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Increasing Prevalence of HCC and Cirrhosis in Patients With Chronic Hepatitis C Virus Infection
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"Results from mathematical models projected an increase in the proportion of patients with HCV who have cirrhosis to ~16% in 2000 and 25% in 2010, with an accompanying increase in decompensation, liver cancer, and liver-related deaths.....First, there was a striking increase in the burden of cirrhosis, hepatic decompensation, and HCC in the VA HCV cohort over the past decade. We found that the prevalence of cirrhosis and hepatic decompensation doubled, whereas the prevalence of HCC increased 19-fold between 1996 and 2006. Thus, 1 of 5 patients with HCV had cirrhosis and 1 of 100 patients with HCV had HCC in 2006. Our results show that aging of the VA HCV-infected patients explains a significant proportion of the rising trend (20% and 47%) in the prevalence of cirrhosis and HCC, respectively, with time. However, even after adjusting for aging, the time trends remained significantly upward, suggesting that other "unmeasured" factors that are in turn associated with the passage of time (such as duration of HCV infection) have a role in explaining the rising burden of cirrhosis and its related complications in HCV. We also found an increase in the proportion of patients with cirrhosis who died each year, with annual mortality rates reaching 7% in 2006. Overall, 23,294, 13,724, and 1619 patients with HCV who sought care at the VA had a diagnosis of cirrhosis, hepatic decompensation, or HCC in 2006 vs 2061, 1012, and 17 patients, respectively, in 1996."
Gastroenterology
April 2011
FASIHA KANWAL,*, TUYEN HOANG, JENNIFER R. KRAMER,, STEVEN M. ASCH,,#,** MATTHEW BIDWELL GOETZ,,** ANGELIQUE ZERINGUE,* PETER RICHARDSON,,,# and HASHEM B. EL-SERAG,,#
*Department of Gastroenterology and Hepatology, John Cochran VA Medical Center, St Louis, Missouri, Saint Louis University School of Medicine, St Louis, Missouri; Department of Medicine and Health Services Research, Greater Los Angeles VA Healthcare System, Los Angeles, California; Houston VA HSR&D Center of Excellence, Health Services Research and Development Service, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Sections of Health Services Research and #Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, Texas; and **Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
Background & Aims
Patients with hepatitis C virus (HCV) infection are at risk for developing costly and morbid complications, although the actual prevalence of these complications is unknown. We examined time trends in the prevalence of cirrhosis and its related complications, such as hepatic decompensation and hepatocellular carcinoma (HCC).
Methods
We calculated the annual prevalence of cirrhosis, decompensated cirrhosis, and HCC in a national sample of veterans diagnosed with HCV between 1996 and 2006. Patients with HCV who had at least one physician visit in a given calendar year were included in the analysis of prevalence for that year. We used direct standardization to adjust the prevalence of cirrhosis and related complications for increasing age of the cohort as well as sex and changes in clinical characteristics.
Results
In this cohort, the number of individuals with HCV increased from 17,261 in 1996 to 106,242 in 2006. The prevalence of cirrhosis increased from 9% in 1996 to 18.5% in 2006. The prevalence of patients with decompensated cirrhosis doubled, from 5% in 1996 to 11% in 2006, whereas the prevalence of HCC increased approximately 20-fold (0.07% in 1996 to 1.3% in 2006). After adjustment, the time trend in the prevalence of cirrhosis (and its complications) was lower than the crude trend, although it still increased significantly.
Conclusions
The prevalence of cirrhosis and HCC in HCV-infected patients has increased significantly over the past 10 years. An aging cohort of patients with HCV could partly explain our findings. Clinicians and health care systems should develop strategies to provide timely and effective care to this high-risk population of patients.
Background
Chronic hepatitis C virus (HCV) infection is a common condition that affects more than 1.3% of the US population.1 Recent data show that antiviral treatment rates are lower than 30% and such treatment results in a response in only half of the treated patients.2, 3, 4, 5 Thus, a significant proportion of patients with HCV remain at risk for progression to advanced liver disease or cirrhosis.
