Prevalence of Cirrhosis in Hepatitis C Patients
Prevalence of Cirrhosis in Hepatitis C Patients
Table 2 shows the demographic characteristics of the study population (n=9,783). The mean age of the patients was 55±10.9 years at the time of most recent follow-up. More than one-half of them were white males and a majority (94%) were insured. Of all patients, 43% had at least one liver biopsy report during follow-up, 17% of whom had a recent biopsy <2 years old. The median follow-up time was 6.4 years.
Of the 9,783 patients in the cohort, cirrhosis was indicated by at least one method in 2,788 patients (28.5%) (Table 3). Of these, 2,194 (22.4%) had FIB-4 scores ≥5.88, 661 patients (6.8%) were diagnosed with cirrhosis by liver biopsy, and 751 patients (7.7%) had diagnostic/procedure codes for cirrhosis or manifestations of hepatic decompensation (of whom 557 patients (5.7%) and 482 patients (4.9%) had diagnostic or procedure codes for cirrhosis and hepatic decompensation, respectively). Cirrhosis was indicated exclusively by FIB-4 scores in 1,727 patients (17.6%) and was indicated by all methods (FIB-4 score, liver biopsy, and presence of a diagnostic/procedure code for cirrhosis or hepatic decompensation) in only 221 patients (2.3%). Notably, of the 661 patients with cirrhosis identified by biopsy, only 356 (53.9%) also had ICD-9-CM/CPT codes for cirrhosis or manifestations of hepatic decompensation (Supplementary Table S1 online http://www.nature.com/ajg/journal/v110/n8/suppinfo/ajg2015203s1.html).
Among the 2,194 patients whose FIB-4 scores were ≥5.88, only 357 patients (16%) had been diagnosed with cirrhosis by liver biopsy results, whereas 326 patients (15%) had ICD-9-CM/CPT codes for cirrhosis or manifestations of hepatic decompensation. When APRI scores >1.0, >1.5, and >2.0 were also taken into consideration, cirrhosis was indicated in 1,659 (75.6%), 1,402 (63.8%), and 1,186 (54.0%) patients, respectively; cirrhosis remained indicated solely by FIB-4 scores in only 433 patients (19.7%) (Supplementary Table S2 http://www.nature.com/ajg/journal/v110/n8/suppinfo/ajg2015203s1.html). Of the 2,194 patients with cirrhosis indicated by FIB-4 scores ≥5.88, only 788 patients (36%) had a biopsy performed at any time (Supplementary Table S3 http://www.nature.com/ajg/journal/v110/n8/suppinfo/ajg2015203s1.html). Of these 788 patients, 357 patients (45%) had a biopsy indicating cirrhosis (concordance), whereas cirrhosis was not indicated in the remaining 431 patients (55%). Discordance between cirrhosis indicated by FIB-4 scores and by biopsy was seen in only 431 of the 2,194 patients (19.6%).
We explored the possibility that this discordance may have been due to the performance of the biopsy significantly earlier than the FIB-4 score calculation. The discordance could indicate that the FIB-4 score represents a true progression to cirrhosis during the time interval between the two tests. We therefore analyzed differences in the timing of the FIB-4 relative to the timing of the biopsy in the 788 patients who had cirrhosis as indicated by FIB-4 scores and had a biopsy performed, comparing patients showing concordance with those showing discordance with regard to the two measures. We compared the elapsed time of the earliest indication of cirrhosis by FIB-4 scores from the time of biopsy. The median elapsed time from biopsy to FIB-4 was 37.9 months among the patients with concordance and 46.8 months in patients with discordance (including negative times in cases where the biopsy was performed after FIB-4 scores were calculated). Although the differences between the two groups was not significant based on a nonparametric Wilcoxon test, it is possible that a cirrhotic FIB-4 score measured almost 4 years after a noncirrhotic biopsy could indeed represent progression to cirrhosis.
In the second sensitivity analysis, exclusion of FIB-4 scores from lab values collected during hospitalizations resulted in a reduction in the number of patients with FIB-4 scores ≥5.88 from 2,185 (22%) to 1,757 (18%). There was a corresponding decrease in the overall number of patients with an indication of cirrhosis by at least one of the methods from 2,788 (28%) to 2,422 (25%).
