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Dr. Jay Adlersberg
More: Bio, News Team
MIAMI (WABC) -- 15,000 men and 6,000 women will be told they have liver cancer this year.
For patients whose cancer hasn't spread, a liver transplant offers the option of a cure, but the surgery comes with a risk of rejection and a lifetime of medications.
One new procedure offers hope of cure a cure without a transplant.
The Gomez's have had 47 years of marriage to make memories, some sweet, and some they want to forget.
"I had a lesion that was 2.5 centimeters," said Maria Gomez.
Maria was diagnosed with liver cancer three years ago, major surgery her only option.
"I was down for about two weeks," Maria said.
Last year, the cancer came back. Maria chose to delay a liver transplant with a new treatment called IRE, or irreversible electroporation. Guided by CT scans, interventional radiologists used thin needles to insert probes around Maria's tumor.
"Once we have identified the appropriate placement of the probes, we then connect them to a generator, and it kills the tumors by using very high-voltage electricity," said Govindarajan Narayanan, M.D., chief of Vascular Interventional Radiology at the University of Miami in Miami, Fla.
The 45-second electrical pulses create multiple holes in the membrane of the cancer cells, destroying the tumor.
"Almost like a neutron bomb, where you kill everything inside but the structure remains," Dr. Narayanan explained.
The body naturally removes the cell structure that's left behind. Unlike traditional ablation, the approach allows radiologists to reach tumors close to blood vessels and leaves no scar tissue behind. No large incisions are required.
"When the healing process takes place, it almost looks like the tumor was not there," Dr. Narayanan said.
Patients are sent home the next day. Forty-eight hours after her procedure, Maria is back soaking in the memories.
Dr. Narayanan says ideal candidates for IRE have liver tumors smaller than 5 centimeters, or they aren't eligible for a transplant.
Patients with tumors on multiple organs or who have a pacemaker aren't candidates for the procedure. Doctors plan to use the treatment for cancers of the lung and kidneys and have successfully performed it on the first case of pancreatic cancer.
(Copyright ©2010 WABC-TV/DT. All Rights Reserved
Monday, March 29, 2010
Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States
Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression
Gastroenterology Feb 2010
"our findings suggest that the CH-C that we have become familiar with during the last 30 years is much different than the hepatitis C we will come to know during the next decade or 2......Currently, only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment.......the proportion of cases with advanced fibrosis will continue to rise during the next 2 decades (Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006, the proportion with cirrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030).....HCC in persons older than the age of 65 years with HCV infection has doubled during the last several years....(The model suggests that decompensation became more common after 1995 and is currently estimated to be present in 11.7% of persons with cirrhosis (Figure 4). The proportion of cirrhotics with decompensation is expected to continue to rise at least through 2030)......critical to identify infected persons and treat their disease before advanced fibrosis or liver failure ensues......It is in the immediate best interest of patients, providers, insurers, and governments to promote guidelines and encourage better screening for infection and early antiviral treatment.68 Without such a proactive policy, it is likely that we will spend a considerable amount of resources during the next 2 or 3 decades dealing with liver failure in our elderly population."
Gary L. Davis, Miriam J. Alter, Hashem El-Serag, Thierry Poynard, Linda W. Jennings Division of Hepatology, Baylor University Medical Center and Baylor Regional Transplant Institute, Dallas, Texas Infectious Disease Epidemiology Program, University of Texas Medical Branch, Galveston, Texas Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas Assistance Publique Hopitaux de Paris, Universite Pierre et Marie Curie Liver Center, Paris, France Received 15 July 2009; accepted 28 September 2009. published online 26 October 2009.
Background & Aims
The prevalence of chronic hepatitis C (CH-C) remains high and the complications of infection are common. Our goal was to project the future prevalence of CH-C and its complications.
Methods
We developed a multicohort natural history model to overcome limitations of previous models for predicting disease outcomes and benefits of therapy.
Results
Prevalence of CH-C peaked in 2001 at 3.6 million. Fibrosis progression was inversely related to age at infection, so cirrhosis and its complications were most common after the age of 60 years, regardless of when infection occurred.
The proportion of CH-C with cirrhosis is projected to reach 25% in 2010 and 45% in 2030, although the total number with cirrhosis will peak at 1.0 million (30.5% higher than the current level) in 2020 and then decline. Hepatic decompensation and liver cancer will continue to increase for another 10 to 13 years. Treatment of all infected patients in 2010 could reduce risk of cirrhosis, decompensation, cancer, and liver-related deaths by 16%, 42%, 31%, and 36% by 2020, given current response rates to antiviral therapy.
Conclusions
Prevalence of hepatitis C cirrhosis and its complications will continue to increase through the next decade and will mostly affect those older than 60 years of age. Current treatment patterns will have little effect on these complications, but wider application of antiviral treatment and better responses with new agents could significantly reduce the impact of this disease in coming years.
It is estimated that up to 4 million persons in the United States have chronic hepatitis C virus (HCV) infection (CH-C).1, 2 Despite the marked decrease in newly acquired infections in recent years, overall prevalence of CH-C has not fallen.2 Most individuals with CH-C acquired their infection 20-40 years ago, before identification of the virus and availability of screening tests.3 Because CH-C typically progresses slowly and does not result in morbidity for many years, most remain undiagnosed. We are only now beginning to recognize the magnitude of the consequences of infection that has persisted for decades.4, 5
Outpatient and hospital visits for CH-C have doubled in recent years and show no sign of leveling off.6, 7, 8 In the United States, complications of CH-C are the leading indication for liver transplantation and the disease is reported to contribute to 4600-12,000 deaths per year based on death certificate documentation,2, 6, 9, 10 despite the limitations of this method in estimating true death rates.11, 12 Although some have suggested that the health care burden resulting from complications of CH-C has reached a plateau,10 others have projected a further increase in cirrhosis and its complications for another 2 to 3 decades.13, 14
Several models have been developed during the last decade to predict the future course of CH-C.13, 14, 15, 16 However, simple transition-state (Markov) models have significant limitations in that the studied cohort is considered homogeneous and traverses through their disease at a fixed and predictable rate over time. In reality, however, the population is quite heterogeneous due to factors such as age at infection, gender, and disease duration; therefore, the course of disease is variable and nonlinear over time.17, 18, 19 Also, previous models used standard population mortality, which recent studies suggest might underestimate true mortality in a chronic disease population.11, 20, 21
Advances in computer software now permit construction of complex models that allow parallel cohorts with different disease states and probabilities to run over time in order to provide a more realistic estimation of end-point events. The purpose of this project was to utilize state-of-the-art statistical modeling techniques and the latest epidemiologic, demographic, and natural history data to more accurately model the evolution of CH-C during the last 60 years and project its course in the coming decades.
Discussion
Our model estimated that the prevalence of CH-C in the United States peaked at 3.6 million in 2001 and will decline to about half this number by 2030. Although the decline in overall infections is encouraging, other trends in the data are of concern. First, similar to reports by others,13, 14, 16 the proportion of cases with advanced fibrosis will continue to rise during the next 2 decades, with the number of cases of cirrhosis and hepatic decompensation peaking after the year 2020. Second, the age of those with cirrhosis and its complications will continue to rise. Because about 40 years elapses from the peak incidence years of HCV infection until the peak prevalence of cirrhosis and other complications (Figure 1), it is not surprising that we found the group of persons aged 60 to 80 years to be those most affected. This phenomenon is already beginning to occur.49, 52, 53, 54 Indeed, Ferenci and colleagues found that 34% of infected paid plasma donors identified in the 1970s had bridging fibrosis, cirrhosis, or HCC 30 years later.51 In addition, Thabut and colleagues reported that cirrhosis was more prevalent in the elderly and 14% of them presented with decompensation compared to just 4% in persons younger than 65 years.52 Indeed, D'Souza and others have even suggested that patients who live long enough will almost invariably develop advanced hepatic fibrosis.54, 55 We also predicted a modest increase in HCV-related HCC in coming years, despite using a very conservative estimate of the annual risk in our model. HCV infection currently accounts for most of the HCC in the United States.49 HCC in persons older than the age of 65 years with HCV infection has doubled during the last several years,48, 56 consistent with our predictions. Taken together, our findings suggest that the CH-C that we have become familiar with during the last 30 years is much different than the hepatitis C we will come to know during the next decade or 2.
Although we purposefully chose conservative estimates of disease progression and complications, it is still possible that we and others might have overestimated the number of cases that will progress to liver failure from CH-C due to the influence of competing risks.11, 12, 20, 57 Indeed, when we increased the background (nonhepatic) mortality by just 50%, there was a striking reduction in the number of cases of cirrhosis, liver failure, and cancer. However, we believe that such high background mortality is unlikely in HCV-infected patients. If it occurs it is probably limited to a short period around the time of acute infection and would be unlikely to influence long-term outcomes. Furthermore, common comorbid conditions, such as diabetes, obesity, and alcohol, lead to more rapid progression of fibrosis, which can offset any potential impact of a change in background mortality.26, 58, 59, 60 Competing risks could certainly influence resource utilization and might explain why, for example, the number of liver transplantations related to hepatitis C has started to plateau, despite our prediction of more disease complications.
These projections emphasize how critical it is to identify infected persons and treat their disease before advanced fibrosis or liver failure ensues. Currently, only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment.61, 62, 63 Many physicians still do not ask their patients about risk factors for HCV infection and some remain confused about treatment options and efficacy.64 And yet, antiviral therapy is becoming increasingly effective65, 66 and eradication of virus clearly reduces risk of liver failure or cancer.27, 67 Certainly, as we have shown, a far higher proportion of cases will need to be identified and treated to impact the dire projections described here. It is in the immediate best interest of patients, providers, insurers, and governments to promote guidelines and encourage better screening for infection and early antiviral treatment.68 Without such a proactive policy, it is likely that we will spend a considerable amount of resources during the next 2 or 3 decades dealing with liver failure in our elderly population.
Results
Population-Based Model Outcomes
There was a rapid increase in the prevalence of CH-C between 1970 and 1990, when the incidence of acute HCV infection was greatest (Figure 1). We estimated 3.49 million infected persons in 1994, which is similar to previous predictions based on NHANES III.13, 14 Estimated prevalence peaked at 3.57 million in 2001 and began to decline slowly thereafter, reaching about half its peak level by the year 2030 (Figure 1). Similarly, the model estimated that the number of persons who had ever been infected (resolved or chronic) peaked in 2001 at 5.04 million.
Figure 1. Estimates by year of prevalent cases ever infected (top line), with chronic hepatitis C (open circles), and cirrhosis (solid squares). Acute infections (solid gray line) peaked between 1970 and 1990. The peak of chronic hepatitis prevalence was 2001, while the highest prevalence of cirrhosis is projected to be between 2010 and 2030, about 40 years after the peak of acute infections.
Predicted distribution of histologic stages of fibrosis over time is shown in Figure 2. In 1970 and throughout the period during which HCV prevalence grew, the majority of cases were stage F0 or F1 (1970: 86.5%, 1980: 84.2%, 1990: 77.6%). Indeed, F0 and F1 fibrosis accounted for the majority of cases of CH-C until just recently. Currently, 41.8% of infected persons have minimal-to-mild fibrosis (F0 or F1), and 39.5% have F3 or F4 fibrosis.
Figure 2. Distribution of histologic stages of fibrosis by year in persons with chronic hepatitis C (F0 = closed black squares, F1 = closed gray diamonds, F2 = open triangles, F3 = solid gray, and cirrhosis (including decompensated and hepatocellular carcinoma) = fine line with closed circles).
Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006 (Figures 1 and 2). This proportion began to rise sharply after 1990, as the age and duration of infection of those infected began to increase. Indeed, the proportion with cirrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030, although the total number of persons with cirrhosis is expected to peak at 1.04 million (30.5% higher than its current level) in 2020 and slowly decline thereafter. Men, particularly those infected before age 50, account for the majority of cases of cirrhosis today (73.6%) because of their more rapid rate of progression (Figure 3). Although men who acquired their infection after age 50 have the most rapid disease progression, they account for a small proportion of all cirrhosis (7.7%) because they often died of other causes before their fibrosis had a chance to progress. Although females who acquired infection before age 50 accounted for almost the same proportion of acute HCV infections as similarly aged men during the peak incidence years (43.0% vs 50.3%), they represent a much smaller proportion of those who have progressed to cirrhosis as of 2009 (16.1%) because chronicity was less likely and CH-C had a slower rate of progression than men.
Figure 3. Stacked prevalence curves showing number of cases by year with cirrhosis according to gender and age at time of initial hepatitis C virus infection.
Hepatic decompensation and HCC are late complications of CH-C occurring in persons with advanced fibrosis. The model suggests that decompensation became more common after 1995 and is currently estimated to be present in 11.7% of persons with cirrhosis (Figure 4). The proportion of cirrhotics with decompensation is expected to continue to rise at least through 2030, although the total number of persons with liver failure will start to decline after 2022. The number with HCC began to rise steeply after 1990 (Figure 4). The model estimated 37,697 cases between 1990 and 1999 compared to 86,765 (+130%), 130,366 (+50%), and 124,298 (-5%), respectively in each of the subsequent decades. The incidence of HCV-related HCC is projected to peak in 2019 at almost 14,000 cases per year if the risk in HCV-infected persons with fibrosis remains stable. Assuming that 55% of HCC cases are due to hepatitis C, the HCC projections in males and females in 2005 approximate estimates from a recent report based on the Surveillance, Epidemiology and End Results database (predicted vs estimated cases: male, 7700 vs 8053; female, 1608 vs 922).48, 49
Figure 4. Projected number of cases by year of decompensated cirrhosis (black) and hepatocellular carcinoma (gray). The model assumes a first year mortality of 80% to 85%, so in contrast to the decompensated cirrhosis projection, the number of cases of hepatocellular carcinoma the prevalence demonstrated here closely resembles annual incidence of liver cancer.
We projected that hepatic deaths due to HCV would continue to increase through 2022, although the rate of year-to-year change began to slowly decline after 1991. Consistent with the increasing average duration of infection in persons with CH-C and the severity of liver disease described here, we estimated 29,090 liver-related deaths from 1980 to 1989, 56,377 (93%) in 1990-1999, 145,667 (+158%) in 2000-2009, 254,550 (+74%) in 2010-2019, and 283,378 from 2020 to 2029.
Cohort Analysis
The proportions with cirrhosis, decompensation, HCC, liver-related death, and non-liver-related death after 10, 20, and 30 years in each of the 6 cohorts are shown in Table 2. These proportions apply to the entire cohort that was ever infected, including those who resolved infection early. For example, although 1.33% of women in the youngest cohort were expected to have cirrhosis after 20 years, these cases occurred only among the 55% who had not resolved acute infection spontaneously; this represented 2.59% of persons with CH-C. Fibrosis and cirrhosis increased over time in all cohorts, but never exceeded 40% within the 30-year observation period. However, if only those who developed CH-C are considered, cirrhosis was predicted in more than half of the 2 older male cohorts after 30 years because progression rates were more rapid in these persons. The majority of these remained compensated.
Duration of infection before the peak prevalence of cirrhosis and its complications always varied inversely with the age at acute infection. Therefore, the estimated average ages at the peaks for disease complications were surprisingly consistent in the 6 cohorts (Supplementary Table 3). In the female cohorts, the peak for cirrhosis appeared at ages 71.5-87.0 years, decompensation at 74.5-82.5 years, and HCC at 72.5-87.0 years. In males, cirrhosis appeared at ages 64.5-79.0 years, decompensation at 68.0-82, and HCC at 65.5-80.0 years.
Effect of Treatment
Our original model was not designed to examine treatment effects so a second model was designed to test the effects of treating various proportions of persons with CH-C and no preexisting complications of liver disease. All treatment was administered in the year 2010. Assuming current estimates that 30% of cases of HCV are diagnosed and up to 25% of those are treated, we would anticipate just a 1.0% reduction in cirrhosis by 2020 compared to 7.8% or 15.6% reductions if half or all of individuals were treated, respectively (Figure 5A). However, if viral clearance increased to 80%, as appears possible with evolving treatments, treatment of half or all of infected persons would reduce cirrhosis by 15.2% or 30.4%, respectively, after just 10 years. The effects are more pronounced when looking at complications of liver disease. Indeed, treatment of half or all of infected persons in 2010 would result decrease cases of liver failure of 39.4% or 78.9%, HCC by 30.2% or 60.4%, and liver-related deaths by 34.0% or 68.0% over the next decade (Figure 5B).
Sensitivity Analyses
One-way sensitivity analysis in the youngest female and male cohorts found the rate of chronicity after acute infection was dominant over all other variables in determining the risk of cirrhosis. No other transition rates significantly impacted the risk of cirrhosis after 20 years. The group's predicted estimates of cirrhosis after 17 and 24 years were 0.8% and 2.3%, respectively. These proportions are similar to the 2.0% and 3.1% reported in young Irish women by Kenny-Walsh and Levine39, 40 (Table 3). Similarly, we predicted that a 1.8% hepatic death rate in men infected before age 30, which is similar to the 5.9% observed in the small study of military recruits reported by Seeff and colleagues41 (Table 3). These projections appear to confirm the accuracy of the assumptions in the younger cohorts. In the oldest males, the initial transition from F0 to F1 had the greatest impact on the risk of cirrhosis. However, when the sensitivity analysis in this group was confined to stage-to-stage fibrosis transition rates, no single transition dominated, and risk of cirrhosis after 20 years varied from just 3.75-6.08% less to 2.39-5.69% more than our model projection. In addition, the projected prevalence of cirrhosis after 20 years in the older male group was 24%, consistent with the high rate of fibrosis progression reported by others in this group.19, 50, 51 (Table 3).
Another potential source of uncertainty stems from our use of tunnel states to slow progression during early fibrosis stages and acceleration of progression rates when younger cohorts reached age 50. We felt that these age- and duration-adjusted fibrosis progression rates best reflected the observations from previous reports.17, 18, 19, 33, 34, 39, 40, 41 However, we also tested a fixed stage-to-stage progression rate as reported in the meta-analysis by Thein and colleagues.23 As expected, this led to front-loading of morbidity and hepatic mortality, particularly in the younger cohorts, during the years when standard age-related mortality was low. As a result, the fixed rate model overestimated cases of cirrhosis, decompensation or HCC, and liver-related death by 41%, 86%, and 41%, respectively, compared to the more conservative base case model, and these estimates were much higher than those reported in previous prospective studies.39, 40, 41 Therefore, we maintained our more conservative assumptions for the base case model.
Finally, we looked at the impact of utilizing higher background (nonhepatic) age- and gender-related mortality rates on our projections of chronic hepatitis and cirrhosis in coming decades. Recent studies have suggested that comorbid medical conditions might increase background mortality in HCV-infected persons by as much as 3 times the reported actuarial rates.11, 12, 20 Increasing background mortality rates in the model by 50% or 100% had no impact on the proportion of infected persons with cirrhosis, but it significantly reduced the total number with cirrhosis. A 50% increase in background mortality decreased the number of persons with chronic hepatitis or cirrhosis in 2020 by 35% and 31%, respectively, compared to the base case model projections. A 100% increase decreased the number with chronic hepatitis or cirrhosis in 2020 by 46% and 43%, respectively, compared to base case projections.
Our sensitivity analysis did not include incidence data because no other estimates exist and these data have previously been shown to be consistent with prevalence data as estimated by NHANES III.1, 14
Materials and Methods
Model Construction
Construction and computer simulations of our model utilized TreeAge Pro 2009 Suite (TreeAge Software, Williamstown, MA) linked with Microsoft Excel 2007 (Microsoft Corporation, Redmond, WA). TreeAge allows construction of complex Markov models with progression rates that can be varied with time according to calendar year, patient age, year of disease, or dwell time within a specific state, eg, years of cirrhosis. It also allows the dynamic import of information such as disease incidence, population demographic change, and other factors from Excel spreadsheets.
The model was developed in stages starting with a traditional bubble diagram of disease states that served as the basis for developing a more detailed mathematical model that followed infected persons from the time of acute infection until death. Both the bubble diagram and the more detailed TreeAge model are provided in Supplementary Figure 1, Supplementary Figure 2 available in the online version of this article. Acute infection could resolve, evolve to fulminant hepatitis, progress to chronic hepatitis, or end with death due to background (nonhepatic) mortality. CH-C was modeled through fibrosis stages (Metavir F0 to F4), disease complications, and death. The model cycled at yearly intervals allowing individuals to move to another state; however, all states except acute infection and fulminant hepatitis could resolve back into themselves indefinitely.
It has become apparent in recent years that age at infection and gender greatly influence the risk of developing chronic infection and progressing to fibrosis.18, 19, 20, 21, 22, 23, 24, 25, 26 To accommodate this heterogeneity, we divided acutely infected individuals into 6 cohorts, each with their own cohort-specific transition states for chronicity, fibrosis progression, and complications (Table 1). The output of the 6 models was then collated and exported as an Excel spreadsheet defining cohort-specific and overall projections by year. Cohort and population projections included numbers with resolved infection, chronic infection, stage of fibrosis (F0 to cirrhosis), liver failure, hepatocellular carcinoma (HCC), liver-related deaths, and age- and gender-specific (nonliver) deaths.
Antiviral treatment, ablation of tumors, and liver transplantation could not be modeled because the indications for these practices and procedures are not standardized, their use varies considerably by geography, none is widely applied, and the outcomes are not well-defined in subgroups. Of these, only antiviral treatment has the possibility of significantly altering disease end points from a population perspective. Therefore, we subsequently modified the model to estimate the potential impact of antiviral treatment on cirrhosis and its complications. To do so, we considered treatment penetrance ranging from 0% to 100% in the infected population and sustained viral response rates of 40% to 80%. All cases were treated in 2010 and outcomes were calculated for the year 2020. It was assumed that patients with sustained viral response had no chance of progressing to cirrhosis or, if already cirrhotic, had no chance of subsequent hepatic failure.27 The risk of progressing from cirrhosis to HCC after sustained viral response was assumed to be 0.66% per annum.27 Other assumptions of the model were unchanged.
Data Sources
Medical literature was reviewed by the authors to provide best estimates of the range of probabilities for moving between disease states. Because reported progression rates vary between studies, a consensus rate was chosen (Table 1). We used conservative estimates when a particular transition was in doubt. Transition rates varied for some states according to the age and gender of the cohorts.23, 24, 25, 26, 27, 28 For example, in the young female cohort, progression from acute to chronic infection was lower (55%) and the rate of fibrosis progression was slower than the oldest male cohort.
Transition rates for moving from one fibrosis stage to another largely utilized the pooled rates from a meta-analysis reported by Thein and colleagues.17, 23 However, our model also included tunnel states that kept a portion of the cohort with minimal fibrosis (F0 and F1) from progressing to the next state for variable periods of time in order to simulate slower rates of progression or no progression in some persons. To accommodate the tunnel states, fibrosis transitions were adjusted accordingly such that overall rates remained consistent with those of Thein and colleagues23 (Table 1). Alcohol intake was not modeled separately because its influence in the different cohorts is unknown; rather our transition rates are based on observational studies in which excessive alcohol use was present in 19% of the cohorts.23 Risks of developing HCC in persons with bridging fibrosis or cirrhosis were taken from longitudinal studies in North America and Europe.19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 HCC risk in those with bridging fibrosis was estimated to be 10% of that in cirrhosis. HCC risk in females was estimated to be 40% of that in males.33 Finally, transition rates for fibrosis progression and HCC risk were allowed to increase after age 50 or 10 years of cirrhosis, respectively, consistent with previous observations that these risks are not linear.17, 18, 19, 33, 34 Confirmation of the accuracy of the estimated transition rates was done by comparing the projected chronic infection prevalence in 1994 to results from the Third National Health and Nutrition Examination survey (NHANES III) and the projected cirrhosis and HCC prevalence in the different cohorts to published observations in similar groups.
