially for ratio measures. However, the performance of risk models was better, as reflected by a higher agreement between observed and fitted cases, a smaller deviance, and thus a better fit (Table 4
). The relative measures of effect obtained were 27.5 (95% CI 6.5115.6) for IRR and 33.1 (95% CI : 7.8139.3) for RR. The IRD was 4 (95% CI : 37) per 103 person-years whereas the RD estimate, in the 10-year period considered, was 0.06 (95% CI : 0.040.08).
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Discussion |
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Competing risks of death related to both HCV infection and other unmeasured exposures, such as Hepatitis B virus (HBV) infection, may have produced biased measures of effect in this study. This implies that subpopulations particularly susceptible to liver-related death due to HCV infection could have been selectively censored from our cohort by other causes of death.35 However, most of the liver-unrelated deaths were due to cardiovascular and non-hepatic neoplastic diseases; besides, none of the subjects who died from renal disease had been diagnosed as having membranoproliferative glomerolunephritis.36 In order to control for confounding due to alcohol consumption, a validated questionnaire was administered. In this geographical area the drinking pattern is characterized by a steady daily intake of wine and drinking is common at meals as it is considered part of the normal diet. Alcohol abuse is not a public health concern. Within Italy, the proportion of mortality from liver cirrhosis associated with alcohol consumption has been reported to be low in this area31 and chronic viral infections are responsible for most cases of cirrhosis.37 It has recently been suggested that, at the population level,32 the risk of developing alcohol induced liver damage is mediated not only by the amount of alcohol drunk, but also by drinking alcohol and multiple different alcoholic beverages outside mealtimes. Other unmeasured confounding factors may also have biased our results, but, since this was a large population random sample, it should have been well able to prevent confounding by unmeasured factors.38
Several studies reporting mortality rates among HCV infected patients have been published. Although these studies were remarkably different in design, characteristics, number of patients and length of follow-up, liver-related mortality rates ranged from 0.8% to 11.7%.210 Several parameters, such as age at infection, gender, genotype, virus load and route of infection have been identified as having a major influence on the natural history of HCV infection,39 with patients infected at an older age being more likely to develop progressive disease. Besides, it has been shown that patients with mild liver disease are the most likely to respond to antiviral therapy.15 However, care should be taken in generalizing results from clinical and epidemiological studies conducted at tertiary care centres.40 As previously reported, HCV infection is highly prevalent in this area of Southern Italy14 with a strong negative cohort effect and a moderate HCV infection incidence rate. HCV types 1b and 2 a/c are the most frequent and are distributed across the population with no particular pattern.41
Since HCV infection is widespread in this area, the comparison of different measures of HCV exposure effect on the mortality rate raises issues concerning public health and patient management. Our results show a strong relative effect of HCV exposure (IRR and RR) on liver-related mortality; this leads to consideration of HCV exposure as an important component cause in at least one complete causal mechanism of liver-related death.42 On the other hand, absolute measures of effect (IRD and RD) were virtually equivalent and showed a weak effect. Subjects in this population-based cohort probably became HCV infected early in life and, taking into account time elapsed from infection to liver disease, HCV exposure may reasonably be lagged for a longer period than 10 years. Consequently, absolute measures should reflect the actual impact of HCV exposure effect on liver-related mortality from the public health point of view in this population. Indeed, the IRD was only 4 x 103 person-years and RD 6% in 10 years and age at death was no different between HCV exposed and unexposed dead subjects. In this sense, a more precise knowledge of the biological mechanisms is needed to establish the effect of HCV exposure on the incidence time of liver-related death and, consequently, to obtain valid estimates of both excess and aetiological fractions attributable to exposure.43
The availability of interferon and antiviral therapies may have a great impact on the course of HCV infection. Results from clinical trials15 have shown that HCV infected young patients with mild disease become virological responders. These seem to be the characteristics of most subjects in this area where HCV infection is highly prevalent.12,13 Thus, from the public health viewpoint, it is important to identify patients at risk of developing progressive disease and the effectiveness, risks, benefits and cost of treatment should also be carefully evaluated. Besides, HCV infection seems to play an important role in decreasing other risk factors for chronic diseases.44,45
Liver disease due to HCV infection requires clinical and epidemiological approaches to find out the causes of cases and determinants of incidence at the population level.46 This means that different causal pathways should be assessed in order to implement prevention strategies for those at high risk and strategies aimed at the population should fight the underlying causes of incidence. Other impact measures such as reduction in life expectancy43 in the meantime may be useful as a means of estimating the impact of HCV infection on mortality, for public health purposes.
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Acknowledgments |
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Notes |
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References |
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