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Insurer denials of DAA therapy for HCV on the rise
About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.
“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.
The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.
Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.
Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).
Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.
While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.
“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.
The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.
SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.
About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.
“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.
The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.
Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.
Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).
Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.
While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.
“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.
The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.
SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.
About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.
“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.
The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.
Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.
Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).
Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.
While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.
“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.
The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.
SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.
FROM OPEN FORUM INFECTIOUS DISEASES
Key clinical point: Insurance denials of direct-acting antiviral (DAA) prescriptions have increased over time, contrary to expectations.
Major finding: A total of 35.5% of patients had an absolute denial of treatment, defined as lack of fill approval by the insurer.
Study details: A cohort study including 9,025 patients who had a DAA prescription submitted to a national specialty pharmacy between January 2016 and April 2017.
Disclosures: The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Two coauthors reported grant support and/or advisory board fees from Gilead.
Source: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7.
Bezafibrate shows promise as second-line option for PBC
Nearly one-third of patients with primary biliary cholangitis treated with bezafibrate showed clinical improvement after 24 months, according to data from a randomized trial of 100 adults.
Ursodeoxycholic acid remains the standard first-line therapy for primary biliary cholangitis (PBC), but many patients have an incomplete response to the treatment, and consequently their long-term survival is limited, wrote Christophe Corpechot, MD, of Sorbonne University, Paris, and his colleagues. PBC is also known as primary biliary cirrhosis.
In the BEZURSO trial (Bezafibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis), published in the New England Journal of Medicine, the researchers randomized 100 primary PBC patients with an inadequate response to ursodeoxycholic acid to receive 400 mg per day of bezafibrate or a placebo for 24 months. Inadequate response was defined as “a serum level of alkaline phosphatase or aspartate aminotransferase more than 1.5 times the upper limit of the normal range or an abnormal total bilirubin level, assessed after at least 6 months of treatment with ursodeoxycholic acid,” the researchers said.
Baseline demographics were not significantly different between the groups. The average age of the patients was 53 years, and 95% were white women.
After 24 months, 31% of the patients in the treatment group met the primary outcome, which was the achievement of normal levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin, plus a normal prothrombin index. By contrast, none of the patients in the placebo group achieved the primary outcome.
In particular, bezafibrate patients showed a 60% reduction in alkaline phosphatase levels from baseline to 3 months, and a 14% decrease in total bilirubin from baseline during the course of the study.
Clinical outcomes were similar between the groups; 20% of the bezafibrate group and 18% of the placebo group developed portal hypertension, and two patients in each group developed liver complications. No deaths occurred in either group during the study. Approximately half of the patients in each group reported adverse events. Serious adverse events occurred in 14 bezafibrate patients and 12 placebo patients.
The findings were limited by the small study population, which prevented assessment of bezafibrate on liver transplantation and death, and by the limited histologic data to look at the impact on liver fibrosis and hepatic inflammation, the researchers said.
However, the results support the use of bezafibrate as an add-on to ursodeoxycholic acid in PBC patients, and merit larger, longer studies, they noted.
The study was supported by the Programme Hospitalier de Recherche Clinique 2010, Ministry of Health, and Arrow Génériques. Dr. Corpechot disclosed relationships with companies including Intercept France, Inventiva Pharma, and GlaxoSmithKline.
SOURCE: Corpechot C et al. N Engl J Med. 2018 June 6. doi: 10.1056/NEJMoa1714519.
The BEZURSO study findings “merit cautious excitement,” Elizabeth J. Carey, MD, wrote in an editorial.
“This pivotal trial effectively doubles the limited options for second-line therapy of primary biliary cholangitis,” she said.
Approximately 40% of primary biliary cholangitis patients fail to respond adequately to ursodeoxycholic acid, the first-line therapy, and they remain at risk for progression of liver disease and liver failure, wrote Dr. Carey. Bezafibrate is the first drug to generate improvement in these patients not only in measures of biochemical markers, but also measures of fibrosis and disease symptoms, she said. Patient reports of reduced itching and lower levels of fatigue are worth noting, although they were not the primary outcomes, said Dr. Carey.
“Improvement in patient-reported outcomes prompts the question of whether there is a role for the use of bezafibrate for the management of fatigue or pruritus, even in patients who have a biochemical response to ursodeoxycholic acid,” she noted (N Engl J Med. 2018 June 6. doi: 10.1056/NEJMe1804945).
Despite the promising results, challenges remain for primary biliary cholangitis patients, as approximately 70% did not meet the primary outcome, and those with more severe disease were less likely to respond, Dr. Carey said. However, she added, any agent “that both delays disease progression and alleviates symptoms is a potential boon for patients with the debilitating symptoms of primary biliary cholangitis.”
Dr. Carey is affiliated with the Mayo Clinic in Phoenix, Ariz. Disclosure forms provided by the author are available at NEJM.org.
The BEZURSO study findings “merit cautious excitement,” Elizabeth J. Carey, MD, wrote in an editorial.
“This pivotal trial effectively doubles the limited options for second-line therapy of primary biliary cholangitis,” she said.
Approximately 40% of primary biliary cholangitis patients fail to respond adequately to ursodeoxycholic acid, the first-line therapy, and they remain at risk for progression of liver disease and liver failure, wrote Dr. Carey. Bezafibrate is the first drug to generate improvement in these patients not only in measures of biochemical markers, but also measures of fibrosis and disease symptoms, she said. Patient reports of reduced itching and lower levels of fatigue are worth noting, although they were not the primary outcomes, said Dr. Carey.
“Improvement in patient-reported outcomes prompts the question of whether there is a role for the use of bezafibrate for the management of fatigue or pruritus, even in patients who have a biochemical response to ursodeoxycholic acid,” she noted (N Engl J Med. 2018 June 6. doi: 10.1056/NEJMe1804945).
Despite the promising results, challenges remain for primary biliary cholangitis patients, as approximately 70% did not meet the primary outcome, and those with more severe disease were less likely to respond, Dr. Carey said. However, she added, any agent “that both delays disease progression and alleviates symptoms is a potential boon for patients with the debilitating symptoms of primary biliary cholangitis.”
Dr. Carey is affiliated with the Mayo Clinic in Phoenix, Ariz. Disclosure forms provided by the author are available at NEJM.org.
The BEZURSO study findings “merit cautious excitement,” Elizabeth J. Carey, MD, wrote in an editorial.
“This pivotal trial effectively doubles the limited options for second-line therapy of primary biliary cholangitis,” she said.
Approximately 40% of primary biliary cholangitis patients fail to respond adequately to ursodeoxycholic acid, the first-line therapy, and they remain at risk for progression of liver disease and liver failure, wrote Dr. Carey. Bezafibrate is the first drug to generate improvement in these patients not only in measures of biochemical markers, but also measures of fibrosis and disease symptoms, she said. Patient reports of reduced itching and lower levels of fatigue are worth noting, although they were not the primary outcomes, said Dr. Carey.
“Improvement in patient-reported outcomes prompts the question of whether there is a role for the use of bezafibrate for the management of fatigue or pruritus, even in patients who have a biochemical response to ursodeoxycholic acid,” she noted (N Engl J Med. 2018 June 6. doi: 10.1056/NEJMe1804945).
Despite the promising results, challenges remain for primary biliary cholangitis patients, as approximately 70% did not meet the primary outcome, and those with more severe disease were less likely to respond, Dr. Carey said. However, she added, any agent “that both delays disease progression and alleviates symptoms is a potential boon for patients with the debilitating symptoms of primary biliary cholangitis.”
Dr. Carey is affiliated with the Mayo Clinic in Phoenix, Ariz. Disclosure forms provided by the author are available at NEJM.org.
Nearly one-third of patients with primary biliary cholangitis treated with bezafibrate showed clinical improvement after 24 months, according to data from a randomized trial of 100 adults.
