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Amyloid depleter/antibody duo reduces systemic amyloidosis severity
A one-two combination consisting of a drug to deplete amyloid fibrils from circulation and a monoclonal antibody to mop up residual amyloid protein appears to be safe and shows promising activity against systemic amyloidosis in an early clinical trial.
Pairing the investigational small molecule agent miridesap and the experimental monoclonal antibody dezamizumab resulted in clearance or reductions in amyloid deposits in the livers, spleens, and kidneys of adults with systemic amyloidosis, reported Prof. Sir Mark B. Pepys of University College, London, and his colleagues.
Systemic amyloidosis is caused by extracellular deposition of amyloid fibrils coated with serum amyloid P component (SAP), a normal plasma protein. Miridesap has been shown to deplete levels of circulating SAP, but fails to clear SAP lingering in amyloid deposits. Dezamizumab is a fully humanized immunoglobulin G1 antibody that is directed against SAP and provokes immune system clearance of residual protein.
The investigators enrolled 23 adults with systemic amyloidosis into an open-label, nonrandomized trial of safety, pharmacokinetics, and dose responses to up to three cycles of miridesap followed by dezamizumab. They used scintigraphy with radiolabeling to measure amyloid burden, equilibrium MRI to measure organ extracellular volume, and transient elastography to evaluate liver stiffness.
They found that a 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients, and that liver stiffness, a sensitive marker for hepatic amyloid load, initially increased in some patients, but then fell “substantially,” suggesting amyloid clearance and resolution of cellular infiltrates. Progressive dose-related clearance of amyloid in the liver was also associated with improvements in liver function tests.
In addition, 7 of 11 patients had reductions in renal amyloid burden, with the greatest benefit seen in patients treated with higher doses of the antibody.
The trial cohort also included six patients with clinical cardiac amyloidosis: three with monoclonal immunoglobulin light-chain amyloidosis (AL), and three with ATTR (transthyretin) amyloidosis. Although the investigators had excluded patients with cardiac amyloidosis in the first part of the study out of safety concerns, there were no new arrhythmias and no increases in cardiac troponin T or creatine kinase concentrations. One patient had a 17% reduction in left ventricular mass, suggesting a reduction in cardiac amyloid burden.
Patients tolerated the treatment, with self-limiting, early-onset rashes after higher antibody doses being the most frequent adverse event.
“However, the identified and potential risks of the intervention are considered manageable, and thus acceptable, in relation to the demonstrable clinical benefits of removing amyloid from vital organs,” the investigators wrote.
GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.
Source: Richards D et al. Sci. Transl. Med. 2018. doi: 10.1126/scitranslmed.aan3128.
A one-two combination consisting of a drug to deplete amyloid fibrils from circulation and a monoclonal antibody to mop up residual amyloid protein appears to be safe and shows promising activity against systemic amyloidosis in an early clinical trial.
Pairing the investigational small molecule agent miridesap and the experimental monoclonal antibody dezamizumab resulted in clearance or reductions in amyloid deposits in the livers, spleens, and kidneys of adults with systemic amyloidosis, reported Prof. Sir Mark B. Pepys of University College, London, and his colleagues.
Systemic amyloidosis is caused by extracellular deposition of amyloid fibrils coated with serum amyloid P component (SAP), a normal plasma protein. Miridesap has been shown to deplete levels of circulating SAP, but fails to clear SAP lingering in amyloid deposits. Dezamizumab is a fully humanized immunoglobulin G1 antibody that is directed against SAP and provokes immune system clearance of residual protein.
The investigators enrolled 23 adults with systemic amyloidosis into an open-label, nonrandomized trial of safety, pharmacokinetics, and dose responses to up to three cycles of miridesap followed by dezamizumab. They used scintigraphy with radiolabeling to measure amyloid burden, equilibrium MRI to measure organ extracellular volume, and transient elastography to evaluate liver stiffness.
They found that a 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients, and that liver stiffness, a sensitive marker for hepatic amyloid load, initially increased in some patients, but then fell “substantially,” suggesting amyloid clearance and resolution of cellular infiltrates. Progressive dose-related clearance of amyloid in the liver was also associated with improvements in liver function tests.
In addition, 7 of 11 patients had reductions in renal amyloid burden, with the greatest benefit seen in patients treated with higher doses of the antibody.
The trial cohort also included six patients with clinical cardiac amyloidosis: three with monoclonal immunoglobulin light-chain amyloidosis (AL), and three with ATTR (transthyretin) amyloidosis. Although the investigators had excluded patients with cardiac amyloidosis in the first part of the study out of safety concerns, there were no new arrhythmias and no increases in cardiac troponin T or creatine kinase concentrations. One patient had a 17% reduction in left ventricular mass, suggesting a reduction in cardiac amyloid burden.
Patients tolerated the treatment, with self-limiting, early-onset rashes after higher antibody doses being the most frequent adverse event.
“However, the identified and potential risks of the intervention are considered manageable, and thus acceptable, in relation to the demonstrable clinical benefits of removing amyloid from vital organs,” the investigators wrote.
GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.
Source: Richards D et al. Sci. Transl. Med. 2018. doi: 10.1126/scitranslmed.aan3128.
A one-two combination consisting of a drug to deplete amyloid fibrils from circulation and a monoclonal antibody to mop up residual amyloid protein appears to be safe and shows promising activity against systemic amyloidosis in an early clinical trial.
Pairing the investigational small molecule agent miridesap and the experimental monoclonal antibody dezamizumab resulted in clearance or reductions in amyloid deposits in the livers, spleens, and kidneys of adults with systemic amyloidosis, reported Prof. Sir Mark B. Pepys of University College, London, and his colleagues.
Systemic amyloidosis is caused by extracellular deposition of amyloid fibrils coated with serum amyloid P component (SAP), a normal plasma protein. Miridesap has been shown to deplete levels of circulating SAP, but fails to clear SAP lingering in amyloid deposits. Dezamizumab is a fully humanized immunoglobulin G1 antibody that is directed against SAP and provokes immune system clearance of residual protein.
The investigators enrolled 23 adults with systemic amyloidosis into an open-label, nonrandomized trial of safety, pharmacokinetics, and dose responses to up to three cycles of miridesap followed by dezamizumab. They used scintigraphy with radiolabeling to measure amyloid burden, equilibrium MRI to measure organ extracellular volume, and transient elastography to evaluate liver stiffness.
They found that a 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients, and that liver stiffness, a sensitive marker for hepatic amyloid load, initially increased in some patients, but then fell “substantially,” suggesting amyloid clearance and resolution of cellular infiltrates. Progressive dose-related clearance of amyloid in the liver was also associated with improvements in liver function tests.
In addition, 7 of 11 patients had reductions in renal amyloid burden, with the greatest benefit seen in patients treated with higher doses of the antibody.
The trial cohort also included six patients with clinical cardiac amyloidosis: three with monoclonal immunoglobulin light-chain amyloidosis (AL), and three with ATTR (transthyretin) amyloidosis. Although the investigators had excluded patients with cardiac amyloidosis in the first part of the study out of safety concerns, there were no new arrhythmias and no increases in cardiac troponin T or creatine kinase concentrations. One patient had a 17% reduction in left ventricular mass, suggesting a reduction in cardiac amyloid burden.
Patients tolerated the treatment, with self-limiting, early-onset rashes after higher antibody doses being the most frequent adverse event.
“However, the identified and potential risks of the intervention are considered manageable, and thus acceptable, in relation to the demonstrable clinical benefits of removing amyloid from vital organs,” the investigators wrote.
GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.
Source: Richards D et al. Sci. Transl. Med. 2018. doi: 10.1126/scitranslmed.aan3128.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: A combination of an amyloid-depleting agent and immunotherapeutic antibody appears effective and safe in patients with systemic amyloidosis.
Major finding: A 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients.
Data source: Open-label, nonrandomized clinical trial of 23 adults with various subtypes of systemic amyloidosis.
Disclosures: GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.
Source: Richards D et al. Sci. Transl. Med. 2018;10:eaan3128.
PBC disease progression no worse for patients with concomitant NAFLD
, according to Gerald Yosel Minuk, MD, and his associates.
At baseline, the 168 patients in the PBC-only group had higher serum alkaline phosphatase and gamma-glutamyl transferase values than the 68 patients in the NAFLD/PBC group, as well as having higher FIB-4 scores. The percentage of patients with aspartate aminotransferase/platelet ratio indexes (APRI) greater than 1.5 was slightly higher in the PBC-only group, but the difference was not significant.
After follow-up periods averaging 6.7 years in the PBC-only group and 6.4 years in the NAFLD/PBC group, yearly increases in FIB-4 and prevalence of APRI greater than 1.5 were greater in the PBC-only group, though the difference did not reach significance. PBC-only patients were more likely to have developed radiologic evidence of cirrhosis during the follow-up period (42% vs. 19%, P less than .001).
“Were the results of the present study to be confirmed by others, the question arises as to why NAFLD does not adversely and may favorably impact on PBC. Here, it is tempting to speculate that because PBC livers are associated with a paucity of immunosuppressive regulator T cells (Tregs) whereas in NAFLD, Tregs are recruited to the liver in increased numbers, a restoration of the immune balance in PBC livers might explain these findings,” the investigators noted.
Find the full study in Liver International (doi: 10.1111/liv.13644).
, according to Gerald Yosel Minuk, MD, and his associates.
At baseline, the 168 patients in the PBC-only group had higher serum alkaline phosphatase and gamma-glutamyl transferase values than the 68 patients in the NAFLD/PBC group, as well as having higher FIB-4 scores. The percentage of patients with aspartate aminotransferase/platelet ratio indexes (APRI) greater than 1.5 was slightly higher in the PBC-only group, but the difference was not significant.
After follow-up periods averaging 6.7 years in the PBC-only group and 6.4 years in the NAFLD/PBC group, yearly increases in FIB-4 and prevalence of APRI greater than 1.5 were greater in the PBC-only group, though the difference did not reach significance. PBC-only patients were more likely to have developed radiologic evidence of cirrhosis during the follow-up period (42% vs. 19%, P less than .001).
“Were the results of the present study to be confirmed by others, the question arises as to why NAFLD does not adversely and may favorably impact on PBC. Here, it is tempting to speculate that because PBC livers are associated with a paucity of immunosuppressive regulator T cells (Tregs) whereas in NAFLD, Tregs are recruited to the liver in increased numbers, a restoration of the immune balance in PBC livers might explain these findings,” the investigators noted.
Find the full study in Liver International (doi: 10.1111/liv.13644).
, according to Gerald Yosel Minuk, MD, and his associates.
At baseline, the 168 patients in the PBC-only group had higher serum alkaline phosphatase and gamma-glutamyl transferase values than the 68 patients in the NAFLD/PBC group, as well as having higher FIB-4 scores. The percentage of patients with aspartate aminotransferase/platelet ratio indexes (APRI) greater than 1.5 was slightly higher in the PBC-only group, but the difference was not significant.
After follow-up periods averaging 6.7 years in the PBC-only group and 6.4 years in the NAFLD/PBC group, yearly increases in FIB-4 and prevalence of APRI greater than 1.5 were greater in the PBC-only group, though the difference did not reach significance. PBC-only patients were more likely to have developed radiologic evidence of cirrhosis during the follow-up period (42% vs. 19%, P less than .001).