Annual numbers with newly acquired HCV infections between 1960 and 2006 were generated from a previously published model that estimated the past incidence of acute HCV infection given the actual prevalence measured at the time (1988-1994) of the NHANES III.1, 14, 35 Annual infections were stratified by age and gender based on actual distributions of these variables for cases of acute hepatitis reported to the Centers for Disease Control and Prevention's Sentinel Counties Study for each year from 1979 to 20062, 36 (personal communication, MJ Alter, November 25, 2008). For years when data from the Sentinel Counties Study were not available, number and distribution were assumed to be the same as the closest year with data. We sequentially entered these incident infections in annual cycles into the cohort models and projected disease outcomes through the year 2030. Annual incidence data and cohort distribution utilized in the model are shown in Supplementary Table 1 available online.
Age- and gender-specific all-cause mortality was derived from standard US mortality tables.37 The ages within each cohort were tracked through the annual cycles of the model such that background mortality would be appropriate as the cohorts aged.
Sensitivity Analysis and Validation
Sensitivity analysis was performed to assess the extent to which the model's calculations were affected by uncertainty in our assumptions. The ranges utilized in the sensitivity analysis were derived from the medical literature.31, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and are reported in Supplementary Table 2 available online. Sensitivity analyses were confined to the young female and oldest male cohorts because these were the most disparate in transition probabilities and, therefore, most likely to identify potential sources of weakness within the model assumptions. First, one-way sensitivity analysis with tornado diagrams were utilized to identify dominant variables and to rank the impact of different variables on disease outcome (cirrhosis). If no dominant variable was identified, a second one-way sensitivity analysis was done. Finally, we examined the impact of increasing background mortality, consistent with some reports that suggest higher all-cause mortality in persons with CH-C.5, 15
Gastroenterology Feb 2010
"our findings suggest that the CH-C that we have become familiar with during the last 30 years is much different than the hepatitis C we will come to know during the next decade or 2......Currently, only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment.......the proportion of cases with advanced fibrosis will continue to rise during the next 2 decades (Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006, the proportion with cirrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030).....HCC in persons older than the age of 65 years with HCV infection has doubled during the last several years....(The model suggests that decompensation became more common after 1995 and is currently estimated to be present in 11.7% of persons with cirrhosis (Figure 4). The proportion of cirrhotics with decompensation is expected to continue to rise at least through 2030)......critical to identify infected persons and treat their disease before advanced fibrosis or liver failure ensues......It is in the immediate best interest of patients, providers, insurers, and governments to promote guidelines and encourage better screening for infection and early antiviral treatment.68 Without such a proactive policy, it is likely that we will spend a considerable amount of resources during the next 2 or 3 decades dealing with liver failure in our elderly population."
Gary L. Davis, Miriam J. Alter, Hashem El-Serag, Thierry Poynard, Linda W. Jennings Division of Hepatology, Baylor University Medical Center and Baylor Regional Transplant Institute, Dallas, Texas Infectious Disease Epidemiology Program, University of Texas Medical Branch, Galveston, Texas Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas Assistance Publique Hopitaux de Paris, Universite Pierre et Marie Curie Liver Center, Paris, France Received 15 July 2009; accepted 28 September 2009. published online 26 October 2009.
Background & Aims
The prevalence of chronic hepatitis C (CH-C) remains high and the complications of infection are common. Our goal was to project the future prevalence of CH-C and its complications.
Methods
We developed a multicohort natural history model to overcome limitations of previous models for predicting disease outcomes and benefits of therapy.
Results
Prevalence of CH-C peaked in 2001 at 3.6 million. Fibrosis progression was inversely related to age at infection, so cirrhosis and its complications were most common after the age of 60 years, regardless of when infection occurred.
The proportion of CH-C with cirrhosis is projected to reach 25% in 2010 and 45% in 2030, although the total number with cirrhosis will peak at 1.0 million (30.5% higher than the current level) in 2020 and then decline. Hepatic decompensation and liver cancer will continue to increase for another 10 to 13 years. Treatment of all infected patients in 2010 could reduce risk of cirrhosis, decompensation, cancer, and liver-related deaths by 16%, 42%, 31%, and 36% by 2020, given current response rates to antiviral therapy.
Conclusions
Prevalence of hepatitis C cirrhosis and its complications will continue to increase through the next decade and will mostly affect those older than 60 years of age. Current treatment patterns will have little effect on these complications, but wider application of antiviral treatment and better responses with new agents could significantly reduce the impact of this disease in coming years.
It is estimated that up to 4 million persons in the United States have chronic hepatitis C virus (HCV) infection (CH-C).1, 2 Despite the marked decrease in newly acquired infections in recent years, overall prevalence of CH-C has not fallen.2 Most individuals with CH-C acquired their infection 20-40 years ago, before identification of the virus and availability of screening tests.3 Because CH-C typically progresses slowly and does not result in morbidity for many years, most remain undiagnosed. We are only now beginning to recognize the magnitude of the consequences of infection that has persisted for decades.4, 5
Outpatient and hospital visits for CH-C have doubled in recent years and show no sign of leveling off.6, 7, 8 In the United States, complications of CH-C are the leading indication for liver transplantation and the disease is reported to contribute to 4600-12,000 deaths per year based on death certificate documentation,2, 6, 9, 10 despite the limitations of this method in estimating true death rates.11, 12 Although some have suggested that the health care burden resulting from complications of CH-C has reached a plateau,10 others have projected a further increase in cirrhosis and its complications for another 2 to 3 decades.13, 14
Several models have been developed during the last decade to predict the future course of CH-C.13, 14, 15, 16 However, simple transition-state (Markov) models have significant limitations in that the studied cohort is considered homogeneous and traverses through their disease at a fixed and predictable rate over time. In reality, however, the population is quite heterogeneous due to factors such as age at infection, gender, and disease duration; therefore, the course of disease is variable and nonlinear over time.17, 18, 19 Also, previous models used standard population mortality, which recent studies suggest might underestimate true mortality in a chronic disease population.11, 20, 21
Advances in computer software now permit construction of complex models that allow parallel cohorts with different disease states and probabilities to run over time in order to provide a more realistic estimation of end-point events. The purpose of this project was to utilize state-of-the-art statistical modeling techniques and the latest epidemiologic, demographic, and natural history data to more accurately model the evolution of CH-C during the last 60 years and project its course in the coming decades.
Discussion
Our model estimated that the prevalence of CH-C in the United States peaked at 3.6 million in 2001 and will decline to about half this number by 2030. Although the decline in overall infections is encouraging, other trends in the data are of concern. First, similar to reports by others,13, 14, 16 the proportion of cases with advanced fibrosis will continue to rise during the next 2 decades, with the number of cases of cirrhosis and hepatic decompensation peaking after the year 2020. Second, the age of those with cirrhosis and its complications will continue to rise. Because about 40 years elapses from the peak incidence years of HCV infection until the peak prevalence of cirrhosis and other complications (Figure 1), it is not surprising that we found the group of persons aged 60 to 80 years to be those most affected. This phenomenon is already beginning to occur.49, 52, 53, 54 Indeed, Ferenci and colleagues found that 34% of infected paid plasma donors identified in the 1970s had bridging fibrosis, cirrhosis, or HCC 30 years later.51 In addition, Thabut and colleagues reported that cirrhosis was more prevalent in the elderly and 14% of them presented with decompensation compared to just 4% in persons younger than 65 years.52 Indeed, D'Souza and others have even suggested that patients who live long enough will almost invariably develop advanced hepatic fibrosis.54, 55 We also predicted a modest increase in HCV-related HCC in coming years, despite using a very conservative estimate of the annual risk in our model. HCV infection currently accounts for most of the HCC in the United States.49 HCC in persons older than the age of 65 years with HCV infection has doubled during the last several years,48, 56 consistent with our predictions. Taken together, our findings suggest that the CH-C that we have become familiar with during the last 30 years is much different than the hepatitis C we will come to know during the next decade or 2.
Although we purposefully chose conservative estimates of disease progression and complications, it is still possible that we and others might have overestimated the number of cases that will progress to liver failure from CH-C due to the influence of competing risks.11, 12, 20, 57 Indeed, when we increased the background (nonhepatic) mortality by just 50%, there was a striking reduction in the number of cases of cirrhosis, liver failure, and cancer. However, we believe that such high background mortality is unlikely in HCV-infected patients. If it occurs it is probably limited to a short period around the time of acute infection and would be unlikely to influence long-term outcomes. Furthermore, common comorbid conditions, such as diabetes, obesity, and alcohol, lead to more rapid progression of fibrosis, which can offset any potential impact of a change in background mortality.26, 58, 59, 60 Competing risks could certainly influence resource utilization and might explain why, for example, the number of liver transplantations related to hepatitis C has started to plateau, despite our prediction of more disease complications.
These projections emphasize how critical it is to identify infected persons and treat their disease before advanced fibrosis or liver failure ensues. Currently, only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment.61, 62, 63 Many physicians still do not ask their patients about risk factors for HCV infection and some remain confused about treatment options and efficacy.64 And yet, antiviral therapy is becoming increasingly effective65, 66 and eradication of virus clearly reduces risk of liver failure or cancer.27, 67 Certainly, as we have shown, a far higher proportion of cases will need to be identified and treated to impact the dire projections described here. It is in the immediate best interest of patients, providers, insurers, and governments to promote guidelines and encourage better screening for infection and early antiviral treatment.68 Without such a proactive policy, it is likely that we will spend a considerable amount of resources during the next 2 or 3 decades dealing with liver failure in our elderly population.
Results
Population-Based Model Outcomes
There was a rapid increase in the prevalence of CH-C between 1970 and 1990, when the incidence of acute HCV infection was greatest (Figure 1). We estimated 3.49 million infected persons in 1994, which is similar to previous predictions based on NHANES III.13, 14 Estimated prevalence peaked at 3.57 million in 2001 and began to decline slowly thereafter, reaching about half its peak level by the year 2030 (Figure 1). Similarly, the model estimated that the number of persons who had ever been infected (resolved or chronic) peaked in 2001 at 5.04 million.
Figure 1. Estimates by year of prevalent cases ever infected (top line), with chronic hepatitis C (open circles), and cirrhosis (solid squares). Acute infections (solid gray line) peaked between 1970 and 1990. The peak of chronic hepatitis prevalence was 2001, while the highest prevalence of cirrhosis is projected to be between 2010 and 2030, about 40 years after the peak of acute infections.
Predicted distribution of histologic stages of fibrosis over time is shown in Figure 2. In 1970 and throughout the period during which HCV prevalence grew, the majority of cases were stage F0 or F1 (1970: 86.5%, 1980: 84.2%, 1990: 77.6%). Indeed, F0 and F1 fibrosis accounted for the majority of cases of CH-C until just recently. Currently, 41.8% of infected persons have minimal-to-mild fibrosis (F0 or F1), and 39.5% have F3 or F4 fibrosis.
Figure 2. Distribution of histologic stages of fibrosis by year in persons with chronic hepatitis C (F0 = closed black squares, F1 = closed gray diamonds, F2 = open triangles, F3 = solid gray, and cirrhosis (including decompensated and hepatocellular carcinoma) = fine line with closed circles).
Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006 (Figures 1 and 2). This proportion began to rise sharply after 1990, as the age and duration of infection of those infected began to increase. Indeed, the proportion with cirrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030, although the total number of persons with cirrhosis is expected to peak at 1.04 million (30.5% higher than its current level) in 2020 and slowly decline thereafter. Men, particularly those infected before age 50, account for the majority of cases of cirrhosis today (73.6%) because of their more rapid rate of progression (Figure 3). Although men who acquired their infection after age 50 have the most rapid disease progression, they account for a small proportion of all cirrhosis (7.7%) because they often died of other causes before their fibrosis had a chance to progress. Although females who acquired infection before age 50 accounted for almost the same proportion of acute HCV infections as similarly aged men during the peak incidence years (43.0% vs 50.3%), they represent a much smaller proportion of those who have progressed to cirrhosis as of 2009 (16.1%) because chronicity was less likely and CH-C had a slower rate of progression than men.
Figure 3. Stacked prevalence curves showing number of cases by year with cirrhosis according to gender and age at time of initial hepatitis C virus infection.
Hepatic decompensation and HCC are late complications of CH-C occurring in persons with advanced fibrosis. The model suggests that decompensation became more common after 1995 and is currently estimated to be present in 11.7% of persons with cirrhosis (Figure 4). The proportion of cirrhotics with decompensation is expected to continue to rise at least through 2030, although the total number of persons with liver failure will start to decline after 2022. The number with HCC began to rise steeply after 1990 (Figure 4). The model estimated 37,697 cases between 1990 and 1999 compared to 86,765 (+130%), 130,366 (+50%), and 124,298 (-5%), respectively in each of the subsequent decades. The incidence of HCV-related HCC is projected to peak in 2019 at almost 14,000 cases per year if the risk in HCV-infected persons with fibrosis remains stable. Assuming that 55% of HCC cases are due to hepatitis C, the HCC projections in males and females in 2005 approximate estimates from a recent report based on the Surveillance, Epidemiology and End Results database (predicted vs estimated cases: male, 7700 vs 8053; female, 1608 vs 922).48, 49
Figure 4. Projected number of cases by year of decompensated cirrhosis (black) and hepatocellular carcinoma (gray). The model assumes a first year mortality of 80% to 85%, so in contrast to the decompensated cirrhosis projection, the number of cases of hepatocellular carcinoma the prevalence demonstrated here closely resembles annual incidence of liver cancer.
We projected that hepatic deaths due to HCV would continue to increase through 2022, although the rate of year-to-year change began to slowly decline after 1991. Consistent with the increasing average duration of infection in persons with CH-C and the severity of liver disease described here, we estimated 29,090 liver-related deaths from 1980 to 1989, 56,377 (93%) in 1990-1999, 145,667 (+158%) in 2000-2009, 254,550 (+74%) in 2010-2019, and 283,378 from 2020 to 2029.
Cohort Analysis
The proportions with cirrhosis, decompensation, HCC, liver-related death, and non-liver-related death after 10, 20, and 30 years in each of the 6 cohorts are shown in Table 2. These proportions apply to the entire cohort that was ever infected, including those who resolved infection early. For example, although 1.33% of women in the youngest cohort were expected to have cirrhosis after 20 years, these cases occurred only among the 55% who had not resolved acute infection spontaneously; this represented 2.59% of persons with CH-C. Fibrosis and cirrhosis increased over time in all cohorts, but never exceeded 40% within the 30-year observation period. However, if only those who developed CH-C are considered, cirrhosis was predicted in more than half of the 2 older male cohorts after 30 years because progression rates were more rapid in these persons. The majority of these remained compensated.
Duration of infection before the peak prevalence of cirrhosis and its complications always varied inversely with the age at acute infection. Therefore, the estimated average ages at the peaks for disease complications were surprisingly consistent in the 6 cohorts (Supplementary Table 3). In the female cohorts, the peak for cirrhosis appeared at ages 71.5-87.0 years, decompensation at 74.5-82.5 years, and HCC at 72.5-87.0 years. In males, cirrhosis appeared at ages 64.5-79.0 years, decompensation at 68.0-82, and HCC at 65.5-80.0 years.
Effect of Treatment
Our original model was not designed to examine treatment effects so a second model was designed to test the effects of treating various proportions of persons with CH-C and no preexisting complications of liver disease. All treatment was administered in the year 2010. Assuming current estimates that 30% of cases of HCV are diagnosed and up to 25% of those are treated, we would anticipate just a 1.0% reduction in cirrhosis by 2020 compared to 7.8% or 15.6% reductions if half or all of individuals were treated, respectively (Figure 5A). However, if viral clearance increased to 80%, as appears possible with evolving treatments, treatment of half or all of infected persons would reduce cirrhosis by 15.2% or 30.4%, respectively, after just 10 years. The effects are more pronounced when looking at complications of liver disease. Indeed, treatment of half or all of infected persons in 2010 would result decrease cases of liver failure of 39.4% or 78.9%, HCC by 30.2% or 60.4%, and liver-related deaths by 34.0% or 68.0% over the next decade (Figure 5B).
Sensitivity Analyses
One-way sensitivity analysis in the youngest female and male cohorts found the rate of chronicity after acute infection was dominant over all other variables in determining the risk of cirrhosis. No other transition rates significantly impacted the risk of cirrhosis after 20 years. The group's predicted estimates of cirrhosis after 17 and 24 years were 0.8% and 2.3%, respectively. These proportions are similar to the 2.0% and 3.1% reported in young Irish women by Kenny-Walsh and Levine39, 40 (Table 3). Similarly, we predicted that a 1.8% hepatic death rate in men infected before age 30, which is similar to the 5.9% observed in the small study of military recruits reported by Seeff and colleagues41 (Table 3). These projections appear to confirm the accuracy of the assumptions in the younger cohorts. In the oldest males, the initial transition from F0 to F1 had the greatest impact on the risk of cirrhosis. However, when the sensitivity analysis in this group was confined to stage-to-stage fibrosis transition rates, no single transition dominated, and risk of cirrhosis after 20 years varied from just 3.75-6.08% less to 2.39-5.69% more than our model projection. In addition, the projected prevalence of cirrhosis after 20 years in the older male group was 24%, consistent with the high rate of fibrosis progression reported by others in this group.19, 50, 51 (Table 3).
Another potential source of uncertainty stems from our use of tunnel states to slow progression during early fibrosis stages and acceleration of progression rates when younger cohorts reached age 50. We felt that these age- and duration-adjusted fibrosis progression rates best reflected the observations from previous reports.17, 18, 19, 33, 34, 39, 40, 41 However, we also tested a fixed stage-to-stage progression rate as reported in the meta-analysis by Thein and colleagues.23 As expected, this led to front-loading of morbidity and hepatic mortality, particularly in the younger cohorts, during the years when standard age-related mortality was low. As a result, the fixed rate model overestimated cases of cirrhosis, decompensation or HCC, and liver-related death by 41%, 86%, and 41%, respectively, compared to the more conservative base case model, and these estimates were much higher than those reported in previous prospective studies.39, 40, 41 Therefore, we maintained our more conservative assumptions for the base case model.
Finally, we looked at the impact of utilizing higher background (nonhepatic) age- and gender-related mortality rates on our projections of chronic hepatitis and cirrhosis in coming decades. Recent studies have suggested that comorbid medical conditions might increase background mortality in HCV-infected persons by as much as 3 times the reported actuarial rates.11, 12, 20 Increasing background mortality rates in the model by 50% or 100% had no impact on the proportion of infected persons with cirrhosis, but it significantly reduced the total number with cirrhosis. A 50% increase in background mortality decreased the number of persons with chronic hepatitis or cirrhosis in 2020 by 35% and 31%, respectively, compared to the base case model projections. A 100% increase decreased the number with chronic hepatitis or cirrhosis in 2020 by 46% and 43%, respectively, compared to base case projections.
Our sensitivity analysis did not include incidence data because no other estimates exist and these data have previously been shown to be consistent with prevalence data as estimated by NHANES III.1, 14
Materials and Methods
Model Construction
Construction and computer simulations of our model utilized TreeAge Pro 2009 Suite (TreeAge Software, Williamstown, MA) linked with Microsoft Excel 2007 (Microsoft Corporation, Redmond, WA). TreeAge allows construction of complex Markov models with progression rates that can be varied with time according to calendar year, patient age, year of disease, or dwell time within a specific state, eg, years of cirrhosis. It also allows the dynamic import of information such as disease incidence, population demographic change, and other factors from Excel spreadsheets.
The model was developed in stages starting with a traditional bubble diagram of disease states that served as the basis for developing a more detailed mathematical model that followed infected persons from the time of acute infection until death. Both the bubble diagram and the more detailed TreeAge model are provided in Supplementary Figure 1, Supplementary Figure 2 available in the online version of this article. Acute infection could resolve, evolve to fulminant hepatitis, progress to chronic hepatitis, or end with death due to background (nonhepatic) mortality. CH-C was modeled through fibrosis stages (Metavir F0 to F4), disease complications, and death. The model cycled at yearly intervals allowing individuals to move to another state; however, all states except acute infection and fulminant hepatitis could resolve back into themselves indefinitely.
It has become apparent in recent years that age at infection and gender greatly influence the risk of developing chronic infection and progressing to fibrosis.18, 19, 20, 21, 22, 23, 24, 25, 26 To accommodate this heterogeneity, we divided acutely infected individuals into 6 cohorts, each with their own cohort-specific transition states for chronicity, fibrosis progression, and complications (Table 1). The output of the 6 models was then collated and exported as an Excel spreadsheet defining cohort-specific and overall projections by year. Cohort and population projections included numbers with resolved infection, chronic infection, stage of fibrosis (F0 to cirrhosis), liver failure, hepatocellular carcinoma (HCC), liver-related deaths, and age- and gender-specific (nonliver) deaths.
Antiviral treatment, ablation of tumors, and liver transplantation could not be modeled because the indications for these practices and procedures are not standardized, their use varies considerably by geography, none is widely applied, and the outcomes are not well-defined in subgroups. Of these, only antiviral treatment has the possibility of significantly altering disease end points from a population perspective. Therefore, we subsequently modified the model to estimate the potential impact of antiviral treatment on cirrhosis and its complications. To do so, we considered treatment penetrance ranging from 0% to 100% in the infected population and sustained viral response rates of 40% to 80%. All cases were treated in 2010 and outcomes were calculated for the year 2020. It was assumed that patients with sustained viral response had no chance of progressing to cirrhosis or, if already cirrhotic, had no chance of subsequent hepatic failure.27 The risk of progressing from cirrhosis to HCC after sustained viral response was assumed to be 0.66% per annum.27 Other assumptions of the model were unchanged.
Data Sources
Medical literature was reviewed by the authors to provide best estimates of the range of probabilities for moving between disease states. Because reported progression rates vary between studies, a consensus rate was chosen (Table 1). We used conservative estimates when a particular transition was in doubt. Transition rates varied for some states according to the age and gender of the cohorts.23, 24, 25, 26, 27, 28 For example, in the young female cohort, progression from acute to chronic infection was lower (55%) and the rate of fibrosis progression was slower than the oldest male cohort.