Cirrhosis develops after prolonged infection in patients with HCV.6 Because a majority of patients are believed to have acquired their infection as young adults in the 1970s,7, 8 the number of patients chronically infected for more than 20 years continues to rise.9, 10 Due to the coupling of prolonged infection with aging of the HCV cohort, the prevalence of cirrhosis and related complications is expected to increase.11 Indeed, a recent cohort study found that HCV-related mortality has increased substantially from 1995 to 2004 and that this rising burden of mortality is likely related to complications of advanced liver disease.12 These data, however, do not provide direct population-based estimates of the number of patients with cirrhosis and related complications in relation to overall infection with HCV, particularly in the era of modern antiviral therapies. Measuring the burden of cirrhosis in HCV is important because these data can help us understand changes in the pattern of care delivery to patients with HCV, provide a critical insight into the magnitude of the problem, and guide both clinicians and the health care system to develop strategies and capacity targeted toward providing timely and effective care to this highly vulnerable group of patients with HCV.
The Veterans Administration (VA) health care system is the largest integrated health care system in the United States and has a disproportionate number of patients with HCV. A recent study found that more than 5% of a nationally representative cohort of VA system enrollees are chronically infected with HCV.13 This makes the VA the flagship health care system in which to examine changes in the burden of cirrhosis. The VA is also a semiclosed system with a relatively stable patient population, making long-term studies possible. We conducted a retrospective cohort study of all VA patients with HCV to quantify changes in the prevalence of cirrhosis and examine trends in its related complications, such as hepatic decompensation and hepatocellular carcinoma (HCC).
Results
Study Cohort
Figure 1 shows the number of patients with HCV for each of the study years from 1996 to 2006. Our cohort consisted of 17,261 patients in 1996. The cohort size increased steadily (about 10,000 patients annually) between 1996 and 1999 and reached 47,000 patients in 1999. This was followed by a relatively steep rise between 2000 and 2004 and likely reflected the wide implementation of the screening program for HCV among VA users. The trend leveled off in the more recent years, with a cohort size of 106,242 patients in 2006.
Crude Prevalence of Cirrhosis, Decompensated Cirrhosis, and HCC
Figure 2 displays the trends in the prevalence of cirrhosis, decompensated cirrhosis (left vertical axis), and HCC (right vertical axis) between 1996 and 2006. There was a significant increase in the prevalence of cirrhosis and its related complications over time. For example, the prevalence of cirrhosis doubled from 9% (95% CI, 8.7%-9.5%) in 1996 to 18.5% (95% CI, 18.3%-18.7%) in 2006 (P < .0001). As shown in Figure 2, the prevalence rose steeply from 1996 to 1998, stabilized between 1999 and 2002, and then started rising again in 2003, with the trend still upward. Similarly, the prevalence of decompensated cirrhosis rose in parallel with the overall prevalence of cirrhosis, with a 2-fold increase from 5% (95% CI, 4.5%-5.3%) in 1996 to 11% (95% CI, 10.7%-11.1%) in 2006 (P < .0001). There was a steady increase in the prevalence of HCC between 1996 and 2002. However, the upward slope became steeper from 2003 onward. The prevalence of HCC increased 19-fold from 0.07% (95% CI, 0.04%-0.1%) to 1.3% (95% CI, 1.23%-1.35%) during the 11 study years (P < .0001).
We found that approximately 20% of all patients with a diagnosis of cirrhosis with or without decompensation and only 10% of patients with HCC had their first ICD-9 code in the first year (Supplementary Table 1). For both cirrhosis and HCC, most of the patients were diagnosed after being in the VA for several years.
As a result of the rising prevalence rates, there were 23,294, 13,724, and 1619 patients with HCV with a diagnosis of cirrhosis, hepatic decompensation, or HCC, respectively, in 2006. Moreover, as shown in Figure 3, mortality in patients with cirrhosis increased over time, with a greater proportion of patients dying in the latter than earlier years.
Crude Prevalence of Demographic and Clinical Characteristics
As expected, the mean age of the cohort increased over time from 46.8 years (SD, 7.6) in 1996 to 55.4 years (SD, 7.2) in 2006 (P < .0001) (Figure 4). Similarly, the proportion of patients with diabetes increased from 12% in 1996 to 23% in 2006 (P < .0001). Other demographic and clinical characteristics of our HCV cohort either declined or remained stable over the 11 study years. Specifically, the proportion of patients with human immunodeficiency virus, HBV, and a diagnosis of alcohol use declined slightly (P < .01), whereas the racial composition was relatively stable.