“Were the results of the present study to be confirmed by others, the question arises as to why NAFLD does not adversely and may favorably impact on PBC. Here, it is tempting to speculate that because PBC livers are associated with a paucity of immunosuppressive regulator T cells (Tregs) whereas in NAFLD, Tregs are recruited to the liver in increased numbers, a restoration of the immune balance in PBC livers might explain these findings,” the investigators noted.
Find the full study in Liver International (doi: 10.1111/liv.13644).
FROM LIVER INTERNATIONAL
VIDEO: Project ECHO would cost-effectively expand HCV treatment
Training community health providers to treat chronic hepatitis C virus infection is a cost-effective way to expand treatment access and reduce the national burden of this prevalent condition, according to research published in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.10.016).
The model, dubbed Project ECHO, “is the best way, to our knowledge, to cost-effectively find and treat HCV patients at scale,” wrote Thilo Rattay, MPH, of the University of Michigan School of Public Health, Ann Arbor, and his associates. “Our analysis demonstrates that fundamentally changing the care delivery model for HCV enables unparalleled reach, in contrast to simply using ever more cost-effective drugs in an inefficient system. Project ECHO can quickly reduce the burden of disease from HCV and accelerate the impact of the new generation of highly effective medications.”
Project ECHO (echo.unm.edu) links multidisciplinary teams of specialists (hubs) to physicians and nurse practitioners in community practice (spokes). Each hub, which is usually based at an academic medical center, holds video conferences to mentor and teach providers about best practices for managing conditions ranging from autism to Zika virus infection. Initial reports suggest that Project ECHO can improve health care quality and access as well as job satisfaction among primary care providers, the researchers noted.
Project ECHO has 127 hubs globally, including 77 in the United States, and receives support from foundations, state legislatures, and government agencies. Because patients with chronic HCV vastly outnumber gastroenterologists in the United States, Mr. Rattay and his coinvestigators used Markov models to evaluate Project ECHO’s cost-effectiveness in the HCV setting. To do so, they created a decision tree and Markov models with Microsoft Excel, PrecisionTree, and @RISK by using data from the U.S. Census Bureau, MarketScan, and an extensive literature review
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
The models yielded an incremental cost-effectiveness ratio of $10,351 per quality-adjusted life year when compared with the status quo, said the researchers. Commonly cited willingness-to-pay thresholds are $50,000 and $100,000, indicating that Project ECHO is a cost-effective way to expand HCV treatment, they added. However, insurers would pay substantially more during the first 5 years of rollout – about $708 million versus $368 million with the status quo. During the first year, ECHO would cost payers about $350.5 million more than would the status quo, but 4,446 more patients would be treated, drastically reducing prevalence in the insurance pool. Consequently, subsequent costs would drop by nearly $11 million over the first 5 years of ECHO. Nonetheless, the “high budgetary costs suggest that incremental rollout of [Project] ECHO may be best,” the investigators wrote.
They were unable to determine whether increased treatment under ECHO relates to expanded screening, treatment adherence, or access, but sensitivity analyses suggested that “results are largely independent of the cause,” the researchers wrote. “Importantly, most of the financial benefits of treating HCV are not immediate, while a majority of the costs are upfront,” they stressed. Stakeholders therefore need to adopt a long-term view and consider population-based health care models and reimbursement strategies that “capture the full benefit of this type of ecosystem.”
The investigators had no external funding sources and no conflicts of interest.
Training community health providers to treat chronic hepatitis C virus infection is a cost-effective way to expand treatment access and reduce the national burden of this prevalent condition, according to research published in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.10.016).
The model, dubbed Project ECHO, “is the best way, to our knowledge, to cost-effectively find and treat HCV patients at scale,” wrote Thilo Rattay, MPH, of the University of Michigan School of Public Health, Ann Arbor, and his associates. “Our analysis demonstrates that fundamentally changing the care delivery model for HCV enables unparalleled reach, in contrast to simply using ever more cost-effective drugs in an inefficient system. Project ECHO can quickly reduce the burden of disease from HCV and accelerate the impact of the new generation of highly effective medications.”
Project ECHO (echo.unm.edu) links multidisciplinary teams of specialists (hubs) to physicians and nurse practitioners in community practice (spokes). Each hub, which is usually based at an academic medical center, holds video conferences to mentor and teach providers about best practices for managing conditions ranging from autism to Zika virus infection. Initial reports suggest that Project ECHO can improve health care quality and access as well as job satisfaction among primary care providers, the researchers noted.
Project ECHO has 127 hubs globally, including 77 in the United States, and receives support from foundations, state legislatures, and government agencies. Because patients with chronic HCV vastly outnumber gastroenterologists in the United States, Mr. Rattay and his coinvestigators used Markov models to evaluate Project ECHO’s cost-effectiveness in the HCV setting. To do so, they created a decision tree and Markov models with Microsoft Excel, PrecisionTree, and @RISK by using data from the U.S. Census Bureau, MarketScan, and an extensive literature review
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
The models yielded an incremental cost-effectiveness ratio of $10,351 per quality-adjusted life year when compared with the status quo, said the researchers. Commonly cited willingness-to-pay thresholds are $50,000 and $100,000, indicating that Project ECHO is a cost-effective way to expand HCV treatment, they added. However, insurers would pay substantially more during the first 5 years of rollout – about $708 million versus $368 million with the status quo. During the first year, ECHO would cost payers about $350.5 million more than would the status quo, but 4,446 more patients would be treated, drastically reducing prevalence in the insurance pool. Consequently, subsequent costs would drop by nearly $11 million over the first 5 years of ECHO. Nonetheless, the “high budgetary costs suggest that incremental rollout of [Project] ECHO may be best,” the investigators wrote.
They were unable to determine whether increased treatment under ECHO relates to expanded screening, treatment adherence, or access, but sensitivity analyses suggested that “results are largely independent of the cause,” the researchers wrote. “Importantly, most of the financial benefits of treating HCV are not immediate, while a majority of the costs are upfront,” they stressed. Stakeholders therefore need to adopt a long-term view and consider population-based health care models and reimbursement strategies that “capture the full benefit of this type of ecosystem.”
The investigators had no external funding sources and no conflicts of interest.
Training community health providers to treat chronic hepatitis C virus infection is a cost-effective way to expand treatment access and reduce the national burden of this prevalent condition, according to research published in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.10.016).
The model, dubbed Project ECHO, “is the best way, to our knowledge, to cost-effectively find and treat HCV patients at scale,” wrote Thilo Rattay, MPH, of the University of Michigan School of Public Health, Ann Arbor, and his associates. “Our analysis demonstrates that fundamentally changing the care delivery model for HCV enables unparalleled reach, in contrast to simply using ever more cost-effective drugs in an inefficient system. Project ECHO can quickly reduce the burden of disease from HCV and accelerate the impact of the new generation of highly effective medications.”
Project ECHO (echo.unm.edu) links multidisciplinary teams of specialists (hubs) to physicians and nurse practitioners in community practice (spokes). Each hub, which is usually based at an academic medical center, holds video conferences to mentor and teach providers about best practices for managing conditions ranging from autism to Zika virus infection. Initial reports suggest that Project ECHO can improve health care quality and access as well as job satisfaction among primary care providers, the researchers noted.
Project ECHO has 127 hubs globally, including 77 in the United States, and receives support from foundations, state legislatures, and government agencies. Because patients with chronic HCV vastly outnumber gastroenterologists in the United States, Mr. Rattay and his coinvestigators used Markov models to evaluate Project ECHO’s cost-effectiveness in the HCV setting. To do so, they created a decision tree and Markov models with Microsoft Excel, PrecisionTree, and @RISK by using data from the U.S. Census Bureau, MarketScan, and an extensive literature review
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
The models yielded an incremental cost-effectiveness ratio of $10,351 per quality-adjusted life year when compared with the status quo, said the researchers. Commonly cited willingness-to-pay thresholds are $50,000 and $100,000, indicating that Project ECHO is a cost-effective way to expand HCV treatment, they added. However, insurers would pay substantially more during the first 5 years of rollout – about $708 million versus $368 million with the status quo. During the first year, ECHO would cost payers about $350.5 million more than would the status quo, but 4,446 more patients would be treated, drastically reducing prevalence in the insurance pool. Consequently, subsequent costs would drop by nearly $11 million over the first 5 years of ECHO. Nonetheless, the “high budgetary costs suggest that incremental rollout of [Project] ECHO may be best,” the investigators wrote.
They were unable to determine whether increased treatment under ECHO relates to expanded screening, treatment adherence, or access, but sensitivity analyses suggested that “results are largely independent of the cause,” the researchers wrote. “Importantly, most of the financial benefits of treating HCV are not immediate, while a majority of the costs are upfront,” they stressed. Stakeholders therefore need to adopt a long-term view and consider population-based health care models and reimbursement strategies that “capture the full benefit of this type of ecosystem.”
The investigators had no external funding sources and no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: A teletraining model called Project ECHO is a cost-effective way to expand access to treatment for chronic hepatitis C virus infection.
Major finding: The incremental cost-effectiveness ratio was $10,351 per quality-adjusted life year, compared with the status quo. Commonly cited willingness-to-pay thresholds are $50,000 and $100,000.
Data source: A decision tree and Markov models created with Microsoft Excel, PrecisionTree, and @RISK using data from the U.S. Census Bureau, MarketScan, and an extensive literature review.
Disclosures: The investigators had no external funding sources and no conflicts of interest.
The Liver Meeting 2017 NAFLD debrief – key abstracts
WASHINGTON – Nonalcoholic fatty liver disease (NAFLD) is a complex disease that involves multiple systems, and several standout abstracts at the annual meeting of the American Association for the Study of Liver Diseases emphasized the importance of multisystem management and the potential of combination therapies, Kymberly D. Watt, MD, said during the final debrief.
“The actual underlying mechanisms and the underlying processes that are going on are way more complicated than just inflammation and scarring,” said Dr. Watt, associate professor of medicine and medical director of liver transplantation at the Mayo Clinic, Rochester, Minn. “We have numerous areas to target, including insulin resistance, lipid metabolism, oxidative stress, inflammation, immune modulation, cell death, etc.”
She noted several studies that evaluated the prevalence of NAFLD, including a study that found that “about one-third of patients walking through the door of the clinic had nonalcoholic steatohepatitis [NASH],” suggesting physicians should consider screening at-risk patients (abstract 58). A Korean study found about 18% of asymptomatic lean individuals (body mass index less than 23 kg/m2) had NAFLD and identified sarcopenia as a significant risk factor for NAFLD in these lean patients (abstract 59). “Sarcopenia is something that we really need to pay a lot more attention to,” Dr. Watt said.
Other studies better outlined the increasing association between NAFLD and hepatocellular carcinoma, Dr. Watt noted (abstracts 2119 and 2102). Another study confirmed that men with NAFLD/NASH have almost twice the incidence of hepatocellular carcinoma (HCC) as women — 0.43%-0.5% vs. 0.22%-0.28%, with both groups significantly higher than the general population (abstract 2116). “And looking further, we can actually quote an HCC incidence in NASH of 0.009%,” she added.
