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Risk of Deferring HCV Treatment - CDC CheCS: "All-Cause Mortality and Progression Risks to Hepatic Decompensation and Hepatocellular Carcinoma in Patients Infected With Hepatitis C Virus"
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[from Jules: although this email reports the CDC CHeCS study just published in CID I have accumulated & report here additional study results showing the risk there is for patients with early HCV (F0-2) if they do not treat HCV: there is cancer & cardiovascular disease risk, and key is that 2 studies listed below from IAS this summer report in sum that delaying therapy until F2 & certainly cirrhosis reduces the chance for the patient to achieve SVR & thus fibrosis regression thus increasing the risk for advanced disease - decompensation, HCC & death. Of note in this new CHecS study is that patients with more advanced HCV disease (f3/4) had double the comorbidities vs patients with F0-2, Table 1): "The proportions of patients who had comorbidities, abnormal liver and renal function tests, and low platelets grew with increasing fibrosis stage, and in the F4 group, only about half (55.9%) did not have any Charlson comorbidity diagnosed (Table 1)." From Jules: the Charleston Index for comorbidities they used includes not only renal & liver diseases but also heart disease, cerebrovascular disease, diabetes, dementia, peripheral vascular disease.
CDC CHeCS Study Reports - Risk for Liver Decompensation is 8.1% for F0/1-2: "Our study provides timely data for understanding the implications in the United States if HCV treatment is delayed in certain patient groups as a national debate is ongoing regarding restrictive policies for access to newer HCV therapies [13]. Our risk estimates in patients with early stages of liver disease are important for cost-effectiveness analyses and policy decisions about timing of treatment [20].......patients staged at F3 and F4 at baseline were treated for HCV, sometimes with >1 attempt, an overall 19.6% of F3 patients and 37.2% of F4 patients went on to experience hepatic decompensation or HCC within 5 year.....In F4 patients, the 1-year progression rate to HCC was 4.8% and to hepatic decompensation was 13.4%.
"Decompensation [included] conditions of hepatic encephalopathy, esophageal varices with bleeding, ascites, or hepatorenal syndrome were defined as the first occurrence of ICD-9 diagnosis or CPT codes in following groups: hepatic encephalopathy (572.2), portal hypertension (572.3, 37140, 37160, 37180, 37181, 37182, 37183), esophageal varices with bleeding (456.0, 456.20, 42.91, 44.91, 96.06, 43204, 43205, 43243, 43244, 43400, 43401), ascites (789.5, 789.59, 54.91, 49080, 49081), or liver failure with hepatorenal syndrome.
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from Jules: Several points, (1) perhaps MOST important are these 2 studies at IAS (Intl AIDS Conference-8/2015) finding that despite an SVR if the patient already had cirrhosis the risk for disease & death persists: in 1 study of patients with cirrhosis who achieved SVR 71% achieved fibrosis regression vs 96% treated with F2 & 87% treated at F3 [http://www.natap.org/2015/IAS/IAS_111.htm].....In the 2nd study at IAS this summer this study was conducted with Peg/Rbv [http://www.natap.org/2015/IAS/IAS_55.htm], in patients had cirrhosis - more patients with less advanced disease achieved SVR - "45% of HIV coinfected patients with cirrhosis who achieved SVR did not achieve fibrosis regression (FR) & 32% of them died vs 17% who died who did achieve fibrosis regression (p=0.01) and 11% with SVR but without FR experienced liver-related complication vs 4% who had SVR but FR (F=0.2) and 16% with SVR but without FR experienced hospital admission vs 9% with SVR but without FR....and "Fibrosis regression cut the overall death risk 64% and and the liver-related death risk 85%".....In the SVR group, 4 of 23 with fibrosis regression died, compared with 6 of 19 without regression (17% versus 32%, P = 0.01).......In the SVR group, 4 of 23 with fibrosis regression died, compared with 6 of 19 without regression (17% versus 32%, P = 0.01). Mortality with versus without regression was 2.45 versus 5.36 per 100 person-years. One person with fibrosis regression and 3 without regression had a liver-related death (4% versus 16%, incidence 0.61 versus 2.68, P = 0.01). Liver-related complications and hospital admissions also proved less frequent in the group with fibrosis regression, but not significantly so.