Transition rates for moving from one fibrosis stage to another largely utilized the pooled rates from a meta-analysis reported by Thein and colleagues.17, 23 However, our model also included tunnel states that kept a portion of the cohort with minimal fibrosis (F0 and F1) from progressing to the next state for variable periods of time in order to simulate slower rates of progression or no progression in some persons. To accommodate the tunnel states, fibrosis transitions were adjusted accordingly such that overall rates remained consistent with those of Thein and colleagues23 (Table 1). Alcohol intake was not modeled separately because its influence in the different cohorts is unknown; rather our transition rates are based on observational studies in which excessive alcohol use was present in 19% of the cohorts.23 Risks of developing HCC in persons with bridging fibrosis or cirrhosis were taken from longitudinal studies in North America and Europe.19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 HCC risk in those with bridging fibrosis was estimated to be 10% of that in cirrhosis. HCC risk in females was estimated to be 40% of that in males.33 Finally, transition rates for fibrosis progression and HCC risk were allowed to increase after age 50 or 10 years of cirrhosis, respectively, consistent with previous observations that these risks are not linear.17, 18, 19, 33, 34 Confirmation of the accuracy of the estimated transition rates was done by comparing the projected chronic infection prevalence in 1994 to results from the Third National Health and Nutrition Examination survey (NHANES III) and the projected cirrhosis and HCC prevalence in the different cohorts to published observations in similar groups.
Annual numbers with newly acquired HCV infections between 1960 and 2006 were generated from a previously published model that estimated the past incidence of acute HCV infection given the actual prevalence measured at the time (1988-1994) of the NHANES III.1, 14, 35 Annual infections were stratified by age and gender based on actual distributions of these variables for cases of acute hepatitis reported to the Centers for Disease Control and Prevention's Sentinel Counties Study for each year from 1979 to 20062, 36 (personal communication, MJ Alter, November 25, 2008). For years when data from the Sentinel Counties Study were not available, number and distribution were assumed to be the same as the closest year with data. We sequentially entered these incident infections in annual cycles into the cohort models and projected disease outcomes through the year 2030. Annual incidence data and cohort distribution utilized in the model are shown in Supplementary Table 1 available online.
Age- and gender-specific all-cause mortality was derived from standard US mortality tables.37 The ages within each cohort were tracked through the annual cycles of the model such that background mortality would be appropriate as the cohorts aged.
Sensitivity Analysis and Validation
Sensitivity analysis was performed to assess the extent to which the model's calculations were affected by uncertainty in our assumptions. The ranges utilized in the sensitivity analysis were derived from the medical literature.31, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and are reported in Supplementary Table 2 available online. Sensitivity analyses were confined to the young female and oldest male cohorts because these were the most disparate in transition probabilities and, therefore, most likely to identify potential sources of weakness within the model assumptions. First, one-way sensitivity analysis with tornado diagrams were utilized to identify dominant variables and to rank the impact of different variables on disease outcome (cirrhosis). If no dominant variable was identified, a second one-way sensitivity analysis was done. Finally, we examined the impact of increasing background mortality, consistent with some reports that suggest higher all-cause mortality in persons with CH-C.5, 15
A Sustained Viral Response Is Associated With Reduced Liver-Related Morbidity and Mortality in Patients With Hepatitis C Virus:
A Sustained Viral Response Is Associated With Reduced Liver-Related Morbidity and Mortality in Patients With Hepatitis C Virus: risk of these outcomes is reduced by 70%–80% for patients who achieve SVR- mortality, hepatic decompensation, HCC - pdf attached
Clinical Gastroenterology & Hepatology March 2010
Amit G. Singal, Michael L. Volk, Donald Jensen‡, Adrian M. Di Bisceglie§, Philip S. Schoenfeld∥
Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan
‡ Division of Gastroenterology-Hepatology Section, University of Chicago School of Medicine, Chicago, Illinois
§ Division of Gastroenterology and Hepatology, St Louis University School of Medicine, St Louis, Missouri
∥ VA Center of Excellence in Health Services Research, Ann Arbor, Michigan
published online 30 November 2009.
Also at AASLD similar finding from HALT-C was presented in an oral talk:
SVR Improves Survival, Risk for Liver Cancer, Decompensated Liver Disease and Liver Transplant/Death - Also, Transient Viral Suppression (breakthroughs/relapsers) Improves Clinical Outcomes Too - (11/09/09)
"On the basis of our meta-analyses, SVR is associated with a significant risk reduction in liver-related mortality, HCC, and hepatic decompensation in patients with advanced fibrosis or cirrhosis.........Our meta-analysis also demonstrated that relapsers were significantly less likely to develop HCC compared with nonresponders (patients who never cleared viremia during treatment) (RR, 2.30; 95% CI, 1.26–4.19.....These data will facilitate decision-making by HCV-infected treatment failure patients and physicians when considering whether to re-treat with currently available therapies or to delay treatment until newer therapies are available.....Physicians and HCV-infected patients should understand the likelihood of developing decompensated cirrhosis, HCC, and liver-related mortality after failing therapy to make appropriate decisions about whether to undergo retreatment.....more advanced fibrosis is associated with higher rates of liver-related morbidity and mortality.36 Results should also be reported separately for patients who achieve SVR because achieving SVR is associated with a large decrease in liver-related morbidity and mortality. Our data demonstrate that rates of liver-related mortality (2.73%/year; 95% CI, 1.38–4.08), HCC (3.22%/year, 95% CI, 2.02–4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61–4.22) are substantial among HCV treatment failures with advanced fibrosis, but the risk of these outcomes is reduced by 70%–80% for patients who achieve SVR....Chronic hepatitis C patients with SVR are much less likely to suffer liver-related mortality compared with chronic hepatitis C patients with treatment failure who do not achieve SVR in studies with HCV patients with all stages of fibrosis (RR, 0.23; 95% CI, 0.10–0.52) (Figure 1C) or studies that only enrolled patients with advanced fibrosis (RR, 0.19; 95% CI, 0.10–0.37)....lso, chronic hepatitis C patients with SVR are much less likely to suffer HCC compared with chronic hepatitis C patients who do not achieve SVR among studies that enrolled patients with any stage of hepatic fibrosis (RR, 0.21; 95% CI, 0.16–0.27) (Figure 2C) and among studies that only enrolled patients with advanced fibrosis or cirrhosis (RR, 0.32; 95% CI, 0.23–0.44)....Chronic hepatitis C patients with SVR are much less likely to suffer liver-related mortality compared with chronic hepatitis C patients with treatment failure who do not achieve SVR in studies with HCV patients with all stages of fibrosis (RR, 0.23; 95% CI, 0.10–0.52) (Figure 1C) or studies that only enrolled patients with advanced fibrosis (RR, 0.19; 95% CI, 0.10–0.37)....lso, chronic hepatitis C patients with SVR are much less likely to suffer HCC compared with chronic hepatitis C patients who do not achieve SVR among studies that enrolled patients with any stage of hepatic fibrosis (RR, 0.21; 95% CI, 0.16–0.27) (Figure 2C) and among studies that only enrolled patients with advanced fibrosis or cirrhosis (RR, 0.32; 95% CI, 0.23–0.44) ....The prevalence of HCV-infected patients with advanced fibrosis in the US is likely to rise precipitously in the near future, producing a corresponding increase in liver-related morbidity and mortality.....In the US, the prevalence of HCV infection in 50- to 59-year-old individuals will be approximately 4% by 2012, and the majority of these patients will have been infected with HCV for 20–30+ years.2.....SVR stops progression of fibrosis or because it leads to regression of fibrosis. Mallet et al32 assessed 96 HCV-infected patients with cirrhosis (Metavir F4) who were treated with interferon-based regimens and had at least 1 post-treatment liver biopsy. Thirty-nine of these patients achieved SVR, and 44% (17/39) of these patients demonstrated cirrhosis regression, defined as a decrease in Metavir score of >2. Although none of the patients with SVR and cirrhosis regression suffered from liver-related morbidity or mortality during follow-up, 18% (4/22) of patients with SVR without cirrhosis regression suffered liver-related morbidity or mortality (3 cases of HCC and 1 variceal bleed). Therefore, future prospective observational studies might consider performance of post-treatment liver biopsy to enhance our understanding of the importance of regression of fibrosis on the natural history of these patients."
ABSTRACT
Background & Aims
The incidences of decompensated cirrhosis (defined by ascites, hepatic encephalopathy, or bleeding esophageal varices), hepatocellular carcinoma (HCC), and liver-related mortality among patients infected with hepatitis C virus (HCV) who achieve a sustained viral response (SVR), compared with patients who fail treatment (treatment failure), are unclear. We performed a meta-analysis to quantify the incidences of these outcomes.
Methods
This meta-analysis included observational cohort studies that followed HCV treatment failure patients; data were collected regarding the incidence of decompensated cirrhosis, HCC, or liver-related mortality and stratified by SVR status. Two investigators independently extracted data on patient populations, study methods, and results by using standardized forms. The agreement between investigators in data extraction was greater than 95%. Data analysis was performed separately for studies that enrolled only HCV patients with advanced fibrosis.
Results
We identified 26 appropriate studies for meta-analysis. Among treatment failure patients with advanced fibrosis, rates of liver-related mortality (2.73%/year; 95% confidence interval [CI], 1.38–4.080), HCC (3.22%/year, 95% CI, 2.02–4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61–4.22) were substantial. Patients with SVR are significantly less likely than patients who experienced treatment failure to develop liver-related mortality (relative risk [RR], 0.23; 95% CI, 0.10–0.52), HCC (RR, 0.21; 95% CI, 0.16–0.27), or hepatic decompensation (RR, 0.16; 95% CI, 0.04–0.59).
Conclusions
HCV patients with advanced fibrosis who do not undergo an SVR have substantial liver-related morbidity and mortality. Achieving SVR is associated with substantially lower liver-related morbidity and mortality.
Abbreviations used in this paper: CI, confidence interval, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, RR, relative risk, SVR, sustained viral response.
Approximately 3% of the world's population is infected with hepatitis C virus (HCV),1 including approximately 3.2 million people in the United States.2 HCV is a leading cause of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation in the US Management of these disorders costs the US health care system more than a billion dollars per year.3 The long incubation time between HCV infection and development of advanced fibrosis suggests that liver-related morbidity and mortality rates will continue to increase despite the declining incidence of new HCV infections.2 In the US, HCV-related mortality is projected to peak in 2030 at approximately 13,000 deaths/year.4
However, many HCV-related deaths are preventable if HCV-infected patients are treated successfully. Among HCV patients with SVR, rates of liver-related mortality, HCC, and hepatic decompensation are very low, and life expectancy might be equivalent to the age-matched and sex-matched general population.5 Unfortunately, more than 50% of HCV patients are treatment failures with pegylated interferon and ribavirin antiviral therapy.6
The natural history of these “treatment failure” patients has not been studied extensively, although patients and physicians need to understand the natural history of these patients as they weigh the potential benefits of antiviral retreatment versus the risks of delaying therapy while awaiting new treatments. The natural history of liver-related morbidity and mortality might need to be assessed separately in HCV treatment failure patients versus HCV patients who have never been treated. HCV-infected patients with treatment failure might be more likely to have significant fibrosis compared with HCV patients who have never been treated because physicians are more likely to recommend antiviral therapy for HCV patients who are at the greatest risk for developing liver-related morbidity and mortality in the near future.7 Alternatively, other patients with significant fibrosis might remain untreated, given comorbid conditions or issues with noncompliance. Although not well studied to date, one cannot assume that the natural histories of these 2 groups are the same.
No previous systematic review has quantitatively assessed the natural history of HCV-infected patients with treatment failure or the reduction in decompensated cirrhosis, HCC, and liver-related mortality for HCV-infected patients who achieve sustained viral response (SVR) versus HCV-infected patients with treatment failure. The primary objective of our meta-analysis is to quantify annual rates of decompensated cirrhosis, HCC, and liver-related mortality among HCV treatment failure patients. We also quantify the risk reduction in decompensated cirrhosis, HCC, and liver-related mortality for HCV-infected patients with SVR versus HCV treatment failure patients.
Discussion
Physicians and HCV-infected patients should understand the likelihood of developing decompensated cirrhosis, HCC, and liver-related mortality after failing therapy to make appropriate decisions about whether to undergo retreatment. Prognostic data should be stratified on the basis of severity of hepatic fibrosis. Stratifying natural history data by stage of hepatic fibrosis is important because more advanced fibrosis is associated with higher rates of liver-related morbidity and mortality.36 Results should also be reported separately for patients who achieve SVR because achieving SVR is associated with a large decrease in liver-related morbidity and mortality. Our data demonstrate that rates of liver-related mortality (2.73%/year; 95% CI, 1.38–4.08), HCC (3.22%/year, 95% CI, 2.02–4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61–4.22) are substantial among HCV treatment failures with advanced fibrosis, but the risk of these outcomes is reduced by 70%–80% for patients who achieve SVR.
The prevalence of HCV-infected patients with advanced fibrosis in the US is likely to rise precipitously in the near future, producing a corresponding increase in liver-related morbidity and mortality. The incubation time between HCV infection and advanced fibrosis is probably 20–30+ years. Minimal fibrosis develops during the first 10 years of infection, but the rate of fibrosis development accelerates with each subsequent decade.37 After 30 years of infection, up to 30% of HCV-infected patients will have developed bridging fibrosis and liver-related morbidity and mortality.38 In the US, the prevalence of HCV infection in 50- to 59-year-old individuals will be approximately 4% by 2012, and the majority of these patients will have been infected with HCV for 20–30+ years.2
On the basis of our meta-analyses, SVR is associated with a significant risk reduction in liver-related mortality, HCC, and hepatic decompensation in patients with advanced fibrosis or cirrhosis. This might occur because SVR stops progression of fibrosis or because it leads to regression of fibrosis. Mallet et al32 assessed 96 HCV-infected patients with cirrhosis (Metavir F4) who were treated with interferon-based regimens and had at least 1 post-treatment liver biopsy. Thirty-nine of these patients achieved SVR, and 44% (17/39) of these patients demonstrated cirrhosis regression, defined as a decrease in Metavir score of >2. Although none of the patients with SVR and cirrhosis regression suffered from liver-related morbidity or mortality during follow-up, 18% (4/22) of patients with SVR without cirrhosis regression suffered liver-related morbidity or mortality (3 cases of HCC and 1 variceal bleed). Therefore, future prospective observational studies might consider performance of post-treatment liver biopsy to enhance our understanding of the importance of regression of fibrosis on the natural history of these patients.
Future prospective studies should also report their results by using Kaplan–Meier plots to enhance our understanding of these issues. Most studies in this meta-analysis did not report their results by using these plots, although limited data suggest that rates of decompensated cirrhosis, HCC, and liver-related mortality decreased virtually to zero for the first 5 years of follow-up after achieving SVR.30, 31, 32, 34, 35 Notably, rates of decompensated cirrhosis remained essentially zero during 5–10 years of follow-up of cirrhotic patients with SVR, although the number of patients available for follow-up was quite small.30, 31, 35
Our meta-analysis also demonstrated that relapsers were significantly less likely to develop HCC compared with nonresponders (patients who never cleared viremia during treatment) (RR, 2.30; 95% CI, 1.26–4.19) (Figure 4). The reason for this finding is unclear. Inadequate data are provided in the individual studies to determine whether there were important differences in fibrosis stage between relapsers and nonresponders. We also speculate on other reasons for this finding. Host-virus interactions resulting in relapse after treatment might be such that they also allow fewer clinical complications of chronic HCV infection. This finding could represent a state of more interferon “inducible” innate immunity or less induced suppressor genes (eg, USP-18). To clarify this finding, future prospective observational studies and randomized controlled trials should stratify their end point analyses between relapsers and nonresponders and seek to determine whether differences in liver-related morbidity and mortality are associated with differences in progression of fibrosis.
This meta-analysis is limited by several factors. First, studies in this meta-analysis did not consistently stratify outcomes by severity of hepatic fibrosis when HCV-infected patients failed treatment. Specifically, we do not have adequate data about the natural history of HCV treatment failures who only had mild-moderate fibrosis (Ishak score 1–2 or Metavir F1/F2) at initiation of HCV treatment. Second, most studies in this meta-analysis did not attempt to estimate duration of HCV infection among their study population. This reinforced our decision to use failure of HCV therapy as the defining characteristic for the inception cohort of included studies. Third, many of these studies were conducted in Asia and examined Asian populations,5, 11, 15, 16, 17, 18, 20, 21, 22, 24, 25, 26, 27, 28, 29, 33, 34, 39 and it is unclear whether these results are generalizable to populations in the US and Europe. Fourth, many investigators published multiple reports about near-identical cohorts of patients. Therefore, we carefully assessed studies for overlapping cohorts of patients and only used the single, most recently published report in this meta-analysis. Finally, studies did not consistently provide data about the initial treatment regimen among HCV-infected patients with treatment failure. It is conceivable that HCV-infected patients who failed after interferon monotherapy might be clinically different from HCV treatment failures after combination therapy (eg, lower HCV RNA levels).
Our meta-analysis is also limited because our estimates about the annual rates of decompensated cirrhosis, HCC, and liver-related mortality demonstrated heterogeneity in individual study results. Study populations might have been substantially different for various reasons, including differences in prevalence of confounding factors (eg, alcohol consumption) or differences in duration of HCV infection. To account for this heterogeneity, we used random-effects meta-analysis, which results in wider confidence intervals around our point estimates of pooled outcomes. Nevertheless, many of the studies in our meta-analysis were relatively small and used a retrospective study design, which might lead to imprecise estimates of liver-related morbidity and mortality. Notably, the HALT-C trial might overcome some of these deficiencies. This trial8 was a large prospective trial with clear criteria for the diagnosis of HCC, but we did not include it in our meta-analysis because patients received maintenance therapy. In this trial, maintenance therapy did not significantly impact outcomes, and a combined cohort of treated and untreated cirrhotic patients produced an annual HCC rate of 1.1%, which is lower than the annual rate estimated in our meta-analysis.
In conclusion, our meta-analysis suggests that HCV-infected treatment failure patients with advanced fibrosis suffer decompensated cirrhosis, HCC, and/or liver-related mortality at an annual rate of approximately 2%–3%. Among studies of patients with varying levels of fibrosis, the annual rates vary from 0.56%–1.39%. Patients who achieve SVR are substantially less likely to suffer from liver-related mortality, HCC, or hepatic decompensation (RR, 0.16–0.23). These data will facilitate decision-making by HCV-infected treatment failure patients and physicians when considering whether to re-treat with currently available therapies or to delay treatment until newer therapies are available.
Results
Results of Literature Search
The computer-assisted search yielded more than 2276 potentially relevant articles (Supplementary Figure 1). After initial review of titles and abstracts, 215 studies were potentially appropriate, and abstracts were reviewed in detail. One hundred four studies were potentially appropriate and underwent full manuscript review along with 3 additional studies identified through recursive literature searches. After application of the inclusion and exclusion criteria, 26 studies were included in our review, and descriptive characteristics can be found in Table 1.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35
Among studies reporting liver-related mortality rates, no evidence of publication bias was present on the basis of Begg's (P = .45) and Egger's (P = .27) tests. Furthermore, neither trimming the outliers nor filling in the missing studies changed the estimate of pooled mortality rate by more than 0.1%. However, visual inspection of the funnel plot suggests that publication bias could be present. Among the studies reporting HCC rates, little evidence of publication bias was seen on visual inspection of the funnel plot by Begg's (P = .2) or Egger's tests (P = .06). Among the studies reporting rates of hepatic decompensation, no evidence of publication bias was present on the basis of Begg's (P = .5) or Egger's tests (P = .2). However, visual inspection of the funnel plot suggested possible publication bias, and trimming the outliers and filling in the missing studies changed the estimate of pooled hepatic decompensation rate from 0.56% to 0.1%, indicating that the pooled estimate is likely to be substantially affected by publication bias. On meta-regression, differences between studies in follow-up time, mean age of the cohort, and median stage of fibrosis at cohort inception were not associated with liver-related morbidity and mortality results.
Liver-Related Mortality
The primary outcomes reported by each study are shown in Table 2. Among studies that enrolled patients with any stage of hepatic fibrosis, the pooled liver-related mortality rate among HCV treatment failures was 0.81%/year (95% confidence interval [CI], 0.55–1.07) (Figure 1A), but the pooled liver-related mortality rate among HCV treatment failures was substantially higher at 2.73%/year (95% CI, 1.38–4.08) (Figure 1B) among studies that only enrolled patients with advanced fibrosis or cirrhosis. Both analyses demonstrated moderate statistical heterogeneity between studies (P = .001 for any stage, P < .001 for advanced fibrosis). Chronic hepatitis C patients with SVR are much less likely to suffer liver-related mortality compared with chronic hepatitis C patients with treatment failure who do not achieve SVR in studies with HCV patients with all stages of fibrosis (RR, 0.23; 95% CI, 0.10–0.52) (Figure 1C) or studies that only enrolled patients with advanced fibrosis (RR, 0.19; 95% CI, 0.10–0.37) (Figure 1D). Neither analysis demonstrated statistical heterogeneity (P = .09 for any stage, I2 = 0%, P = .75 for advanced fibrosis).
Hepatocellular Carcinoma
Among studies that enrolled patients with any stage of hepatic fibrosis, the pooled HCC rate among HCV treatment failures was 1.84%/year (95% CI, 1.36–2.32) (Figure 2A), but the pooled HCC rate among HCV treatment failures was numerically higher at 3.22%/year (95% CI, 2.02–4.42) (Figure 2B) among studies that only enrolled patients with advanced fibrosis. Again, both analyses demonstrated moderate statistical heterogeneity between individual studies (P < .001 for any stage, P < .001 for advanced fibrosis). Also, chronic hepatitis C patients with SVR are much less likely to suffer HCC compared with chronic hepatitis C patients who do not achieve SVR among studies that enrolled patients with any stage of hepatic fibrosis (RR, 0.21; 95% CI, 0.16–0.27) (Figure 2C) and among studies that only enrolled patients with advanced fibrosis or cirrhosis (RR, 0.32; 95% CI, 0.23–0.44) (Figure 2D). Again, neither of these analyses demonstrated statistical heterogeneity (P = .93 for any stage, P = .61 for advanced fibrosis).
Hepatic Decompensation
Among studies that enrolled patients with any stage of hepatic fibrosis, the pooled hepatic decompensation rate among HCV treatment failures was 0.54%/year (95% CI, 0.11–0.97) (Figure 3A), but the pooled hepatic decompensation rate among HCV treatment failures was substantially higher at 2.92%/year (95% CI, 1.61–4.22) (Figure 3B) in studies that only enrolled patients with advanced fibrosis or cirrhosis. Both of these analyses demonstrated moderate statistical heterogeneity (P < .001 for any stage, P < .001 for advanced fibrosis). Chronic hepatitis C patients with SVR are much less likely to suffer hepatic decompensation compared with chronic hepatitis C patients who do not achieve SVR in studies that enrolled patients with any stage of hepatic fibrosis (RR, 0.16; 95% CI, 0.04–0.59) (Figure 3C) and studies that only enrolled patients with advanced fibrosis or cirrhosis failures (RR, 0.13; 95% CI, 0.06-0.27) (Figure 3D). No statistical heterogeneity was identified between studies (P = .69 for any stage, P = .27 for advanced fibrosis).