Again emphasizing the multisystem impact of NAFLD, Dr. Watt cited a study that calculated the cardiovascular risks incumbent with liver disease. Researchers reported that men and women at the time of NAFLD diagnosis had significantly higher rates of either angina/ischemic heart disease or heart failure (abstract 55). Women, specifically, had a higher risk for cardiovascular events earlier than men and overall are at equal risk to men, unlike in the general population where women are at lower risk. “We need to start looking at screening and prevention of other diseases in our patients with NASH,” Dr. Watt said. “In addition, we need to be more aware of the elevated risk in these patients and not just approach them in the same way as the general population.”
Physicians may be tempted to discontinue statin therapy in patients with chronic liver disease, but Dr. Watt cited a poster that showed that this results in worse outcomes (abstract 2106). The researchers found that continued statin use was associated with a lower risk of death with compensated and decompensated liver function. “These data help to educate certain patients of their risk of decompensation over time,” Dr. Watt said.
An international study determined that the severity of advanced compensated liver disease is a key determinant in outcomes, finding that those with bridging fibrosis are at greater risk of vascular events, but those with cirrhosis and Child-Turcotte-Pugh A5 and A6 disease have much higher risks of hepatic decompensation and HCC out to 14 years (abstract 60). “The reason to look at these is to be able to tell your patients that they probably have a 30% increased risk of decompensation by 4 years,” Dr. Watt said.
Dr. Watt pointed out three studies that shed more light on important biomarkers of NAFLD. One study reported that three biomarkers – alpha-2-macroglobulin, hyaluronic acid, and tissue inhibitor of metalloproteinase-1 – have a high sensitivity for differentiating low-stage and stage F3-F4 disease (abstract 95). Another study found that a measure using Pro-C3 and other clinical markers were predictive of F3 or F4 fibrosis in NAFLD (abstract 93). And, other researchers found that a HepQuant-STAT measure of greater than 0.50 microM in patients who ingested deuterated cholic acid (d4-CA) solution may be a minimally invasive alternative to biopsy for diagnosing NASH (abstract 96).
Management studies focusing on varying targets were also presented. A trial of fibroblast growth factor–21 for treatment of NAFLD found that patients in the 10- and 20-mg dose arms showed improvement in MRI hepatic fat fraction, ALT, AST, and liver stiffness at 16 weeks vs. placebo. A few patients had some mild elevation to their liver enzymes on treatment (abstract 182). “So I think we need to remain cautious and watch these patients closely, but overall it seems to be reasonably safe data,” she said. Another drug trial of the acetyl-CoA carboxylase inhibitor GS-0976 also showed promise for overall improvement in MRI steatosis measures (abstract LB-9).
Three preclinical studies of dual-agent therapies in animals have demonstrated improvement in inflammatory and fibrosis scores, Dr. Watt noted (abstracts 2,000, 2,002 and 2,052). “There’s no one drug that’s going to be likely the magic cure,” Dr. Watt said. “There will likely be a lot more focus and data coming out on dual-action agents.” Another animal study addressed the burning question if decaffeinated coffee has the same protective effect against NASH as caffeinated coffee (abstract 2093). Said Dr. Watt: “If you are interested in the potential benefits of coffee but really can’t handle the caffeine, this study suggests, you may still be OK.”
Finally, Dr. Watt noted an early study of three-dimensional printing has shown potential for replicating NASH tissue for bench studies (abstract 1963). “3-D printing is certainly a wave of the future,” she said, pointing out that researchers have created a 3-D model that has some metabolic equivalency to NASH, with the inflammatory cytokine release, hepatic stellate cell activation, “and all of the features that we see in NASH. This may be of potential use down the road to avoid relying on animal models in preclinical studies.”
The Liver Meeting next convenes Nov. 9-13, 2018, in San Francisco.
Dr. Watt disclosed ties to Bristol-Myers Squibb, Exelixis, and Seattle Genetics.
WASHINGTON – Nonalcoholic fatty liver disease (NAFLD) is a complex disease that involves multiple systems, and several standout abstracts at the annual meeting of the American Association for the Study of Liver Diseases emphasized the importance of multisystem management and the potential of combination therapies, Kymberly D. Watt, MD, said during the final debrief.
“The actual underlying mechanisms and the underlying processes that are going on are way more complicated than just inflammation and scarring,” said Dr. Watt, associate professor of medicine and medical director of liver transplantation at the Mayo Clinic, Rochester, Minn. “We have numerous areas to target, including insulin resistance, lipid metabolism, oxidative stress, inflammation, immune modulation, cell death, etc.”
She noted several studies that evaluated the prevalence of NAFLD, including a study that found that “about one-third of patients walking through the door of the clinic had nonalcoholic steatohepatitis [NASH],” suggesting physicians should consider screening at-risk patients (abstract 58). A Korean study found about 18% of asymptomatic lean individuals (body mass index less than 23 kg/m2) had NAFLD and identified sarcopenia as a significant risk factor for NAFLD in these lean patients (abstract 59). “Sarcopenia is something that we really need to pay a lot more attention to,” Dr. Watt said.
Other studies better outlined the increasing association between NAFLD and hepatocellular carcinoma, Dr. Watt noted (abstracts 2119 and 2102). Another study confirmed that men with NAFLD/NASH have almost twice the incidence of hepatocellular carcinoma (HCC) as women — 0.43%-0.5% vs. 0.22%-0.28%, with both groups significantly higher than the general population (abstract 2116). “And looking further, we can actually quote an HCC incidence in NASH of 0.009%,” she added.
Again emphasizing the multisystem impact of NAFLD, Dr. Watt cited a study that calculated the cardiovascular risks incumbent with liver disease. Researchers reported that men and women at the time of NAFLD diagnosis had significantly higher rates of either angina/ischemic heart disease or heart failure (abstract 55). Women, specifically, had a higher risk for cardiovascular events earlier than men and overall are at equal risk to men, unlike in the general population where women are at lower risk. “We need to start looking at screening and prevention of other diseases in our patients with NASH,” Dr. Watt said. “In addition, we need to be more aware of the elevated risk in these patients and not just approach them in the same way as the general population.”
Physicians may be tempted to discontinue statin therapy in patients with chronic liver disease, but Dr. Watt cited a poster that showed that this results in worse outcomes (abstract 2106). The researchers found that continued statin use was associated with a lower risk of death with compensated and decompensated liver function. “These data help to educate certain patients of their risk of decompensation over time,” Dr. Watt said.
An international study determined that the severity of advanced compensated liver disease is a key determinant in outcomes, finding that those with bridging fibrosis are at greater risk of vascular events, but those with cirrhosis and Child-Turcotte-Pugh A5 and A6 disease have much higher risks of hepatic decompensation and HCC out to 14 years (abstract 60). “The reason to look at these is to be able to tell your patients that they probably have a 30% increased risk of decompensation by 4 years,” Dr. Watt said.
Dr. Watt pointed out three studies that shed more light on important biomarkers of NAFLD. One study reported that three biomarkers – alpha-2-macroglobulin, hyaluronic acid, and tissue inhibitor of metalloproteinase-1 – have a high sensitivity for differentiating low-stage and stage F3-F4 disease (abstract 95). Another study found that a measure using Pro-C3 and other clinical markers were predictive of F3 or F4 fibrosis in NAFLD (abstract 93). And, other researchers found that a HepQuant-STAT measure of greater than 0.50 microM in patients who ingested deuterated cholic acid (d4-CA) solution may be a minimally invasive alternative to biopsy for diagnosing NASH (abstract 96).
Management studies focusing on varying targets were also presented. A trial of fibroblast growth factor–21 for treatment of NAFLD found that patients in the 10- and 20-mg dose arms showed improvement in MRI hepatic fat fraction, ALT, AST, and liver stiffness at 16 weeks vs. placebo. A few patients had some mild elevation to their liver enzymes on treatment (abstract 182). “So I think we need to remain cautious and watch these patients closely, but overall it seems to be reasonably safe data,” she said. Another drug trial of the acetyl-CoA carboxylase inhibitor GS-0976 also showed promise for overall improvement in MRI steatosis measures (abstract LB-9).
Three preclinical studies of dual-agent therapies in animals have demonstrated improvement in inflammatory and fibrosis scores, Dr. Watt noted (abstracts 2,000, 2,002 and 2,052). “There’s no one drug that’s going to be likely the magic cure,” Dr. Watt said. “There will likely be a lot more focus and data coming out on dual-action agents.” Another animal study addressed the burning question if decaffeinated coffee has the same protective effect against NASH as caffeinated coffee (abstract 2093). Said Dr. Watt: “If you are interested in the potential benefits of coffee but really can’t handle the caffeine, this study suggests, you may still be OK.”
Finally, Dr. Watt noted an early study of three-dimensional printing has shown potential for replicating NASH tissue for bench studies (abstract 1963). “3-D printing is certainly a wave of the future,” she said, pointing out that researchers have created a 3-D model that has some metabolic equivalency to NASH, with the inflammatory cytokine release, hepatic stellate cell activation, “and all of the features that we see in NASH. This may be of potential use down the road to avoid relying on animal models in preclinical studies.”
The Liver Meeting next convenes Nov. 9-13, 2018, in San Francisco.
Dr. Watt disclosed ties to Bristol-Myers Squibb, Exelixis, and Seattle Genetics.
WASHINGTON – Nonalcoholic fatty liver disease (NAFLD) is a complex disease that involves multiple systems, and several standout abstracts at the annual meeting of the American Association for the Study of Liver Diseases emphasized the importance of multisystem management and the potential of combination therapies, Kymberly D. Watt, MD, said during the final debrief.
“The actual underlying mechanisms and the underlying processes that are going on are way more complicated than just inflammation and scarring,” said Dr. Watt, associate professor of medicine and medical director of liver transplantation at the Mayo Clinic, Rochester, Minn. “We have numerous areas to target, including insulin resistance, lipid metabolism, oxidative stress, inflammation, immune modulation, cell death, etc.”
She noted several studies that evaluated the prevalence of NAFLD, including a study that found that “about one-third of patients walking through the door of the clinic had nonalcoholic steatohepatitis [NASH],” suggesting physicians should consider screening at-risk patients (abstract 58). A Korean study found about 18% of asymptomatic lean individuals (body mass index less than 23 kg/m2) had NAFLD and identified sarcopenia as a significant risk factor for NAFLD in these lean patients (abstract 59). “Sarcopenia is something that we really need to pay a lot more attention to,” Dr. Watt said.
Other studies better outlined the increasing association between NAFLD and hepatocellular carcinoma, Dr. Watt noted (abstracts 2119 and 2102). Another study confirmed that men with NAFLD/NASH have almost twice the incidence of hepatocellular carcinoma (HCC) as women — 0.43%-0.5% vs. 0.22%-0.28%, with both groups significantly higher than the general population (abstract 2116). “And looking further, we can actually quote an HCC incidence in NASH of 0.009%,” she added.
Again emphasizing the multisystem impact of NAFLD, Dr. Watt cited a study that calculated the cardiovascular risks incumbent with liver disease. Researchers reported that men and women at the time of NAFLD diagnosis had significantly higher rates of either angina/ischemic heart disease or heart failure (abstract 55). Women, specifically, had a higher risk for cardiovascular events earlier than men and overall are at equal risk to men, unlike in the general population where women are at lower risk. “We need to start looking at screening and prevention of other diseases in our patients with NASH,” Dr. Watt said. “In addition, we need to be more aware of the elevated risk in these patients and not just approach them in the same way as the general population.”