(2) what is often not considered when weighing early vs deferred treatment are the risks for cancers & extraheptic manifestations & the increased risk for mortality by not treating early in disease, recently reported from the CDC CHeCS study [http://www.natap.org/2015/HCV/091815_03.htm], 60% increased risk for NHL in HCV+: "The incidence of NHL was higher in the HCV-infected group (1.6 [1.2-2.1]), a cancer that is not associated with smoking or alcohol use, but has been associated with HIV"
-(2) Recently several studies reported that HCV is associated with causing cardiovascular disease [http://www.natap.org/2015/IAS/IAS_105.htm] and this recent study reported SVR decreased by 30% hospitalization for CVD & a 32% reduced risk for all-cause mortality [http://www.natap.org/2015/HCV/090915_01.htm].
(3) further, another recent CDC CHeCS study found: cirrhosis in USA may be highly underestimated: estimated prevalence of cirrhosis of 25-28% in the CHC population at four health systems in the United States is in agreement with the previously modeled projection of 25% prevalence of cirrhosis in 2010 [http://www.natap.org/2015/HCV/090215_01.htm]
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from Jules: and this data from the new CID CHeCS Study published below shows further the risk of delaying therapy to F3 & F4: "Treatment programs in 2012 or earlier were not effective. Although a majority of patients staged at F3 and F4 at baseline were treated for HCV, sometimes with >1 attempt, an overall 19.6% of F3 patients and 37.2% of F4 patients went on to experience hepatic decompensation or HCC within 5 years before treatment could lead to testing negative for HCV RNA. In F4 patients, the 1-year progression rate to HCC was 4.8% and to hepatic decompensation was 13.4%. Newer and more effective treatments in these patients are needed to reduce the risks of mortality and liver complications."
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this CDC now published study was presented at AASLD 2014:
http://www.natap.org/2014/AASLD/AASLD_46.htm......."Mortality and progression to decompensated cirrhosis in chronic hepatitis C patients with liver biopsy confirmed fibrosis in the Chronic Hepatitis Cohort Study (CHeCS)"
Among 9912 HCV-monoinfected patients enrolled in CHeCS, 3091 (31%) persons had at least 1 biopsy performed during 2001-2012. Although 621 patients had 2 or more biopsies, the results from any repeated biopsy were not considered. After applying the study exclusion criteria, a total of 2799 patients were included in this analysis.
The mean age was 50.7 years overall, and was 48.2 years among F0-F1 patients, compared with 53.0 years among those with F4 (P < .0001); the proportion of men increased significantly as biopsy stage advanced (52.0% in F0-F1 to 68.9% in F4) (Table 1). Most patients were white, and more than one-half of the patients had private insurance......the majority (at least 66.5%) of patients were genotype 1......The proportions of patients who had comorbidities, abnormal liver and renal function tests, and low platelets grew with increasing fibrosis stage, and in the F4 group, only about half (55.9%) did not have any Charlson comorbidity diagnosed (Table 1)......Mean observation time after biopsy was about 5.0 years in all stage groups (Table 2).
RESULTS: Risks of all adverse clinical outcomes approximately doubled with each increase in fibrosis stage (Table 2). No one with baseline F0-F1 developed HCC. In contrast, among the baseline F4 group, 8.8% developed HCC, 26.5% decompensated, 4.9% had a transplant, and almost one-quarter had died by the end of observation (Table 2).
The estimated probabilities by liver fibrosis stage over 1, 2, and 5 years are shown in Table 3. The 1-year risk for liver transplant increased from 0.1% (95% confidence interval [CI], .01-.6) among patients with baseline stage F0-F1 to 1.6% (95% CI, .6-3.4) among those with baseline stage F4. The cumulative incidence of HCC at 2 years after biopsy was 6.3% in F4, and was lower at 0.3% in F2 patients. Patients starting baseline at F4 experienced high cumulative incidence of decompensation: 33.6% by 5 years after biopsy, compared with 18.6% in F3, 3.5% in F2, and 2.3% in F0-F1 (Table 3). Further analysis showed no difference in the cumulative incidence of decompensation between patients starting at F0-F1 and those at F2 (P = .09, data not shown). At 5 years after baseline biopsy, all-cause mortality was 31.5% in F4, 13.7% in F3, 6.9% in F2, and 6.8% in F0-F1 patients (Table 3).