Natural History of Relapsers Versus Nonresponders
Four of the studies12, 18, 22, 23 reported outcomes according to whether the patients initially became virus-negative (relapsers) versus remaining persistently viremic (nonresponders). The study by Coverdale et al12 was the only one to report mortality outcomes with liver-related mortality occurring in relapsers at a rate of 0.7%/year and in nonresponders at a rate of 1.8%/year (P = .4). The study by Pradat et al23 was the only one to report rates of hepatic decompensation that occurred at 1.7%/year in relapsers versus 2.9%/year in nonresponders (P = .5). All 4 studies reported rates of HCC, and nonresponders were more likely to develop HCC compared with relapsers (RR, 2.30; 95% CI, 1.26–4.19) (Figure 4). There was no evidence of statistical heterogeneity (P = .49).
Methods
Literature Search
A computer-assisted search with the Ovid interface to Medline was conducted to identify potentially relevant published articles. A search of the Medline database from 1966 to 2008 was performed by using the exploded (exp) medical subject heading (MeSH) terms (exp Hepatitis C) AND (exp Treatment Failure OR exp Retreatment OR exp Recurrence OR exp Drug Resistance OR keywords refractory, relapse, retreatment, nonrespond, non-respond, fail, unsuccess). The results of all searches were limited to human studies published in the English language. Manual searches of reference lists from potentially relevant articles were also performed to identify any additional studies that might have been missed by using the computer-assisted strategy.
Study Selection Criteria
Two investigators (M.V., A.S.) independently reviewed the titles and abstracts of all citations identified by the literature search. Potentially relevant studies were retrieved, and the selection criteria were applied. The inclusion criteria were (1) cohort studies of treatment failure HCV patients who were treated with interferon/pegylated interferon ± ribavirin; (2) reporting of liver-related morbidity or mortality end points stratified by SVR status; and (3) published in the English language in full manuscript form. Treatment success was defined as HCV-infected patients who achieve an SVR, undetectable virus in the serum 6 months after the end of therapy. Treatment failure was defined as HCV patients who do not achieve SVR. Morbidity end points were defined as HCC or decompensated cirrhosis (defined by ascites, hepatic encephalopathy, or bleeding esophageal varices). Liver-related mortality was defined as death as a result of complications of decompensated cirrhosis, HCC, and/or liver transplantation, even if patients survived the procedure. The following types of studies were excluded: (1) cross-sectional studies with short-term follow-up (<1 year); (2) studies reporting only surrogate end points such as stage of fibrosis on liver biopsy or AST/ALT levels; (3) studies with unclear follow-up time; (4) studies that enrolled patients with evidence of decompensated cirrhosis at inception of the cohort; (5) studies in which the primary end point was response to therapy; (6) studies of patients with human immunodeficiency virus coinfection, on dialysis, or post-transplant; (7) duplicative studies reporting on the same cohort of patients; and (8) studies in which patients received maintenance treatment or studies in which patients were initially treated with agents other than interferon alfa/pegylated interferon ± ribavirin (eg, interferon beta or glycyrrhizin). Maintenance therapy was defined as any continuous interferon-based treatment beyond a standard course (ie, 48 weeks for genotype 1 patients) with the intent of suppressing hepatic inflammation and fibrosis.8 Studies that only enrolled patients with advanced fibrosis or cirrhosis were included, although these studies were analyzed separately from studies enrolling HCV-infected patients with treatment failure with all stages of fibrosis.
Data Extraction
The eligible articles were reviewed in a duplicate, independent manner by 2 investigators (M.V., A.S.). Data extraction on standardized forms was also performed in a duplicate, independent manner by the 2 investigators.9 Data were collected on annual rates of liver-related mortality, HCC, and decompensated cirrhosis among patients failing to achieve SVR and patients who achieved SVR. Data were also collected on the design of each study (retrospective vs prospective), the number of patients in each group, demographic characteristics of the patient population, median stage of fibrosis at cohort inception, proportion of patients with advanced fibrosis (Metavir stages F2–F4 or Ishak stages 3–6) at cohort inception, and the duration of follow-up.
Statistical Analysis
Pooled rates of liver-related mortality, HCC, and decompensated cirrhosis in HCV treatment failure patients were calculated by using random-effects meta-analysis according to the method of DerSimonian and Laird.10 Separate pooled rates are provided for HCV treatment failure patients from studies that only enrolled patients with advanced fibrosis or cirrhosis (Metavir stages F3-F4 or Ishak stages 3-6) at cohort inception. Also, the relative risk (RR) of each end point is compared between HCV treatment failure patients versus patients who achieved SVR. Finally, the RR of each end point is also compared between patients who became virus-negative during treatment (relapsers) versus those remaining persistently virus-positive (nonresponders) to determine whether natural history differs between these groups of HCV treatment failure patients.
Heterogeneity was assessed by using the I2 index or the variation in effect size attributable to heterogeneity. Meta-regression was then used to assess the following prespecified reasons for heterogeneity: differences between studies in follow-up time, mean age of the cohort, and median stage of fibrosis at cohort inception. Visual inspection of funnel plots, as well as statistical testing according to the methods of Begg and Egger, were used to assess for publication bias. These analyses were limited to studies including all stages of fibrosis to prevent heterogeneity from obscuring evidence of publication bias. The impact of publication bias on the pooled rates was then estimated by the trim and fill method.
Clinical Gastroenterology & Hepatology March 2010
Amit G. Singal, Michael L. Volk, Donald Jensen‡, Adrian M. Di Bisceglie§, Philip S. Schoenfeld∥
Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan
‡ Division of Gastroenterology-Hepatology Section, University of Chicago School of Medicine, Chicago, Illinois
§ Division of Gastroenterology and Hepatology, St Louis University School of Medicine, St Louis, Missouri
∥ VA Center of Excellence in Health Services Research, Ann Arbor, Michigan
published online 30 November 2009.
Also at AASLD similar finding from HALT-C was presented in an oral talk:
SVR Improves Survival, Risk for Liver Cancer, Decompensated Liver Disease and Liver Transplant/Death - Also, Transient Viral Suppression (breakthroughs/relapsers) Improves Clinical Outcomes Too - (11/09/09)
"On the basis of our meta-analyses, SVR is associated with a significant risk reduction in liver-related mortality, HCC, and hepatic decompensation in patients with advanced fibrosis or cirrhosis.........Our meta-analysis also demonstrated that relapsers were significantly less likely to develop HCC compared with nonresponders (patients who never cleared viremia during treatment) (RR, 2.30; 95% CI, 1.26–4.19.....These data will facilitate decision-making by HCV-infected treatment failure patients and physicians when considering whether to re-treat with currently available therapies or to delay treatment until newer therapies are available.....Physicians and HCV-infected patients should understand the likelihood of developing decompensated cirrhosis, HCC, and liver-related mortality after failing therapy to make appropriate decisions about whether to undergo retreatment.....more advanced fibrosis is associated with higher rates of liver-related morbidity and mortality.36 Results should also be reported separately for patients who achieve SVR because achieving SVR is associated with a large decrease in liver-related morbidity and mortality. Our data demonstrate that rates of liver-related mortality (2.73%/year; 95% CI, 1.38–4.08), HCC (3.22%/year, 95% CI, 2.02–4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61–4.22) are substantial among HCV treatment failures with advanced fibrosis, but the risk of these outcomes is reduced by 70%–80% for patients who achieve SVR....Chronic hepatitis C patients with SVR are much less likely to suffer liver-related mortality compared with chronic hepatitis C patients with treatment failure who do not achieve SVR in studies with HCV patients with all stages of fibrosis (RR, 0.23; 95% CI, 0.10–0.52) (Figure 1C) or studies that only enrolled patients with advanced fibrosis (RR, 0.19; 95% CI, 0.10–0.37)....lso, chronic hepatitis C patients with SVR are much less likely to suffer HCC compared with chronic hepatitis C patients who do not achieve SVR among studies that enrolled patients with any stage of hepatic fibrosis (RR, 0.21; 95% CI, 0.16–0.27) (Figure 2C) and among studies that only enrolled patients with advanced fibrosis or cirrhosis (RR, 0.32; 95% CI, 0.23–0.44)....Chronic hepatitis C patients with SVR are much less likely to suffer liver-related mortality compared with chronic hepatitis C patients with treatment failure who do not achieve SVR in studies with HCV patients with all stages of fibrosis (RR, 0.23; 95% CI, 0.10–0.52) (Figure 1C) or studies that only enrolled patients with advanced fibrosis (RR, 0.19; 95% CI, 0.10–0.37)....lso, chronic hepatitis C patients with SVR are much less likely to suffer HCC compared with chronic hepatitis C patients who do not achieve SVR among studies that enrolled patients with any stage of hepatic fibrosis (RR, 0.21; 95% CI, 0.16–0.27) (Figure 2C) and among studies that only enrolled patients with advanced fibrosis or cirrhosis (RR, 0.32; 95% CI, 0.23–0.44) ....The prevalence of HCV-infected patients with advanced fibrosis in the US is likely to rise precipitously in the near future, producing a corresponding increase in liver-related morbidity and mortality.....In the US, the prevalence of HCV infection in 50- to 59-year-old individuals will be approximately 4% by 2012, and the majority of these patients will have been infected with HCV for 20–30+ years.2.....SVR stops progression of fibrosis or because it leads to regression of fibrosis. Mallet et al32 assessed 96 HCV-infected patients with cirrhosis (Metavir F4) who were treated with interferon-based regimens and had at least 1 post-treatment liver biopsy. Thirty-nine of these patients achieved SVR, and 44% (17/39) of these patients demonstrated cirrhosis regression, defined as a decrease in Metavir score of >2. Although none of the patients with SVR and cirrhosis regression suffered from liver-related morbidity or mortality during follow-up, 18% (4/22) of patients with SVR without cirrhosis regression suffered liver-related morbidity or mortality (3 cases of HCC and 1 variceal bleed). Therefore, future prospective observational studies might consider performance of post-treatment liver biopsy to enhance our understanding of the importance of regression of fibrosis on the natural history of these patients."
ABSTRACT
Background & Aims
The incidences of decompensated cirrhosis (defined by ascites, hepatic encephalopathy, or bleeding esophageal varices), hepatocellular carcinoma (HCC), and liver-related mortality among patients infected with hepatitis C virus (HCV) who achieve a sustained viral response (SVR), compared with patients who fail treatment (treatment failure), are unclear. We performed a meta-analysis to quantify the incidences of these outcomes.
Methods
This meta-analysis included observational cohort studies that followed HCV treatment failure patients; data were collected regarding the incidence of decompensated cirrhosis, HCC, or liver-related mortality and stratified by SVR status. Two investigators independently extracted data on patient populations, study methods, and results by using standardized forms. The agreement between investigators in data extraction was greater than 95%. Data analysis was performed separately for studies that enrolled only HCV patients with advanced fibrosis.
Results
We identified 26 appropriate studies for meta-analysis. Among treatment failure patients with advanced fibrosis, rates of liver-related mortality (2.73%/year; 95% confidence interval [CI], 1.38–4.080), HCC (3.22%/year, 95% CI, 2.02–4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61–4.22) were substantial. Patients with SVR are significantly less likely than patients who experienced treatment failure to develop liver-related mortality (relative risk [RR], 0.23; 95% CI, 0.10–0.52), HCC (RR, 0.21; 95% CI, 0.16–0.27), or hepatic decompensation (RR, 0.16; 95% CI, 0.04–0.59).
Conclusions
HCV patients with advanced fibrosis who do not undergo an SVR have substantial liver-related morbidity and mortality. Achieving SVR is associated with substantially lower liver-related morbidity and mortality.
Abbreviations used in this paper: CI, confidence interval, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, RR, relative risk, SVR, sustained viral response.
Approximately 3% of the world's population is infected with hepatitis C virus (HCV),1 including approximately 3.2 million people in the United States.2 HCV is a leading cause of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation in the US Management of these disorders costs the US health care system more than a billion dollars per year.3 The long incubation time between HCV infection and development of advanced fibrosis suggests that liver-related morbidity and mortality rates will continue to increase despite the declining incidence of new HCV infections.2 In the US, HCV-related mortality is projected to peak in 2030 at approximately 13,000 deaths/year.4
However, many HCV-related deaths are preventable if HCV-infected patients are treated successfully. Among HCV patients with SVR, rates of liver-related mortality, HCC, and hepatic decompensation are very low, and life expectancy might be equivalent to the age-matched and sex-matched general population.5 Unfortunately, more than 50% of HCV patients are treatment failures with pegylated interferon and ribavirin antiviral therapy.6
The natural history of these “treatment failure” patients has not been studied extensively, although patients and physicians need to understand the natural history of these patients as they weigh the potential benefits of antiviral retreatment versus the risks of delaying therapy while awaiting new treatments. The natural history of liver-related morbidity and mortality might need to be assessed separately in HCV treatment failure patients versus HCV patients who have never been treated. HCV-infected patients with treatment failure might be more likely to have significant fibrosis compared with HCV patients who have never been treated because physicians are more likely to recommend antiviral therapy for HCV patients who are at the greatest risk for developing liver-related morbidity and mortality in the near future.7 Alternatively, other patients with significant fibrosis might remain untreated, given comorbid conditions or issues with noncompliance. Although not well studied to date, one cannot assume that the natural histories of these 2 groups are the same.
No previous systematic review has quantitatively assessed the natural history of HCV-infected patients with treatment failure or the reduction in decompensated cirrhosis, HCC, and liver-related mortality for HCV-infected patients who achieve sustained viral response (SVR) versus HCV-infected patients with treatment failure. The primary objective of our meta-analysis is to quantify annual rates of decompensated cirrhosis, HCC, and liver-related mortality among HCV treatment failure patients. We also quantify the risk reduction in decompensated cirrhosis, HCC, and liver-related mortality for HCV-infected patients with SVR versus HCV treatment failure patients.
Discussion
Physicians and HCV-infected patients should understand the likelihood of developing decompensated cirrhosis, HCC, and liver-related mortality after failing therapy to make appropriate decisions about whether to undergo retreatment. Prognostic data should be stratified on the basis of severity of hepatic fibrosis. Stratifying natural history data by stage of hepatic fibrosis is important because more advanced fibrosis is associated with higher rates of liver-related morbidity and mortality.36 Results should also be reported separately for patients who achieve SVR because achieving SVR is associated with a large decrease in liver-related morbidity and mortality. Our data demonstrate that rates of liver-related mortality (2.73%/year; 95% CI, 1.38–4.08), HCC (3.22%/year, 95% CI, 2.02–4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61–4.22) are substantial among HCV treatment failures with advanced fibrosis, but the risk of these outcomes is reduced by 70%–80% for patients who achieve SVR.
The prevalence of HCV-infected patients with advanced fibrosis in the US is likely to rise precipitously in the near future, producing a corresponding increase in liver-related morbidity and mortality. The incubation time between HCV infection and advanced fibrosis is probably 20–30+ years. Minimal fibrosis develops during the first 10 years of infection, but the rate of fibrosis development accelerates with each subsequent decade.37 After 30 years of infection, up to 30% of HCV-infected patients will have developed bridging fibrosis and liver-related morbidity and mortality.38 In the US, the prevalence of HCV infection in 50- to 59-year-old individuals will be approximately 4% by 2012, and the majority of these patients will have been infected with HCV for 20–30+ years.2
On the basis of our meta-analyses, SVR is associated with a significant risk reduction in liver-related mortality, HCC, and hepatic decompensation in patients with advanced fibrosis or cirrhosis. This might occur because SVR stops progression of fibrosis or because it leads to regression of fibrosis. Mallet et al32 assessed 96 HCV-infected patients with cirrhosis (Metavir F4) who were treated with interferon-based regimens and had at least 1 post-treatment liver biopsy. Thirty-nine of these patients achieved SVR, and 44% (17/39) of these patients demonstrated cirrhosis regression, defined as a decrease in Metavir score of >2. Although none of the patients with SVR and cirrhosis regression suffered from liver-related morbidity or mortality during follow-up, 18% (4/22) of patients with SVR without cirrhosis regression suffered liver-related morbidity or mortality (3 cases of HCC and 1 variceal bleed). Therefore, future prospective observational studies might consider performance of post-treatment liver biopsy to enhance our understanding of the importance of regression of fibrosis on the natural history of these patients.
Future prospective studies should also report their results by using Kaplan–Meier plots to enhance our understanding of these issues. Most studies in this meta-analysis did not report their results by using these plots, although limited data suggest that rates of decompensated cirrhosis, HCC, and liver-related mortality decreased virtually to zero for the first 5 years of follow-up after achieving SVR.30, 31, 32, 34, 35 Notably, rates of decompensated cirrhosis remained essentially zero during 5–10 years of follow-up of cirrhotic patients with SVR, although the number of patients available for follow-up was quite small.30, 31, 35
Our meta-analysis also demonstrated that relapsers were significantly less likely to develop HCC compared with nonresponders (patients who never cleared viremia during treatment) (RR, 2.30; 95% CI, 1.26–4.19) (Figure 4). The reason for this finding is unclear. Inadequate data are provided in the individual studies to determine whether there were important differences in fibrosis stage between relapsers and nonresponders. We also speculate on other reasons for this finding. Host-virus interactions resulting in relapse after treatment might be such that they also allow fewer clinical complications of chronic HCV infection. This finding could represent a state of more interferon “inducible” innate immunity or less induced suppressor genes (eg, USP-18). To clarify this finding, future prospective observational studies and randomized controlled trials should stratify their end point analyses between relapsers and nonresponders and seek to determine whether differences in liver-related morbidity and mortality are associated with differences in progression of fibrosis.
This meta-analysis is limited by several factors. First, studies in this meta-analysis did not consistently stratify outcomes by severity of hepatic fibrosis when HCV-infected patients failed treatment. Specifically, we do not have adequate data about the natural history of HCV treatment failures who only had mild-moderate fibrosis (Ishak score 1–2 or Metavir F1/F2) at initiation of HCV treatment. Second, most studies in this meta-analysis did not attempt to estimate duration of HCV infection among their study population. This reinforced our decision to use failure of HCV therapy as the defining characteristic for the inception cohort of included studies. Third, many of these studies were conducted in Asia and examined Asian populations,5, 11, 15, 16, 17, 18, 20, 21, 22, 24, 25, 26, 27, 28, 29, 33, 34, 39 and it is unclear whether these results are generalizable to populations in the US and Europe. Fourth, many investigators published multiple reports about near-identical cohorts of patients. Therefore, we carefully assessed studies for overlapping cohorts of patients and only used the single, most recently published report in this meta-analysis. Finally, studies did not consistently provide data about the initial treatment regimen among HCV-infected patients with treatment failure. It is conceivable that HCV-infected patients who failed after interferon monotherapy might be clinically different from HCV treatment failures after combination therapy (eg, lower HCV RNA levels).
Our meta-analysis is also limited because our estimates about the annual rates of decompensated cirrhosis, HCC, and liver-related mortality demonstrated heterogeneity in individual study results. Study populations might have been substantially different for various reasons, including differences in prevalence of confounding factors (eg, alcohol consumption) or differences in duration of HCV infection. To account for this heterogeneity, we used random-effects meta-analysis, which results in wider confidence intervals around our point estimates of pooled outcomes. Nevertheless, many of the studies in our meta-analysis were relatively small and used a retrospective study design, which might lead to imprecise estimates of liver-related morbidity and mortality. Notably, the HALT-C trial might overcome some of these deficiencies. This trial8 was a large prospective trial with clear criteria for the diagnosis of HCC, but we did not include it in our meta-analysis because patients received maintenance therapy. In this trial, maintenance therapy did not significantly impact outcomes, and a combined cohort of treated and untreated cirrhotic patients produced an annual HCC rate of 1.1%, which is lower than the annual rate estimated in our meta-analysis.
In conclusion, our meta-analysis suggests that HCV-infected treatment failure patients with advanced fibrosis suffer decompensated cirrhosis, HCC, and/or liver-related mortality at an annual rate of approximately 2%–3%. Among studies of patients with varying levels of fibrosis, the annual rates vary from 0.56%–1.39%. Patients who achieve SVR are substantially less likely to suffer from liver-related mortality, HCC, or hepatic decompensation (RR, 0.16–0.23). These data will facilitate decision-making by HCV-infected treatment failure patients and physicians when considering whether to re-treat with currently available therapies or to delay treatment until newer therapies are available.
Results
Results of Literature Search
The computer-assisted search yielded more than 2276 potentially relevant articles (Supplementary Figure 1). After initial review of titles and abstracts, 215 studies were potentially appropriate, and abstracts were reviewed in detail. One hundred four studies were potentially appropriate and underwent full manuscript review along with 3 additional studies identified through recursive literature searches. After application of the inclusion and exclusion criteria, 26 studies were included in our review, and descriptive characteristics can be found in Table 1.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35
Among studies reporting liver-related mortality rates, no evidence of publication bias was present on the basis of Begg's (P = .45) and Egger's (P = .27) tests. Furthermore, neither trimming the outliers nor filling in the missing studies changed the estimate of pooled mortality rate by more than 0.1%. However, visual inspection of the funnel plot suggests that publication bias could be present. Among the studies reporting HCC rates, little evidence of publication bias was seen on visual inspection of the funnel plot by Begg's (P = .2) or Egger's tests (P = .06). Among the studies reporting rates of hepatic decompensation, no evidence of publication bias was present on the basis of Begg's (P = .5) or Egger's tests (P = .2). However, visual inspection of the funnel plot suggested possible publication bias, and trimming the outliers and filling in the missing studies changed the estimate of pooled hepatic decompensation rate from 0.56% to 0.1%, indicating that the pooled estimate is likely to be substantially affected by publication bias. On meta-regression, differences between studies in follow-up time, mean age of the cohort, and median stage of fibrosis at cohort inception were not associated with liver-related morbidity and mortality results.
Liver-Related Mortality
The primary outcomes reported by each study are shown in Table 2. Among studies that enrolled patients with any stage of hepatic fibrosis, the pooled liver-related mortality rate among HCV treatment failures was 0.81%/year (95% confidence interval [CI], 0.55–1.07) (Figure 1A), but the pooled liver-related mortality rate among HCV treatment failures was substantially higher at 2.73%/year (95% CI, 1.38–4.08) (Figure 1B) among studies that only enrolled patients with advanced fibrosis or cirrhosis. Both analyses demonstrated moderate statistical heterogeneity between studies (P = .001 for any stage, P < .001 for advanced fibrosis). Chronic hepatitis C patients with SVR are much less likely to suffer liver-related mortality compared with chronic hepatitis C patients with treatment failure who do not achieve SVR in studies with HCV patients with all stages of fibrosis (RR, 0.23; 95% CI, 0.10–0.52) (Figure 1C) or studies that only enrolled patients with advanced fibrosis (RR, 0.19; 95% CI, 0.10–0.37) (Figure 1D). Neither analysis demonstrated statistical heterogeneity (P = .09 for any stage, I2 = 0%, P = .75 for advanced fibrosis).
Hepatocellular Carcinoma
Among studies that enrolled patients with any stage of hepatic fibrosis, the pooled HCC rate among HCV treatment failures was 1.84%/year (95% CI, 1.36–2.32) (Figure 2A), but the pooled HCC rate among HCV treatment failures was numerically higher at 3.22%/year (95% CI, 2.02–4.42) (Figure 2B) among studies that only enrolled patients with advanced fibrosis. Again, both analyses demonstrated moderate statistical heterogeneity between individual studies (P < .001 for any stage, P < .001 for advanced fibrosis). Also, chronic hepatitis C patients with SVR are much less likely to suffer HCC compared with chronic hepatitis C patients who do not achieve SVR among studies that enrolled patients with any stage of hepatic fibrosis (RR, 0.21; 95% CI, 0.16–0.27) (Figure 2C) and among studies that only enrolled patients with advanced fibrosis or cirrhosis (RR, 0.32; 95% CI, 0.23–0.44) (Figure 2D). Again, neither of these analyses demonstrated statistical heterogeneity (P = .93 for any stage, P = .61 for advanced fibrosis).