Physicians may be tempted to discontinue statin therapy in patients with chronic liver disease, but Dr. Watt cited a poster that showed that this results in worse outcomes (abstract 2106). The researchers found that continued statin use was associated with a lower risk of death with compensated and decompensated liver function. “These data help to educate certain patients of their risk of decompensation over time,” Dr. Watt said.
An international study determined that the severity of advanced compensated liver disease is a key determinant in outcomes, finding that those with bridging fibrosis are at greater risk of vascular events, but those with cirrhosis and Child-Turcotte-Pugh A5 and A6 disease have much higher risks of hepatic decompensation and HCC out to 14 years (abstract 60). “The reason to look at these is to be able to tell your patients that they probably have a 30% increased risk of decompensation by 4 years,” Dr. Watt said.
Dr. Watt pointed out three studies that shed more light on important biomarkers of NAFLD. One study reported that three biomarkers – alpha-2-macroglobulin, hyaluronic acid, and tissue inhibitor of metalloproteinase-1 – have a high sensitivity for differentiating low-stage and stage F3-F4 disease (abstract 95). Another study found that a measure using Pro-C3 and other clinical markers were predictive of F3 or F4 fibrosis in NAFLD (abstract 93). And, other researchers found that a HepQuant-STAT measure of greater than 0.50 microM in patients who ingested deuterated cholic acid (d4-CA) solution may be a minimally invasive alternative to biopsy for diagnosing NASH (abstract 96).
Management studies focusing on varying targets were also presented. A trial of fibroblast growth factor–21 for treatment of NAFLD found that patients in the 10- and 20-mg dose arms showed improvement in MRI hepatic fat fraction, ALT, AST, and liver stiffness at 16 weeks vs. placebo. A few patients had some mild elevation to their liver enzymes on treatment (abstract 182). “So I think we need to remain cautious and watch these patients closely, but overall it seems to be reasonably safe data,” she said. Another drug trial of the acetyl-CoA carboxylase inhibitor GS-0976 also showed promise for overall improvement in MRI steatosis measures (abstract LB-9).
Three preclinical studies of dual-agent therapies in animals have demonstrated improvement in inflammatory and fibrosis scores, Dr. Watt noted (abstracts 2,000, 2,002 and 2,052). “There’s no one drug that’s going to be likely the magic cure,” Dr. Watt said. “There will likely be a lot more focus and data coming out on dual-action agents.” Another animal study addressed the burning question if decaffeinated coffee has the same protective effect against NASH as caffeinated coffee (abstract 2093). Said Dr. Watt: “If you are interested in the potential benefits of coffee but really can’t handle the caffeine, this study suggests, you may still be OK.”
Finally, Dr. Watt noted an early study of three-dimensional printing has shown potential for replicating NASH tissue for bench studies (abstract 1963). “3-D printing is certainly a wave of the future,” she said, pointing out that researchers have created a 3-D model that has some metabolic equivalency to NASH, with the inflammatory cytokine release, hepatic stellate cell activation, “and all of the features that we see in NASH. This may be of potential use down the road to avoid relying on animal models in preclinical studies.”
The Liver Meeting next convenes Nov. 9-13, 2018, in San Francisco.
Dr. Watt disclosed ties to Bristol-Myers Squibb, Exelixis, and Seattle Genetics.
AT THE LIVER MEETING 2017
Key clinical point: Nonalcoholic fatty liver disease involves treatment and management of multiple systems.
Major finding: Physicians managing NAFLD must target insulin resistance, lipid metabolism, oxidative stress, and more.
Data source: Debrief of key abstracts on NAFLD presented at the Liver Meeting 2017.
Disclosures: Dr. Watt reported having relationships with Bristol-Myers Squibb, Exelixis, and Seattle Genetics.
Living liver donation safety supported in single-center study
SCOTTSDALE, ARIZ. – A single-center analysis of complications following living liver donation found a low rate of severe complications, and a high quality of life among donors. The results are similar to what has been seen in a previous multicenter study in the United States, and the authors hope that the results can help inform potential donors and their physicians.
There is a significant shortage of deceased liver donors, leading to the death of about 3,500 liver transplant hopefuls in 2016, compared with about 2,900 who received a transplant. Living donor transplant was developed and first attempted in 1996 as an attempt to counter this shortage, and for a brief period it was popular, peaking at 500 donor surgeries in 2001. But that year the death of a donor occurred in New York and received widespread publicity.
Overall, though, the study showed relatively few complications, and that donors reported good quality of life. “There was a slight dip in health-related quality of life at 5 years and 10 years, but at all times the donors had significantly better quality of life compared to the standard population,” said Dr. Chinnakotla, clinical director of pediatric transplantation at the University of Minnesota, Minneapolis.
The researchers examined long-term complications and quality of life among 176 liver donors who underwent surgery between 1997 and 2016 at the University of Minnesota. At total of 140 donors underwent a right-lobe hepatectomy without middle hepatic vein, 14 underwent right lobe with middle hepatic vein, 4 underwent left lobe, and 18 underwent left lateral segmentectomy.
The researchers then analyzed complications graded by the Clavien scale. They found that 59.1% of right-lobe donors experienced no complications at all; 5.8% had Clavien scale 1 complications, meaning something abnormal occurred but required no intervention; and 27.3% had a Clavien 2 complication, requiring pharmaceutical treatment, a blood transfusion, or parenteral nutrition. Clavien 3a complications, which required an intervention without general anesthesia, occurred in 1.9% of cases, and Clavien 3b complications, which required anesthesia, occurred in 5.8%.
A total of 81.8% of left-lobe donors experienced no complications, 4.5% had a Clavien 1 complication, and 13.6% a Clavien 2. There were no Clavien 3 or 4 complications in left-lobe donors.
Overall, the incidence of Clavien grade 3 or higher complications was 7%, there were no complications involving organ failure, and there were no deaths.
Quality of life, as measured by the 36-item Short Form Health Survey and an internally designed donor-specific survey, was higher among recipients than in the general population at all time points. The primary long-term complaints were incisional discomfort, which ranged from about 23% to 38% in frequency, and intolerance to fatty meals, which had a frequency of 20%-30%, and is likely attributable to accompanying cholecystectomy, according to Dr. Chinnakotla.
“The overall results appear to have been excellent,” said William C. Chapman, MD, who was invited by the meeting organizers to review and comment on the study. Dr. Chapman is surgical director of transplant surgery at Washington University in St. Louis.
Dr. Chapman also noted that some studies in Asia have looked at reducing complications in donors, while avoiding a small-for-size graft, by using two left-lobe grafts from separate living donors (Liver Transpl 2015;21[11]1438-48). “We haven’t been brave enough to do that in the United States, but I think that is a strategy we can look forward to in the future,” said Dr. Chinnakotla.
No funding source was disclosed.
SCOTTSDALE, ARIZ. – A single-center analysis of complications following living liver donation found a low rate of severe complications, and a high quality of life among donors. The results are similar to what has been seen in a previous multicenter study in the United States, and the authors hope that the results can help inform potential donors and their physicians.
There is a significant shortage of deceased liver donors, leading to the death of about 3,500 liver transplant hopefuls in 2016, compared with about 2,900 who received a transplant. Living donor transplant was developed and first attempted in 1996 as an attempt to counter this shortage, and for a brief period it was popular, peaking at 500 donor surgeries in 2001. But that year the death of a donor occurred in New York and received widespread publicity.
Overall, though, the study showed relatively few complications, and that donors reported good quality of life. “There was a slight dip in health-related quality of life at 5 years and 10 years, but at all times the donors had significantly better quality of life compared to the standard population,” said Dr. Chinnakotla, clinical director of pediatric transplantation at the University of Minnesota, Minneapolis.
The researchers examined long-term complications and quality of life among 176 liver donors who underwent surgery between 1997 and 2016 at the University of Minnesota. At total of 140 donors underwent a right-lobe hepatectomy without middle hepatic vein, 14 underwent right lobe with middle hepatic vein, 4 underwent left lobe, and 18 underwent left lateral segmentectomy.
The researchers then analyzed complications graded by the Clavien scale. They found that 59.1% of right-lobe donors experienced no complications at all; 5.8% had Clavien scale 1 complications, meaning something abnormal occurred but required no intervention; and 27.3% had a Clavien 2 complication, requiring pharmaceutical treatment, a blood transfusion, or parenteral nutrition. Clavien 3a complications, which required an intervention without general anesthesia, occurred in 1.9% of cases, and Clavien 3b complications, which required anesthesia, occurred in 5.8%.
A total of 81.8% of left-lobe donors experienced no complications, 4.5% had a Clavien 1 complication, and 13.6% a Clavien 2. There were no Clavien 3 or 4 complications in left-lobe donors.
Overall, the incidence of Clavien grade 3 or higher complications was 7%, there were no complications involving organ failure, and there were no deaths.
Quality of life, as measured by the 36-item Short Form Health Survey and an internally designed donor-specific survey, was higher among recipients than in the general population at all time points. The primary long-term complaints were incisional discomfort, which ranged from about 23% to 38% in frequency, and intolerance to fatty meals, which had a frequency of 20%-30%, and is likely attributable to accompanying cholecystectomy, according to Dr. Chinnakotla.
“The overall results appear to have been excellent,” said William C. Chapman, MD, who was invited by the meeting organizers to review and comment on the study. Dr. Chapman is surgical director of transplant surgery at Washington University in St. Louis.
Dr. Chapman also noted that some studies in Asia have looked at reducing complications in donors, while avoiding a small-for-size graft, by using two left-lobe grafts from separate living donors (Liver Transpl 2015;21[11]1438-48). “We haven’t been brave enough to do that in the United States, but I think that is a strategy we can look forward to in the future,” said Dr. Chinnakotla.
No funding source was disclosed.
SCOTTSDALE, ARIZ. – A single-center analysis of complications following living liver donation found a low rate of severe complications, and a high quality of life among donors. The results are similar to what has been seen in a previous multicenter study in the United States, and the authors hope that the results can help inform potential donors and their physicians.
There is a significant shortage of deceased liver donors, leading to the death of about 3,500 liver transplant hopefuls in 2016, compared with about 2,900 who received a transplant. Living donor transplant was developed and first attempted in 1996 as an attempt to counter this shortage, and for a brief period it was popular, peaking at 500 donor surgeries in 2001. But that year the death of a donor occurred in New York and received widespread publicity.
Overall, though, the study showed relatively few complications, and that donors reported good quality of life. “There was a slight dip in health-related quality of life at 5 years and 10 years, but at all times the donors had significantly better quality of life compared to the standard population,” said Dr. Chinnakotla, clinical director of pediatric transplantation at the University of Minnesota, Minneapolis.
The researchers examined long-term complications and quality of life among 176 liver donors who underwent surgery between 1997 and 2016 at the University of Minnesota. At total of 140 donors underwent a right-lobe hepatectomy without middle hepatic vein, 14 underwent right lobe with middle hepatic vein, 4 underwent left lobe, and 18 underwent left lateral segmentectomy.