Ursodeoxycholic acid remains the standard first-line therapy for primary biliary cholangitis (PBC), but many patients have an incomplete response to the treatment, and consequently their long-term survival is limited, wrote Christophe Corpechot, MD, of Sorbonne University, Paris, and his colleagues. PBC is also known as primary biliary cirrhosis.
In the BEZURSO trial (Bezafibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis), published in the New England Journal of Medicine, the researchers randomized 100 primary PBC patients with an inadequate response to ursodeoxycholic acid to receive 400 mg per day of bezafibrate or a placebo for 24 months. Inadequate response was defined as “a serum level of alkaline phosphatase or aspartate aminotransferase more than 1.5 times the upper limit of the normal range or an abnormal total bilirubin level, assessed after at least 6 months of treatment with ursodeoxycholic acid,” the researchers said.
Baseline demographics were not significantly different between the groups. The average age of the patients was 53 years, and 95% were white women.
After 24 months, 31% of the patients in the treatment group met the primary outcome, which was the achievement of normal levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin, plus a normal prothrombin index. By contrast, none of the patients in the placebo group achieved the primary outcome.
In particular, bezafibrate patients showed a 60% reduction in alkaline phosphatase levels from baseline to 3 months, and a 14% decrease in total bilirubin from baseline during the course of the study.
Clinical outcomes were similar between the groups; 20% of the bezafibrate group and 18% of the placebo group developed portal hypertension, and two patients in each group developed liver complications. No deaths occurred in either group during the study. Approximately half of the patients in each group reported adverse events. Serious adverse events occurred in 14 bezafibrate patients and 12 placebo patients.
The findings were limited by the small study population, which prevented assessment of bezafibrate on liver transplantation and death, and by the limited histologic data to look at the impact on liver fibrosis and hepatic inflammation, the researchers said.
However, the results support the use of bezafibrate as an add-on to ursodeoxycholic acid in PBC patients, and merit larger, longer studies, they noted.
The study was supported by the Programme Hospitalier de Recherche Clinique 2010, Ministry of Health, and Arrow Génériques. Dr. Corpechot disclosed relationships with companies including Intercept France, Inventiva Pharma, and GlaxoSmithKline.
SOURCE: Corpechot C et al. N Engl J Med. 2018 June 6. doi: 10.1056/NEJMoa1714519.
Nearly one-third of patients with primary biliary cholangitis treated with bezafibrate showed clinical improvement after 24 months, according to data from a randomized trial of 100 adults.
Ursodeoxycholic acid remains the standard first-line therapy for primary biliary cholangitis (PBC), but many patients have an incomplete response to the treatment, and consequently their long-term survival is limited, wrote Christophe Corpechot, MD, of Sorbonne University, Paris, and his colleagues. PBC is also known as primary biliary cirrhosis.
In the BEZURSO trial (Bezafibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis), published in the New England Journal of Medicine, the researchers randomized 100 primary PBC patients with an inadequate response to ursodeoxycholic acid to receive 400 mg per day of bezafibrate or a placebo for 24 months. Inadequate response was defined as “a serum level of alkaline phosphatase or aspartate aminotransferase more than 1.5 times the upper limit of the normal range or an abnormal total bilirubin level, assessed after at least 6 months of treatment with ursodeoxycholic acid,” the researchers said.
Baseline demographics were not significantly different between the groups. The average age of the patients was 53 years, and 95% were white women.
After 24 months, 31% of the patients in the treatment group met the primary outcome, which was the achievement of normal levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin, plus a normal prothrombin index. By contrast, none of the patients in the placebo group achieved the primary outcome.
In particular, bezafibrate patients showed a 60% reduction in alkaline phosphatase levels from baseline to 3 months, and a 14% decrease in total bilirubin from baseline during the course of the study.
Clinical outcomes were similar between the groups; 20% of the bezafibrate group and 18% of the placebo group developed portal hypertension, and two patients in each group developed liver complications. No deaths occurred in either group during the study. Approximately half of the patients in each group reported adverse events. Serious adverse events occurred in 14 bezafibrate patients and 12 placebo patients.
The findings were limited by the small study population, which prevented assessment of bezafibrate on liver transplantation and death, and by the limited histologic data to look at the impact on liver fibrosis and hepatic inflammation, the researchers said.
However, the results support the use of bezafibrate as an add-on to ursodeoxycholic acid in PBC patients, and merit larger, longer studies, they noted.
The study was supported by the Programme Hospitalier de Recherche Clinique 2010, Ministry of Health, and Arrow Génériques. Dr. Corpechot disclosed relationships with companies including Intercept France, Inventiva Pharma, and GlaxoSmithKline.
SOURCE: Corpechot C et al. N Engl J Med. 2018 June 6. doi: 10.1056/NEJMoa1714519.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Primary biliary cholangitis patients who took bezafibrate showed decreases in alkaline phosphatase levels and total bilirubin.
Major finding: A total of 31% of patients who took bezafibrate achieved normal levels of disease biomarkers after 24 months compared with 0% of placebo patients.
Study details: The data come from a double-blind, placebo-controlled trial of 100 adults with primary biliary cholangitis at 21 medical centers in France.
Disclosures: Programme Hospitalier de Recherche Clinique 2010 (Ministry of Health) and Arrow Génériques supported the study. Dr. Corpechot disclosed relationships with companies including Intercept France, Inventiva Pharma, and GlaxoSmithKline.
Source: Corpechot C et al. N Engl J Med. 2018 June 6. doi: 10.1056/NEJMoa1714519.
Liver enzyme a marker of disease progression in primary biliary cholangitis
The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.
Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.
Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.
While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.
Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.
Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.
They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.
Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).
Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).
The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”
For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).
Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).
According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.
A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).
Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).
Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”
However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.
Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.
SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.
The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.
Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.
Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.
While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.
Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.
Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.
They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.
Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).
Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).
The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”
For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).
Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).
According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.
A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).
Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).
Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”
However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.
Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.
SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.
The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.
Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.
Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.
While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.
Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.
Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.
They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.
Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).
Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).
The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”
For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).
Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).
According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.
A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).
Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).
Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”
However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.
Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.
SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.
REPORTING FROM SCIENTIFIC REPORTS
Key clinical point: The liver enzyme autotaxin (ATX) may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC).
Major finding: The ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L; P less than .0001).
Study details: A case-controlled study of 128 patients with PBC and 80 healthy controls, plus a longitudinal study of 29 patients.
Disclosures: Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.
Source: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0
VIDEO: Hepatitis C eradication cuts nonliver cancer rate
WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.
The data also showed compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.®
The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.
“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.
The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.
The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.
The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.
“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.
WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.
The data also showed compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.®
The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.
“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.
The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.
The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.
The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.
“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.
WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.
The data also showed compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.®
The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.
“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.
The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.
The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.
The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.
“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.
REPORTING FROM DDW 2018
Key clinical point: Eradicating hepatitis C with direct-acting antivirals significantly cut the incidence of many nonliver cancers.
Major finding: Direct-acting antiviral treatment linked with a 14% drop in nonhepatic cancers, compared with patients not getting this treatment.
Study details: Analysis of 33,883 Americans treated for hepatitis C during 2007-2017 in an insurance claims database.
Disclosures: The study was funded by Gilead, a company that markets direct-acting antiviral drugs for hepatitis C virus. Dr. Charlton has been a consultant to and has received research funding from Gilead and several other companies that market drugs from this class.
Multiple therapies for NAFLD and NASH are now in phase 3 clinical trials
WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
REPORTING FROM DDW 2018
NAFLD patients with abnormal liver tests may not get statins when indicated
WASHINGTON – Though the liver safety of statins in patients with low-level liver enzyme elevations has long been established, some providers still hesitate to prescribe them to the patients with the conditions for which they are indicated.
Nonalcoholic fatty liver disease (NAFLD), hyperlipidemia, metabolic syndrome, and diabetes, which often co-occur, are also involved in cardiovascular disease. Cardiovascular disease is the most common cause of mortality in NAFLD, before liver disease.