After adjusting for age, race, and other factors included in the model, higher baseline stage, higher comorbidity score, platelet count below normal, and bilirubin level above normal were significantly associated with the development of HCC or decompensation (Table 4). Of these, baseline fibrosis stage F3 (adjusted hazard ratio [aHR], 4.2) or F4 (aHR, 7.05) vs F2, and platelet count below normal (aHR, 3.45) were the strongest predictors of progression to HCC or decompensation (Table 4).
FROM JULES: in looking at Table 2 just below the risk for F0/1 to get hepatic decompensation is 1.7% but in table 3 after 5 years the highest potential risk increases to 3.8%. Similarly for F2 risk is 2.6% in Table 2 and increases to 5.5% after 5 years so together for F0/1-2 risk is as high as 8.1%
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All-Cause Mortality and Progression Risks to Hepatic Decompensation and Hepatocellular Carcinoma in Patients Infected With Hepatitis C Virus
Clinical Infectious Diseases Advance Access published October 19, 2015
Fujie Xu,1 Anne C. Moorman,1 Xin Tong,1 Stuart C. Gordon,2 Loralee B. Rupp,2 Mei Lu,2 Eyasu H. Teshale,1 Philip R. Spradling,1 Joseph A. Boscarino,3 Connie M. Trinacty,4 Mark A. Schmidt,5 and Scott D. Holmberg1; for the Chronic
Hepatitis Cohort Study (CHeCS) Investigatorsa
1Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia; 2Henry Ford Health System, Detroit, Michigan; 3Geisinger Health System, Danville, Pennsylvania; 4Kaiser Permanente Hawaii, Honolulu; and 5Kaiser Permanente Northwest, Portland, Oregon
Abstract
Background. A key question in care of patients with chronic hepatitis C virus (HCV) infection is beginning treatment immediately vs delaying treatment. Risks of mortality and disease progression in "real world" settings are important to assess the implications of delaying HCV treatment.
Methods. This was a cohort study of HCV patients identified from 4 integrated health systems in the United States who had liver biopsies during 2001-2012. The probabilities of death and progression to hepatocellular carcinoma, hepatic decompensation (hepatic encephalopathy, esophageal varices, ascites, or portal hypertension) or liver transplant were estimated over 1, 2, or 5 years by fibrosis stage (Metavir F0-F4) determined by biopsy at beginning of observation.
Results. Among 2799 HCV-monoinfected patients who had a qualifying liver biopsy, the mean age at the time of biopsy was 50.7 years. The majority were male (58.9%) and non-Hispanic white (66.9%). Over a mean observation of 5.0 years, 261 (9.3%) patients died and 34 (1.2%) received liver transplants.
At 5 years after biopsy, the estimated risk of progression to hepatic decompensation or hepatocellular carcinoma was 37.2% in stage F4, 19.6% in F3, 4.7% in F2, and 2.3% in F0-F1 patients. Baseline biopsy stage F3 or F4 and platelet count below normal were the strongest predictors of progression to hepatic decompensation or hepatocellular carcinoma.
Conclusions. The risks of death and progression to liver failure varied greatly by fibrosis stage. Clinicians and policy makers could use these progression risk data in prioritization and in determining the timing of treatment for patients in early stages of liver disease.