The researchers then analyzed complications graded by the Clavien scale. They found that 59.1% of right-lobe donors experienced no complications at all; 5.8% had Clavien scale 1 complications, meaning something abnormal occurred but required no intervention; and 27.3% had a Clavien 2 complication, requiring pharmaceutical treatment, a blood transfusion, or parenteral nutrition. Clavien 3a complications, which required an intervention without general anesthesia, occurred in 1.9% of cases, and Clavien 3b complications, which required anesthesia, occurred in 5.8%.
A total of 81.8% of left-lobe donors experienced no complications, 4.5% had a Clavien 1 complication, and 13.6% a Clavien 2. There were no Clavien 3 or 4 complications in left-lobe donors.
Overall, the incidence of Clavien grade 3 or higher complications was 7%, there were no complications involving organ failure, and there were no deaths.
Quality of life, as measured by the 36-item Short Form Health Survey and an internally designed donor-specific survey, was higher among recipients than in the general population at all time points. The primary long-term complaints were incisional discomfort, which ranged from about 23% to 38% in frequency, and intolerance to fatty meals, which had a frequency of 20%-30%, and is likely attributable to accompanying cholecystectomy, according to Dr. Chinnakotla.
“The overall results appear to have been excellent,” said William C. Chapman, MD, who was invited by the meeting organizers to review and comment on the study. Dr. Chapman is surgical director of transplant surgery at Washington University in St. Louis.
Dr. Chapman also noted that some studies in Asia have looked at reducing complications in donors, while avoiding a small-for-size graft, by using two left-lobe grafts from separate living donors (Liver Transpl 2015;21[11]1438-48). “We haven’t been brave enough to do that in the United States, but I think that is a strategy we can look forward to in the future,” said Dr. Chinnakotla.
No funding source was disclosed.
AT WSA 2017
Statin didn’t slow hepatic steatosis in HIV patients
SAN DIEGO – Statin therapy wasn’t effective against a rising rate of hepatic steatosis in HIV patients, and may increase nonalcoholic fatty liver disease (NAFLD) risk, according to a small study.
The findings are contrary to the limited data currently available, which suggest statins can have a beneficial effect on hepatic steatosis, according to the study’s investigators.
NAFLD is one of the leading causes of mortality and morbidity in people living with HIV, said Vanessa El Kamari, MD, of Case Western Reserve University, Cleveland, and rates are continuing to increase. With a lack of therapeutic interventions for NAFLD in patients with HIV, finding effective treatments is a major concern for providers.
Dr. El Kamari and her colleagues conducted a secondary analysis of the SATURN-HIV trial, a randomized, placebo-controlled trial of 147 patients with HIV who were on stable antiretroviral therapy (ART) with LDL cholesterol levels at or below 130 mg/dL. Patients were either treated with 10 mg rosuvastatin or placebo.
Patients in the treatment and placebo arms were an average age of 45 years, most patients were male (81% and 76%, respectively), and a majority was African American (69% and 67%, respectively). The two groups reported average CD4+ counts of 644 and 636, respectively.
Investigators used validated scores to determine hepatic steatosis in patients, although researchers acknowledged that liver biopsy is the gold standard for hepatic steatosis measurement.
“We understand liver fat score has its limitation,” said Dr. El Kamari in a question and answer session following the presentation at an annual scientific meeting on infectious diseases. “Further studies are needed in this area in order to detect, in noninvasive ways, hepatic steatosis.”
Liver fat scores (LFS) were measured on entry, at week 48, and week 96.
After 96 weeks, investigators saw significant increases in LFS in both the placebo and rosuvastatin groups (P = .01 and P less than .01, respectively). Progression from nonsteatosis at baseline to steatosis over 96 weeks was greater in patients given rosuvastatin than in those given placebo (odds ratio, 4.3; P = .03).
Studying predictors for LFS changes, a trend toward insignificance among the randomization group led investigators to the conclusion that statin may have negatively affected the liver fat score of patients over the 96-week time period.
The study researchers identified 92 patients who did not have hepatic steatosis at baseline to study how statins influenced the development of hepatic steatosis.
Of the 13 patients who developed steatosis during the trial period, 10 were part of the rosuvastatin group, while only 3 were from the placebo group.
Increases in LFS were associated with increases in insulin resistance, detected presence of HIV-1 RNA, and higher interferon-inducible proteins, according to Dr. El Kamari.
While increased homeostatic assessment of insulin resistance was associated with increased hepatic homeostasis, Dr. El Kamari was not able to determine if statins that are not associated with insulin resistance will have different outcomes.
The investigators cautioned that the findings may not be generalizable to the entire HIV population due to the overwhelming majority of African American patients with increased inflammation, as well as the study patients’ LDL cholesterol levels of less than or equal to 130 mg/dL.
The National Institutes of Health funded the study. Dr. El Kamari had no disclosures.
[email protected]
On Twitter @eaztweets
SAN DIEGO – Statin therapy wasn’t effective against a rising rate of hepatic steatosis in HIV patients, and may increase nonalcoholic fatty liver disease (NAFLD) risk, according to a small study.
The findings are contrary to the limited data currently available, which suggest statins can have a beneficial effect on hepatic steatosis, according to the study’s investigators.
NAFLD is one of the leading causes of mortality and morbidity in people living with HIV, said Vanessa El Kamari, MD, of Case Western Reserve University, Cleveland, and rates are continuing to increase. With a lack of therapeutic interventions for NAFLD in patients with HIV, finding effective treatments is a major concern for providers.
Dr. El Kamari and her colleagues conducted a secondary analysis of the SATURN-HIV trial, a randomized, placebo-controlled trial of 147 patients with HIV who were on stable antiretroviral therapy (ART) with LDL cholesterol levels at or below 130 mg/dL. Patients were either treated with 10 mg rosuvastatin or placebo.
Patients in the treatment and placebo arms were an average age of 45 years, most patients were male (81% and 76%, respectively), and a majority was African American (69% and 67%, respectively). The two groups reported average CD4+ counts of 644 and 636, respectively.
Investigators used validated scores to determine hepatic steatosis in patients, although researchers acknowledged that liver biopsy is the gold standard for hepatic steatosis measurement.
“We understand liver fat score has its limitation,” said Dr. El Kamari in a question and answer session following the presentation at an annual scientific meeting on infectious diseases. “Further studies are needed in this area in order to detect, in noninvasive ways, hepatic steatosis.”
Liver fat scores (LFS) were measured on entry, at week 48, and week 96.
After 96 weeks, investigators saw significant increases in LFS in both the placebo and rosuvastatin groups (P = .01 and P less than .01, respectively). Progression from nonsteatosis at baseline to steatosis over 96 weeks was greater in patients given rosuvastatin than in those given placebo (odds ratio, 4.3; P = .03).
Studying predictors for LFS changes, a trend toward insignificance among the randomization group led investigators to the conclusion that statin may have negatively affected the liver fat score of patients over the 96-week time period.
The study researchers identified 92 patients who did not have hepatic steatosis at baseline to study how statins influenced the development of hepatic steatosis.
Of the 13 patients who developed steatosis during the trial period, 10 were part of the rosuvastatin group, while only 3 were from the placebo group.
Increases in LFS were associated with increases in insulin resistance, detected presence of HIV-1 RNA, and higher interferon-inducible proteins, according to Dr. El Kamari.
While increased homeostatic assessment of insulin resistance was associated with increased hepatic homeostasis, Dr. El Kamari was not able to determine if statins that are not associated with insulin resistance will have different outcomes.
The investigators cautioned that the findings may not be generalizable to the entire HIV population due to the overwhelming majority of African American patients with increased inflammation, as well as the study patients’ LDL cholesterol levels of less than or equal to 130 mg/dL.
The National Institutes of Health funded the study. Dr. El Kamari had no disclosures.
[email protected]
On Twitter @eaztweets
SAN DIEGO – Statin therapy wasn’t effective against a rising rate of hepatic steatosis in HIV patients, and may increase nonalcoholic fatty liver disease (NAFLD) risk, according to a small study.
The findings are contrary to the limited data currently available, which suggest statins can have a beneficial effect on hepatic steatosis, according to the study’s investigators.
NAFLD is one of the leading causes of mortality and morbidity in people living with HIV, said Vanessa El Kamari, MD, of Case Western Reserve University, Cleveland, and rates are continuing to increase. With a lack of therapeutic interventions for NAFLD in patients with HIV, finding effective treatments is a major concern for providers.
Dr. El Kamari and her colleagues conducted a secondary analysis of the SATURN-HIV trial, a randomized, placebo-controlled trial of 147 patients with HIV who were on stable antiretroviral therapy (ART) with LDL cholesterol levels at or below 130 mg/dL. Patients were either treated with 10 mg rosuvastatin or placebo.
Patients in the treatment and placebo arms were an average age of 45 years, most patients were male (81% and 76%, respectively), and a majority was African American (69% and 67%, respectively). The two groups reported average CD4+ counts of 644 and 636, respectively.
Investigators used validated scores to determine hepatic steatosis in patients, although researchers acknowledged that liver biopsy is the gold standard for hepatic steatosis measurement.
“We understand liver fat score has its limitation,” said Dr. El Kamari in a question and answer session following the presentation at an annual scientific meeting on infectious diseases. “Further studies are needed in this area in order to detect, in noninvasive ways, hepatic steatosis.”
Liver fat scores (LFS) were measured on entry, at week 48, and week 96.
After 96 weeks, investigators saw significant increases in LFS in both the placebo and rosuvastatin groups (P = .01 and P less than .01, respectively). Progression from nonsteatosis at baseline to steatosis over 96 weeks was greater in patients given rosuvastatin than in those given placebo (odds ratio, 4.3; P = .03).
Studying predictors for LFS changes, a trend toward insignificance among the randomization group led investigators to the conclusion that statin may have negatively affected the liver fat score of patients over the 96-week time period.
The study researchers identified 92 patients who did not have hepatic steatosis at baseline to study how statins influenced the development of hepatic steatosis.
Of the 13 patients who developed steatosis during the trial period, 10 were part of the rosuvastatin group, while only 3 were from the placebo group.
Increases in LFS were associated with increases in insulin resistance, detected presence of HIV-1 RNA, and higher interferon-inducible proteins, according to Dr. El Kamari.
While increased homeostatic assessment of insulin resistance was associated with increased hepatic homeostasis, Dr. El Kamari was not able to determine if statins that are not associated with insulin resistance will have different outcomes.
The investigators cautioned that the findings may not be generalizable to the entire HIV population due to the overwhelming majority of African American patients with increased inflammation, as well as the study patients’ LDL cholesterol levels of less than or equal to 130 mg/dL.
The National Institutes of Health funded the study. Dr. El Kamari had no disclosures.
[email protected]
On Twitter @eaztweets
AT IDWEEK 2017
Key clinical point:
Major finding: Progression from nonsteatosis at baseline to steatosis over 96 weeks was greater in patients given rosuvastatin than in those given placebo (odds ratio, 4.3; P = .03).
Data source: A randomized, placebo-controlled study of 147 patients with HIV on stable ART.
Disclosures: The National Institutes of Health funded the study. Dr. El Kamari had no disclosures.
FDA approves first two-dose HBV vaccine
When the Food and Drug Administration approved Heplisav-B Nov. 9, it marked the first new vaccine for hepatitis B virus (HBV) to be sanctioned in over 25 years.