Sonal Kumar, MD, MPH, of New York–Presbyterian Hospital described in a video interview at the annual Digestive Disease Week® a study she and her colleagues conducted to evaluate statin use in patients with hyperlipidemia by using data from the National Health and Nutrition Examination Survey during 2005-2014 (NHANES). Adult patients aged over 18 years were included if they did not have viral hepatitis, did not excessively consume alcohol, were not pregnant, and did not have transaminase levels over 500 IU/L.
Statin use was assessed in 136,833,627 participants by NHANES interviewers. Of these participants, 74.6% had hyperlipidemia (defined as LDL cholesterol greater than 130 mg/dL) and 93.5% were taking a statin. Patients with hyperlipidemia with abnormal alanine aminotransferase values were significantly less likely to be taking a statin (86.3% vs. 89.1%, P = .001). With multivariate analysis, abnormal ALT significantly decreased the odds of patients receiving a statin if they had diabetes (odds ratio, 0.75; 95% confidence interval, 0.57-0.99) when sex and age were controlled for.
Statins are underutilized in patients with NAFLD and diabetes, patient groups in whom they could help control cardiovascular disease risk factors, said Dr. Kumar. Providers need to be educated on the safety of statins in these patients to improve cardiovascular outcomes.
Dr. Kumar reported receiving support from Gilead and AbbVie.
WASHINGTON – Though the liver safety of statins in patients with low-level liver enzyme elevations has long been established, some providers still hesitate to prescribe them to the patients with the conditions for which they are indicated.
Nonalcoholic fatty liver disease (NAFLD), hyperlipidemia, metabolic syndrome, and diabetes, which often co-occur, are also involved in cardiovascular disease. Cardiovascular disease is the most common cause of mortality in NAFLD, before liver disease.
Sonal Kumar, MD, MPH, of New York–Presbyterian Hospital described in a video interview at the annual Digestive Disease Week® a study she and her colleagues conducted to evaluate statin use in patients with hyperlipidemia by using data from the National Health and Nutrition Examination Survey during 2005-2014 (NHANES). Adult patients aged over 18 years were included if they did not have viral hepatitis, did not excessively consume alcohol, were not pregnant, and did not have transaminase levels over 500 IU/L.
Statin use was assessed in 136,833,627 participants by NHANES interviewers. Of these participants, 74.6% had hyperlipidemia (defined as LDL cholesterol greater than 130 mg/dL) and 93.5% were taking a statin. Patients with hyperlipidemia with abnormal alanine aminotransferase values were significantly less likely to be taking a statin (86.3% vs. 89.1%, P = .001). With multivariate analysis, abnormal ALT significantly decreased the odds of patients receiving a statin if they had diabetes (odds ratio, 0.75; 95% confidence interval, 0.57-0.99) when sex and age were controlled for.
Statins are underutilized in patients with NAFLD and diabetes, patient groups in whom they could help control cardiovascular disease risk factors, said Dr. Kumar. Providers need to be educated on the safety of statins in these patients to improve cardiovascular outcomes.
Dr. Kumar reported receiving support from Gilead and AbbVie.
WASHINGTON – Though the liver safety of statins in patients with low-level liver enzyme elevations has long been established, some providers still hesitate to prescribe them to the patients with the conditions for which they are indicated.
Nonalcoholic fatty liver disease (NAFLD), hyperlipidemia, metabolic syndrome, and diabetes, which often co-occur, are also involved in cardiovascular disease. Cardiovascular disease is the most common cause of mortality in NAFLD, before liver disease.
Sonal Kumar, MD, MPH, of New York–Presbyterian Hospital described in a video interview at the annual Digestive Disease Week® a study she and her colleagues conducted to evaluate statin use in patients with hyperlipidemia by using data from the National Health and Nutrition Examination Survey during 2005-2014 (NHANES). Adult patients aged over 18 years were included if they did not have viral hepatitis, did not excessively consume alcohol, were not pregnant, and did not have transaminase levels over 500 IU/L.
Statin use was assessed in 136,833,627 participants by NHANES interviewers. Of these participants, 74.6% had hyperlipidemia (defined as LDL cholesterol greater than 130 mg/dL) and 93.5% were taking a statin. Patients with hyperlipidemia with abnormal alanine aminotransferase values were significantly less likely to be taking a statin (86.3% vs. 89.1%, P = .001). With multivariate analysis, abnormal ALT significantly decreased the odds of patients receiving a statin if they had diabetes (odds ratio, 0.75; 95% confidence interval, 0.57-0.99) when sex and age were controlled for.
Statins are underutilized in patients with NAFLD and diabetes, patient groups in whom they could help control cardiovascular disease risk factors, said Dr. Kumar. Providers need to be educated on the safety of statins in these patients to improve cardiovascular outcomes.
Dr. Kumar reported receiving support from Gilead and AbbVie.
REPORTING FROM DDW 2018
Key clinical point: Patients diagnosed with hyperlipidemia who had abnormal ALT levels were less likely to take a statin (86.3% vs. 89.1%, P = .001).
Major finding: Abnormal ALT significantly decreased the odds of patients receiving a statin if they had diabetes (odds ratio, 0.75; 95% confidence interval, 0.57-0.99) when sex and age were controlled for.
Data source: Data from 136,833,627 adult patients from the National Health and Nutrition Examination Survey collected during 2005-2014.
Disclosures: Dr. Kumar reported receiving support from Gilead and AbbVie.
Percutaneous procedure gives alternative to anticoagulation for portal vein thrombosis
WASHINGTON – Catheter-directed clot lysis and thrombectomy with creation of a bypass shunt is a reasonable alternative to prolonged anticoagulation for treating patients with portal vein thrombosis (PVT) based on the accumulated reported experience since 1993 using this percutaneous treatment.
” Nelson Valentin, MD, said at the annual Digestive Disease Week.® “TIPS should be considered a viable treatment option for patients with PVT,” said Dr. Valentin, a gastroenterology fellow at Mount Sinai Beth Israel hospital in New York.
“There is sufficient evidence from these reports to at least consider TIPS as an adjunct to anticoagulation or perhaps as primary therapy,” especially for patients with PVT who have a contraindication for anticoagulation, Dr. Valentin said in an interview. Standard anticoagulation for PVT would today involve acute treatment with a low-molecular-weight heparin followed by oral anticoagulation for a total treatment time of at least 6 months and continued for a year or longer in some patients. A recently published review of reported experience using anticoagulation to treat PVT found a complete recanalization rate of 41% and a complete or partial rate of 66%, which suggests that TIPS is at least as effective, although Dr. Valentin cautioned that no reported study has directly compared the two alternative approaches. A study designed to make this direct comparison is warranted by the reported results using TIPS, Dr. Valentin said. And the experience with TIPS positions it as an option for patients who do not respond to anticoagulation or would prefer an alternative to prolonged anticoagulation.
One factor currently limiting use of TIPS, which is usually performed by an interventional radiologist, is that the procedure is technically demanding, with a limited number of operators with the expertise to perform it. If TIPS became more widely accepted as an option for treating PVT, then the pool of interventionalists experienced with performing the procedure would grow, Dr. Valentin noted.
mzoler@mdedge.com
On Twitter @mitchelzoler
SOURCE: Valentin N et al. Digestive Disease Week, Presentation 361.
WASHINGTON – Catheter-directed clot lysis and thrombectomy with creation of a bypass shunt is a reasonable alternative to prolonged anticoagulation for treating patients with portal vein thrombosis (PVT) based on the accumulated reported experience since 1993 using this percutaneous treatment.
” Nelson Valentin, MD, said at the annual Digestive Disease Week.® “TIPS should be considered a viable treatment option for patients with PVT,” said Dr. Valentin, a gastroenterology fellow at Mount Sinai Beth Israel hospital in New York.