Adjusted Prevalence of Cirrhosis, Decompensated Cirrhosis, and HCC
As shown in Figure 5, after adjustment for sex and increasing age of the HCV cohort, the upward slopes in the prevalence of cirrhosis and HCC were lower than the corresponding slopes in the crude rates. This divergence was apparent after 1998 for cirrhosis and after 2001 for HCC and became more pronounced with time. For example, the adjusted prevalence of cirrhosis was 20% lower whereas that of HCC was 47% lower than the corresponding crude prevalence rates in 2006. Nonetheless, the trend remained upward with a significant increase from 9% (95% CI, 8.7%-9.5%) in 1996 to 15% (95% CI, 14.3%-15.3%) in 2006 for cirrhosis and from 0.07% (95% CI, 0.04%-0.1%) in 1996 to 0.7% (95% CI, 0.6%-0.8%) in 2006 for HCC (P < .001).
Because diabetes was the only other risk factor that increased over time (Figure 4), we calculated the age/diabetes-adjusted trends for the prevalence of cirrhosis, decompensation, and HCC. These trends were very similar to those of the age/sex-adjusted trends displayed in Figure 5 (data not shown).
Discussion
There are few indirect data suggesting a rise in the burden of illness in HCV and the relative contribution of cirrhosis in this rise. Using the US Census and cause-of-death data, Wise et al reported that age-adjusted HCV-related mortality rates increased from 1995 to 2002 but reached a plateau since 2002.12 Results from mathematical models projected an increase in the proportion of patients with HCV who have cirrhosis to ~16% in 2000 and 25% in 2010, with an accompanying increase in decompensation, liver cancer, and liver-related deaths.11 Our data are the first to provide direct and contemporary estimates of the time trends in the burden of cirrhosis from the largest assembled group of patients with HCV anywhere in the world.
Our study has 2 major findings. First, there was a striking increase in the burden of cirrhosis, hepatic decompensation, and HCC in the VA HCV cohort over the past decade. We found that the prevalence of cirrhosis and hepatic decompensation doubled, whereas the prevalence of HCC increased 19-fold between 1996 and 2006. Thus, 1 of 5 patients with HCV had cirrhosis and 1 of 100 patients with HCV had HCC in 2006. Our results show that aging of the VA HCV-infected patients explains a significant proportion of the rising trend (20% and 47%) in the prevalence of cirrhosis and HCC, respectively, with time. However, even after adjusting for aging, the time trends remained significantly upward, suggesting that other "unmeasured" factors that are in turn associated with the passage of time (such as duration of HCV infection) have a role in explaining the rising burden of cirrhosis and its related complications in HCV. We also found an increase in the proportion of patients with cirrhosis who died each year, with annual mortality rates reaching 7% in 2006. Overall, 23,294, 13,724, and 1619 patients with HCV who sought care at the VA had a diagnosis of cirrhosis, hepatic decompensation, or HCC in 2006 vs 2061, 1012, and 17 patients, respectively, in 1996.
Second, we found that the rise in the burden of HCC was significantly greater than predicted by previous mathematical models. Specifically, we found that although only 0.26% of the patients with HCV had HCC in 2000-an estimate very similar to that reported in the previous mathematical models-this proportion increased significantly to 1.3% in 2006, which is an estimate that is remarkably higher than some have previously projected (eg, 0.39% by Davis et al11). It is plausible that transferring care to the VA after development of HCC might have contributed to the prevalence, but we found that most of the patients with HCC had their condition diagnosed after being in the VA for several years, suggesting that care transfer plays a relatively small role. Another explanation is that our patient population may be at higher risk for progression to cirrhosis and HCC than nonveteran patients with HCV because of the high prevalence of several comorbid conditions (such as alcohol use) in our cohort (Figure 4). It is also possible that veterans with HCV acquired their infection earlier than nonveteran patients with HCV and thus would have had their infection for a longer time compared with nonveterans. If true, then it would mean that the HCC prevalence curve in the general (or nonveteran) population with HCV is lagging behind that of HCV-infected veterans and that there might be a greater epidemic of HCC than we were expecting. Last, it is also possible that data from previous studies may be an underestimate. In fact, data from recalibrated mathematical models suggest that the projected prevalence of HCC may indeed be higher than previously reported.29 These new and concurrent estimates, therefore, provide convergent validity to our report. In contrast to the higher than expected prevalence of HCC, we found the prevalence of cirrhosis to be somewhat lower than previously predicted. Based on previous data, this disconnect is likely related to underdiagnosis of early-stage cirrhosis, possibly due to low rates of biopsy in the VA.2, 30 Thus, the prevalence of histologic cirrhosis may indeed be significantly higher than seen in our analysis.