Patients with chronic hepatitis C virus (HCV) infection are at risk for progressive hepatic fibrosis and cirrhosis, leading to hepatic decompensation (ie, hepatic encephalopathy, esophageal varices, or ascites) and hepatocellular carcinoma (HCC) [1, 2]. Decedents with HCV infection listed among causes of death on their death certificates died at an age >20 years younger than decedents without HCV infection [3, 4]. Thus, there is an urgent need for effective interventions in HCV-infected patients at most risk of immediate morbidity and mortality. The American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) treatment guidance that was published in 2014 conferred "highest" priority to patients with Metavir stage F3 (advanced fibrosis), Metavir stage F4 (compensated cirrhosis), liver transplant, or severe extrahepatic hepatitis C, and "high" priority to those at Metavir stage F2 (moderate fibrosis) or with certain coinfections or comorbidities [5].
Previously, pegylated interferon plus ribavirin was the standard treatment for chronic HCV infection, and sustained virologic response (SVR) was only achieved in about 50% of patients infected with genotype 1a and 1b, the usual genotypes seen in the United States [6, 7]. SVR achieved on interferon-based regimens has been shown to be associated with resolution of liver disease and prevention of long-term complications in patients without cirrhosis; however, achievement of SVR after the development of cirrhosis greatly reduces but does not completely eliminate the risk of HCC [8, 9]. With the recent introduction of oral, curative, but highly expensive antiviral drugs [10], a priority research question is comparative benefits and harms of treating patients with HCV infection at the time of diagnosis vs waiting to treat only those patients who show early signs of progression of liver disease or other manifestations of HCV infection [11]. Furthermore, since some payers introduced policies to limit access to treatment in reaction to the high cost of newer regimens, there has been an ongoing debate regarding whether delaying therapy is justifiable, and thus, data about the progression of untreated early-stage HCV infection from large and diverse cohorts are critical [12, 13].
We describe all-cause mortality and progressing risks among cohort patients chronically infected with HCV according to fibrosis stage determined by liver biopsy at beginning of observation. The 1, 2, and 5-year risks of progression to liver complications in the absence of successful treatment were estimated in a large cohort with enrollment from population-based healthcare systems. These risk estimates may help inform decisions about the timing of antiviral treatment and about prioritizing antiviral treatment among patients according to liver fibrosis stage and other selected clinical factors.
METHODS
Data Source
We analyzed data from the Chronic Hepatitis Cohort Study (CHeCS). CHeCS is a "dynamic" observational study conducted at 4 large, integrated healthcare systems located in the United States, and represents a geographically, ethnically, and clinically diverse cohort of patients with chronic hepatitis B and C [14]. The data collected are solely based on routine clinical care and thus representative of the uncontrolled healthcare environment of the real-world clinical setting. Criteria for inclusion and composition of the CHeCS cohort have been summarized in a previous report [14]. In brief, the CHeCS cohort was created based on analysis of electronic health records (EHR) and administrative data of >2.7 million patients aged 18 years or older who had a clinical service (ie, outpatient or inpatient, emergency department, or laboratory test) provided between 1 January 2006 and 31 December 2012 at 1 of 4 sites: Geisinger Health System in Danville, Pennsylvania, which serves approximately 2.6 million Pennsylvania residents; Henry Ford Health System in Detroit, Michigan, which serves >1 million southeastern Michigan residents; Kaiser Permanente Northwest in Portland, Oregon, which serves approximately 500 000 members; and Kaiser Permanente of Honolulu, Hawaii, which serves about 220 000 persons or approximately one-sixth of Hawaii residents.
Patients were identified principally by laboratory and secondarily by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) criteria. EHR data and administrative data were supplemented with individual chart review by trained data abstractors, who also reviewed and verified chronic HCV infection. Once HCV infection was confirmed, all available retrospective and prospective data annually through 2012 were abstracted. Abstractors follow a standard abstraction manual and collect data about patients' demographics, medical encounters, treatment data, and laboratory, radiology, and biopsy results.