“There is sufficient evidence from these reports to at least consider TIPS as an adjunct to anticoagulation or perhaps as primary therapy,” especially for patients with PVT who have a contraindication for anticoagulation, Dr. Valentin said in an interview. Standard anticoagulation for PVT would today involve acute treatment with a low-molecular-weight heparin followed by oral anticoagulation for a total treatment time of at least 6 months and continued for a year or longer in some patients. A recently published review of reported experience using anticoagulation to treat PVT found a complete recanalization rate of 41% and a complete or partial rate of 66%, which suggests that TIPS is at least as effective, although Dr. Valentin cautioned that no reported study has directly compared the two alternative approaches. A study designed to make this direct comparison is warranted by the reported results using TIPS, Dr. Valentin said. And the experience with TIPS positions it as an option for patients who do not respond to anticoagulation or would prefer an alternative to prolonged anticoagulation.
One factor currently limiting use of TIPS, which is usually performed by an interventional radiologist, is that the procedure is technically demanding, with a limited number of operators with the expertise to perform it. If TIPS became more widely accepted as an option for treating PVT, then the pool of interventionalists experienced with performing the procedure would grow, Dr. Valentin noted.
mzoler@mdedge.com
On Twitter @mitchelzoler
SOURCE: Valentin N et al. Digestive Disease Week, Presentation 361.
WASHINGTON – Catheter-directed clot lysis and thrombectomy with creation of a bypass shunt is a reasonable alternative to prolonged anticoagulation for treating patients with portal vein thrombosis (PVT) based on the accumulated reported experience since 1993 using this percutaneous treatment.
” Nelson Valentin, MD, said at the annual Digestive Disease Week.® “TIPS should be considered a viable treatment option for patients with PVT,” said Dr. Valentin, a gastroenterology fellow at Mount Sinai Beth Israel hospital in New York.
“There is sufficient evidence from these reports to at least consider TIPS as an adjunct to anticoagulation or perhaps as primary therapy,” especially for patients with PVT who have a contraindication for anticoagulation, Dr. Valentin said in an interview. Standard anticoagulation for PVT would today involve acute treatment with a low-molecular-weight heparin followed by oral anticoagulation for a total treatment time of at least 6 months and continued for a year or longer in some patients. A recently published review of reported experience using anticoagulation to treat PVT found a complete recanalization rate of 41% and a complete or partial rate of 66%, which suggests that TIPS is at least as effective, although Dr. Valentin cautioned that no reported study has directly compared the two alternative approaches. A study designed to make this direct comparison is warranted by the reported results using TIPS, Dr. Valentin said. And the experience with TIPS positions it as an option for patients who do not respond to anticoagulation or would prefer an alternative to prolonged anticoagulation.
One factor currently limiting use of TIPS, which is usually performed by an interventional radiologist, is that the procedure is technically demanding, with a limited number of operators with the expertise to perform it. If TIPS became more widely accepted as an option for treating PVT, then the pool of interventionalists experienced with performing the procedure would grow, Dr. Valentin noted.
mzoler@mdedge.com
On Twitter @mitchelzoler
SOURCE: Valentin N et al. Digestive Disease Week, Presentation 361.
REPORTING FROM DDW 2018
Key clinical point: Reported worldwide experience with TIPS in 439 patients shows it works and is relatively safe.
Major finding: TIPS was technically successful in 87% of reported patients and achieved complete portal recanalization in 74% of patients.
Study details: Systematic review of 18 published case series from 1993 to 2016 with 439 total patients.
Disclosures: Dr. Valentin had no disclosures.
Source: Valentin N et al. Digestive Disease Week, Presentation 361.
Mediterranean diet cut fatty liver risk
Middle-aged and older adults who closely followed a Mediterranean-style diet for 6 years were at significantly lower risk of developing fatty liver disease than others in a large prospective study.
Each 1-standard-deviation rise in Mediterranean-style Diet Score (MDS) correlated with significantly decreased hepatic fat accumulation and a 26% lower odds of new onset fatty liver disease (P = .002). “To our knowledge, ours is the first prospective study to examine the relations of long-term habitual diet to fatty liver,” Jiantao Ma, MBBS, PhD, and his associates wrote in Gastroenterology. “Our findings indicate that improved diet quality may be particularly important for those with high genetic risk for NAFLD.”
Over a median 6 years of follow-up, each 1-standard deviation rise in MDS correlated with a 26% decrease in odds of new-onset fatty liver (95% CI, 10% to 39%; P = .002) and with a significant increase in liver phantom ratio (0.57; 95% confidence interval, 0.27 to 0.86; P less than .001), which signifies lower accumulation of liver fat. Similarly, every 1-standard deviation rise in the AHEI dietary score correlated with a 0.56 rise in liver phantom ratio (95% CI, 0.29 to 0.84; P less than .001) and with a 21% lower odds of incident fatty liver disease (95% CI, 5% to 35%; P = .02).
Individuals whose diets improved the most (those in the highest quartile of dietary score change) over time had about 80% less liver fat accumulate between baseline and follow-up compared with those whose diets worsened the most (those in the lowest quartile of dietary score change). Furthermore, relationship between diet and liver fat remained statistically significant (P = .02) even after accounting for changes in body mass index.
The investigators also studied whether the presence of single nucleotide polymorphisms (SNPs) linked with NAFLD modified dietary effects. High genetic risk for NAFLD did not appear to lead to increased liver fat as long as diet improved or remained stable over time, they found. But when diet worsened over time, high genetic NAFLD risk did correlate with significantly greater accumulation of liver fat (P less than .001).
“Future intervention studies are needed to test the efficacy and efficiency of diet-based approaches for NAFLD prevention as well as to examine mechanisms underlying the association between diet and NAFLD,” the researchers wrote.
The National Heart, Lung and Blood Institute’s Framingham Heart Study provided funding. Affymetrix provided genotyping. The researchers reported having no financial conflicts of interest.
SOURCE: Ma J, et al. Gastroenterology. 2018 Mar 28. doi: 10.1053/j.gastro.2018.03.038
Middle-aged and older adults who closely followed a Mediterranean-style diet for 6 years were at significantly lower risk of developing fatty liver disease than others in a large prospective study.
Each 1-standard-deviation rise in Mediterranean-style Diet Score (MDS) correlated with significantly decreased hepatic fat accumulation and a 26% lower odds of new onset fatty liver disease (P = .002). “To our knowledge, ours is the first prospective study to examine the relations of long-term habitual diet to fatty liver,” Jiantao Ma, MBBS, PhD, and his associates wrote in Gastroenterology. “Our findings indicate that improved diet quality may be particularly important for those with high genetic risk for NAFLD.”
Over a median 6 years of follow-up, each 1-standard deviation rise in MDS correlated with a 26% decrease in odds of new-onset fatty liver (95% CI, 10% to 39%; P = .002) and with a significant increase in liver phantom ratio (0.57; 95% confidence interval, 0.27 to 0.86; P less than .001), which signifies lower accumulation of liver fat. Similarly, every 1-standard deviation rise in the AHEI dietary score correlated with a 0.56 rise in liver phantom ratio (95% CI, 0.29 to 0.84; P less than .001) and with a 21% lower odds of incident fatty liver disease (95% CI, 5% to 35%; P = .02).
Individuals whose diets improved the most (those in the highest quartile of dietary score change) over time had about 80% less liver fat accumulate between baseline and follow-up compared with those whose diets worsened the most (those in the lowest quartile of dietary score change). Furthermore, relationship between diet and liver fat remained statistically significant (P = .02) even after accounting for changes in body mass index.
The investigators also studied whether the presence of single nucleotide polymorphisms (SNPs) linked with NAFLD modified dietary effects. High genetic risk for NAFLD did not appear to lead to increased liver fat as long as diet improved or remained stable over time, they found. But when diet worsened over time, high genetic NAFLD risk did correlate with significantly greater accumulation of liver fat (P less than .001).