Univariate analysis of the demographic and clinical characteristics of patients with an indication of cirrhosis (by any of the four methods), compared with those without indication of cirrhosis, revealed that age, gender, race/ethnicity, median annual household income, insurance status, receipt of any HCV antiviral therapy, HCV genotype, history of alcohol abuse, HIV coinfection, and diabetes (as assessed by the Charlson/Deyo comorbidity subscore) were significantly associated with prevalence of cirrhosis in this cohort (Table 4). Multivariable logistic modeling for characteristics associated with cirrhosis revealed that older age, male gender, Asian race (compared with White race), Hispanic ethnicity, lack of insurance coverage or coverage by Medicare or Medicaid (compared with private insurance), history of receipt of antiviral therapy, infection by HCV genotype 3 (compared with infection by genotype 1), history of alcohol abuse, HIV coinfection, and diabetes were associated with being cirrhotic (Table 5). Conversely, Black race and infection with HCV genotype 2 were associated with lower odds of being cirrhotic.
We collected data regarding source of infection among a subgroup of 4,218 patients who completed a survey to examine whether mode of infection was associated with development of cirrhosis (indicated by FIB-4 ≥5.88, biopsy, or diagnosis codes). In univariate analysis, we found that contracting hepatitis C through occupational exposure, blood transfusion, or a medical procedure was associated with higher rates of cirrhosis, whereas exposure by injection drug use or sex with males was associated with lower rates of cirrhosis (Supplementary Table S4 http://www.nature.com/ajg/journal/v110/n8/suppinfo/ajg2015203s1.html).
Data on the duration of infection were available for a subgroup of patients who completed a survey and were able to estimate when they became infected (n=2,389). Of these, 365 patients were indicated as having cirrhosis by FIB-4 ≥5.88, whereas 2,024 patients were determined not to have cirrhosis by FIB-4. To improve our confidence in FIB-4 as a predictor of cirrhosis, we used logistic regression analysis to examine whether, as we hypothesized, a longer duration of infection was associated with FIB-4-cirrhosis. We found that the odds of cirrhosis as indicated by FIB-4 increased with duration of infection (odds ratio=1.09 for each 5-year duration of infection; 95% Wald confidence interval 1.04–1.14, P<0.0001).
Results
Population Characteristics
Table 2 shows the demographic characteristics of the study population (n=9,783). The mean age of the patients was 55±10.9 years at the time of most recent follow-up. More than one-half of them were white males and a majority (94%) were insured. Of all patients, 43% had at least one liver biopsy report during follow-up, 17% of whom had a recent biopsy <2 years old. The median follow-up time was 6.4 years.
Indication of Cirrhosis
Of the 9,783 patients in the cohort, cirrhosis was indicated by at least one method in 2,788 patients (28.5%) (Table 3). Of these, 2,194 (22.4%) had FIB-4 scores ≥5.88, 661 patients (6.8%) were diagnosed with cirrhosis by liver biopsy, and 751 patients (7.7%) had diagnostic/procedure codes for cirrhosis or manifestations of hepatic decompensation (of whom 557 patients (5.7%) and 482 patients (4.9%) had diagnostic or procedure codes for cirrhosis and hepatic decompensation, respectively). Cirrhosis was indicated exclusively by FIB-4 scores in 1,727 patients (17.6%) and was indicated by all methods (FIB-4 score, liver biopsy, and presence of a diagnostic/procedure code for cirrhosis or hepatic decompensation) in only 221 patients (2.3%). Notably, of the 661 patients with cirrhosis identified by biopsy, only 356 (53.9%) also had ICD-9-CM/CPT codes for cirrhosis or manifestations of hepatic decompensation (Supplementary Table S1 online http://www.nature.com/ajg/journal/v110/n8/suppinfo/ajg2015203s1.html).
Among the 2,194 patients whose FIB-4 scores were ≥5.88, only 357 patients (16%) had been diagnosed with cirrhosis by liver biopsy results, whereas 326 patients (15%) had ICD-9-CM/CPT codes for cirrhosis or manifestations of hepatic decompensation. When APRI scores >1.0, >1.5, and >2.0 were also taken into consideration, cirrhosis was indicated in 1,659 (75.6%), 1,402 (63.8%), and 1,186 (54.0%) patients, respectively; cirrhosis remained indicated solely by FIB-4 scores in only 433 patients (19.7%) (Supplementary Table S2 http://www.nature.com/ajg/journal/v110/n8/suppinfo/ajg2015203s1.html). Of the 2,194 patients with cirrhosis indicated by FIB-4 scores ≥5.88, only 788 patients (36%) had a biopsy performed at any time (Supplementary Table S3 http://www.nature.com/ajg/journal/v110/n8/suppinfo/ajg2015203s1.html). Of these 788 patients, 357 patients (45%) had a biopsy indicating cirrhosis (concordance), whereas cirrhosis was not indicated in the remaining 431 patients (55%). Discordance between cirrhosis indicated by FIB-4 scores and by biopsy was seen in only 431 of the 2,194 patients (19.6%).