Study Participants
We limited our analysis to HCV-monoinfected patients who had at least 1 liver biopsy performed between 2001 and 2012. Patients with human immunodeficiency virus or hepatitis B, those who achieved SVR before biopsy, or those with <90 days of follow-up were excluded. To determine progression probabilities, patients who had developed decompensation or HCC prior to or within 90 days after biopsy were excluded. For patients who received antiviral treatment for HCV during the observation period, we only included the observation time prior to the date when the first HCV RNA test became negative or undetectable. Because the purpose of this analysis was to estimate the risk for disease progression among patients who were still infected with HCV, patients' observation time after the negative HCV RNA test (technically no longer infected) was excluded. The observation periods were further restricted to the first liver biopsy that occurred after the diagnosis of chronic HCV infection. The first biopsy during the observation period was the starting point for analysis (baseline). In CHeCS, liver biopsies are performed as part of routine clinical practice, and reports from pathologists are standardized: Fibrosis scores from different scoring systems (International Association for the Study of the Liver, Batts-Ludwig, Metavir, Ishak, Knodell, Scheuer) were mapped to a F0-F4 equivalency scale and ranked as follows: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis [15].
Clinical Endpoints
In our analysis, liver transplant was based on ICD-9-CM diagnosis and Current Procedural Terminology (CPT) codes of 996.82, 50.5, 50.51, 50.59, 47135, 47136, or V42.7. Decompensation conditions of hepatic encephalopathy, esophageal varices with bleeding, ascites, or hepatorenal syndrome were defined as the first occurrence of ICD-9 diagnosis or CPT codes in following groups: hepatic encephalopathy (572.2), portal hypertension (572.3, 37140, 37160, 37180, 37181, 37182, 37183), esophageal varices with bleeding (456.0, 456.20, 42.91, 44.91, 96.06, 43204, 43205, 43243, 43244, 43400, 43401), ascites (789.5, 789.59, 54.91, 49080, 49081), or liver failure with hepatorenal syndrome (572.4). These conditions were used by others [16]; we also conducted a pilot study comparing the selected ICD-9/CPT codes with independent chart review by 2 gastroenterology fellows, which validated that these codes could reliably determine whether or not a CHeCS patient had decompensation. Cases of primary HCC and diagnosis dates were derived from validated tumor registry reports [17]. To ascertain mortality status, each health system matched cohort patient records to the most recent National Death Index, Social Security Death Index, or electronic state death registries to find out the date of death [18].
Statistical Methods
We examined the demographic and clinical characteristics at time of the first biopsy, defined as the baseline. We calculated the Charlson/Deyo comorbidity index score from diagnosis codes in inpatient, outpatient, and claims data during the year when the biopsy was performed [19]. Differences in patients' clinical outcomes by fibrosis stage following biopsy were analyzed by the Fisher exact or χ2 test for categorical variables, and nonparametric tests for the continuous variables. Mortality and probability of progression were estimated by the Kaplan-Meier method. The time during which a patient was at risk for hepatic decompensation or HCC was defined as the time from the date of biopsy to the date of diagnosis of decompensation, HCC, death, liver transplant, first negative test for HCV RNA after treatment, or last contact, whichever was earliest. In calculating the cumulative incidence of decompensation or HCC, the occurrence of death or transplant was considered as competing risks. We also performed a proportional hazards model to determine factors independently associated with progression to decompensation or HCC among patients whose fibrosis stage was F2 or above.
To evaluate possible selection biases for liver biopsy, we compared demographic and clinical characteristics (measured <90 days of HCV diagnosis) in patients who did and did not have biopsy after diagnosis. To make the observation period comparable between these 2 groups, this comparison was made in a subgroup of patients whose HCV diagnosis was first made during 2009-2012.
The study protocol was reviewed and approved by an institutional review board at each CHeCS participating site.
RESULTS
Patient Characteristics
Among 9912 HCV-monoinfected patients enrolled in CHeCS, 3091 (31%) persons had at least 1 biopsy performed during 2001-2012. Although 621 patients had 2 or more biopsies, the results from any repeated biopsy were not considered. After applying the study exclusion criteria, a total of 2799 patients were included in this analysis.