The morbidity and mortality associated with cirrhosis and HCC may be greatly reduced if potentially life-saving interventions-such as liver transplantation and, for HCC, local ablation and surgical resection-are applied in a timely manner. However, liver transplantation is a resource-intensive and scarce treatment modality, and only a few patients with HCC are eligible for potentially curative therapy due to advanced stage of HCC at diagnosis. Moreover, recent data show deficits in the care provided to patients with cirrhosis. For example, Julapalli et al found that only 20% of patients with cirrhosis who satisfied American Association for the Study of Liver Diseases guidelines for referral had a mention of liver transplantation in their medical charts.31 Wilbur et al found that 94% of patients with variceal bleeding had not received any primary prophylaxis, and Singh et al found that follow-up endoscopy for secondary prophylaxis was arranged for only 65% of patients after the initial bleeding episode.32, 33 In our previous studies, we found that less than one-third of patients who were diagnosed with HCC received screening before their diagnosis.34 In addition, we have found that the quality of health care given to patients with HCV infection falls far short of that recommended by practice guidelines.35 These deficits in HCV care in general and cirrhosis care in particular, combined with the relative scarcity of available treatment modalities for cirrhosis, further limit the effectiveness of these treatments in clinical care. Given the significant increase in the number of patients with cirrhosis, and given the data suggesting marked gaps in the quality of care, the health care system may need to rechannel its efforts in patients with HCV to provide timely and effective care to the patients with cirrhosis.
Our study has several strengths, including the long period of follow-up, use of previously validated definitions of cirrhosis and HCC, and examination of demographic and clinical variables that may impact the burden of cirrhosis in HCV. Moreover, most of the patients with HCV in the VA are diagnosed as a result of a system-wide screening program, rather than after development of complications from liver disease. The presence of this unique screening mechanism makes our sample a relatively unbiased cohort. The availability of laboratory data allowed us to identify a cohort of patients with chronic HCV infection. To achieve high accuracy of case definitions, we excluded patients without documented viremia from our denominator; therefore, the absolute number of patients with cirrhosis might be even higher than reported. However, prevalence estimates are less likely to be affected.
Our study is limited by the observational retrospective nature of its design. Several unmeasured patient characteristics could have affected our results. Specifically, we could not determine the presence of coexisting nonalcoholic steatohepatitis. However, given the strong association between metabolic syndrome and nonalcoholic steatohepatitis, we hypothesized that diabetes would act as a surrogate for nonalcoholic steatohepatitis. Although we had information on antiviral treatment in our database, we opted not to include this variable in our analysis. Conceptually, we expected the antiviral treatment variable to have 2 opposing effects on the prevalence of cirrhosis: (1) patients with successful antiviral treatment would be less likely to progress to cirrhosis (negative association), and (2) because patients with cirrhosis are at the highest risk for adverse disease outcomes, they would also be more likely to receive antiviral treatment (positive association). Given the low rates of antiviral treatment in our study population (16% of our cohort had ever received at least one prescription of interferon; data not shown), we do not anticipate any bias in our analysis. We did not analyze any care that occurred before January 1, 1996, and it is possible that some patients, particularly those included in the database during the earlier years, might have been diagnosed with HCV before 1996. This might have caused an overestimation of the prevalence of cirrhosis in the earlier years. However, we believe that this effect is likely small because most of the patients with HCV in the VA were diagnosed as a result of a widely implemented screening program for HCV in the late 1990s (Figure 1 depicts the impact of this screening program). Our analysis was not designed to identify causative elements that lead to progression of liver disease; therefore, we cannot imply causative relationships about progression from this study. Instead, we planned this analysis to shed light on the burden of illness and its related implications from the perspective of a health care system that is managing a large cohort of patients with HCV. Our results are derived from diagnosed HCV-infected patients who sought care in the VA health care system, and although the generalizability of the biologic process of cirrhosis progression probably extends from these veterans to other HCV-infected individuals in the VA as well as nonveterans, further research would be needed to confirm that. We are also limited by the sensitivities and specificities of the ICD-9 coding system for our outcomes, which may vary between VA and non-VA practitioners, thus limiting the generalizability of overall rates of cirrhosis and its complications to patients with HCV outside of the VA.
Our analysis highlights that the prevalence of cirrhosis has reached very high proportions among veterans with HCV infection. Given low antiviral treatment rates for HCV, we believe that the burden of cirrhosis will continue to grow as the HCV cohort ages unless effective treatment can be provided to patients with HCV in a timely manner. In light of the increasing burden of cirrhosis and HCC in patients with HCV, clinicians and the health care system may need to develop strategies targeted to provide timely and effective care to this high-risk patient population.
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