Hepatic Decompensation
Among studies that enrolled patients with any stage of hepatic fibrosis, the pooled hepatic decompensation rate among HCV treatment failures was 0.54%/year (95% CI, 0.11–0.97) (Figure 3A), but the pooled hepatic decompensation rate among HCV treatment failures was substantially higher at 2.92%/year (95% CI, 1.61–4.22) (Figure 3B) in studies that only enrolled patients with advanced fibrosis or cirrhosis. Both of these analyses demonstrated moderate statistical heterogeneity (P < .001 for any stage, P < .001 for advanced fibrosis). Chronic hepatitis C patients with SVR are much less likely to suffer hepatic decompensation compared with chronic hepatitis C patients who do not achieve SVR in studies that enrolled patients with any stage of hepatic fibrosis (RR, 0.16; 95% CI, 0.04–0.59) (Figure 3C) and studies that only enrolled patients with advanced fibrosis or cirrhosis failures (RR, 0.13; 95% CI, 0.06-0.27) (Figure 3D). No statistical heterogeneity was identified between studies (P = .69 for any stage, P = .27 for advanced fibrosis).
Natural History of Relapsers Versus Nonresponders
Four of the studies12, 18, 22, 23 reported outcomes according to whether the patients initially became virus-negative (relapsers) versus remaining persistently viremic (nonresponders). The study by Coverdale et al12 was the only one to report mortality outcomes with liver-related mortality occurring in relapsers at a rate of 0.7%/year and in nonresponders at a rate of 1.8%/year (P = .4). The study by Pradat et al23 was the only one to report rates of hepatic decompensation that occurred at 1.7%/year in relapsers versus 2.9%/year in nonresponders (P = .5). All 4 studies reported rates of HCC, and nonresponders were more likely to develop HCC compared with relapsers (RR, 2.30; 95% CI, 1.26–4.19) (Figure 4). There was no evidence of statistical heterogeneity (P = .49).
Methods
Literature Search
A computer-assisted search with the Ovid interface to Medline was conducted to identify potentially relevant published articles. A search of the Medline database from 1966 to 2008 was performed by using the exploded (exp) medical subject heading (MeSH) terms (exp Hepatitis C) AND (exp Treatment Failure OR exp Retreatment OR exp Recurrence OR exp Drug Resistance OR keywords refractory, relapse, retreatment, nonrespond, non-respond, fail, unsuccess). The results of all searches were limited to human studies published in the English language. Manual searches of reference lists from potentially relevant articles were also performed to identify any additional studies that might have been missed by using the computer-assisted strategy.
Study Selection Criteria
Two investigators (M.V., A.S.) independently reviewed the titles and abstracts of all citations identified by the literature search. Potentially relevant studies were retrieved, and the selection criteria were applied. The inclusion criteria were (1) cohort studies of treatment failure HCV patients who were treated with interferon/pegylated interferon ± ribavirin; (2) reporting of liver-related morbidity or mortality end points stratified by SVR status; and (3) published in the English language in full manuscript form. Treatment success was defined as HCV-infected patients who achieve an SVR, undetectable virus in the serum 6 months after the end of therapy. Treatment failure was defined as HCV patients who do not achieve SVR. Morbidity end points were defined as HCC or decompensated cirrhosis (defined by ascites, hepatic encephalopathy, or bleeding esophageal varices). Liver-related mortality was defined as death as a result of complications of decompensated cirrhosis, HCC, and/or liver transplantation, even if patients survived the procedure. The following types of studies were excluded: (1) cross-sectional studies with short-term follow-up (<1 year); (2) studies reporting only surrogate end points such as stage of fibrosis on liver biopsy or AST/ALT levels; (3) studies with unclear follow-up time; (4) studies that enrolled patients with evidence of decompensated cirrhosis at inception of the cohort; (5) studies in which the primary end point was response to therapy; (6) studies of patients with human immunodeficiency virus coinfection, on dialysis, or post-transplant; (7) duplicative studies reporting on the same cohort of patients; and (8) studies in which patients received maintenance treatment or studies in which patients were initially treated with agents other than interferon alfa/pegylated interferon ± ribavirin (eg, interferon beta or glycyrrhizin). Maintenance therapy was defined as any continuous interferon-based treatment beyond a standard course (ie, 48 weeks for genotype 1 patients) with the intent of suppressing hepatic inflammation and fibrosis.8 Studies that only enrolled patients with advanced fibrosis or cirrhosis were included, although these studies were analyzed separately from studies enrolling HCV-infected patients with treatment failure with all stages of fibrosis.
Data Extraction
The eligible articles were reviewed in a duplicate, independent manner by 2 investigators (M.V., A.S.). Data extraction on standardized forms was also performed in a duplicate, independent manner by the 2 investigators.9 Data were collected on annual rates of liver-related mortality, HCC, and decompensated cirrhosis among patients failing to achieve SVR and patients who achieved SVR. Data were also collected on the design of each study (retrospective vs prospective), the number of patients in each group, demographic characteristics of the patient population, median stage of fibrosis at cohort inception, proportion of patients with advanced fibrosis (Metavir stages F2–F4 or Ishak stages 3–6) at cohort inception, and the duration of follow-up.
Statistical Analysis
Pooled rates of liver-related mortality, HCC, and decompensated cirrhosis in HCV treatment failure patients were calculated by using random-effects meta-analysis according to the method of DerSimonian and Laird.10 Separate pooled rates are provided for HCV treatment failure patients from studies that only enrolled patients with advanced fibrosis or cirrhosis (Metavir stages F3-F4 or Ishak stages 3-6) at cohort inception. Also, the relative risk (RR) of each end point is compared between HCV treatment failure patients versus patients who achieved SVR. Finally, the RR of each end point is also compared between patients who became virus-negative during treatment (relapsers) versus those remaining persistently virus-positive (nonresponders) to determine whether natural history differs between these groups of HCV treatment failure patients.
Heterogeneity was assessed by using the I2 index or the variation in effect size attributable to heterogeneity. Meta-regression was then used to assess the following prespecified reasons for heterogeneity: differences between studies in follow-up time, mean age of the cohort, and median stage of fibrosis at cohort inception. Visual inspection of funnel plots, as well as statistical testing according to the methods of Begg and Egger, were used to assess for publication bias. These analyses were limited to studies including all stages of fibrosis to prevent heterogeneity from obscuring evidence of publication bias. The impact of publication bias on the pooled rates was then estimated by the trim and fill method.
Institute of Medicine recommendations for the prevention and control of hepatitis B and C
Institute of Medicine recommendations for the prevention and control of hepatitis B and C
Hepatology March 2010
Abigail E. Mitchell 1 *§, Heather M. Colvin 1, R. Palmer Beasley 2
1Board on Population Health and Public Health Practice, Institute of Medicine of the National Academies, Washington, DC
2Division of Epidemiology and Disease Control, University of Texas School of Public Health, Houston, Texas
email: Abigail E. Mitchell (amitchell@nas.edu)
"Federally funded health-insurance programs - such as Medicare, Medicaid, and the Federal Employees Health Benefits Program - should incorporate guidelines for risk-factor screening for hepatitis B and hepatitis C as a required core component of preventive care so that at-risk people receive serologic testing for HBV and HCV and chronically infected patients receive appropriate medical management."
"The Health Resources and Services Administration should provide adequate resources to federally funded community health facilities for provision of comprehensive viral hepatitis services."
Abstract
Despite federal, state, and local public health efforts to prevent and control hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, these diseases remain serious health problems in the United States. About 1%-2% of the U.S. population has chronic HBV or HCV infections, and each year about 15,000 people die from liver cancer or liver disease related to these preventable infections. The Institute of Medicine formed an expert committee to determine ways to reduce new HBV and HCV infections and the morbidity and mortality related to chronic viral hepatitis and released its findings in a report. The major factor found to impede current efforts to prevent and control HBV and HCV is lack of knowledge and awareness about these diseases among healthcare and social-service providers, members of the public, and policy makers. Because the extent and seriousness of this public health problem is not appreciated, inadequate resources are being allocated to prevention, control, and surveillance programs. This situation has led to continued transmission of HBV and HCV and inadequate identification of and medical management for chronically infected people. Conclusion: To address the situation, the Institute of Medicine report makes recommendations in four areas: improved surveillance for HBV and HCV; improved knowledge and awareness among healthcare and social-service providers and the public, especially at-risk people; improved HBV vaccine coverage; and improved viral hepatitis services and access to those services.
Received: 12 January 2010; Accepted: 13 January 2010
Article Text
In the next 10 years, about 150,000 people in the United States will die from liver cancer and liver disease associated with chronic hepatitis B and hepatitis C.[1] It is estimated that 3.5 to 5.3 million people - 1%-2% of the U.S. population - are living with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. Of those, 800,000 to 1.4 million have chronic HBV infections and 2.7 to 3.9 million have chronic HCV infections. About 65% and 75% of the infected population are unaware that they are infected with HBV and HCV, respectively.[2][3]
Although the incidence of acute HBV infection is declining in the U.S., due to the availability of HBV vaccines, about 43,000 new acute HBV infections still occur each year.[4] Of those new infections, about 1,000 infants acquire the infection from their HBV-positive mothers.[5] HBV is also transmitted by sexual contact with an infected person, sharing injection drug equipment, and needlestick injuries. The number of people in the U.S. who are living with chronic HBV infection may be increasing as a result of legal immigration from highly endemic countries (especially countries in the western Pacific region, Asia, and sub-Saharan Africa).
HCV is efficiently transmitted by direct percutaneous exposure to infectious blood. Persons likely to have chronic HCV infection include those who received a blood transfusion before 1992 and past or current injection-drug users (IDUs). Most IDUs in the United States have serologic evidence of HCV infection.[6][7] While HCV incidence appears to have declined over the last decade, a large portion of IDUs, who often do not have access to healthcare services, are not identified by current surveillance systems making interpretation of that trend complicated.
Despite federal, state, and local public health efforts to prevent and control HBV and HCV, these diseases remain serious health problems in the U.S. Therefore, the Centers for Disease Control and Prevention (CDC), the Department of Health and Human Services' Office of Minority Health, the Department of Veterans Affairs, and the National Viral Hepatitis Roundtable sought guidance from the Institute of Medicine (IOM) in identifying missed opportunities related to the prevention and control of HBV and HCV infections. The IOM assembled an expert committee to address that task; its findings and recommendations are published in a report. This article summarizes the IOM's report Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C.[8]
Abbreviations: CDC, Centers for Disease Control and Prevention; HBV, hepatitis B virus; HCV, hepatitis C virus; IDU, injection drug user; IOM, Institute of Medicine.
Findings and Recommendations
The IOM committee's overall approach to its task is presented in Fig. 1. Major factors that impede efforts to prevent and control hepatitis B and C are the lack of knowledge and awareness on the part of healthcare providers, at-risk populations, the public, and policy makers. Insufficient understanding about the seriousness of this public health problem has led to inadequate allocation of public resources for viral hepatitis prevention, control, and surveillance programs. For example, although there are three to five times more people living with chronic viral hepatitis infections than with HIV infection, just 2% of the CDC NCHHSTP (National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention) fiscal year 2008 budget was allocated for viral hepatitis, but 69% was allocated for HIV/AIDS (J. Ward, CDC, presentation to the IOM committee, December 4, 2008). Inadequate resources for viral hepatitis programs are leading to continued transmission of HBV and HCV and high rates of morbidity and mortality from hepatitis B and hepatitis C. The committee made recommendations in four areas: surveillance, knowledge and awareness, hepatitis B immunization, and services.
Surveillance.
The viral hepatitis surveillance system in the U.S. is highly fragmented and poorly developed. The federal government has provided few resources to local and state health departments to perform surveillance for viral hepatitis. Additional funding sources for surveillance, such as funding from states and cities, vary among jurisdictions. The committee made the following recommendations aimed at making viral hepatitis surveillance systems more consistent among jurisdictions and improving their ability to collect and report data more accurately:
The CDC should develop specific cooperative viral-hepatitis agreements with all state and territorial health departments to support core surveillance for acute and chronic hepatitis B and hepatitis C.
The agreements should include:
(1) A funding mechanism and guidance for core surveillance activities.
(2) Implementation of performance standards regarding revised and standardized case definitions, specifically through the use of:
(a) Revised case-reporting forms with required, standardized components.
(b) Case evaluation and follow-up.
(3) Support for developing and implementing automated data-collection systems, including:
(a) Electronic laboratory reporting.
(b) Electronic medical-record extraction systems.
(c) Web-based, Public Health Information Network-compliant reporting systems.
The CDC should support and conduct targeted active surveillance, including serologic testing, to monitor incidence and prevalence of HBV and HCV infections in populations not fully captured by core surveillance.
(1) Active surveillance should be conducted in specific geographic regions and populations.
(2) Appropriate serology, molecular biology, and follow-up will allow for distinction between acute and chronic hepatitis B and hepatitis C.
Knowledge and Awareness.
The committee found relatively poor awareness about hepatitis B and hepatitis C among healthcare providers, social-service providers (such as staff at drug-treatment facilities and immigrant-services centers), and the public. Lack of awareness about the prevalence of chronic viral hepatitis in the U.S., the target populations, and the appropriate methodology for risk-factor screening, serologic testing, and medical management probably contributes to continuing transmission; missed opportunities for prevention, early diagnosis, and medical care; and poor health outcomes in infected people. To improve knowledge and awareness among healthcare providers and social-service providers, the committee recommends:
The CDC should work with key stakeholders (other government agencies, professional organizations, healthcare organizations, and educational institutions) to develop hepatitis B and hepatitis C educational programs for healthcare and social-service providers.
The educational programs should include at least the following components:
(1) Information about the prevalence and incidence of acute and chronic hepatitis B and hepatitis C both in the general U.S. population and in at-risk populations, particularly foreign-born populations for hepatitis B, and IDUs and incarcerated populations for hepatitis C.
(2) Guidance on screening for risk factors.
(3) Information about prevention, immunization, and monitoring of chronically infected patients.
(4) Information about prevention of HBV and HCV transmission in health-care settings.
To increase knowledge and awareness about hepatitis B and hepatitis C in at-risk populations and the general population, the committee recommends:
The CDC should work with key stakeholders to develop, coordinate, and evaluate innovative and effective outreach and education programs to target at-risk populations and to increase awareness in the general population about hepatitis B and hepatitis C.
The programs should be linguistically and culturally appropriate and should integrate viral hepatitis and liver-health education into other health programs that serve at-risk populations. They should:
(1) Promote better understanding of HBV and HCV infections, transmission, prevention, and treatment in the at-risk and general populations.
(2) Educate pregnant women and women of childbearing age about hepatitis B prevention.
(3) Increase testing rates in at-risk populations.
(4) Promote safe injections among IDUs and safe drug use among noninjection drug users.
(5) Provide educational information for all people who have tested positive for chronic HBV or HCV infections and those receiving treatment.
Immunization.
The longstanding availability of effective hepatitis B vaccines makes the elimination of new HBV infections possible, particularly in children. As noted above, about 1,000 newborns are infected by their HBV-positive mothers at birth each year in the U.S. That number has not declined in the last decade. To prevent transmission of HBV from mothers to newborns, the Advisory Committee on Immunization Practices recommends that infants born to mothers who are positive for hepatitis B surface antigen receive hepatitis B immune globulin and a first dose of the hepatitis B vaccine within 12 hours of birth. To improve adherence to that guideline, the committee recommends:
All infants weighing at least 2,000 g and born to hepatitis B surface antigen-positive women should receive single-antigen hepatitis B vaccine and hepatitis B immune globulin in the delivery room as soon as they are stable and washed.
The Advisory Committee on Immunization Practices recommends administration of the hepatitis B vaccine series to unvaccinated children under 19 years old. School-entry mandates have been shown to increase hepatitis B vaccination rates and to reduce disparities in vaccination rates. Overall, hepatitis B vaccination rates in school-age children are high, but coverage varies among states. Additionally, there are racial and ethnic disparities in childhood vaccination rates - Asian and Pacific Islander, Hispanic, and African American children have lower vaccination rates than non-Hispanic white children. Regarding vaccination of children, the committee recommends:
All states should mandate that the hepatitis B vaccine series be completed or in progress as a requirement for school attendance.
Hepatitis B vaccination for adults is directed at high-risk groups - people at risk for HBV infection from infected sex partners, from IDU, from occupational exposure to infected blood or body fluids, and from travel to regions that have high or intermediate HBV endemicity. Only about half the adults at high risk for HBV infection receive the vaccine. Low coverage of high-risk adults is attributed to the lack of dedicated vaccine programs; limitations of funding, insurance coverage, and cost-sharing; and noncompliance of the involved populations. To increase the rate of vaccination of at-risk adults, the committee recommends:
Additional federal and state resources should be devoted to increasing hepatitis B vaccination of at-risk adults.
(1) Correctional institutions should offer hepatitis B vaccination to all incarcerated persons.
(2) Organizations that serve high-risk populations should offer the vaccine.
(3) Efforts should be made to improve identification of at-risk adults.
(4) Efforts should be made to increase rates of completion of the vaccine series in adults.
(5) Government agencies should annually determine gaps in hepatitis B vaccine coverage among at-risk adults and estimate the resources needed to fill those gaps.
Viral Hepatitis Services.
At the federal, state, and local levels, health services related to viral hepatitis prevention, risk-factor screening and serologic testing, and medical management are both sparse and fragmented. The committee believes that a coordinated approach is necessary. Comprehensive viral hepatitis services should have five core components: outreach and awareness; prevention of new infections; identification of infected people; social and peer support; and medical management of infected people. The committee identified major deficiencies in viral hepatitis services and made recommendations to address the deficiencies for different populations and healthcare venues.
For the general population:
Federally funded health-insurance programs - such as Medicare, Medicaid, and the Federal Employees Health Benefits Program - should incorporate guidelines for risk-factor screening for hepatitis B and hepatitis C as a required core component of preventive care so that at-risk people receive serologic testing for HBV and HCV and chronically infected patients receive appropriate medical management.
For foreign-born populations:
The CDC, in conjunction with other government agencies, should provide resources for the expansion of community-based programs that provide hepatitis B screening, testing, and vaccination services that target foreign-born populations.
For illicit-drug users:
Government agencies should expand programs to reduce the risk of HCV infection through IDU by providing comprehensive HCV prevention programs. The programs should include access to sterile needle syringes and drug-preparation equipment because the shared use of these materials has been shown to lead to transmission of HCV.
In addition,
Federal and state governments should expand services to reduce the harm caused by chronic hepatitis B and hepatitis C. The services should include testing to detect infection, counseling to reduce alcohol use and secondary transmission, hepatitis B vaccination, and referral for or provision of medical management.
For pregnant women:
The CDC should provide additional resources and guidance to perinatal hepatitis B prevention program coordinators to expand and enhance the capacity to identify chronically infected pregnant women and provide case-management services, including referral for appropriate medical management.
For incarcerated populations:
The CDC and the Department of Justice should create an initiative to foster partnerships between health departments and corrections systems to ensure the availability of comprehensive viral hepatitis services for incarcerated people.
For community health centers:
The Health Resources and Services Administration should provide adequate resources to federally funded community health facilities for provision of comprehensive viral hepatitis services.
For other settings that target at-risk populations, such as sexually transmitted disease and HIV clinics, shelter-based programs, and mobile health units:
The Health Resources and Services Administration and CDC should provide resources and guidance to integrate comprehensive viral hepatitis services into those settings that serve high-risk populations.
Discussion
s
The IOM committee believes that implementation of these and other recommendations in its report would lead to reductions in new HBV and HCV infections, fewer medical complications and deaths as a result of these viral infections of the liver, and lower total health costs. Advances will be needed: in knowledge and awareness about chronic viral hepatitis, in improvement of hepatitis B vaccine coverage, in improvement and better integration of viral hepatitis services, and in improvement of estimates of the burden of disease for resource-allocation purposes.
Acknowledgements
The authors thank the members of the IOM's Committee on Prevention and Control of Viral Hepatitis Infections: Harvey J. Alter, Margaret L. Brandeau, Daniel R. Church, Alison A. Evans, Holly Hagan, Sandral Hullett, Stacene R. Maroushek, Randall R. Mayer, Brian J. McMahon, Martín Jose Sepúlveda, Samuel So, David L. Thomas, and Lester N. Wright.
References
1 Centers for Disease Control and Prevention. Viral hepatitis: statistics and surveillance. http://www.cdc.gov/hepatitis/statistics.htm. Accessed January 2010.
2 Lin SY, Chang ET, So SK. Why we should routinely screen Asian American adults for hepatitis B: a cross-sectional study of Asians in California. HEPATOLOGY 2007; 46: 1034-1040. Links
3 Hagan H, Campbell J, Thiede H, Strathdee S, Ouellet L, Kapadia F, et al. Self-reported hepatitis C virus antibody status and risk behavior in young injectors. Public Health Rep 2006; 121: 710-719. Links
4 Daniels D, Grytdal S, Wasley A. Surveillance for acute viral hepatitis - United States, 2007. MMWR Surveill Summ 2009; 58: 1-27. Links
5 Ward JW. Time for renewed commitment to viral hepatitis prevention. Am J Public Health 2008; 98: 779-781. Links
6 Amon JJ, Garfein RS, Ahdieh-Grant L, Armstrong GL, Ouellet LJ, Latka MH, et al. Prevalence of hepatitis C virus infection among injection drug users in the United States, 1994-2004. Clin Infect Dis 2008; 46: 1852-1858. Links
7 Hagan H, Pouget ER, Des Jarlais DC, Lelutiu-Weinberger C. Meta-regression of hepatitis C virus infection in relation to time since onset of illicit drug injection: the influence of time and place. Am J Epidemiol 2008; 168: 1099-1109. Links
8 IOM. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC: National Academies Press; 2010.
Hepatology March 2010
Abigail E. Mitchell 1 *§, Heather M. Colvin 1, R. Palmer Beasley 2
1Board on Population Health and Public Health Practice, Institute of Medicine of the National Academies, Washington, DC
2Division of Epidemiology and Disease Control, University of Texas School of Public Health, Houston, Texas
email: Abigail E. Mitchell (amitchell@nas.edu)
"Federally funded health-insurance programs - such as Medicare, Medicaid, and the Federal Employees Health Benefits Program - should incorporate guidelines for risk-factor screening for hepatitis B and hepatitis C as a required core component of preventive care so that at-risk people receive serologic testing for HBV and HCV and chronically infected patients receive appropriate medical management."
"The Health Resources and Services Administration should provide adequate resources to federally funded community health facilities for provision of comprehensive viral hepatitis services."