Based on each patient's first biopsy result, the classification by fibrosis stage was as follows: 309 (11.0%) were at Metavir stage F0, 724 (25.9%) at F1, 849 (30.3%) at F2, 509 (18.2%) at F3, and 408 (14.6%) at F4. Demographic characteristics were different between the groups (Table 1): The mean age was 50.7 years overall, and was 48.2 years among F0-F1 patients, compared with 53.0 years among those with F4 (P < .0001); the proportion of men increased significantly as biopsy stage advanced (52.0% in F0-F1 to 68.9% in F4) (Table 1). Most patients were white, and more than one-half of the patients had private insurance. As expected of HCV patients in the United States, the majority (at least 66.5%) of patients were genotype 1. The proportions of patients who had comorbidities, abnormal liver and renal function tests, and low platelets grew with increasing fibrosis stage, and in the F4 group, only about half (55.9%) did not have any Charlson comorbidity diagnosed (Table 1).
Progression Risks and All-Cause Mortality
Mean observation time after biopsy was about 5.0 years in all stage groups (Table 2). During this observation period, more than half (54.1%) of patients had treatment prescribed and 24.0% had 2 or more courses of treatment attempted; the observation time was truncated for 910 persons at the time when their first HCV RNA test was negative after treatment. Risks of all adverse clinical outcomes approximately doubled with each increase in fibrosis stage (Table 2). No one with baseline F0-F1 developed HCC. In contrast, among the baseline F4 group, 8.8% developed HCC, 26.5% decompensated, 4.9% had a transplant, and almost one-quarter had died by the end of observation (Table 2).
We plotted the progression to initial HCC or decompensation over the first 7 years after baseline biopsy (Figure 1A), and there were significant differences in the cumulative incidence by baseline fibrosis stage. We also examined the time to initial HCC and hepatic decompensation events separately (Figure 1B and 1C). No diagnoses of HCC were observed among baseline F0-F1 patients (Figure 1B), but otherwise the 2 cumulative incidence curves by baseline stage showed similar patterns over time. Clearly, the overall progression risks were much lower in F0 and F1 patients (gaps were small between these 2 groups) (Figure 1A).
The estimated probabilities by liver fibrosis stage over 1, 2, and 5 years are shown in Table 3. The 1-year risk for liver transplant increased from 0.1% (95% confidence interval [CI], .01-.6) among patients with baseline stage F0-F1 to 1.6% (95% CI, .6-3.4) among those with baseline stage F4. The cumulative incidence of HCC at 2 years after biopsy was 6.3% in F4, and was lower at 0.3% in F2 patients. Patients starting baseline at F4 experienced high cumulative incidence of decompensation: 33.6% by 5 years after biopsy, compared with 18.6% in F3, 3.5% in F2, and 2.3% in F0-F1 (Table 3). Further analysis showed no difference in the cumulative incidence of decompensation between patients starting at F0-F1 and those at F2 (P = .09, data not shown). At 5 years after baseline biopsy, all-cause mortality was 31.5% in F4, 13.7% in F3, 6.9% in F2, and 6.8% in F0-F1 patients (Table 3).
Factors Associated With Progression
We used a Cox proportional hazards model to identify patient characteristics at the time of biopsy that were independently associated with the development of HCC or decompensation; this analysis was in patients staged at F2, F3, or F4 only (Table 4). After adjusting for age, race, and other factors included in the model, higher baseline stage, higher comorbidity score, platelet count below normal, and bilirubin level above normal were significantly associated with the development of HCC or decompensation (Table 4). Of these, baseline fibrosis stage F3 (adjusted hazard ratio [aHR], 4.2) or F4 (aHR, 7.05) vs F2, and platelet count below normal (aHR, 3.45) were the strongest predictors of progression to HCC or decompensation (Table 4).
Additional Analyses
We compared the demographic and clinical characteristic, assessed at the time of HCV diagnosis, among patients who were and were not biopsied after diagnosis. Of the 870 patients whose HCV diagnosis was first made during 2009-2012, 156 (17.9%) were biopsied at least once (Supplementary Table). The differences between the biopsied and nonbiopsied groups were relatively small, and statistically significant differences were limited to insurance type and study site: the percentage of patients who had private insurance was significantly higher in the biopsied group than the nonbiopsied group (63.5% vs 45.9%, P < .0001; Supplementary Table).