Heplisav-B is the only two-dose regimen that protects against all known subtypes of HBV in adults 18 years and older, according to a statement released by Dynavax Technologies, the creator of the drug.
“Heplisav-B is the first FDA-approved product for Dynavax and demonstrates our ability to develop innovative products and progress them from discovery to commercialization,” according to Eddie Gray, chief executive officer of Dynavax. “We expect that it will become an essential tool in the public health community’s fight to prevent hepatitis B [infection], and we look forward to making Heplisav-B available to clinicians and their adult patients.”
Incidence of HBV has increased sharply from 2012 to 2015 in the United States, with reported cases rising from 2,895 to 3,370, according to the Centers for Disease Control and Prevention.
From 2014 to 2015, acute HBV infection increased 20.7%, according to the CDC report.
The new vaccine’s approval came after review of safety and efficacy data from three phase 3 trials comparing Heplisav-B with Engerix-B, another HBV vaccine currently available, that is given in a three-dose regimen.
In one study of 2,032 patients between the ages of 18 and 55 years, seroprotection rate in the Heplisav-B group (1,511) was 95%, compared with 81.5% in the Engerix-B group (521).
Heplisav-B patients were given a two-dose regimen of the drug at 0 and 1 months, followed by a placebo at 6 months, while investigators administered Engerix-B at all three intervals in the comparator subjects.
The FDA’s decision to green-light the new vaccine follows a recommendation for approval from the FDA’s Vaccines and Related Biological Products Advisory Committee, held at the end of July this year.
During the advisory committee meeting, members were concerned about an increased relative risk for acute myocardial infarction of 6.97 in Heplisav-B patients (14), compared with Engerix-B patients (1).
The recommendation for approval came with the caveat of conducting postmarketing analysis for the risk of AMI in Heplisav-B patients, which Dynavax is conducting through the Kaiser Permanente system in California.
“To evaluate the risk of AMIs, the study will enroll 25,000 Heplisav-B patients and 25,000 Engerix-B patients over approximately 10 months and follow them for 1 year after vaccination,” according to a statement from Dynavax. “In addition we will evaluate the rate of immune-mediated diseases in these patients in an additional 5,000 Heplisav-B recipients and 5,000 Engerix-B recipients.”
Dynavax is currently set to introduce Heplisav-B commercially in the United States in 2018, with the cost of the drug set to be released soon.
“Dynavax is in the process of finalizing the price of a two-dose series of Heplisav-B, and they plan to disclose it shortly after approval,” according to the company. “Their pricing and access strategy will be aimed at ensuring that populations at risk of infection are able to access this new vaccine, while recognizing the value it brings to the health care system with a two-dose regimen and higher rates of protection compared to Engerix-B.”
[email protected]
On Twitter @eaztweets
When the Food and Drug Administration approved Heplisav-B Nov. 9, it marked the first new vaccine for hepatitis B virus (HBV) to be sanctioned in over 25 years.
Heplisav-B is the only two-dose regimen that protects against all known subtypes of HBV in adults 18 years and older, according to a statement released by Dynavax Technologies, the creator of the drug.
“Heplisav-B is the first FDA-approved product for Dynavax and demonstrates our ability to develop innovative products and progress them from discovery to commercialization,” according to Eddie Gray, chief executive officer of Dynavax. “We expect that it will become an essential tool in the public health community’s fight to prevent hepatitis B [infection], and we look forward to making Heplisav-B available to clinicians and their adult patients.”
Incidence of HBV has increased sharply from 2012 to 2015 in the United States, with reported cases rising from 2,895 to 3,370, according to the Centers for Disease Control and Prevention.
From 2014 to 2015, acute HBV infection increased 20.7%, according to the CDC report.
The new vaccine’s approval came after review of safety and efficacy data from three phase 3 trials comparing Heplisav-B with Engerix-B, another HBV vaccine currently available, that is given in a three-dose regimen.
In one study of 2,032 patients between the ages of 18 and 55 years, seroprotection rate in the Heplisav-B group (1,511) was 95%, compared with 81.5% in the Engerix-B group (521).
Heplisav-B patients were given a two-dose regimen of the drug at 0 and 1 months, followed by a placebo at 6 months, while investigators administered Engerix-B at all three intervals in the comparator subjects.
The FDA’s decision to green-light the new vaccine follows a recommendation for approval from the FDA’s Vaccines and Related Biological Products Advisory Committee, held at the end of July this year.
During the advisory committee meeting, members were concerned about an increased relative risk for acute myocardial infarction of 6.97 in Heplisav-B patients (14), compared with Engerix-B patients (1).
The recommendation for approval came with the caveat of conducting postmarketing analysis for the risk of AMI in Heplisav-B patients, which Dynavax is conducting through the Kaiser Permanente system in California.
“To evaluate the risk of AMIs, the study will enroll 25,000 Heplisav-B patients and 25,000 Engerix-B patients over approximately 10 months and follow them for 1 year after vaccination,” according to a statement from Dynavax. “In addition we will evaluate the rate of immune-mediated diseases in these patients in an additional 5,000 Heplisav-B recipients and 5,000 Engerix-B recipients.”
Dynavax is currently set to introduce Heplisav-B commercially in the United States in 2018, with the cost of the drug set to be released soon.
“Dynavax is in the process of finalizing the price of a two-dose series of Heplisav-B, and they plan to disclose it shortly after approval,” according to the company. “Their pricing and access strategy will be aimed at ensuring that populations at risk of infection are able to access this new vaccine, while recognizing the value it brings to the health care system with a two-dose regimen and higher rates of protection compared to Engerix-B.”
[email protected]
On Twitter @eaztweets
When the Food and Drug Administration approved Heplisav-B Nov. 9, it marked the first new vaccine for hepatitis B virus (HBV) to be sanctioned in over 25 years.
Heplisav-B is the only two-dose regimen that protects against all known subtypes of HBV in adults 18 years and older, according to a statement released by Dynavax Technologies, the creator of the drug.
“Heplisav-B is the first FDA-approved product for Dynavax and demonstrates our ability to develop innovative products and progress them from discovery to commercialization,” according to Eddie Gray, chief executive officer of Dynavax. “We expect that it will become an essential tool in the public health community’s fight to prevent hepatitis B [infection], and we look forward to making Heplisav-B available to clinicians and their adult patients.”
Incidence of HBV has increased sharply from 2012 to 2015 in the United States, with reported cases rising from 2,895 to 3,370, according to the Centers for Disease Control and Prevention.
From 2014 to 2015, acute HBV infection increased 20.7%, according to the CDC report.
The new vaccine’s approval came after review of safety and efficacy data from three phase 3 trials comparing Heplisav-B with Engerix-B, another HBV vaccine currently available, that is given in a three-dose regimen.
In one study of 2,032 patients between the ages of 18 and 55 years, seroprotection rate in the Heplisav-B group (1,511) was 95%, compared with 81.5% in the Engerix-B group (521).
Heplisav-B patients were given a two-dose regimen of the drug at 0 and 1 months, followed by a placebo at 6 months, while investigators administered Engerix-B at all three intervals in the comparator subjects.
The FDA’s decision to green-light the new vaccine follows a recommendation for approval from the FDA’s Vaccines and Related Biological Products Advisory Committee, held at the end of July this year.
During the advisory committee meeting, members were concerned about an increased relative risk for acute myocardial infarction of 6.97 in Heplisav-B patients (14), compared with Engerix-B patients (1).
The recommendation for approval came with the caveat of conducting postmarketing analysis for the risk of AMI in Heplisav-B patients, which Dynavax is conducting through the Kaiser Permanente system in California.
“To evaluate the risk of AMIs, the study will enroll 25,000 Heplisav-B patients and 25,000 Engerix-B patients over approximately 10 months and follow them for 1 year after vaccination,” according to a statement from Dynavax. “In addition we will evaluate the rate of immune-mediated diseases in these patients in an additional 5,000 Heplisav-B recipients and 5,000 Engerix-B recipients.”
Dynavax is currently set to introduce Heplisav-B commercially in the United States in 2018, with the cost of the drug set to be released soon.
“Dynavax is in the process of finalizing the price of a two-dose series of Heplisav-B, and they plan to disclose it shortly after approval,” according to the company. “Their pricing and access strategy will be aimed at ensuring that populations at risk of infection are able to access this new vaccine, while recognizing the value it brings to the health care system with a two-dose regimen and higher rates of protection compared to Engerix-B.”
[email protected]
On Twitter @eaztweets
Clinical hepatology debrief wraps up 2017 Liver Meeting
WASHINGTON – Research into alcoholic liver disease, drug-induced liver injury, the complications of chronic liver disease, and cholestatic liver diseases were among the clinical hepatology highlights presented at the annual meeting of the American Association for the Study of Liver Diseases.
This year’s debrief was given by Kris V. Kowdley, MD, of Swedish Medical Center in Seattle.
Over a median of 1.6 years of follow-up, 27% of patients resumed alcohol consumption post transplant with a median time to alcohol of 160 days, according to Brian Lee, MD, of the University of California, San Francisco. Younger age and lack of complete acceptance of their alcoholic hepatitis diagnosis were significant predictors of alcohol use post transplant while factors such as length of abstinence, race/ethnicity, insurance status, history of illicit drug use, and history of failed rehab attempts were not. Further, heavy drinking at presentation (more than 10 drinks per day), any alcohol use post transplant, and sustained alcohol use post transplant were significant predictors of posttransplant death.
Alcoholic hepatitis now “appears to be affecting more and more younger women, who present with a higher level of acuity,” Dr. Kowdley noted. He added that, while recent advances have decreased the absolute number of hepatitis C patients with decompensated liver disease who are listed for liver transplant, “the number is increasing rapidly in alcoholic liver disease, approaching the rate of patients being listed for hepatitis C.”
Unknown ingredients in herbal and dietary supplements continue to be of concern, Dr. Kowdley noted, as highlighted by Victor J. Navarro, MD, of Einstein Healthcare Network, Philadelphia, and his colleagues at the Drug-Induced Liver Injury Network (DILIN).
Investigators collected herbal and dietary supplements from patients enrolled in the DILIN prospective study and had chemical analysis performed by an outside laboratory. Labeled contents could not be verified in over half of the supplements collected and several unlabeled hepatotoxic ingredients were identified, Dr. Navarro and colleagues found (abstract 264).
“Even though we collect the supplements and review them with the patients, it’s not clear that we even know what it is that they are taking,” Dr. Kowdley commented.
Another DILIN study, this one presented by Jawad Ahmad, MD, of the Icahn School of Medicine at Mount Sinai, New York, “provided an opportunity for pause,” Dr. Kowdley said.
Dr. Ahmad and colleagues looked at hepatitis C virus (HCV) testing in DILIN patients and were able to correlate anti-HCV test results with HCV RNA tests results in more than 95% of 1,500 patients (abstract 16). About 7% of patients were HCV positive, and 23 cases of acute hepatitis were identified (16 with anti-HCV antibodies and HCV RNA, 7 with HCV RNA alone, and none with anti-HCV antibodies alone).
“So the take-home message here for me is, even if we think the patient has drug-induced liver injury, if they have not been tested for hepatitis C, especially if in the hospitalized setting … it is important to check not only the antibody test but also the RNA test,” Dr. Kowdley said.