Abstract
Despite federal, state, and local public health efforts to prevent and control hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, these diseases remain serious health problems in the United States. About 1%-2% of the U.S. population has chronic HBV or HCV infections, and each year about 15,000 people die from liver cancer or liver disease related to these preventable infections. The Institute of Medicine formed an expert committee to determine ways to reduce new HBV and HCV infections and the morbidity and mortality related to chronic viral hepatitis and released its findings in a report. The major factor found to impede current efforts to prevent and control HBV and HCV is lack of knowledge and awareness about these diseases among healthcare and social-service providers, members of the public, and policy makers. Because the extent and seriousness of this public health problem is not appreciated, inadequate resources are being allocated to prevention, control, and surveillance programs. This situation has led to continued transmission of HBV and HCV and inadequate identification of and medical management for chronically infected people. Conclusion: To address the situation, the Institute of Medicine report makes recommendations in four areas: improved surveillance for HBV and HCV; improved knowledge and awareness among healthcare and social-service providers and the public, especially at-risk people; improved HBV vaccine coverage; and improved viral hepatitis services and access to those services.
Received: 12 January 2010; Accepted: 13 January 2010
Article Text
In the next 10 years, about 150,000 people in the United States will die from liver cancer and liver disease associated with chronic hepatitis B and hepatitis C.[1] It is estimated that 3.5 to 5.3 million people - 1%-2% of the U.S. population - are living with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. Of those, 800,000 to 1.4 million have chronic HBV infections and 2.7 to 3.9 million have chronic HCV infections. About 65% and 75% of the infected population are unaware that they are infected with HBV and HCV, respectively.[2][3]
Although the incidence of acute HBV infection is declining in the U.S., due to the availability of HBV vaccines, about 43,000 new acute HBV infections still occur each year.[4] Of those new infections, about 1,000 infants acquire the infection from their HBV-positive mothers.[5] HBV is also transmitted by sexual contact with an infected person, sharing injection drug equipment, and needlestick injuries. The number of people in the U.S. who are living with chronic HBV infection may be increasing as a result of legal immigration from highly endemic countries (especially countries in the western Pacific region, Asia, and sub-Saharan Africa).
HCV is efficiently transmitted by direct percutaneous exposure to infectious blood. Persons likely to have chronic HCV infection include those who received a blood transfusion before 1992 and past or current injection-drug users (IDUs). Most IDUs in the United States have serologic evidence of HCV infection.[6][7] While HCV incidence appears to have declined over the last decade, a large portion of IDUs, who often do not have access to healthcare services, are not identified by current surveillance systems making interpretation of that trend complicated.
Despite federal, state, and local public health efforts to prevent and control HBV and HCV, these diseases remain serious health problems in the U.S. Therefore, the Centers for Disease Control and Prevention (CDC), the Department of Health and Human Services' Office of Minority Health, the Department of Veterans Affairs, and the National Viral Hepatitis Roundtable sought guidance from the Institute of Medicine (IOM) in identifying missed opportunities related to the prevention and control of HBV and HCV infections. The IOM assembled an expert committee to address that task; its findings and recommendations are published in a report. This article summarizes the IOM's report Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C.[8]
Abbreviations: CDC, Centers for Disease Control and Prevention; HBV, hepatitis B virus; HCV, hepatitis C virus; IDU, injection drug user; IOM, Institute of Medicine.
Findings and Recommendations
The IOM committee's overall approach to its task is presented in Fig. 1. Major factors that impede efforts to prevent and control hepatitis B and C are the lack of knowledge and awareness on the part of healthcare providers, at-risk populations, the public, and policy makers. Insufficient understanding about the seriousness of this public health problem has led to inadequate allocation of public resources for viral hepatitis prevention, control, and surveillance programs. For example, although there are three to five times more people living with chronic viral hepatitis infections than with HIV infection, just 2% of the CDC NCHHSTP (National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention) fiscal year 2008 budget was allocated for viral hepatitis, but 69% was allocated for HIV/AIDS (J. Ward, CDC, presentation to the IOM committee, December 4, 2008). Inadequate resources for viral hepatitis programs are leading to continued transmission of HBV and HCV and high rates of morbidity and mortality from hepatitis B and hepatitis C. The committee made recommendations in four areas: surveillance, knowledge and awareness, hepatitis B immunization, and services.
Surveillance.
The viral hepatitis surveillance system in the U.S. is highly fragmented and poorly developed. The federal government has provided few resources to local and state health departments to perform surveillance for viral hepatitis. Additional funding sources for surveillance, such as funding from states and cities, vary among jurisdictions. The committee made the following recommendations aimed at making viral hepatitis surveillance systems more consistent among jurisdictions and improving their ability to collect and report data more accurately:
The CDC should develop specific cooperative viral-hepatitis agreements with all state and territorial health departments to support core surveillance for acute and chronic hepatitis B and hepatitis C.
The agreements should include:
(1) A funding mechanism and guidance for core surveillance activities.
(2) Implementation of performance standards regarding revised and standardized case definitions, specifically through the use of:
(a) Revised case-reporting forms with required, standardized components.
(b) Case evaluation and follow-up.
(3) Support for developing and implementing automated data-collection systems, including:
(a) Electronic laboratory reporting.
(b) Electronic medical-record extraction systems.
(c) Web-based, Public Health Information Network-compliant reporting systems.
The CDC should support and conduct targeted active surveillance, including serologic testing, to monitor incidence and prevalence of HBV and HCV infections in populations not fully captured by core surveillance.
(1) Active surveillance should be conducted in specific geographic regions and populations.
(2) Appropriate serology, molecular biology, and follow-up will allow for distinction between acute and chronic hepatitis B and hepatitis C.
Knowledge and Awareness.
The committee found relatively poor awareness about hepatitis B and hepatitis C among healthcare providers, social-service providers (such as staff at drug-treatment facilities and immigrant-services centers), and the public. Lack of awareness about the prevalence of chronic viral hepatitis in the U.S., the target populations, and the appropriate methodology for risk-factor screening, serologic testing, and medical management probably contributes to continuing transmission; missed opportunities for prevention, early diagnosis, and medical care; and poor health outcomes in infected people. To improve knowledge and awareness among healthcare providers and social-service providers, the committee recommends:
The CDC should work with key stakeholders (other government agencies, professional organizations, healthcare organizations, and educational institutions) to develop hepatitis B and hepatitis C educational programs for healthcare and social-service providers.
The educational programs should include at least the following components:
(1) Information about the prevalence and incidence of acute and chronic hepatitis B and hepatitis C both in the general U.S. population and in at-risk populations, particularly foreign-born populations for hepatitis B, and IDUs and incarcerated populations for hepatitis C.
(2) Guidance on screening for risk factors.
(3) Information about prevention, immunization, and monitoring of chronically infected patients.
(4) Information about prevention of HBV and HCV transmission in health-care settings.
To increase knowledge and awareness about hepatitis B and hepatitis C in at-risk populations and the general population, the committee recommends:
The CDC should work with key stakeholders to develop, coordinate, and evaluate innovative and effective outreach and education programs to target at-risk populations and to increase awareness in the general population about hepatitis B and hepatitis C.
The programs should be linguistically and culturally appropriate and should integrate viral hepatitis and liver-health education into other health programs that serve at-risk populations. They should:
(1) Promote better understanding of HBV and HCV infections, transmission, prevention, and treatment in the at-risk and general populations.
(2) Educate pregnant women and women of childbearing age about hepatitis B prevention.
(3) Increase testing rates in at-risk populations.
(4) Promote safe injections among IDUs and safe drug use among noninjection drug users.
(5) Provide educational information for all people who have tested positive for chronic HBV or HCV infections and those receiving treatment.
Immunization.
The longstanding availability of effective hepatitis B vaccines makes the elimination of new HBV infections possible, particularly in children. As noted above, about 1,000 newborns are infected by their HBV-positive mothers at birth each year in the U.S. That number has not declined in the last decade. To prevent transmission of HBV from mothers to newborns, the Advisory Committee on Immunization Practices recommends that infants born to mothers who are positive for hepatitis B surface antigen receive hepatitis B immune globulin and a first dose of the hepatitis B vaccine within 12 hours of birth. To improve adherence to that guideline, the committee recommends:
All infants weighing at least 2,000 g and born to hepatitis B surface antigen-positive women should receive single-antigen hepatitis B vaccine and hepatitis B immune globulin in the delivery room as soon as they are stable and washed.
The Advisory Committee on Immunization Practices recommends administration of the hepatitis B vaccine series to unvaccinated children under 19 years old. School-entry mandates have been shown to increase hepatitis B vaccination rates and to reduce disparities in vaccination rates. Overall, hepatitis B vaccination rates in school-age children are high, but coverage varies among states. Additionally, there are racial and ethnic disparities in childhood vaccination rates - Asian and Pacific Islander, Hispanic, and African American children have lower vaccination rates than non-Hispanic white children. Regarding vaccination of children, the committee recommends:
All states should mandate that the hepatitis B vaccine series be completed or in progress as a requirement for school attendance.
Hepatitis B vaccination for adults is directed at high-risk groups - people at risk for HBV infection from infected sex partners, from IDU, from occupational exposure to infected blood or body fluids, and from travel to regions that have high or intermediate HBV endemicity. Only about half the adults at high risk for HBV infection receive the vaccine. Low coverage of high-risk adults is attributed to the lack of dedicated vaccine programs; limitations of funding, insurance coverage, and cost-sharing; and noncompliance of the involved populations. To increase the rate of vaccination of at-risk adults, the committee recommends:
Additional federal and state resources should be devoted to increasing hepatitis B vaccination of at-risk adults.
(1) Correctional institutions should offer hepatitis B vaccination to all incarcerated persons.
(2) Organizations that serve high-risk populations should offer the vaccine.
(3) Efforts should be made to improve identification of at-risk adults.
(4) Efforts should be made to increase rates of completion of the vaccine series in adults.
(5) Government agencies should annually determine gaps in hepatitis B vaccine coverage among at-risk adults and estimate the resources needed to fill those gaps.
Viral Hepatitis Services.
At the federal, state, and local levels, health services related to viral hepatitis prevention, risk-factor screening and serologic testing, and medical management are both sparse and fragmented. The committee believes that a coordinated approach is necessary. Comprehensive viral hepatitis services should have five core components: outreach and awareness; prevention of new infections; identification of infected people; social and peer support; and medical management of infected people. The committee identified major deficiencies in viral hepatitis services and made recommendations to address the deficiencies for different populations and healthcare venues.
For the general population:
Federally funded health-insurance programs - such as Medicare, Medicaid, and the Federal Employees Health Benefits Program - should incorporate guidelines for risk-factor screening for hepatitis B and hepatitis C as a required core component of preventive care so that at-risk people receive serologic testing for HBV and HCV and chronically infected patients receive appropriate medical management.
For foreign-born populations:
The CDC, in conjunction with other government agencies, should provide resources for the expansion of community-based programs that provide hepatitis B screening, testing, and vaccination services that target foreign-born populations.
For illicit-drug users:
Government agencies should expand programs to reduce the risk of HCV infection through IDU by providing comprehensive HCV prevention programs. The programs should include access to sterile needle syringes and drug-preparation equipment because the shared use of these materials has been shown to lead to transmission of HCV.
In addition,
Federal and state governments should expand services to reduce the harm caused by chronic hepatitis B and hepatitis C. The services should include testing to detect infection, counseling to reduce alcohol use and secondary transmission, hepatitis B vaccination, and referral for or provision of medical management.
For pregnant women:
The CDC should provide additional resources and guidance to perinatal hepatitis B prevention program coordinators to expand and enhance the capacity to identify chronically infected pregnant women and provide case-management services, including referral for appropriate medical management.
For incarcerated populations:
The CDC and the Department of Justice should create an initiative to foster partnerships between health departments and corrections systems to ensure the availability of comprehensive viral hepatitis services for incarcerated people.
For community health centers:
The Health Resources and Services Administration should provide adequate resources to federally funded community health facilities for provision of comprehensive viral hepatitis services.
For other settings that target at-risk populations, such as sexually transmitted disease and HIV clinics, shelter-based programs, and mobile health units:
The Health Resources and Services Administration and CDC should provide resources and guidance to integrate comprehensive viral hepatitis services into those settings that serve high-risk populations.
Discussion
s
The IOM committee believes that implementation of these and other recommendations in its report would lead to reductions in new HBV and HCV infections, fewer medical complications and deaths as a result of these viral infections of the liver, and lower total health costs. Advances will be needed: in knowledge and awareness about chronic viral hepatitis, in improvement of hepatitis B vaccine coverage, in improvement and better integration of viral hepatitis services, and in improvement of estimates of the burden of disease for resource-allocation purposes.
Acknowledgements
The authors thank the members of the IOM's Committee on Prevention and Control of Viral Hepatitis Infections: Harvey J. Alter, Margaret L. Brandeau, Daniel R. Church, Alison A. Evans, Holly Hagan, Sandral Hullett, Stacene R. Maroushek, Randall R. Mayer, Brian J. McMahon, Martín Jose Sepúlveda, Samuel So, David L. Thomas, and Lester N. Wright.
References
1 Centers for Disease Control and Prevention. Viral hepatitis: statistics and surveillance. http://www.cdc.gov/hepatitis/statistics.htm. Accessed January 2010.
2 Lin SY, Chang ET, So SK. Why we should routinely screen Asian American adults for hepatitis B: a cross-sectional study of Asians in California. HEPATOLOGY 2007; 46: 1034-1040. Links
3 Hagan H, Campbell J, Thiede H, Strathdee S, Ouellet L, Kapadia F, et al. Self-reported hepatitis C virus antibody status and risk behavior in young injectors. Public Health Rep 2006; 121: 710-719. Links
4 Daniels D, Grytdal S, Wasley A. Surveillance for acute viral hepatitis - United States, 2007. MMWR Surveill Summ 2009; 58: 1-27. Links
5 Ward JW. Time for renewed commitment to viral hepatitis prevention. Am J Public Health 2008; 98: 779-781. Links
6 Amon JJ, Garfein RS, Ahdieh-Grant L, Armstrong GL, Ouellet LJ, Latka MH, et al. Prevalence of hepatitis C virus infection among injection drug users in the United States, 1994-2004. Clin Infect Dis 2008; 46: 1852-1858. Links
7 Hagan H, Pouget ER, Des Jarlais DC, Lelutiu-Weinberger C. Meta-regression of hepatitis C virus infection in relation to time since onset of illicit drug injection: the influence of time and place. Am J Epidemiol 2008; 168: 1099-1109. Links
8 IOM. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC: National Academies Press; 2010.
The Institute of Medicine report on viral hepatitis: A call to action
The Institute of Medicine report on viral hepatitis: A call to action
Hepatology March 2010
Arun J. Sanyal *, On behalf of the Governing Board the Public Policy, Clinical Practice, Manpower committees of the AASLD
Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University School of Medicine Richmond, VA
email: Arun J. Sanyal (asanyal@mcvh-vcu.edu)
*Correspondence to Arun J. Sanyal, Professor of Medicine, Pharmacology and Molecular Pathology, Virginia Commonwealth University School of Medicine, MCV Box 980341, Richmond, VA 23298-0341
telephone: 804-828-6314
Chronic viral hepatitis remains a major cause of preventable morbidity and mortality in the world. The landmark study from the prestigious Institute of Medicine (IOM) summarized in this issue of HEPATOLOGY defines the issues that drive this problem and the need to tackle this aggressively,[1] an issue advocated by the American Association for the Study of Liver Diseases (AASLD) for many years.[2] The AASLD applauds this major effort that not only highlights the urgent need to address this public health problem but also provides direction for policy makers to begin to tackle the scourge of hepatitis B and C.
The public health impact of a disease depends on its prevalence and its consequences for the affected individual. The IOM report notes that one of every 50 Americans is affected by hepatitis B or C and that the majority of afflicted individuals are unaware of their disease. Many of these subjects thus go undetected and contribute to the burden of advanced liver disease and the rising tide of hepatocellular carcinoma. A principal cause for this is a lack of knowledge and awareness of chronic viral hepatitis on the part of health care and social-service providers. This is, in turn, driven by a lack of resources allocated to the eradication of these conditions at a national and state level. A major consequence of the failure to detect the disease early is that the treatment options available for those who have progressed to cirrhosis are more limited and require more resources. The decreased ability to tolerate t reatments and the impact of end-stage liver disease on the patient add a further social and economic burden on the affected individual and their family. These add to the cost of medical care nationally and negatively impact the ability of many small businesses to obtain affordable health care coverage. The implications of the IOM report for American, and indeed the world, are therefore highly significant.
The AASLD is committed to working toward the ultimate eradication of hepatitis B and C. This can be accomplished by prevention of acquisition of new infection and elimination of the virus in those already infected, thus getting rid of the reservoir of infection. These can only be accomplished by implementation of educational and preventive programs, active surveillance and identification of infected subjects, development of effective therapy, ensuring access to care, and mechanisms to make these treatments affordable. The availability of an adequately trained and educated workforce is essential to meet these goals. The IOM report is highly laudable because it makes specific recommendations to take on these issues. The AASLD is committed to working with the Centers for Disease Control and Prevention (CDC) and other federal agencies and stakeholders to get these recommendations implemented and further the goal o f eradication of chronic viral hepatitis.
Chronic viral hepatitis cuts across all socioeconomic sections of society. However, those who are most disadvantaged from a social and economic perspective often have the highest burden of disease and the most limited access to care. The AASLD strongly supports the recommendations for a comprehensive assessment of the hepatitis B and C evaluation program made by the IOM. However, the ability of the CDC to perform such an evaluation is likely to be limited by the modest US$19.3 million budget allocated for the Division of Viral Hepatitis in the current fiscal year, which constitutes only 1.8% of the budget for the Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention. The AASLD remains committed to advocating for greater funding for this division within the CDC and supports its effort in this area. The AASLD also supports the efforts of the CDC foundation to bring stake holders together to share research data and provide feedback on information and tools required to appropriately respond to the recommendations in the IOM report, and the AASLD and CDC will co-organize a workshop on this later this year. Finally, the AASLD has been and will remain a strong advocate for the bipartisan legislation The Viral Hepatitis and Liver Cancer Control and Prevention Act that was recently introduced by Representatives Mike Honda (D-Calif.) and Charles Dent (R-Pa.). This bill will authorize an initial US$90 million in funding in 2011 and additional funding later for the CDC to work with state health departments in their prevention, immunization, and surveillance programs.
A major recommendation of the IOM report is for the development of educational programs directed not only at the population but also to health care providers. Given the high prevalence of chronic viral hepatitis and its frequent clinically silent nature through the early phases of the disease, it is likely that many such individuals are normally only seen by family practitioners, primary care physicians, nurse practitioners, obstetricians, and gynecologists. As the leading professional society dedicated to the care of individuals with liver disease, the AASLD plans to develop educational materials and programming directed to these diverse groups to further actualize the recommendations of the IOM. It will also work in concert with the CDC and other agencies which are already active in the areas of education for health care providers. It will also be valuable to learn from the experience gained from other group s such as the Veterans Health Administration, and the AASLD will work toward developing partnerships to use the knowledge and information from such entities to promote the recommendations of the IOM for the general population. The Hepatitis B Special Interest Group of the AASLD is currently developing an initial educational module directed toward primary care providers.
The AASLD also strongly endorses the recommendations of the IOM for the development of programs designed to prevent the acquisition of new infection with hepatitis B or C. These programs are also likely to require substantial resource allocation, and the AASLD urges the federal government to act expeditiously on these recommendations. This will remain a cornerstone of the advocacy efforts of the AASLD.
Perhaps an area where the IOM report does not go far enough is to make specific recommendations about providing access and support for treatment of infected individuals via Medicare and other third-party payors. The report recommends referral for medical management without specific recommendations for provision of access to treatment. The AASLD believes that, given the availability of effective therapies, it is vitally important to treat appropriate populations of infected individuals. The achievement of a sustained virologic response to anti-hepatitis C virus therapy and viral suppression in those with active hepatitis B has already been shown to diminish the risks of disease progression. By treating the disease earlier in its course, it is likely that the social, medical, and economic burden of advanced liver disease and drain on the pool of organs available for liver transplantation will be alleviated. The AASLD supports and will advocate for the appropriate studies to be performed by federal agencies to validate this possibility and provide an evidence-based rationale for early detection and treatment of chronic viral hepatitis. The ability to provide access to effective treatment by the Ryan White Act made a great impact on the burden of human immunodeficiency virus. It is now time for similar legislation to help the millions with viral hepatitis.
A key factor that will determine the success of any initiative to control the burden of chronic viral hepatitis is the availability of an adequately trained workforce. Traditionally, the educational and training programs related to viral hepatitis have focused on gastroenterologists and hepatologists, who often practice in a tertiary care setting. Chronic viral hepatitis is largely present in the general population who do not normally see such physicians. It is therefore a national imperative to train additional classes of hepatologists and other health care providers who focus on community-based efforts to prevent, detect, and treat chronic liver disease including viral hepatitis. These will require restructuring of training in liver diseases across many specialties and nonphysician health care providers. The AASLD will use its committee structure to begin to develop an approach and work with sister societies and the American Board of Internal Medicine, family practices, etc., to actualize this recommendation of the IOM.
Finally, as noted by the IOM report, hepatitis B and C remain important causes of preventable death worldwide. The implications of the IOM report are therefore global and are likely to be helpful to the WHO as they respond to a proposed global resolution on viral hepatitis prevention and control at the 63rd World Health Assembly. We hope that by the synergistic activities of the federal agencies such as the CDC, NIH etc and other stakeholders such as the AASLD and WHO, we will map out the way towards global prevention and control of chronic viral hepatitis.
Hepatology March 2010
Arun J. Sanyal *, On behalf of the Governing Board the Public Policy, Clinical Practice, Manpower committees of the AASLD
Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University School of Medicine Richmond, VA
email: Arun J. Sanyal (asanyal@mcvh-vcu.edu)
*Correspondence to Arun J. Sanyal, Professor of Medicine, Pharmacology and Molecular Pathology, Virginia Commonwealth University School of Medicine, MCV Box 980341, Richmond, VA 23298-0341
telephone: 804-828-6314
Chronic viral hepatitis remains a major cause of preventable morbidity and mortality in the world. The landmark study from the prestigious Institute of Medicine (IOM) summarized in this issue of HEPATOLOGY defines the issues that drive this problem and the need to tackle this aggressively,[1] an issue advocated by the American Association for the Study of Liver Diseases (AASLD) for many years.[2] The AASLD applauds this major effort that not only highlights the urgent need to address this public health problem but also provides direction for policy makers to begin to tackle the scourge of hepatitis B and C.
The public health impact of a disease depends on its prevalence and its consequences for the affected individual. The IOM report notes that one of every 50 Americans is affected by hepatitis B or C and that the majority of afflicted individuals are unaware of their disease. Many of these subjects thus go undetected and contribute to the burden of advanced liver disease and the rising tide of hepatocellular carcinoma. A principal cause for this is a lack of knowledge and awareness of chronic viral hepatitis on the part of health care and social-service providers. This is, in turn, driven by a lack of resources allocated to the eradication of these conditions at a national and state level. A major consequence of the failure to detect the disease early is that the treatment options available for those who have progressed to cirrhosis are more limited and require more resources. The decreased ability to tolerate t reatments and the impact of end-stage liver disease on the patient add a further social and economic burden on the affected individual and their family. These add to the cost of medical care nationally and negatively impact the ability of many small businesses to obtain affordable health care coverage. The implications of the IOM report for American, and indeed the world, are therefore highly significant.