“Future intervention studies are needed to test the efficacy and efficiency of diet-based approaches for NAFLD prevention as well as to examine mechanisms underlying the association between diet and NAFLD,” the researchers wrote.
The National Heart, Lung and Blood Institute’s Framingham Heart Study provided funding. Affymetrix provided genotyping. The researchers reported having no financial conflicts of interest.
SOURCE: Ma J, et al. Gastroenterology. 2018 Mar 28. doi: 10.1053/j.gastro.2018.03.038
Middle-aged and older adults who closely followed a Mediterranean-style diet for 6 years were at significantly lower risk of developing fatty liver disease than others in a large prospective study.
Each 1-standard-deviation rise in Mediterranean-style Diet Score (MDS) correlated with significantly decreased hepatic fat accumulation and a 26% lower odds of new onset fatty liver disease (P = .002). “To our knowledge, ours is the first prospective study to examine the relations of long-term habitual diet to fatty liver,” Jiantao Ma, MBBS, PhD, and his associates wrote in Gastroenterology. “Our findings indicate that improved diet quality may be particularly important for those with high genetic risk for NAFLD.”
Over a median 6 years of follow-up, each 1-standard deviation rise in MDS correlated with a 26% decrease in odds of new-onset fatty liver (95% CI, 10% to 39%; P = .002) and with a significant increase in liver phantom ratio (0.57; 95% confidence interval, 0.27 to 0.86; P less than .001), which signifies lower accumulation of liver fat. Similarly, every 1-standard deviation rise in the AHEI dietary score correlated with a 0.56 rise in liver phantom ratio (95% CI, 0.29 to 0.84; P less than .001) and with a 21% lower odds of incident fatty liver disease (95% CI, 5% to 35%; P = .02).
Individuals whose diets improved the most (those in the highest quartile of dietary score change) over time had about 80% less liver fat accumulate between baseline and follow-up compared with those whose diets worsened the most (those in the lowest quartile of dietary score change). Furthermore, relationship between diet and liver fat remained statistically significant (P = .02) even after accounting for changes in body mass index.
The investigators also studied whether the presence of single nucleotide polymorphisms (SNPs) linked with NAFLD modified dietary effects. High genetic risk for NAFLD did not appear to lead to increased liver fat as long as diet improved or remained stable over time, they found. But when diet worsened over time, high genetic NAFLD risk did correlate with significantly greater accumulation of liver fat (P less than .001).
“Future intervention studies are needed to test the efficacy and efficiency of diet-based approaches for NAFLD prevention as well as to examine mechanisms underlying the association between diet and NAFLD,” the researchers wrote.
The National Heart, Lung and Blood Institute’s Framingham Heart Study provided funding. Affymetrix provided genotyping. The researchers reported having no financial conflicts of interest.
SOURCE: Ma J, et al. Gastroenterology. 2018 Mar 28. doi: 10.1053/j.gastro.2018.03.038
FROM GASTROENTEROLOGY
Key clinical point: A Mediterranean-style diet was associated with significantly less liver fat accumulation and significantly lower risk of fatty liver disease.
Major finding: Each 1-standard-deviation increase in the Mediterranean Diet Score (MDS) correlated with a 26% lower odds of de novo NAFLD (P = .002).
Study details: Prospective study of 1,521 adults from the Framingham Heart Study.
Disclosures: The National Heart, Lung and Blood Institute’s Framingham Heart Study provided funding. Affymetrix provided genotyping. The researchers reported having no conflicts of interest.
Source: Ma J, et al. Gastroenterology. 2018 Mar 28.
Scoring system quantified chances of HCV treatment benefit
A new scoring system predicted which patients with decompensated cirrhosis caused by hepatitis C virus (HCV) infection were most likely to experience meaningful benefits from direct-acting antiviral (DAA) therapy.
Dubbed BEA3, their scoring system assigns one point each for body mass index under 25 kg/m2, absence of encephalopathy, absence of ascites, ALT more than 1.5 times the upper limit of normal, and albumin above 3.5 g/dL. Patients who scored 4 or 5 were more than 50 times more likely to improve to Child-Pugh Turcotte (CPT) class A (compensated) cirrhosis with DAA therapy than were patients who scored 0 (hazard ratio, 52.3; 95% confidence interval, 15.2-179.7; P less than .001), wrote Omar El-Sherif, MB, BCh, of St. James’s Hospital, Dublin, together with his associates in the June issue of Gastroenterology.
Eradicating HCV does not necessarily improve the odds of transplant-free survival in the setting of decompensated cirrhosis, the researchers noted. Patients can end up in “MELD [Model for End-Stage Liver Disease] purgatory,” meaning they are still decompensated despite achieving sustained virologic response and improved MELD scores. Such patients can face longer waits for liver transplantation than if they had foregone DAA therapy. “There is an urgent need for data to refine our understanding of the reversibility of hepatic decompensation with viral eradication, and, ultimately, define the “point of no return,” the degree of liver dysfunction at which HCV therapy does not yield any meaningful clinical benefit, the researchers wrote.
Their study included 622 patients from the SOLAR-1, SOLAR-2, ASTRAL-4, and GS-US-334-0125 trials, which evaluated interferon-free sofosbuvir-based DAA therapy in patients with chronic hepatitis C virus infection and advanced liver disease. Patients received 12 or 24 weeks of therapy with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin.
A total of 32% of patients with CPT class B cirrhosis improved to class A, as did 12% of patients with class C cirrhosis. Each factor in the scoring system independently affected the chances of reaching CPT class A cirrhosis, even after accounting for SVR.
Notably, patients with intermediate BEA3 scores of 1, 2, or 3 were significantly more likely to reach CPT class A cirrhosis than were patients with scores of 0, with hazard ratios ranging from 4.2 (for a score of 1) to 21.2 (for a score of 3). Most patients had scores of 0 (106 individuals), 1 (219 individuals), or 2 (180 individuals), and only 23 patients scored a 4 or a 5.
CPT score reflects prothrombin time, serum albumin and bilirubin, and the presence or severity of ascites. The investigators called the new scoring system “a tool that can enhance shared decision making at the point of care, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis in the pretransplant setting.”Dr. El-Sherif disclosed ties to Gilead Sciences, Bristol-Myers Squibb, and the Health Research Board of Ireland. Four coinvestigators disclosed employment with Gilead, and several other coinvestigators disclosed ties to Gilead, BMS, AbbVie, and other companies.
SOURCE: El-Sherif O et al. Gastroenterology. 2018 Mar 10. doi: 10.1053/j.gastro.2018.03.022.
Patients with decompensated cirrhosis are now able to receive antiviral therapy without risk of worsening symptoms of decompensation. More clinics are able to offer DAA therapy to patients with hepatitis C, without the need for expertise in managing the side effects of interferon-based therapy.
The study by El-Sherif et al. summarizes well the benefits and potential pitfalls of treatment of hepatitis C in patients with decompensated cirrhosis. Their scoring system is largely intuitive and mirrors the traditional Child-Turcotte-Pugh score in that patients with low serum albumin, hepatic encephalopathy, and ascites are at risk of failing to improve clinically. Patients can have their hepatitis C successfully treated but can be trapped in “MELD purgatory,” a state of significant symptoms of liver disease, without the objective priority points necessary to be candidates for liver transplantation.
As experience is gained in the use of DAA medications for HCV, it is incumbent on physicians to gather knowledge that will further refine their understanding of which patients with signs of liver decompensation might benefit. It is also clear that patients with decompensated cirrhosis should be managed by clinicians who have experience in liver transplantation, to ensure that patients are counseled regarding not just the benefits, but potential risks of DAA therapy for hepatitis C.