Finally, in children, minocycline and valproate were the most commonly indicated agents in pediatric drug-induced liver injury, according to Frank DiPaola, MD, of the University of Michigan, and colleagues, on behalf of DILIN (abstract 13).
Dr. Kowdley also highlighted a couple of studies that addressed the complications of chronic liver disease.
The ADAPT-1 and ADAPT-2 trials (abstract 217) studied the use of avatrombopag, a thrombopoietin (TPO)–receptor agonist, to reduce severe thrombocytopenia in patients with chronic liver disease. Platelet transfusion is the current standard of care to reduce the risk of bleeding during invasive procedures in these patients; currently there are no drugs approved for this indication, Dr. Kowdley said.
Avatrombopag is an oral, small molecule TPO-receptor agonist, he said. “Because it binds to a different site on the TPO receptor than endogenous TPO, the effects are additive.”
In the phase 3 ADAPT-1 and ADAPT-2, the proportion of patients who did not require platelet transfusion or any rescue procedure for bleeding was significantly less in avatrombopag-treated patients than those receiving placebo. The effect was the same for patients with a low baseline platelet count (less than 40,000 platelets per mcL) as well as those with a high baseline platelet count (between 40,000/mcL and 50,000/mcL). Further, the proportion of patients who by procedure day achieved platelet count of at least 50,000/mcL was significantly higher in patients on the study drug.
Data on lusutrombopag, another TPO-receptor agonist, was presented as a late-breaker at the meeting, with very similar results in avoiding platelet transfusion, Dr. Kowdley noted.Two abstracts (502 and 219) focused on reducing ammonia levels in hospitalized cirrhosis patients with hepatic encephalitis.
Patients in the STOP-HE trial were randomized to either physician’s choice for standard of care or standard of care plus continuous infusion of ornithine phenylacetate for up to 5 days. Patients were assigned to one of three dosing groups (20 g, 15 g, or 10 g), based on severity of underlying liver disease; those with the most severe disease received the lowest dose.
Reduction in plasma ammonia levels correlated significantly with clinical improvement. At 48 hours, meaningful clinical improvement occurred in 84% of patients on ornithine phenylacetate, compared with 58% of placebo patients, according to Robert S. Rahimi, MD, of Baylor University, Dallas, and his colleagues.
“So, this may be an option for our hepatic encephalopathy patients who are admitted to the hospital and need acute treatment,” Dr. Kowdley said.
Dr. Kowdley finished up with two studies on primary biliary cholangitis (PBC).
Carla Murillo Perez, MD, of Toronto General Hospital and her colleagues in the Global PBC Study Group investigated the role of serum bilirubin in predicting transplant-free survival in patients with PBC (abstract 70).
When serum bilirubin levels from a previous study were input into a Cox regression analysis as a cubic spline function, then adjusted for factors such as age, sex, treatment with ursodeoxycholic acid, and year of diagnosis, the investigators found that patients with serum bilirubin levels of 0.7 times the upper limit of normal had a significantly increased risk of liver transplantation or death.
“We may want to be more sensitive in looking at bilirubin levels,” Dr. Kowdley said.
Another small but notable study presented by Gideon M. Hirschfield, MD, of the University of Birmingham (England), looked into whether a lower dose of seladelpar would safely and effectively lower alkaline phosphatase (AP) levels in PBC patients. A previous study of seladelpar at 50 mg and 200 mg doses indicated the drug’s effectiveness; however, the study was stopped because of the development of grade 3 alanine aminotransferase increases in a number of patients (Lancet Gastroenterol Hepatol. 2017;2;716-26).
Dr. Hirschfield and colleagues enrolled 24 patients and randomized 12 to seladelpar 5 mg and another 12 to 10 mg. The study cohort was mostly female, with an average age of 58 years. Most were either intolerant of or inadequately treated by ursodeoxycholic acid. AP levels were reduced significantly over time in both groups; however, differences between the groups were not significant, the investigators noted.
The Liver Meeting will be held in San Francisco in 2018, taking place Nov. 9-13. Many investigators in these trials reported relevant conflicts of interest; information is available (open access) in a supplement to Hepatology.
[email protected]
On Twitter @denisefulton
WASHINGTON – Research into alcoholic liver disease, drug-induced liver injury, the complications of chronic liver disease, and cholestatic liver diseases were among the clinical hepatology highlights presented at the annual meeting of the American Association for the Study of Liver Diseases.
This year’s debrief was given by Kris V. Kowdley, MD, of Swedish Medical Center in Seattle.
Over a median of 1.6 years of follow-up, 27% of patients resumed alcohol consumption post transplant with a median time to alcohol of 160 days, according to Brian Lee, MD, of the University of California, San Francisco. Younger age and lack of complete acceptance of their alcoholic hepatitis diagnosis were significant predictors of alcohol use post transplant while factors such as length of abstinence, race/ethnicity, insurance status, history of illicit drug use, and history of failed rehab attempts were not. Further, heavy drinking at presentation (more than 10 drinks per day), any alcohol use post transplant, and sustained alcohol use post transplant were significant predictors of posttransplant death.
Alcoholic hepatitis now “appears to be affecting more and more younger women, who present with a higher level of acuity,” Dr. Kowdley noted. He added that, while recent advances have decreased the absolute number of hepatitis C patients with decompensated liver disease who are listed for liver transplant, “the number is increasing rapidly in alcoholic liver disease, approaching the rate of patients being listed for hepatitis C.”
Unknown ingredients in herbal and dietary supplements continue to be of concern, Dr. Kowdley noted, as highlighted by Victor J. Navarro, MD, of Einstein Healthcare Network, Philadelphia, and his colleagues at the Drug-Induced Liver Injury Network (DILIN).
Investigators collected herbal and dietary supplements from patients enrolled in the DILIN prospective study and had chemical analysis performed by an outside laboratory. Labeled contents could not be verified in over half of the supplements collected and several unlabeled hepatotoxic ingredients were identified, Dr. Navarro and colleagues found (abstract 264).
“Even though we collect the supplements and review them with the patients, it’s not clear that we even know what it is that they are taking,” Dr. Kowdley commented.
Another DILIN study, this one presented by Jawad Ahmad, MD, of the Icahn School of Medicine at Mount Sinai, New York, “provided an opportunity for pause,” Dr. Kowdley said.
Dr. Ahmad and colleagues looked at hepatitis C virus (HCV) testing in DILIN patients and were able to correlate anti-HCV test results with HCV RNA tests results in more than 95% of 1,500 patients (abstract 16). About 7% of patients were HCV positive, and 23 cases of acute hepatitis were identified (16 with anti-HCV antibodies and HCV RNA, 7 with HCV RNA alone, and none with anti-HCV antibodies alone).
“So the take-home message here for me is, even if we think the patient has drug-induced liver injury, if they have not been tested for hepatitis C, especially if in the hospitalized setting … it is important to check not only the antibody test but also the RNA test,” Dr. Kowdley said.
Finally, in children, minocycline and valproate were the most commonly indicated agents in pediatric drug-induced liver injury, according to Frank DiPaola, MD, of the University of Michigan, and colleagues, on behalf of DILIN (abstract 13).
Dr. Kowdley also highlighted a couple of studies that addressed the complications of chronic liver disease.
The ADAPT-1 and ADAPT-2 trials (abstract 217) studied the use of avatrombopag, a thrombopoietin (TPO)–receptor agonist, to reduce severe thrombocytopenia in patients with chronic liver disease. Platelet transfusion is the current standard of care to reduce the risk of bleeding during invasive procedures in these patients; currently there are no drugs approved for this indication, Dr. Kowdley said.
Avatrombopag is an oral, small molecule TPO-receptor agonist, he said. “Because it binds to a different site on the TPO receptor than endogenous TPO, the effects are additive.”
In the phase 3 ADAPT-1 and ADAPT-2, the proportion of patients who did not require platelet transfusion or any rescue procedure for bleeding was significantly less in avatrombopag-treated patients than those receiving placebo. The effect was the same for patients with a low baseline platelet count (less than 40,000 platelets per mcL) as well as those with a high baseline platelet count (between 40,000/mcL and 50,000/mcL). Further, the proportion of patients who by procedure day achieved platelet count of at least 50,000/mcL was significantly higher in patients on the study drug.
Data on lusutrombopag, another TPO-receptor agonist, was presented as a late-breaker at the meeting, with very similar results in avoiding platelet transfusion, Dr. Kowdley noted.Two abstracts (502 and 219) focused on reducing ammonia levels in hospitalized cirrhosis patients with hepatic encephalitis.
Patients in the STOP-HE trial were randomized to either physician’s choice for standard of care or standard of care plus continuous infusion of ornithine phenylacetate for up to 5 days. Patients were assigned to one of three dosing groups (20 g, 15 g, or 10 g), based on severity of underlying liver disease; those with the most severe disease received the lowest dose.
Reduction in plasma ammonia levels correlated significantly with clinical improvement. At 48 hours, meaningful clinical improvement occurred in 84% of patients on ornithine phenylacetate, compared with 58% of placebo patients, according to Robert S. Rahimi, MD, of Baylor University, Dallas, and his colleagues.
“So, this may be an option for our hepatic encephalopathy patients who are admitted to the hospital and need acute treatment,” Dr. Kowdley said.
Dr. Kowdley finished up with two studies on primary biliary cholangitis (PBC).
Carla Murillo Perez, MD, of Toronto General Hospital and her colleagues in the Global PBC Study Group investigated the role of serum bilirubin in predicting transplant-free survival in patients with PBC (abstract 70).
When serum bilirubin levels from a previous study were input into a Cox regression analysis as a cubic spline function, then adjusted for factors such as age, sex, treatment with ursodeoxycholic acid, and year of diagnosis, the investigators found that patients with serum bilirubin levels of 0.7 times the upper limit of normal had a significantly increased risk of liver transplantation or death.
“We may want to be more sensitive in looking at bilirubin levels,” Dr. Kowdley said.
Another small but notable study presented by Gideon M. Hirschfield, MD, of the University of Birmingham (England), looked into whether a lower dose of seladelpar would safely and effectively lower alkaline phosphatase (AP) levels in PBC patients. A previous study of seladelpar at 50 mg and 200 mg doses indicated the drug’s effectiveness; however, the study was stopped because of the development of grade 3 alanine aminotransferase increases in a number of patients (Lancet Gastroenterol Hepatol. 2017;2;716-26).
Dr. Hirschfield and colleagues enrolled 24 patients and randomized 12 to seladelpar 5 mg and another 12 to 10 mg. The study cohort was mostly female, with an average age of 58 years. Most were either intolerant of or inadequately treated by ursodeoxycholic acid. AP levels were reduced significantly over time in both groups; however, differences between the groups were not significant, the investigators noted.
The Liver Meeting will be held in San Francisco in 2018, taking place Nov. 9-13. Many investigators in these trials reported relevant conflicts of interest; information is available (open access) in a supplement to Hepatology.
[email protected]
On Twitter @denisefulton
WASHINGTON – Research into alcoholic liver disease, drug-induced liver injury, the complications of chronic liver disease, and cholestatic liver diseases were among the clinical hepatology highlights presented at the annual meeting of the American Association for the Study of Liver Diseases.
This year’s debrief was given by Kris V. Kowdley, MD, of Swedish Medical Center in Seattle.