The AASLD is committed to working toward the ultimate eradication of hepatitis B and C. This can be accomplished by prevention of acquisition of new infection and elimination of the virus in those already infected, thus getting rid of the reservoir of infection. These can only be accomplished by implementation of educational and preventive programs, active surveillance and identification of infected subjects, development of effective therapy, ensuring access to care, and mechanisms to make these treatments affordable. The availability of an adequately trained and educated workforce is essential to meet these goals. The IOM report is highly laudable because it makes specific recommendations to take on these issues. The AASLD is committed to working with the Centers for Disease Control and Prevention (CDC) and other federal agencies and stakeholders to get these recommendations implemented and further the goal o f eradication of chronic viral hepatitis.
Chronic viral hepatitis cuts across all socioeconomic sections of society. However, those who are most disadvantaged from a social and economic perspective often have the highest burden of disease and the most limited access to care. The AASLD strongly supports the recommendations for a comprehensive assessment of the hepatitis B and C evaluation program made by the IOM. However, the ability of the CDC to perform such an evaluation is likely to be limited by the modest US$19.3 million budget allocated for the Division of Viral Hepatitis in the current fiscal year, which constitutes only 1.8% of the budget for the Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention. The AASLD remains committed to advocating for greater funding for this division within the CDC and supports its effort in this area. The AASLD also supports the efforts of the CDC foundation to bring stake holders together to share research data and provide feedback on information and tools required to appropriately respond to the recommendations in the IOM report, and the AASLD and CDC will co-organize a workshop on this later this year. Finally, the AASLD has been and will remain a strong advocate for the bipartisan legislation The Viral Hepatitis and Liver Cancer Control and Prevention Act that was recently introduced by Representatives Mike Honda (D-Calif.) and Charles Dent (R-Pa.). This bill will authorize an initial US$90 million in funding in 2011 and additional funding later for the CDC to work with state health departments in their prevention, immunization, and surveillance programs.
A major recommendation of the IOM report is for the development of educational programs directed not only at the population but also to health care providers. Given the high prevalence of chronic viral hepatitis and its frequent clinically silent nature through the early phases of the disease, it is likely that many such individuals are normally only seen by family practitioners, primary care physicians, nurse practitioners, obstetricians, and gynecologists. As the leading professional society dedicated to the care of individuals with liver disease, the AASLD plans to develop educational materials and programming directed to these diverse groups to further actualize the recommendations of the IOM. It will also work in concert with the CDC and other agencies which are already active in the areas of education for health care providers. It will also be valuable to learn from the experience gained from other group s such as the Veterans Health Administration, and the AASLD will work toward developing partnerships to use the knowledge and information from such entities to promote the recommendations of the IOM for the general population. The Hepatitis B Special Interest Group of the AASLD is currently developing an initial educational module directed toward primary care providers.
The AASLD also strongly endorses the recommendations of the IOM for the development of programs designed to prevent the acquisition of new infection with hepatitis B or C. These programs are also likely to require substantial resource allocation, and the AASLD urges the federal government to act expeditiously on these recommendations. This will remain a cornerstone of the advocacy efforts of the AASLD.
Perhaps an area where the IOM report does not go far enough is to make specific recommendations about providing access and support for treatment of infected individuals via Medicare and other third-party payors. The report recommends referral for medical management without specific recommendations for provision of access to treatment. The AASLD believes that, given the availability of effective therapies, it is vitally important to treat appropriate populations of infected individuals. The achievement of a sustained virologic response to anti-hepatitis C virus therapy and viral suppression in those with active hepatitis B has already been shown to diminish the risks of disease progression. By treating the disease earlier in its course, it is likely that the social, medical, and economic burden of advanced liver disease and drain on the pool of organs available for liver transplantation will be alleviated. The AASLD supports and will advocate for the appropriate studies to be performed by federal agencies to validate this possibility and provide an evidence-based rationale for early detection and treatment of chronic viral hepatitis. The ability to provide access to effective treatment by the Ryan White Act made a great impact on the burden of human immunodeficiency virus. It is now time for similar legislation to help the millions with viral hepatitis.
A key factor that will determine the success of any initiative to control the burden of chronic viral hepatitis is the availability of an adequately trained workforce. Traditionally, the educational and training programs related to viral hepatitis have focused on gastroenterologists and hepatologists, who often practice in a tertiary care setting. Chronic viral hepatitis is largely present in the general population who do not normally see such physicians. It is therefore a national imperative to train additional classes of hepatologists and other health care providers who focus on community-based efforts to prevent, detect, and treat chronic liver disease including viral hepatitis. These will require restructuring of training in liver diseases across many specialties and nonphysician health care providers. The AASLD will use its committee structure to begin to develop an approach and work with sister societies and the American Board of Internal Medicine, family practices, etc., to actualize this recommendation of the IOM.
Finally, as noted by the IOM report, hepatitis B and C remain important causes of preventable death worldwide. The implications of the IOM report are therefore global and are likely to be helpful to the WHO as they respond to a proposed global resolution on viral hepatitis prevention and control at the 63rd World Health Assembly. We hope that by the synergistic activities of the federal agencies such as the CDC, NIH etc and other stakeholders such as the AASLD and WHO, we will map out the way towards global prevention and control of chronic viral hepatitis.
FDA approves Salix’ Xifaxan for liver failure disorder
FDA approves Salix’ Xifaxan for liver failure disorder
26 March 2010 pharmatimes.com
Observers are suggesting that the USA’s Salix Pharmaceuticals could become a takeover target after the country’s regulators gave the thumbs-up to the antibiotic Xifaxan for a disorder caused by chronic liver failure.
The US Food and Drug Administration has granted marketing approval for Xifaxan (rifaximin) tablets for reduction in the risk of overt hepatic encephalopathy (HE) recurrence in patients aged 18 or older. The disorder occurs frequently in patients with cirrhosis as a result of end–stage liver disease and there are more than 600,000 cases of cirrhosis in the USA, making it the third most common cause of death, after heart disease and cancer, in people aged 45–65.
Xifaxan has been granted orphan drug status by the FDA for HE and is already approved as a treatment for travellers' diarrhoea. Salix says that it will start shipping the product to wholesalers in early May and complete the training of its 160–member sales force soon after.
Analysts believe that this new indication could push sales of Xifaxan up to the $1 billion mark (full-year 2009 sales came in at $117.9 million) and many have suggested that an acquisition of the company could be on the horizon. Corey Davis at Jefferies & Co issued a research note saying that Salix has “proved it has the credibility to execute an on-time FDA approval, adding that “attention will quickly turn to the late-stage trial data for Xifaxan in irritable bowel syndrome, a much larger commercial opportunity”.
26 March 2010 pharmatimes.com
Observers are suggesting that the USA’s Salix Pharmaceuticals could become a takeover target after the country’s regulators gave the thumbs-up to the antibiotic Xifaxan for a disorder caused by chronic liver failure.
The US Food and Drug Administration has granted marketing approval for Xifaxan (rifaximin) tablets for reduction in the risk of overt hepatic encephalopathy (HE) recurrence in patients aged 18 or older. The disorder occurs frequently in patients with cirrhosis as a result of end–stage liver disease and there are more than 600,000 cases of cirrhosis in the USA, making it the third most common cause of death, after heart disease and cancer, in people aged 45–65.
Xifaxan has been granted orphan drug status by the FDA for HE and is already approved as a treatment for travellers' diarrhoea. Salix says that it will start shipping the product to wholesalers in early May and complete the training of its 160–member sales force soon after.
Analysts believe that this new indication could push sales of Xifaxan up to the $1 billion mark (full-year 2009 sales came in at $117.9 million) and many have suggested that an acquisition of the company could be on the horizon. Corey Davis at Jefferies & Co issued a research note saying that Salix has “proved it has the credibility to execute an on-time FDA approval, adding that “attention will quickly turn to the late-stage trial data for Xifaxan in irritable bowel syndrome, a much larger commercial opportunity”.
Rifaximin Treatment in Hepatic Encephalopathy
Rifaximin Treatment in Hepatic Encephalopathy
NEJM March 25 2020
Nathan M. Bass, M.B., Ch.B., Ph.D., Kevin D. Mullen, M.D., Arun Sanyal, M.D., Fred Poordad, M.D., Guy Neff, M.D., Carroll B. Leevy, M.D., Samuel Sigal, M.D., Muhammad Y. Sheikh, M.D., Kimberly Beavers, M.D., Todd Frederick, M.D., Lewis Teperman, M.D., Donald Hillebrand, M.D., Shirley Huang, M.S., Kunal Merchant, Ph.D., Audrey Shaw, Ph.D., Enoch Bortey, Ph.D., and William P. Forbes, Pharm.D.
"For patients in remission from hepatic encephalopathy, the minimally absorbed antibiotic rifaximin (Xifaxan) reduces the risk of recurrence by nearly 60%, researchers said.....Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tract, has broad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance"
ABSTRACT
Background - Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established.
Methods - In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy.
Results - Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events.
Conclusions - Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038 [ClinicalTrials.gov] .)
Approximately 5.5 million persons in the United States have hepatic cirrhosis, a major cause of complications and death.1,2,3 Hepatic encephalopathy, a complication of hepatic cirrhosis, imposes a formidable burden on patients, their families, and the health care system.1,4 Overt episodes of hepatic encephalopathy are debilitating, can occur without warning, render the patient incapable of self-care, and frequently result in hospitalization.1,4 In 2003, more than 40,000 patients were hospitalized with hepatic encephalopathy, a number that increased to over 50,000 in 2004.4 Although the occurrence of episodes of hepatic encephalopathy appears to be unrelated to the cause of cirrhosis,5 increases in the frequency and severity of such episodes predict an increased risk of death.6,7
Hepatic encephalopathy is a neuropsychiatric syndrome for which symptoms, manifested on a continuum, are deterioration in mental status, with psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration, disorientation, and — in severe forms — coma.1,7,8 The clinical diagnosis of overt hepatic encephalopathy is based on two concurrent types of symptoms: impaired mental status, as defined by the Conn score (also called West Haven criteria) (on a scale from 0 to 4, with higher scores indicating more severe impairment),9 and impaired neuromotor function.1,10 The Conn score is recommended by the Working Party on Hepatic Encephalopathy8 for assessment of overt hepatic encephalopathy in clinical trials. Signs of neuromotor impairment include hyperreflexia, rigidity, myoclonus, and asterixis (a coarse, myoclonic, "flapping" muscle tremor), which is measured with the use of an asterixis severity scale.10,11,12
Most therapies for hepatic encephalopathy focus on treating episodes as they occur and are directed at reducing the nitrogenous load in the gut, an approach that is consistent with the hypothesis that this disorder results from the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and portosystemic shunting.2,3,13 The current standard of care for patients with hepatic encephalopathy, treatment with nonabsorbable disaccharides lactitol or lactulose, decreases the absorption of ammonia through cathartic effects and by altering colonic pH.14
In an open-label, single-site study, Sharma et al. reported that lactulose, as compared with placebo, was effective in the prevention of overt hepatic encephalopathy.15 In that study, 125 patients who had recovered from a recent episode of hepatic encephalopathy were randomly assigned, in a 1:1 ratio, to receive either lactulose or placebo for up to 20 months. During a median study period of 14 months, the proportion of patients with episodes was smaller in the lactulose group than in the placebo group (19.6% vs. 46.8%, P=0.001). However, side effects of lactulose therapy — including an excessively sweet taste and gastrointestinal side effects such as bloating, flatulence, and severe and unpredictable diarrhea possibly leading to dehydration — result in frequent noncompliance.16,17,18
In general, the oral antibiotics neomycin, paromomycin, vancomycin, and metronidazole have been effectively used, with or without lactulose, to reduce ammonia-producing enteric bacteria in patients with hepatic encephalopathy.14,16,17 However, some oral antibiotics are not recommended for long-term use because of nephrotoxicity, ototoxicity, and peripheral neuropathy19,20 and are specifically contraindicated in patients with liver disease.19,21,22
Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tract, has broad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance.23,24,25 In randomized studies, rifaximin was more effective than nonabsorbable disaccharides and had efficacy that was equivalent to or greater than that of other antibiotics used in the treatment of acute hepatic encephalopathy.26,27,28,29,30,31,32,33,34,35,36,37,38,39 Furthermore, with minimal systemic bioavailability, rifaximin may be more conducive to long-term use than other, more bioavailable antibiotics with detrimental side effects.
In this phase 3, multicenter, randomized, double-blind, placebo-controlled study conducted over a 6-month period, we evaluated the efficacy and safety of rifaximin, used concomitantly with lactulose, for the maintenance of remission from episodes of hepatic encephalopathy in outpatients with a recent history of recurrent, overt hepatic encephalopathy.
Discussion
The prevention of episodes of hepatic encephalopathy is an important goal in the treatment of patients with liver disease,1,2,4,6,7 especially since symptoms of overt encephalopathy are debilitating and decrease the ability for self-care, leading to improper nutrition and nonadherence to a therapeutic regimen, which in turn leads to severe symptoms, frequent hospitalizations, and a poor quality of life. Our study showed that the use of rifaximin reduced the risk of a breakthrough episode of hepatic encephalopathy during a 6-month period among patients in remission who had a recent history of recurrent overt hepatic encephalopathy (≥2 episodes within the previous 6 months) before enrollment. The reduced risk was seen across subgroups, further showing the consistency of the results, which expand previously reported findings of the efficacy of rifaximin in the treatment of overt hepatic encephalopathy.26,27,28,29,30,31,32,33,34,39
The current study differs from previous randomized studies in that it examined the protective effect of rifaximin against breakthrough episodes of hepatic encephalopathy rather than its effect in the treatment of acute, overt symptoms; the study also involved a larger group of patients and a longer study period. In previous randomized studies, rifaximin was administered for 21 days or less26,27,28,29,30,32,33 or intermittently, for 14 or 15 days per month for 3 or 6 months.33,34,39
Our study shows the superiority of rifaximin therapy over treatment with lactulose alone. More than 90% of patients received concomitant lactulose during the study period, and a significant treatment effect was noted within 28 days after randomization. In contrast, a recent single-center, open-label study of 120 patients showed that although lactulose therapy was more effective than no active treatment in the prevention of overt hepatic encephalopathy,15 the treatment effects favoring lactulose were apparent only after approximately 4 months.
In the current, prospective study, rifaximin therapy reduced the risk of hospitalization involving hepatic encephalopathy, reflecting the clinical significance of our efficacy findings. Also, the reduced risk of hospitalization supports the results of retrospective chart reviews,4,43 which have shown that rifaximin, as compared with lactulose, is associated with a significantly lower frequency and duration of hospitalization and lower hospital costs.
The incidences of adverse events in general and adverse events consisting of infection in particular were similar in the rifaximin group and the placebo group. The safety profile of rifaximin appears to be superior to that of systemic antibiotics, particularly for patients with liver disease.31 The occurrence of nephrotoxicity and ototoxicity with the use of aminoglycosides (e.g., neomycin and paromomycin) and of nausea and peripheral neuropathy with prolonged use of metronidazole restricts their use in patients with hepatic encephalopathy.19,21,22
The risk of bacterial resistance appears to be lower with rifaximin than with systemic antibiotics. Plasma levels of rifaximin are negligible; therefore, bacteria outside the gastrointestinal tract are not exposed to appreciable selective pressure. In addition, whereas resistance to other antimicrobial agents is plasma-mediated, resistance to rifaximin is mediated through reversible genomic change. For chromosomally mediated mutation and selection to result in clinically relevant resistance, the mutation cannot be lethal and cannot significantly decrease virulence; otherwise, the resistant trait will not be transmitted. Both in vitro and in vivo studies of the effects of rifaximin on commensal flora suggest that rifaximin-resistant organisms have low viability.25,44,45
In summary, this study shows a robust protective effect of rifaximin against episodes of hepatic encephalopathy. Rifaximin also reduces the risk of hospitalization involving hepatic encephalopathy.1,31
Results
Study Patients
A total of 299 patients in the United States (205 patients), Canada (14 patients), and Russia (80 patients) were randomly assigned to receive a study drug at 70 investigative sites. The study began on December 5, 2005, and was completed on August 15, 2008. All patients received at least one dose of study medication and underwent at least one safety assessment after enrollment. Therefore, all patients were included in both the intention-to-treat population and the safety population (Figure 1). As specified by the study protocol, the study drug was discontinued at the time of the first breakthrough episode of hepatic encephalopathy. The incidence of early withdrawal for any reason other than a breakthrough episode was similar in the rifaximin group and the placebo group.
Supported by Salix Pharmaceuticals (study RFHE3001).
Dr. Bass reports receiving consulting or advisory fees from Salix and Hyperion and lecture fees from Salix; Dr. Mullen, steering committee and lecture fees from Salix; Dr. Sanyal, consulting fees or advisory fees from Salix, Takeda, Sanofi-Aventis, Ikaria, Astellas, Pfizer, Gilead, Vertex, Exhalenz, Bayer-Onyx, Amylin, and Norgine and grant support from Salix, Sanofi-Aventis, Gilead, Intercept, and Roche; Dr. Poordad, advisory fees from Salix; Dr. Neff, lecture fees from Roche, Three Rivers, and Bristol-Myers Squibb; Dr. Sigal, consulting fees or advisory fees from Salix, Otsuka, Ikaria, and Roche, lecture fees from Otsuka, and grant support from Salix and Gilead; Dr. Sheikh, grant support from Salix; Dr. Frederick, consulting fees or advisory fees from Salix and Hyperion and lecture fees from Salix; Ms. Huang, Dr. Merchant, Dr. Shaw, and Dr. Bortey report being employees of and holding stock in Salix; and Dr. Forbes reports being an officer and employee of Salix and holding stock in the company. No other potential conflict of interest relevant to this article was reported.
We thank Jane Saiers, Ph.D., of WriteMedicine and David Sorscher, Ph.D., of Salix Pharmaceuticals for their assistance in the preparation of a previous draft of the manuscript.
Baseline characteristics were similar in the two groups (Table 1). Patients were predominantly white, male, and younger than 65 years of age. All patients had a history of overt episodic hepatic encephalopathy associated with advanced liver disease, diagnosed on the basis of two or more episodes of overt hepatic encephalopathy (Conn score, ≥2) within 6 months before the screening visit.
Similar percentages of patients in the placebo group (91.2%) and rifaximin group (91.4%) were receiving lactulose at baseline, and the mean daily doses of lactulose during the study period were stable (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Commonly used concomitant medications were those that would be expected for patients with chronic liver disease (Table 1).
The mean (±SD) duration of treatment was 130.3±56.5 days in the rifaximin group and 105.7±62.7 days in the placebo group. The rate of compliance, defined as use of at least 80% of the dispensed tablets, was high in both study groups (84.3% in the rifaximin group and 84.9% in the placebo group).
Breakthrough Episodes
Breakthrough episodes of hepatic encephalopathy were reported in 31 of 140 patients in the rifaximin group (22.1%) and 73 of 159 patients in the placebo group (45.9%). Figure 2A shows the time to a breakthrough episode (the primary end point). The hazard ratio for the risk of a breakthrough episode in the rifaximin group, as compared with the placebo group, was 0.42 (95% confidence interval [CI], 0.28 to 0.64; P<0.001), reflecting a relative reduction in the risk of a breakthrough episode by 58% with rifaximin as compared with placebo during the 6-month study period. These data suggest that four patients would need to be treated with rifaximin for 6 months to prevent one episode of overt hepatic encephalopathy. The degree to which rifaximin reduced the risk of a breakthrough episode was consistent across subgroups (Figure 3).
Hospitalizations
Hospitalization involving hepatic encephalopathy was reported for 19 of 140 patients in the rifaximin group (13.6%) and 36 of 159 patients in the placebo group (22.6%). The hazard ratio for the risk of such hospitalization in the rifaximin group, as compared with the placebo group, was 0.50 (95% CI, 0.29 to 0.87; P=0.01), reflecting a reduction in the risk by 50% with rifaximin as compared with placebo (Figure 2B). Thus, nine patients would need to be treated with rifaximin for 6 months to prevent one hospitalization involving hepatic encephalopathy.
Safety
The incidence of adverse events reported during the study was similar in the rifaximin group (80.0%) and the placebo group (79.9%), as was the incidence of the more common serious adverse events (Table 2). Among the adverse events related to infection, Clostridium difficile infection was reported in two patients in the rifaximin group and none in the placebo group; both affected patients had several concurrent risk factors for C. difficile infection, such as advanced age, numerous recent hospitalizations involving multiple courses of antibiotic therapy, and use of the proton-pump inhibitor pantoprazole. In both patients, rifaximin therapy was continued concomitantly with treatment for the infection, from which they fully recovered.
A total of 20 patients died during the study (9 in the rifaximin group and 11 in the placebo group). Most of the deaths were attributed to conditions associated with disease progression: five patients in each of the two groups had hepatic cirrhosis, decompensated cirrhosis, hepatic failure, alcoholic cirrhosis, or end-stage liver failure, and two patients in each of the two groups had esophageal varices or hemorrhage from esophageal varices. Nearly all the patients who died had had evidence at baseline, apart from hepatic encephalopathy, of decompensated liver cirrhosis (i.e., portal hypertension, ascites or edema, or jaundice), which is associated with a reduced probability of survival.41,42
Methods
Study Patients
Eligibility criteria were an age of at least 18 years, at least two episodes of overt hepatic encephalopathy (Conn score, ≥2)9,12 associated with hepatic cirrhosis during the previous 6 months, remission (Conn score, 0 or 1) at enrollment, and a score of 25 or less on the Model for End-Stage Liver Disease (MELD) scale40 (on which scores can range from 6 to 40, with higher scores indicating more severe disease). Episodes of hepatic encephalopathy that were precipitated by gastrointestinal hemorrhage requiring transfusion of at least 2 units of blood, by medication use, by renal failure requiring dialysis, or by injury to the central nervous system were not counted as previous episodes.
Exclusion criteria included the expectation of liver transplantation within 1 month after the screening visit and the presence of conditions that are known precipitants of hepatic encephalopathy (including gastrointestinal hemorrhage and the placement of a portosystemic shunt or a transjugular intrahepatic portosystemic shunt) within 3 months before the screening visit, chronic renal insufficiency (creatinine level, >2.0 mg per deciliter [177 µmol per liter]) or respiratory insufficiency, anemia (hemoglobin level, <8 g per deciliter), an electrolyte abnormality (serum sodium level, <125 mmol per liter; serum calcium level, >10 mg per deciliter [2.5 mmol per liter]; or potassium level, <2.5 mmol per liter), intercurrent infection, or active spontaneous bacterial peritonitis. All patients or their legally authorized representatives provided written informed consent.
Study Design and Procedures
The protocol was approved by the institutional review board or ethics committee at each center and was conducted in accordance with International Conference on Harmonisation guidelines and other applicable laws and regulations. The study included a screening visit, an observation period between the screening visit and enrollment, and a 6-month treatment phase. On day 0, eligible patients were randomly assigned, in a 1:1 ratio, to receive either 550 mg of rifaximin or placebo, twice daily, for 6 months or until they discontinued the study drug because of a breakthrough episode of hepatic encephalopathy or another reason. Concomitant administration of lactulose was permitted during the study.