We explored the possibility that this discordance may have been due to the performance of the biopsy significantly earlier than the FIB-4 score calculation. The discordance could indicate that the FIB-4 score represents a true progression to cirrhosis during the time interval between the two tests. We therefore analyzed differences in the timing of the FIB-4 relative to the timing of the biopsy in the 788 patients who had cirrhosis as indicated by FIB-4 scores and had a biopsy performed, comparing patients showing concordance with those showing discordance with regard to the two measures. We compared the elapsed time of the earliest indication of cirrhosis by FIB-4 scores from the time of biopsy. The median elapsed time from biopsy to FIB-4 was 37.9 months among the patients with concordance and 46.8 months in patients with discordance (including negative times in cases where the biopsy was performed after FIB-4 scores were calculated). Although the differences between the two groups was not significant based on a nonparametric Wilcoxon test, it is possible that a cirrhotic FIB-4 score measured almost 4 years after a noncirrhotic biopsy could indeed represent progression to cirrhosis.
Sensitivity Analysis
In the second sensitivity analysis, exclusion of FIB-4 scores from lab values collected during hospitalizations resulted in a reduction in the number of patients with FIB-4 scores ≥5.88 from 2,185 (22%) to 1,757 (18%). There was a corresponding decrease in the overall number of patients with an indication of cirrhosis by at least one of the methods from 2,788 (28%) to 2,422 (25%).
Demographic and Clinical Characteristics of Patients With Cirrhosis
Univariate analysis of the demographic and clinical characteristics of patients with an indication of cirrhosis (by any of the four methods), compared with those without indication of cirrhosis, revealed that age, gender, race/ethnicity, median annual household income, insurance status, receipt of any HCV antiviral therapy, HCV genotype, history of alcohol abuse, HIV coinfection, and diabetes (as assessed by the Charlson/Deyo comorbidity subscore) were significantly associated with prevalence of cirrhosis in this cohort (Table 4). Multivariable logistic modeling for characteristics associated with cirrhosis revealed that older age, male gender, Asian race (compared with White race), Hispanic ethnicity, lack of insurance coverage or coverage by Medicare or Medicaid (compared with private insurance), history of receipt of antiviral therapy, infection by HCV genotype 3 (compared with infection by genotype 1), history of alcohol abuse, HIV coinfection, and diabetes were associated with being cirrhotic (Table 5). Conversely, Black race and infection with HCV genotype 2 were associated with lower odds of being cirrhotic.
Source of Infection
We collected data regarding source of infection among a subgroup of 4,218 patients who completed a survey to examine whether mode of infection was associated with development of cirrhosis (indicated by FIB-4 ≥5.88, biopsy, or diagnosis codes). In univariate analysis, we found that contracting hepatitis C through occupational exposure, blood transfusion, or a medical procedure was associated with higher rates of cirrhosis, whereas exposure by injection drug use or sex with males was associated with lower rates of cirrhosis (Supplementary Table S4 http://www.nature.com/ajg/journal/v110/n8/suppinfo/ajg2015203s1.html).
Duration of Infection
Data on the duration of infection were available for a subgroup of patients who completed a survey and were able to estimate when they became infected (n=2,389). Of these, 365 patients were indicated as having cirrhosis by FIB-4 ≥5.88, whereas 2,024 patients were determined not to have cirrhosis by FIB-4. To improve our confidence in FIB-4 as a predictor of cirrhosis, we used logistic regression analysis to examine whether, as we hypothesized, a longer duration of infection was associated with FIB-4-cirrhosis. We found that the odds of cirrhosis as indicated by FIB-4 increased with duration of infection (odds ratio=1.09 for each 5-year duration of infection; 95% Wald confidence interval 1.04–1.14, P<0.0001).
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