Roman E. Perri, MD, is assistant professor of medicine, division of gastroenterology and hepatology, Medical Director for Liver Transplantion, Vanderbilt University, Nashville, Tenn. He has no conflicts of interest.
Patients with decompensated cirrhosis are now able to receive antiviral therapy without risk of worsening symptoms of decompensation. More clinics are able to offer DAA therapy to patients with hepatitis C, without the need for expertise in managing the side effects of interferon-based therapy.
The study by El-Sherif et al. summarizes well the benefits and potential pitfalls of treatment of hepatitis C in patients with decompensated cirrhosis. Their scoring system is largely intuitive and mirrors the traditional Child-Turcotte-Pugh score in that patients with low serum albumin, hepatic encephalopathy, and ascites are at risk of failing to improve clinically. Patients can have their hepatitis C successfully treated but can be trapped in “MELD purgatory,” a state of significant symptoms of liver disease, without the objective priority points necessary to be candidates for liver transplantation.
As experience is gained in the use of DAA medications for HCV, it is incumbent on physicians to gather knowledge that will further refine their understanding of which patients with signs of liver decompensation might benefit. It is also clear that patients with decompensated cirrhosis should be managed by clinicians who have experience in liver transplantation, to ensure that patients are counseled regarding not just the benefits, but potential risks of DAA therapy for hepatitis C.
Roman E. Perri, MD, is assistant professor of medicine, division of gastroenterology and hepatology, Medical Director for Liver Transplantion, Vanderbilt University, Nashville, Tenn. He has no conflicts of interest.
Patients with decompensated cirrhosis are now able to receive antiviral therapy without risk of worsening symptoms of decompensation. More clinics are able to offer DAA therapy to patients with hepatitis C, without the need for expertise in managing the side effects of interferon-based therapy.
The study by El-Sherif et al. summarizes well the benefits and potential pitfalls of treatment of hepatitis C in patients with decompensated cirrhosis. Their scoring system is largely intuitive and mirrors the traditional Child-Turcotte-Pugh score in that patients with low serum albumin, hepatic encephalopathy, and ascites are at risk of failing to improve clinically. Patients can have their hepatitis C successfully treated but can be trapped in “MELD purgatory,” a state of significant symptoms of liver disease, without the objective priority points necessary to be candidates for liver transplantation.
As experience is gained in the use of DAA medications for HCV, it is incumbent on physicians to gather knowledge that will further refine their understanding of which patients with signs of liver decompensation might benefit. It is also clear that patients with decompensated cirrhosis should be managed by clinicians who have experience in liver transplantation, to ensure that patients are counseled regarding not just the benefits, but potential risks of DAA therapy for hepatitis C.
Roman E. Perri, MD, is assistant professor of medicine, division of gastroenterology and hepatology, Medical Director for Liver Transplantion, Vanderbilt University, Nashville, Tenn. He has no conflicts of interest.
A new scoring system predicted which patients with decompensated cirrhosis caused by hepatitis C virus (HCV) infection were most likely to experience meaningful benefits from direct-acting antiviral (DAA) therapy.
Dubbed BEA3, their scoring system assigns one point each for body mass index under 25 kg/m2, absence of encephalopathy, absence of ascites, ALT more than 1.5 times the upper limit of normal, and albumin above 3.5 g/dL. Patients who scored 4 or 5 were more than 50 times more likely to improve to Child-Pugh Turcotte (CPT) class A (compensated) cirrhosis with DAA therapy than were patients who scored 0 (hazard ratio, 52.3; 95% confidence interval, 15.2-179.7; P less than .001), wrote Omar El-Sherif, MB, BCh, of St. James’s Hospital, Dublin, together with his associates in the June issue of Gastroenterology.
Eradicating HCV does not necessarily improve the odds of transplant-free survival in the setting of decompensated cirrhosis, the researchers noted. Patients can end up in “MELD [Model for End-Stage Liver Disease] purgatory,” meaning they are still decompensated despite achieving sustained virologic response and improved MELD scores. Such patients can face longer waits for liver transplantation than if they had foregone DAA therapy. “There is an urgent need for data to refine our understanding of the reversibility of hepatic decompensation with viral eradication, and, ultimately, define the “point of no return,” the degree of liver dysfunction at which HCV therapy does not yield any meaningful clinical benefit, the researchers wrote.
Their study included 622 patients from the SOLAR-1, SOLAR-2, ASTRAL-4, and GS-US-334-0125 trials, which evaluated interferon-free sofosbuvir-based DAA therapy in patients with chronic hepatitis C virus infection and advanced liver disease. Patients received 12 or 24 weeks of therapy with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin.
A total of 32% of patients with CPT class B cirrhosis improved to class A, as did 12% of patients with class C cirrhosis. Each factor in the scoring system independently affected the chances of reaching CPT class A cirrhosis, even after accounting for SVR.
Notably, patients with intermediate BEA3 scores of 1, 2, or 3 were significantly more likely to reach CPT class A cirrhosis than were patients with scores of 0, with hazard ratios ranging from 4.2 (for a score of 1) to 21.2 (for a score of 3). Most patients had scores of 0 (106 individuals), 1 (219 individuals), or 2 (180 individuals), and only 23 patients scored a 4 or a 5.
CPT score reflects prothrombin time, serum albumin and bilirubin, and the presence or severity of ascites. The investigators called the new scoring system “a tool that can enhance shared decision making at the point of care, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis in the pretransplant setting.”Dr. El-Sherif disclosed ties to Gilead Sciences, Bristol-Myers Squibb, and the Health Research Board of Ireland. Four coinvestigators disclosed employment with Gilead, and several other coinvestigators disclosed ties to Gilead, BMS, AbbVie, and other companies.
SOURCE: El-Sherif O et al. Gastroenterology. 2018 Mar 10. doi: 10.1053/j.gastro.2018.03.022.
A new scoring system predicted which patients with decompensated cirrhosis caused by hepatitis C virus (HCV) infection were most likely to experience meaningful benefits from direct-acting antiviral (DAA) therapy.
Dubbed BEA3, their scoring system assigns one point each for body mass index under 25 kg/m2, absence of encephalopathy, absence of ascites, ALT more than 1.5 times the upper limit of normal, and albumin above 3.5 g/dL. Patients who scored 4 or 5 were more than 50 times more likely to improve to Child-Pugh Turcotte (CPT) class A (compensated) cirrhosis with DAA therapy than were patients who scored 0 (hazard ratio, 52.3; 95% confidence interval, 15.2-179.7; P less than .001), wrote Omar El-Sherif, MB, BCh, of St. James’s Hospital, Dublin, together with his associates in the June issue of Gastroenterology.
Eradicating HCV does not necessarily improve the odds of transplant-free survival in the setting of decompensated cirrhosis, the researchers noted. Patients can end up in “MELD [Model for End-Stage Liver Disease] purgatory,” meaning they are still decompensated despite achieving sustained virologic response and improved MELD scores. Such patients can face longer waits for liver transplantation than if they had foregone DAA therapy. “There is an urgent need for data to refine our understanding of the reversibility of hepatic decompensation with viral eradication, and, ultimately, define the “point of no return,” the degree of liver dysfunction at which HCV therapy does not yield any meaningful clinical benefit, the researchers wrote.
Their study included 622 patients from the SOLAR-1, SOLAR-2, ASTRAL-4, and GS-US-334-0125 trials, which evaluated interferon-free sofosbuvir-based DAA therapy in patients with chronic hepatitis C virus infection and advanced liver disease. Patients received 12 or 24 weeks of therapy with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin.
A total of 32% of patients with CPT class B cirrhosis improved to class A, as did 12% of patients with class C cirrhosis. Each factor in the scoring system independently affected the chances of reaching CPT class A cirrhosis, even after accounting for SVR.