DISCUSSION
We observed significant progression to liver failure and death among patients with advanced liver fibrosis or cirrhosis in the absence of successful treatment. Our results emphasize that effective treatment is urgently needed in these groups of patients to preserve remaining liver function to improve survival and to reduce the risk of liver cancer and hepatic decompensation. Our risk estimates in patients with early stages of liver disease are important for cost-effectiveness analyses and policy decisions about timing of treatment [20]. Our study provides timely data for understanding the implications in the United States if HCV treatment is delayed in certain patient groups as a national debate is ongoing regarding restrictive policies for access to newer HCV therapies [13].
Treatment programs in 2012 or earlier were not effective. Although a majority of patients staged at F3 and F4 at baseline were treated for HCV, sometimes with >1 attempt, an overall 19.6% of F3 patients and 37.2% of F4 patients went on to experience hepatic decompensation or HCC within 5 years before treatment could lead to testing negative for HCV RNA. In F4 patients, the 1-year progression rate to HCC was 4.8% and to hepatic decompensation was 13.4%. Newer and more effective treatments in these patients are needed to reduce the risks of mortality and liver complications.
The 1-year risk of developing hepatic decompensation or HCC was 0.4% and 1.3% for F0-F1 and F2 patients, respectively, and these probabilities are less than one-tenth of the respective risks in F3 patients (5.0%) and F4 patients (14.5%); thus, our data support the guidance provided by AASLD/IDSA [5]. Although no HCC case was detected in F0-F1 patients, HCC cases were detected in F2 and F3 patients in the short term, probably because a subset of these patients may have rapidly progressed to cirrhosis. It is also possible that some patients may have been misclassified, due to biopsy sampling and/or interpretation error, and may have actually had more advanced fibrosis than indicated. Because our risk estimates were drawn from a large cohort of HCV-infected patients in real-world settings, the findings of our study are likely less affected by selection bias than the previous clinic-based studies.
The baseline liver fibrosis was staged by biopsy, which is traditionally viewed as the gold standard in staging liver fibrosis. Our stage-specific estimates based on biopsy results should be highly relevant to alternative staging approaches, such as transient elastography, which is increasingly used to guide patient management. Given that repeated biopsy is not practical, long-term monitoring of patients with lesser degrees of fibrosis using noninvasive methods of transient elastography and FIB-4 score should be further studied [15, 21].
Our study has several limitations. First, although we used more reliable sources for HCC events and death, the occurrences of decompensation and liver transplant were ascertained by ICD-9/CPT codes. Based on our validation study in CHeCS patients, the subset of ICD-9/CPT codes we used can correctly identify decompensation in 81.7% of cases. Our estimates of progression to HCC are not precise, due to small numbers of cases in subgroups, but are consistent with the literature [22-24]. However, the progression risks to hepatic decompensation are on the high side compared with the risks reported by Dienstag et al [24] and Bruno et al [22], suggesting that a portion of the occurrences identified by ICD-9/CPT codes might include rule-out or suspected diagnoses. Second, the selection of patients for biopsy was not random and may have been based on clinical status, desire to ascertain treatment eligibility, or access to specialty care. However, in a group of patients newly diagnosed with HCV infection, we did not find any differences in clinical factors predictive of liver disease progression between patients who did and did not undergo biopsy. Finally, although CHeCS patients were geographically, clinically, and demographically diverse, the prevalence of comorbidity and behavioral factors such as alcohol abuse in CHeCS patients may not be generalizable to all HCV-infected persons who have been diagnosed.
The trend of increasing morbidity associated with advanced liver diseases in the United States [25] may be rapidly changed if access to care and effective treatment become widely available for persons who are at high risk of morbidity and mortality. This natural history study provides real-world data about the probability of, time to, and risk factors for HCV-related morbidity and mortality. These timely data can help evidence-based decision making by clinicians and policy makers about HCV management, and can help inform the debate regarding the comparative benefits and harms of treating HCV patients at the time of diagnosis vs waiting to treat only those patients who show early signs of progression of liver disease (eg, F2) or other manifestations of the infection.
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