The study protocol was designed by representatives of Salix Pharmaceuticals and the academic authors. Data were collected by the principal investigators at each center (see the Appendix) and were monitored by Omnicare Clinical Research, Clinical Trial Management Services (now Chiltern International), and ClinStar Europe under the supervision of Salix representatives, who also analyzed the data. All authors participated in the interpretation of the data and the writing of the manuscript. An editorial consultant was paid by Salix to assist in the revision of subsequent drafts before submission. All authors vouch for the completeness and veracity of the data and data analyses.
Efficacy and Safety Assessments
Clinic visits occurred on days 7 and 14 and every 2 weeks thereafter through day 168 (end of the treatment period), with optional visits on days 42, 70, 98, 126, and 154. Patients were monitored by telephone during the weeks without clinic visits. Assessments included the Conn score and asterixis grade. Conn scores are defined as follows: 0, no personality or behavioral abnormality detected; 1, trivial lack of awareness, euphoria or anxiety, shortened attention span, or impairment of ability to add or subtract; 2, lethargy, disorientation with respect to time, obvious personality change, or inappropriate behavior; 3, somnolence or semistupor, responsiveness to stimuli, confusion, gross disorientation, or bizarre behavior; and 4, coma.9 Asterixis was assessed according to standard practice, by asking patients to extend their arms with wrists flexed backward and fingers open for 30 seconds or more.11,39 Asterixis was then graded as follows: 0, no tremors; 1, few flapping motions; 2, occasional flapping motions; 3, frequent flapping motions; and 4, almost continuous flapping motions.11 Investigators and site personnel who performed assessments were trained in order to ensure consistency across sites.
Statistical Analysis
Efficacy data were analyzed for the intention-to-treat population, which included patients who received at least one dose of the study medication. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy, defined as the time from the first dose of the study drug to an increase from a baseline Conn score of 0 or 1 to a score of 2 or more or from a baseline Conn score of 0 to a Conn score of 1 plus a 1-unit increase in the asterixis grade. The key secondary efficacy end point was the time to the first hospitalization involving hepatic encephalopathy (defined as hospitalization because of the disorder or hospitalization during which an episode of hepatic encephalopathy occurred).
The Cox proportional-hazards model was used, with a 2-sided test and a significance level of 0.05, to compare the time to a breakthrough episode between the rifaximin group and the placebo group (after adjustment for geographic region). Kaplan–Meier methods were used to estimate the proportions of patients having a breakthrough episode at successive time points during the study. Patients who withdrew from the study early for reasons other than the development of hepatic encephalopathy (e.g., another adverse event or the subject's request) were contacted 6 months after randomization to determine whether a breakthrough episode of hepatic encephalopathy had occurred since withdrawal. Data for patients who did not have breakthrough hepatic encephalopathy before day 168 were censored at the time of last contact or on day 168, whichever was earlier. Data for patients who did not have a hospitalization involving hepatic encephalopathy before day 168 were censored at the time of study termination or on day 168, whichever was earlier. The same statistical methods were used to analyze the key secondary end point: time to the first hospitalization involving hepatic encephalopathy.
The primary efficacy end point was evaluated in subgroups of patients according to the following characteristics: geographic region, sex, age, race or ethnic group, baseline MELD score, baseline Conn score, diabetes at baseline, duration of current verified remission, number of episodes of hepatic encephalopathy within the 6-month period before randomization, lactulose use at baseline, and previous placement of a transjugular intrahepatic portosystemic shunt.
Sample-size calculations were based on an assumption of breakthrough episodes of hepatic encephalopathy occurring in 50% and 70% of patients receiving rifaximin and placebo, respectively. These calculations indicated that to show the superiority of rifaximin over placebo with a statistical power of more than 80%, we would need to evaluate 100 patients per group. Safety data were summarized with the use of descriptive statistics. Safety assessments included adverse events, serious adverse events, and adverse events specifically consisting of infection, including respiratory and gastrointestinal infections and their symptoms. Infections are of special interest because of known potential side effects of systemic antibiotics, as a drug class, and known effects of rifaximin.
NEJM March 25 2020
Nathan M. Bass, M.B., Ch.B., Ph.D., Kevin D. Mullen, M.D., Arun Sanyal, M.D., Fred Poordad, M.D., Guy Neff, M.D., Carroll B. Leevy, M.D., Samuel Sigal, M.D., Muhammad Y. Sheikh, M.D., Kimberly Beavers, M.D., Todd Frederick, M.D., Lewis Teperman, M.D., Donald Hillebrand, M.D., Shirley Huang, M.S., Kunal Merchant, Ph.D., Audrey Shaw, Ph.D., Enoch Bortey, Ph.D., and William P. Forbes, Pharm.D.
"For patients in remission from hepatic encephalopathy, the minimally absorbed antibiotic rifaximin (Xifaxan) reduces the risk of recurrence by nearly 60%, researchers said.....Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tract, has broad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance"
ABSTRACT
Background - Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established.
Methods - In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy.
Results - Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events.
Conclusions - Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038 [ClinicalTrials.gov] .)
Approximately 5.5 million persons in the United States have hepatic cirrhosis, a major cause of complications and death.1,2,3 Hepatic encephalopathy, a complication of hepatic cirrhosis, imposes a formidable burden on patients, their families, and the health care system.1,4 Overt episodes of hepatic encephalopathy are debilitating, can occur without warning, render the patient incapable of self-care, and frequently result in hospitalization.1,4 In 2003, more than 40,000 patients were hospitalized with hepatic encephalopathy, a number that increased to over 50,000 in 2004.4 Although the occurrence of episodes of hepatic encephalopathy appears to be unrelated to the cause of cirrhosis,5 increases in the frequency and severity of such episodes predict an increased risk of death.6,7
Hepatic encephalopathy is a neuropsychiatric syndrome for which symptoms, manifested on a continuum, are deterioration in mental status, with psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration, disorientation, and — in severe forms — coma.1,7,8 The clinical diagnosis of overt hepatic encephalopathy is based on two concurrent types of symptoms: impaired mental status, as defined by the Conn score (also called West Haven criteria) (on a scale from 0 to 4, with higher scores indicating more severe impairment),9 and impaired neuromotor function.1,10 The Conn score is recommended by the Working Party on Hepatic Encephalopathy8 for assessment of overt hepatic encephalopathy in clinical trials. Signs of neuromotor impairment include hyperreflexia, rigidity, myoclonus, and asterixis (a coarse, myoclonic, "flapping" muscle tremor), which is measured with the use of an asterixis severity scale.10,11,12
Most therapies for hepatic encephalopathy focus on treating episodes as they occur and are directed at reducing the nitrogenous load in the gut, an approach that is consistent with the hypothesis that this disorder results from the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and portosystemic shunting.2,3,13 The current standard of care for patients with hepatic encephalopathy, treatment with nonabsorbable disaccharides lactitol or lactulose, decreases the absorption of ammonia through cathartic effects and by altering colonic pH.14
In an open-label, single-site study, Sharma et al. reported that lactulose, as compared with placebo, was effective in the prevention of overt hepatic encephalopathy.15 In that study, 125 patients who had recovered from a recent episode of hepatic encephalopathy were randomly assigned, in a 1:1 ratio, to receive either lactulose or placebo for up to 20 months. During a median study period of 14 months, the proportion of patients with episodes was smaller in the lactulose group than in the placebo group (19.6% vs. 46.8%, P=0.001). However, side effects of lactulose therapy — including an excessively sweet taste and gastrointestinal side effects such as bloating, flatulence, and severe and unpredictable diarrhea possibly leading to dehydration — result in frequent noncompliance.16,17,18
In general, the oral antibiotics neomycin, paromomycin, vancomycin, and metronidazole have been effectively used, with or without lactulose, to reduce ammonia-producing enteric bacteria in patients with hepatic encephalopathy.14,16,17 However, some oral antibiotics are not recommended for long-term use because of nephrotoxicity, ototoxicity, and peripheral neuropathy19,20 and are specifically contraindicated in patients with liver disease.19,21,22
Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tract, has broad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance.23,24,25 In randomized studies, rifaximin was more effective than nonabsorbable disaccharides and had efficacy that was equivalent to or greater than that of other antibiotics used in the treatment of acute hepatic encephalopathy.26,27,28,29,30,31,32,33,34,35,36,37,38,39 Furthermore, with minimal systemic bioavailability, rifaximin may be more conducive to long-term use than other, more bioavailable antibiotics with detrimental side effects.
In this phase 3, multicenter, randomized, double-blind, placebo-controlled study conducted over a 6-month period, we evaluated the efficacy and safety of rifaximin, used concomitantly with lactulose, for the maintenance of remission from episodes of hepatic encephalopathy in outpatients with a recent history of recurrent, overt hepatic encephalopathy.
Discussion
The prevention of episodes of hepatic encephalopathy is an important goal in the treatment of patients with liver disease,1,2,4,6,7 especially since symptoms of overt encephalopathy are debilitating and decrease the ability for self-care, leading to improper nutrition and nonadherence to a therapeutic regimen, which in turn leads to severe symptoms, frequent hospitalizations, and a poor quality of life. Our study showed that the use of rifaximin reduced the risk of a breakthrough episode of hepatic encephalopathy during a 6-month period among patients in remission who had a recent history of recurrent overt hepatic encephalopathy (≥2 episodes within the previous 6 months) before enrollment. The reduced risk was seen across subgroups, further showing the consistency of the results, which expand previously reported findings of the efficacy of rifaximin in the treatment of overt hepatic encephalopathy.26,27,28,29,30,31,32,33,34,39
The current study differs from previous randomized studies in that it examined the protective effect of rifaximin against breakthrough episodes of hepatic encephalopathy rather than its effect in the treatment of acute, overt symptoms; the study also involved a larger group of patients and a longer study period. In previous randomized studies, rifaximin was administered for 21 days or less26,27,28,29,30,32,33 or intermittently, for 14 or 15 days per month for 3 or 6 months.33,34,39
Our study shows the superiority of rifaximin therapy over treatment with lactulose alone. More than 90% of patients received concomitant lactulose during the study period, and a significant treatment effect was noted within 28 days after randomization. In contrast, a recent single-center, open-label study of 120 patients showed that although lactulose therapy was more effective than no active treatment in the prevention of overt hepatic encephalopathy,15 the treatment effects favoring lactulose were apparent only after approximately 4 months.
In the current, prospective study, rifaximin therapy reduced the risk of hospitalization involving hepatic encephalopathy, reflecting the clinical significance of our efficacy findings. Also, the reduced risk of hospitalization supports the results of retrospective chart reviews,4,43 which have shown that rifaximin, as compared with lactulose, is associated with a significantly lower frequency and duration of hospitalization and lower hospital costs.
The incidences of adverse events in general and adverse events consisting of infection in particular were similar in the rifaximin group and the placebo group. The safety profile of rifaximin appears to be superior to that of systemic antibiotics, particularly for patients with liver disease.31 The occurrence of nephrotoxicity and ototoxicity with the use of aminoglycosides (e.g., neomycin and paromomycin) and of nausea and peripheral neuropathy with prolonged use of metronidazole restricts their use in patients with hepatic encephalopathy.19,21,22
The risk of bacterial resistance appears to be lower with rifaximin than with systemic antibiotics. Plasma levels of rifaximin are negligible; therefore, bacteria outside the gastrointestinal tract are not exposed to appreciable selective pressure. In addition, whereas resistance to other antimicrobial agents is plasma-mediated, resistance to rifaximin is mediated through reversible genomic change. For chromosomally mediated mutation and selection to result in clinically relevant resistance, the mutation cannot be lethal and cannot significantly decrease virulence; otherwise, the resistant trait will not be transmitted. Both in vitro and in vivo studies of the effects of rifaximin on commensal flora suggest that rifaximin-resistant organisms have low viability.25,44,45
In summary, this study shows a robust protective effect of rifaximin against episodes of hepatic encephalopathy. Rifaximin also reduces the risk of hospitalization involving hepatic encephalopathy.1,31
Results
Study Patients
A total of 299 patients in the United States (205 patients), Canada (14 patients), and Russia (80 patients) were randomly assigned to receive a study drug at 70 investigative sites. The study began on December 5, 2005, and was completed on August 15, 2008. All patients received at least one dose of study medication and underwent at least one safety assessment after enrollment. Therefore, all patients were included in both the intention-to-treat population and the safety population (Figure 1). As specified by the study protocol, the study drug was discontinued at the time of the first breakthrough episode of hepatic encephalopathy. The incidence of early withdrawal for any reason other than a breakthrough episode was similar in the rifaximin group and the placebo group.
Supported by Salix Pharmaceuticals (study RFHE3001).
Dr. Bass reports receiving consulting or advisory fees from Salix and Hyperion and lecture fees from Salix; Dr. Mullen, steering committee and lecture fees from Salix; Dr. Sanyal, consulting fees or advisory fees from Salix, Takeda, Sanofi-Aventis, Ikaria, Astellas, Pfizer, Gilead, Vertex, Exhalenz, Bayer-Onyx, Amylin, and Norgine and grant support from Salix, Sanofi-Aventis, Gilead, Intercept, and Roche; Dr. Poordad, advisory fees from Salix; Dr. Neff, lecture fees from Roche, Three Rivers, and Bristol-Myers Squibb; Dr. Sigal, consulting fees or advisory fees from Salix, Otsuka, Ikaria, and Roche, lecture fees from Otsuka, and grant support from Salix and Gilead; Dr. Sheikh, grant support from Salix; Dr. Frederick, consulting fees or advisory fees from Salix and Hyperion and lecture fees from Salix; Ms. Huang, Dr. Merchant, Dr. Shaw, and Dr. Bortey report being employees of and holding stock in Salix; and Dr. Forbes reports being an officer and employee of Salix and holding stock in the company. No other potential conflict of interest relevant to this article was reported.
We thank Jane Saiers, Ph.D., of WriteMedicine and David Sorscher, Ph.D., of Salix Pharmaceuticals for their assistance in the preparation of a previous draft of the manuscript.
Baseline characteristics were similar in the two groups (Table 1). Patients were predominantly white, male, and younger than 65 years of age. All patients had a history of overt episodic hepatic encephalopathy associated with advanced liver disease, diagnosed on the basis of two or more episodes of overt hepatic encephalopathy (Conn score, ≥2) within 6 months before the screening visit.
Similar percentages of patients in the placebo group (91.2%) and rifaximin group (91.4%) were receiving lactulose at baseline, and the mean daily doses of lactulose during the study period were stable (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Commonly used concomitant medications were those that would be expected for patients with chronic liver disease (Table 1).
The mean (±SD) duration of treatment was 130.3±56.5 days in the rifaximin group and 105.7±62.7 days in the placebo group. The rate of compliance, defined as use of at least 80% of the dispensed tablets, was high in both study groups (84.3% in the rifaximin group and 84.9% in the placebo group).
Breakthrough Episodes
Breakthrough episodes of hepatic encephalopathy were reported in 31 of 140 patients in the rifaximin group (22.1%) and 73 of 159 patients in the placebo group (45.9%). Figure 2A shows the time to a breakthrough episode (the primary end point). The hazard ratio for the risk of a breakthrough episode in the rifaximin group, as compared with the placebo group, was 0.42 (95% confidence interval [CI], 0.28 to 0.64; P<0.001), reflecting a relative reduction in the risk of a breakthrough episode by 58% with rifaximin as compared with placebo during the 6-month study period. These data suggest that four patients would need to be treated with rifaximin for 6 months to prevent one episode of overt hepatic encephalopathy. The degree to which rifaximin reduced the risk of a breakthrough episode was consistent across subgroups (Figure 3).
Hospitalizations
Hospitalization involving hepatic encephalopathy was reported for 19 of 140 patients in the rifaximin group (13.6%) and 36 of 159 patients in the placebo group (22.6%). The hazard ratio for the risk of such hospitalization in the rifaximin group, as compared with the placebo group, was 0.50 (95% CI, 0.29 to 0.87; P=0.01), reflecting a reduction in the risk by 50% with rifaximin as compared with placebo (Figure 2B). Thus, nine patients would need to be treated with rifaximin for 6 months to prevent one hospitalization involving hepatic encephalopathy.
Safety
The incidence of adverse events reported during the study was similar in the rifaximin group (80.0%) and the placebo group (79.9%), as was the incidence of the more common serious adverse events (Table 2). Among the adverse events related to infection, Clostridium difficile infection was reported in two patients in the rifaximin group and none in the placebo group; both affected patients had several concurrent risk factors for C. difficile infection, such as advanced age, numerous recent hospitalizations involving multiple courses of antibiotic therapy, and use of the proton-pump inhibitor pantoprazole. In both patients, rifaximin therapy was continued concomitantly with treatment for the infection, from which they fully recovered.
A total of 20 patients died during the study (9 in the rifaximin group and 11 in the placebo group). Most of the deaths were attributed to conditions associated with disease progression: five patients in each of the two groups had hepatic cirrhosis, decompensated cirrhosis, hepatic failure, alcoholic cirrhosis, or end-stage liver failure, and two patients in each of the two groups had esophageal varices or hemorrhage from esophageal varices. Nearly all the patients who died had had evidence at baseline, apart from hepatic encephalopathy, of decompensated liver cirrhosis (i.e., portal hypertension, ascites or edema, or jaundice), which is associated with a reduced probability of survival.41,42
Methods
Study Patients
Eligibility criteria were an age of at least 18 years, at least two episodes of overt hepatic encephalopathy (Conn score, ≥2)9,12 associated with hepatic cirrhosis during the previous 6 months, remission (Conn score, 0 or 1) at enrollment, and a score of 25 or less on the Model for End-Stage Liver Disease (MELD) scale40 (on which scores can range from 6 to 40, with higher scores indicating more severe disease). Episodes of hepatic encephalopathy that were precipitated by gastrointestinal hemorrhage requiring transfusion of at least 2 units of blood, by medication use, by renal failure requiring dialysis, or by injury to the central nervous system were not counted as previous episodes.
Exclusion criteria included the expectation of liver transplantation within 1 month after the screening visit and the presence of conditions that are known precipitants of hepatic encephalopathy (including gastrointestinal hemorrhage and the placement of a portosystemic shunt or a transjugular intrahepatic portosystemic shunt) within 3 months before the screening visit, chronic renal insufficiency (creatinine level, >2.0 mg per deciliter [177 µmol per liter]) or respiratory insufficiency, anemia (hemoglobin level, <8 g per deciliter), an electrolyte abnormality (serum sodium level, <125 mmol per liter; serum calcium level, >10 mg per deciliter [2.5 mmol per liter]; or potassium level, <2.5 mmol per liter), intercurrent infection, or active spontaneous bacterial peritonitis. All patients or their legally authorized representatives provided written informed consent.
Study Design and Procedures
The protocol was approved by the institutional review board or ethics committee at each center and was conducted in accordance with International Conference on Harmonisation guidelines and other applicable laws and regulations. The study included a screening visit, an observation period between the screening visit and enrollment, and a 6-month treatment phase. On day 0, eligible patients were randomly assigned, in a 1:1 ratio, to receive either 550 mg of rifaximin or placebo, twice daily, for 6 months or until they discontinued the study drug because of a breakthrough episode of hepatic encephalopathy or another reason. Concomitant administration of lactulose was permitted during the study.
The study protocol was designed by representatives of Salix Pharmaceuticals and the academic authors. Data were collected by the principal investigators at each center (see the Appendix) and were monitored by Omnicare Clinical Research, Clinical Trial Management Services (now Chiltern International), and ClinStar Europe under the supervision of Salix representatives, who also analyzed the data. All authors participated in the interpretation of the data and the writing of the manuscript. An editorial consultant was paid by Salix to assist in the revision of subsequent drafts before submission. All authors vouch for the completeness and veracity of the data and data analyses.
Efficacy and Safety Assessments
Clinic visits occurred on days 7 and 14 and every 2 weeks thereafter through day 168 (end of the treatment period), with optional visits on days 42, 70, 98, 126, and 154. Patients were monitored by telephone during the weeks without clinic visits. Assessments included the Conn score and asterixis grade. Conn scores are defined as follows: 0, no personality or behavioral abnormality detected; 1, trivial lack of awareness, euphoria or anxiety, shortened attention span, or impairment of ability to add or subtract; 2, lethargy, disorientation with respect to time, obvious personality change, or inappropriate behavior; 3, somnolence or semistupor, responsiveness to stimuli, confusion, gross disorientation, or bizarre behavior; and 4, coma.9 Asterixis was assessed according to standard practice, by asking patients to extend their arms with wrists flexed backward and fingers open for 30 seconds or more.11,39 Asterixis was then graded as follows: 0, no tremors; 1, few flapping motions; 2, occasional flapping motions; 3, frequent flapping motions; and 4, almost continuous flapping motions.11 Investigators and site personnel who performed assessments were trained in order to ensure consistency across sites.
Statistical Analysis
Efficacy data were analyzed for the intention-to-treat population, which included patients who received at least one dose of the study medication. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy, defined as the time from the first dose of the study drug to an increase from a baseline Conn score of 0 or 1 to a score of 2 or more or from a baseline Conn score of 0 to a Conn score of 1 plus a 1-unit increase in the asterixis grade. The key secondary efficacy end point was the time to the first hospitalization involving hepatic encephalopathy (defined as hospitalization because of the disorder or hospitalization during which an episode of hepatic encephalopathy occurred).
The Cox proportional-hazards model was used, with a 2-sided test and a significance level of 0.05, to compare the time to a breakthrough episode between the rifaximin group and the placebo group (after adjustment for geographic region). Kaplan–Meier methods were used to estimate the proportions of patients having a breakthrough episode at successive time points during the study. Patients who withdrew from the study early for reasons other than the development of hepatic encephalopathy (e.g., another adverse event or the subject's request) were contacted 6 months after randomization to determine whether a breakthrough episode of hepatic encephalopathy had occurred since withdrawal. Data for patients who did not have breakthrough hepatic encephalopathy before day 168 were censored at the time of last contact or on day 168, whichever was earlier. Data for patients who did not have a hospitalization involving hepatic encephalopathy before day 168 were censored at the time of study termination or on day 168, whichever was earlier. The same statistical methods were used to analyze the key secondary end point: time to the first hospitalization involving hepatic encephalopathy.
The primary efficacy end point was evaluated in subgroups of patients according to the following characteristics: geographic region, sex, age, race or ethnic group, baseline MELD score, baseline Conn score, diabetes at baseline, duration of current verified remission, number of episodes of hepatic encephalopathy within the 6-month period before randomization, lactulose use at baseline, and previous placement of a transjugular intrahepatic portosystemic shunt.
Sample-size calculations were based on an assumption of breakthrough episodes of hepatic encephalopathy occurring in 50% and 70% of patients receiving rifaximin and placebo, respectively. These calculations indicated that to show the superiority of rifaximin over placebo with a statistical power of more than 80%, we would need to evaluate 100 patients per group. Safety data were summarized with the use of descriptive statistics. Safety assessments included adverse events, serious adverse events, and adverse events specifically consisting of infection, including respiratory and gastrointestinal infections and their symptoms. Infections are of special interest because of known potential side effects of systemic antibiotics, as a drug class, and known effects of rifaximin.
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