Notably, patients with intermediate BEA3 scores of 1, 2, or 3 were significantly more likely to reach CPT class A cirrhosis than were patients with scores of 0, with hazard ratios ranging from 4.2 (for a score of 1) to 21.2 (for a score of 3). Most patients had scores of 0 (106 individuals), 1 (219 individuals), or 2 (180 individuals), and only 23 patients scored a 4 or a 5.
CPT score reflects prothrombin time, serum albumin and bilirubin, and the presence or severity of ascites. The investigators called the new scoring system “a tool that can enhance shared decision making at the point of care, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis in the pretransplant setting.”Dr. El-Sherif disclosed ties to Gilead Sciences, Bristol-Myers Squibb, and the Health Research Board of Ireland. Four coinvestigators disclosed employment with Gilead, and several other coinvestigators disclosed ties to Gilead, BMS, AbbVie, and other companies.
SOURCE: El-Sherif O et al. Gastroenterology. 2018 Mar 10. doi: 10.1053/j.gastro.2018.03.022.
FROM GASTROENTEROLOGY
Study eyes liver transplantation after Region 5 UNOS downstaging
Liver transplantation led to “excellent outcomes” when performed after downstaging hepatocellular carcinoma using the UNOS (United Network for Organ Sharing) Region 5 protocol, investigators reported.
Downstaging succeeded for 58% of patients, and an estimated 87% of transplantation recipients were alive and recurrence free at 5 years, said Neil Mehta, MD, of the University of California, San Francisco, and his associates. The findings support expanding priority access to liver transplantation to include patients whose hepatocellular carcinoma (HCC) has been successfully downstaged, they said. “In the meantime, UNOS has recently approved the Region 5 downstaging protocol for receiving automatic HCC-MELD exception listing,” they wrote. The report was published in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.11.037).
This is the first multicenter study of HCC downstaging according to a uniform protocol, the researchers noted. In multivariable analyses, downstaging was significantly more likely to fail in the setting of moderate to severe (Child Pugh B or C) hepatic impairment (hazard ratio, 3.3; 95% confidence interval, 3.0 to 3.6; P less than .001) or baseline alpha-fetoprotein level above 1,000 ng/mL (HR, 1.6; 95% CI, 1.4 to 1.9; P less than .001).
The incidence of HCC in the United States is expected to keep rising for at least another decade because of epidemic levels of fatty liver disease and chronic hepatitis C, the investigators noted. Downstaging HCC with local-regional therapy is a common bridge to transplantation, and successful treatment tends to reflect favorable tumor biology, which bodes well for transplantation. However, no multicenter study had evaluated these associations. Therefore, the investigators retrospectively studied 187 patients with HCC from three centers in California who underwent downstaging according to the UNOS Region 5 protocol between 2002 and 2012.
A total of 156 patients (83%) were successfully downstaged to within Milan criteria after a median of 2.7 months (interquartile range, 1.4 to 4.9 months), said the researchers. Among patients who were successfully downstaged but did not undergo transplantation, 37 patients had tumor progression or died from liver-related causes after a median of 6 months, while 10 patients remained on the transplant list. Among the 109 patients who underwent transplantation after a median of 13 months (interquartile range 6 to 19 months), median follow-up time was 4.3 years and estimated 5-year survival was 80%, and estimated recurrence-free survival was 87%.
Fully 68% of successfully downstaged patients required only one local-regional treatment, the researchers said. The Region 5 protocol considers patients eligible for downstaging if they have a single HCC lesion measuring up to 8 cm or multiple lesions whose combined diameters do not exceed 8 cm, and no evidence of extrahepatic disease or vascular invasion on multiphase computed tomography or magnetic resonance imaging.
The protocol considers downstaging successful if it results in one lesion measuring up to 5 cm or no more than three lesions of up to 3 cm each. Thus, patients who start out with four or five lesions must have complete necrosis of at least one to two tumors. Successfully downstaged patients must remain free of acute hepatic decompensation for at least 3 consecutive months before undergoing transplantation, according to the protocol.
“Slight refinements in the inclusion criteria for downstaging seem warranted [given] that all Child’s B/C patients with pretreatment alpha-fetoprotein greater than 1000 ng/mL suffered poor outcomes when downstaging was attempted,” the investigators noted. They reported that the 1-year risk of failed downstaging was 70% among patients with both Child’s B/C cirrhosis and alpha-fetoprotein level at or above 1000 ng/mL, 32% among patients with one risk factor, and 14% among patients with no risk factors (P less than .001).
The National Institutes of Health provided partial funding. The investigators reported having no conflicts of interest.
SOURCE: Mehta N, et al. Clin Gastroenterol Hepatol. 2017 Nov 23. doi: 10.1016/j.cgh.2017.11.037.
Liver transplantation of selected patients with hepatocellular carcinoma (HCC) is an accepted indication and associated with excellent outcomes. Until recently, criteria for liver transplantation were based on the Milan criteria that only took size and number of tumors under consideration. In this multicenter study, patients who were outside of Milan criteria were successfully downstaged to within Milan criteria with locoregional therapy and subsequently transplanted with excellent outcomes. Salient features included the following. 1) Six months waiting after the first treatment and 3 months after downstaging was required to ensure that the tumor stage remained within Milan criteria. 2) Any specific type of locoregional therapy was allowed. 3) Downstaging was possible in a majority of patients after a single treatment. 4) Patients with alpha-fetoprotein greater than 1000 ng/mL (approximately 10%) as well as presence of substantial decompensated liver disease (approximately 40%) did not have favorable outcomes. 4) On multivariable analysis, tumor biology was a stronger predictor of poor outcomes than was stage of liver disease.
Sumeet K. Asrani, MD, MSc, is associate professor in medicine and hepatologist at Baylor University Medical Center, and medical director of the Center for Advanced Liver Disease, Dallas. He has no conflicts of interest.
Liver transplantation of selected patients with hepatocellular carcinoma (HCC) is an accepted indication and associated with excellent outcomes. Until recently, criteria for liver transplantation were based on the Milan criteria that only took size and number of tumors under consideration. In this multicenter study, patients who were outside of Milan criteria were successfully downstaged to within Milan criteria with locoregional therapy and subsequently transplanted with excellent outcomes. Salient features included the following. 1) Six months waiting after the first treatment and 3 months after downstaging was required to ensure that the tumor stage remained within Milan criteria. 2) Any specific type of locoregional therapy was allowed. 3) Downstaging was possible in a majority of patients after a single treatment. 4) Patients with alpha-fetoprotein greater than 1000 ng/mL (approximately 10%) as well as presence of substantial decompensated liver disease (approximately 40%) did not have favorable outcomes. 4) On multivariable analysis, tumor biology was a stronger predictor of poor outcomes than was stage of liver disease.
Sumeet K. Asrani, MD, MSc, is associate professor in medicine and hepatologist at Baylor University Medical Center, and medical director of the Center for Advanced Liver Disease, Dallas. He has no conflicts of interest.
Liver transplantation of selected patients with hepatocellular carcinoma (HCC) is an accepted indication and associated with excellent outcomes. Until recently, criteria for liver transplantation were based on the Milan criteria that only took size and number of tumors under consideration. In this multicenter study, patients who were outside of Milan criteria were successfully downstaged to within Milan criteria with locoregional therapy and subsequently transplanted with excellent outcomes. Salient features included the following. 1) Six months waiting after the first treatment and 3 months after downstaging was required to ensure that the tumor stage remained within Milan criteria. 2) Any specific type of locoregional therapy was allowed. 3) Downstaging was possible in a majority of patients after a single treatment. 4) Patients with alpha-fetoprotein greater than 1000 ng/mL (approximately 10%) as well as presence of substantial decompensated liver disease (approximately 40%) did not have favorable outcomes. 4) On multivariable analysis, tumor biology was a stronger predictor of poor outcomes than was stage of liver disease.
Sumeet K. Asrani, MD, MSc, is associate professor in medicine and hepatologist at Baylor University Medical Center, and medical director of the Center for Advanced Liver Disease, Dallas. He has no conflicts of interest.
Liver transplantation led to “excellent outcomes” when performed after downstaging hepatocellular carcinoma using the UNOS (United Network for Organ Sharing) Region 5 protocol, investigators reported.
Downstaging succeeded for 58% of patients, and an estimated 87% of transplantation recipients were alive and recurrence free at 5 years, said Neil Mehta, MD, of the University of California, San Francisco, and his associates. The findings support expanding priority access to liver transplantation to include patients whose hepatocellular carcinoma (HCC) has been successfully downstaged, they said. “In the meantime, UNOS has recently approved the Region 5 downstaging protocol for receiving automatic HCC-MELD exception listing,” they wrote. The report was published in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.11.037).
This is the first multicenter study of HCC downstaging according to a uniform protocol, the researchers noted. In multivariable analyses, downstaging was significantly more likely to fail in the setting of moderate to severe (Child Pugh B or C) hepatic impairment (hazard ratio, 3.3; 95% confidence interval, 3.0 to 3.6; P less than .001) or baseline alpha-fetoprotein level above 1,000 ng/mL (HR, 1.6; 95% CI, 1.4 to 1.9; P less than .001).
The incidence of HCC in the United States is expected to keep rising for at least another decade because of epidemic levels of fatty liver disease and chronic hepatitis C, the investigators noted. Downstaging HCC with local-regional therapy is a common bridge to transplantation, and successful treatment tends to reflect favorable tumor biology, which bodes well for transplantation. However, no multicenter study had evaluated these associations. Therefore, the investigators retrospectively studied 187 patients with HCC from three centers in California who underwent downstaging according to the UNOS Region 5 protocol between 2002 and 2012.
A total of 156 patients (83%) were successfully downstaged to within Milan criteria after a median of 2.7 months (interquartile range, 1.4 to 4.9 months), said the researchers. Among patients who were successfully downstaged but did not undergo transplantation, 37 patients had tumor progression or died from liver-related causes after a median of 6 months, while 10 patients remained on the transplant list. Among the 109 patients who underwent transplantation after a median of 13 months (interquartile range 6 to 19 months), median follow-up time was 4.3 years and estimated 5-year survival was 80%, and estimated recurrence-free survival was 87%.
Fully 68% of successfully downstaged patients required only one local-regional treatment, the researchers said. The Region 5 protocol considers patients eligible for downstaging if they have a single HCC lesion measuring up to 8 cm or multiple lesions whose combined diameters do not exceed 8 cm, and no evidence of extrahepatic disease or vascular invasion on multiphase computed tomography or magnetic resonance imaging.
The protocol considers downstaging successful if it results in one lesion measuring up to 5 cm or no more than three lesions of up to 3 cm each. Thus, patients who start out with four or five lesions must have complete necrosis of at least one to two tumors. Successfully downstaged patients must remain free of acute hepatic decompensation for at least 3 consecutive months before undergoing transplantation, according to the protocol.
“Slight refinements in the inclusion criteria for downstaging seem warranted [given] that all Child’s B/C patients with pretreatment alpha-fetoprotein greater than 1000 ng/mL suffered poor outcomes when downstaging was attempted,” the investigators noted. They reported that the 1-year risk of failed downstaging was 70% among patients with both Child’s B/C cirrhosis and alpha-fetoprotein level at or above 1000 ng/mL, 32% among patients with one risk factor, and 14% among patients with no risk factors (P less than .001).
The National Institutes of Health provided partial funding. The investigators reported having no conflicts of interest.
SOURCE: Mehta N, et al. Clin Gastroenterol Hepatol. 2017 Nov 23. doi: 10.1016/j.cgh.2017.11.037.
Liver transplantation led to “excellent outcomes” when performed after downstaging hepatocellular carcinoma using the UNOS (United Network for Organ Sharing) Region 5 protocol, investigators reported.
Downstaging succeeded for 58% of patients, and an estimated 87% of transplantation recipients were alive and recurrence free at 5 years, said Neil Mehta, MD, of the University of California, San Francisco, and his associates. The findings support expanding priority access to liver transplantation to include patients whose hepatocellular carcinoma (HCC) has been successfully downstaged, they said. “In the meantime, UNOS has recently approved the Region 5 downstaging protocol for receiving automatic HCC-MELD exception listing,” they wrote. The report was published in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.11.037).
This is the first multicenter study of HCC downstaging according to a uniform protocol, the researchers noted. In multivariable analyses, downstaging was significantly more likely to fail in the setting of moderate to severe (Child Pugh B or C) hepatic impairment (hazard ratio, 3.3; 95% confidence interval, 3.0 to 3.6; P less than .001) or baseline alpha-fetoprotein level above 1,000 ng/mL (HR, 1.6; 95% CI, 1.4 to 1.9; P less than .001).
The incidence of HCC in the United States is expected to keep rising for at least another decade because of epidemic levels of fatty liver disease and chronic hepatitis C, the investigators noted. Downstaging HCC with local-regional therapy is a common bridge to transplantation, and successful treatment tends to reflect favorable tumor biology, which bodes well for transplantation. However, no multicenter study had evaluated these associations. Therefore, the investigators retrospectively studied 187 patients with HCC from three centers in California who underwent downstaging according to the UNOS Region 5 protocol between 2002 and 2012.
A total of 156 patients (83%) were successfully downstaged to within Milan criteria after a median of 2.7 months (interquartile range, 1.4 to 4.9 months), said the researchers. Among patients who were successfully downstaged but did not undergo transplantation, 37 patients had tumor progression or died from liver-related causes after a median of 6 months, while 10 patients remained on the transplant list. Among the 109 patients who underwent transplantation after a median of 13 months (interquartile range 6 to 19 months), median follow-up time was 4.3 years and estimated 5-year survival was 80%, and estimated recurrence-free survival was 87%.
Fully 68% of successfully downstaged patients required only one local-regional treatment, the researchers said. The Region 5 protocol considers patients eligible for downstaging if they have a single HCC lesion measuring up to 8 cm or multiple lesions whose combined diameters do not exceed 8 cm, and no evidence of extrahepatic disease or vascular invasion on multiphase computed tomography or magnetic resonance imaging.
The protocol considers downstaging successful if it results in one lesion measuring up to 5 cm or no more than three lesions of up to 3 cm each. Thus, patients who start out with four or five lesions must have complete necrosis of at least one to two tumors. Successfully downstaged patients must remain free of acute hepatic decompensation for at least 3 consecutive months before undergoing transplantation, according to the protocol.
“Slight refinements in the inclusion criteria for downstaging seem warranted [given] that all Child’s B/C patients with pretreatment alpha-fetoprotein greater than 1000 ng/mL suffered poor outcomes when downstaging was attempted,” the investigators noted. They reported that the 1-year risk of failed downstaging was 70% among patients with both Child’s B/C cirrhosis and alpha-fetoprotein level at or above 1000 ng/mL, 32% among patients with one risk factor, and 14% among patients with no risk factors (P less than .001).
The National Institutes of Health provided partial funding. The investigators reported having no conflicts of interest.
SOURCE: Mehta N, et al. Clin Gastroenterol Hepatol. 2017 Nov 23. doi: 10.1016/j.cgh.2017.11.037.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Liver transplantation led to excellent outcomes when performed after downstaging hepatocellular carcinoma according to the UNOS (United Network for Organ Sharing) Region 5 protocol.
Major finding: Downstaging succeeded in 58% of patients. Estimated 5-year posttransplantation recurrence-free survival was 87%.
Study details: Retrospective multicenter study of 187 patients with hepatocellular carcinoma.
Disclosures: The National Institutes of Health provided partial funding. The investigators reported having no conflicts of interest.
Source: Mehta N et al. Clin Gastroenterol Hepatol. 2017 Nov 23. doi: 10.1016/j.cgh.2017.11.037.