Over a median of 1.6 years of follow-up, 27% of patients resumed alcohol consumption post transplant with a median time to alcohol of 160 days, according to Brian Lee, MD, of the University of California, San Francisco. Younger age and lack of complete acceptance of their alcoholic hepatitis diagnosis were significant predictors of alcohol use post transplant while factors such as length of abstinence, race/ethnicity, insurance status, history of illicit drug use, and history of failed rehab attempts were not. Further, heavy drinking at presentation (more than 10 drinks per day), any alcohol use post transplant, and sustained alcohol use post transplant were significant predictors of posttransplant death.
Alcoholic hepatitis now “appears to be affecting more and more younger women, who present with a higher level of acuity,” Dr. Kowdley noted. He added that, while recent advances have decreased the absolute number of hepatitis C patients with decompensated liver disease who are listed for liver transplant, “the number is increasing rapidly in alcoholic liver disease, approaching the rate of patients being listed for hepatitis C.”
Unknown ingredients in herbal and dietary supplements continue to be of concern, Dr. Kowdley noted, as highlighted by Victor J. Navarro, MD, of Einstein Healthcare Network, Philadelphia, and his colleagues at the Drug-Induced Liver Injury Network (DILIN).
Investigators collected herbal and dietary supplements from patients enrolled in the DILIN prospective study and had chemical analysis performed by an outside laboratory. Labeled contents could not be verified in over half of the supplements collected and several unlabeled hepatotoxic ingredients were identified, Dr. Navarro and colleagues found (abstract 264).
“Even though we collect the supplements and review them with the patients, it’s not clear that we even know what it is that they are taking,” Dr. Kowdley commented.
Another DILIN study, this one presented by Jawad Ahmad, MD, of the Icahn School of Medicine at Mount Sinai, New York, “provided an opportunity for pause,” Dr. Kowdley said.
Dr. Ahmad and colleagues looked at hepatitis C virus (HCV) testing in DILIN patients and were able to correlate anti-HCV test results with HCV RNA tests results in more than 95% of 1,500 patients (abstract 16). About 7% of patients were HCV positive, and 23 cases of acute hepatitis were identified (16 with anti-HCV antibodies and HCV RNA, 7 with HCV RNA alone, and none with anti-HCV antibodies alone).
“So the take-home message here for me is, even if we think the patient has drug-induced liver injury, if they have not been tested for hepatitis C, especially if in the hospitalized setting … it is important to check not only the antibody test but also the RNA test,” Dr. Kowdley said.
Finally, in children, minocycline and valproate were the most commonly indicated agents in pediatric drug-induced liver injury, according to Frank DiPaola, MD, of the University of Michigan, and colleagues, on behalf of DILIN (abstract 13).
Dr. Kowdley also highlighted a couple of studies that addressed the complications of chronic liver disease.
The ADAPT-1 and ADAPT-2 trials (abstract 217) studied the use of avatrombopag, a thrombopoietin (TPO)–receptor agonist, to reduce severe thrombocytopenia in patients with chronic liver disease. Platelet transfusion is the current standard of care to reduce the risk of bleeding during invasive procedures in these patients; currently there are no drugs approved for this indication, Dr. Kowdley said.
Avatrombopag is an oral, small molecule TPO-receptor agonist, he said. “Because it binds to a different site on the TPO receptor than endogenous TPO, the effects are additive.”
In the phase 3 ADAPT-1 and ADAPT-2, the proportion of patients who did not require platelet transfusion or any rescue procedure for bleeding was significantly less in avatrombopag-treated patients than those receiving placebo. The effect was the same for patients with a low baseline platelet count (less than 40,000 platelets per mcL) as well as those with a high baseline platelet count (between 40,000/mcL and 50,000/mcL). Further, the proportion of patients who by procedure day achieved platelet count of at least 50,000/mcL was significantly higher in patients on the study drug.
Data on lusutrombopag, another TPO-receptor agonist, was presented as a late-breaker at the meeting, with very similar results in avoiding platelet transfusion, Dr. Kowdley noted.Two abstracts (502 and 219) focused on reducing ammonia levels in hospitalized cirrhosis patients with hepatic encephalitis.
Patients in the STOP-HE trial were randomized to either physician’s choice for standard of care or standard of care plus continuous infusion of ornithine phenylacetate for up to 5 days. Patients were assigned to one of three dosing groups (20 g, 15 g, or 10 g), based on severity of underlying liver disease; those with the most severe disease received the lowest dose.
Reduction in plasma ammonia levels correlated significantly with clinical improvement. At 48 hours, meaningful clinical improvement occurred in 84% of patients on ornithine phenylacetate, compared with 58% of placebo patients, according to Robert S. Rahimi, MD, of Baylor University, Dallas, and his colleagues.
“So, this may be an option for our hepatic encephalopathy patients who are admitted to the hospital and need acute treatment,” Dr. Kowdley said.
Dr. Kowdley finished up with two studies on primary biliary cholangitis (PBC).
Carla Murillo Perez, MD, of Toronto General Hospital and her colleagues in the Global PBC Study Group investigated the role of serum bilirubin in predicting transplant-free survival in patients with PBC (abstract 70).
When serum bilirubin levels from a previous study were input into a Cox regression analysis as a cubic spline function, then adjusted for factors such as age, sex, treatment with ursodeoxycholic acid, and year of diagnosis, the investigators found that patients with serum bilirubin levels of 0.7 times the upper limit of normal had a significantly increased risk of liver transplantation or death.
“We may want to be more sensitive in looking at bilirubin levels,” Dr. Kowdley said.
Another small but notable study presented by Gideon M. Hirschfield, MD, of the University of Birmingham (England), looked into whether a lower dose of seladelpar would safely and effectively lower alkaline phosphatase (AP) levels in PBC patients. A previous study of seladelpar at 50 mg and 200 mg doses indicated the drug’s effectiveness; however, the study was stopped because of the development of grade 3 alanine aminotransferase increases in a number of patients (Lancet Gastroenterol Hepatol. 2017;2;716-26).
Dr. Hirschfield and colleagues enrolled 24 patients and randomized 12 to seladelpar 5 mg and another 12 to 10 mg. The study cohort was mostly female, with an average age of 58 years. Most were either intolerant of or inadequately treated by ursodeoxycholic acid. AP levels were reduced significantly over time in both groups; however, differences between the groups were not significant, the investigators noted.
The Liver Meeting will be held in San Francisco in 2018, taking place Nov. 9-13. Many investigators in these trials reported relevant conflicts of interest; information is available (open access) in a supplement to Hepatology.
[email protected]
On Twitter @denisefulton
AT THE LIVER MEETING 2017
Study examines intestinal microbiota role post liver transplant
WASHINGTON – During and after liver transplant, the reaction of the intestinal microbiota may be a critical determinant of outcomes; preliminary data from a cohort study may provide some clarification of what modulates gut microbiota post transplantation and shed light on predictive factors.
Anna-Catrin Uhlemann, MD, PhD, of Columbia University Medical Center, New York, noted that several studies in recent years sought to clarify influences on gut microbiota in people receiving liver transplants, but “there are still a number of important gaps in knowledge, including what exactly is the longitudinal evolution of the host transplant microbiome and what is the predictive value of pre- and early posttransplant dysbiosis on outcomes and complications.”
The researchers collected more than 1,000 samples to screen for colonization by the following MDR organisms: carbapenem-resistant Enterobacteriaceae (CRE), Enterobacteriaceae resistant to third-generation cephalosporins (ESBL), and vancomycin-resistant enterococci (VRE). Over the 1-year follow-up period, 19% (P =.031) of patients had CRE colonization associated with subsequent infection, 41% (P = .003) had ESBL colonization, and 46% (P = .021) had VRE colonization, Dr. Uhlemann said at the annual meeting of the American Association for the Study of Liver Diseases. The researchers then selected 484 samples for sequencing of the 16S ribosomal RNA gene to determine the composition of gut microbiota.
The study used two indexes to determine the alpha diversity of microbiota: the Chao index to estimate richness and the Shannon diversity index to determine the abundance of species in different settings. “We observed dynamic temporal evolution of alpha diversity and taxa abundance over the 1-year follow-up period,” Dr. Uhlemann said. “The diagnosis, the Child-Pugh class, and changes in perioperative antibiotics were important predictors of posttransplant alpha diversity.”
The study also found that Enterobacteriaceae and enterococci increased post transplant in general and as MDR organisms, and that a patient’s MDR status was an important modulator of the posttransplant microbiome, as was the lack of protective operational taxonomic units (OTUs).
The researchers evaluated the relative abundance of taxa and beta diversity. For example, pretransplant patients with a Model for End-stage Liver Disease (MELD) score greater than 25 showed enrichment of Enterobacteriaceae as well as different taxa of the Bacteroidiaceae, while those with MELD scores below 25 showed enrichment of Veillonellaceae. “The significance of this is not clear yet,” Dr. Uhlemann said.
Liver disease severity can also influence gut microbes. Those with Child-Pugh class C disease have the highest numbers in terms of richness and lowest in terms of diversity, Dr. Uhlemann said. “However, at the moment when we are looking at the differential abundance of the taxa, we don’t see quite as clear a pattern, although we noticed in the high group a higher abundance of Bacteroidiaceae,” she said.
Hepatitis B and C patients also presented divergent microbiota profiles. Hepatitis B virus patients “in general are always relatively healthy, and we actually see that these indices are relatively preserved,” Dr. Uhlemann said. “When we look at hepatitis C, however, we see that these patients are starting off quite low and then have an increase in alpha-diversity measures at around month 6.” A subset of patients with alcoholic liver disease also didn’t reach higher Chao and Shannon levels until 6 months after transplant.
“We also find that adjustment of periodic antibiotics for allergy or history of prior infection is significantly associated with a decrease in alpha diversity several months into the posttransplant course,” said Dr. Uhlemann. This is driven by an increase in the abundance of Enterococcaceae and Enterobacteriaceae. “And when we look at MDR colonization as a predictor of alpha diversity, we see that those who have MDR colonization, irrespective of the species, also have the lower alpha diversity.”
The researchers also started to look at pretransplant alpha diversity as a predictor of transplant outcomes, and while the analysis is still in progress, the Shannon indices were significantly different between patients who died and those who survived a year. “There was a trend for significant differences for posttransplant infection and the length of the hospital stay,” Dr. Uhlemann said. “However, we did not see any association with posttransplant ICU readmission, rejection, or VRE complications.”
She added that future analyses are needed to further evaluate the interaction between the clinical comorbidities in the microbiome and vice versa.
Dr. Uhlemann disclosed links to Merck.
WASHINGTON – During and after liver transplant, the reaction of the intestinal microbiota may be a critical determinant of outcomes; preliminary data from a cohort study may provide some clarification of what modulates gut microbiota post transplantation and shed light on predictive factors.
Anna-Catrin Uhlemann, MD, PhD, of Columbia University Medical Center, New York, noted that several studies in recent years sought to clarify influences on gut microbiota in people receiving liver transplants, but “there are still a number of important gaps in knowledge, including what exactly is the longitudinal evolution of the host transplant microbiome and what is the predictive value of pre- and early posttransplant dysbiosis on outcomes and complications.”
The researchers collected more than 1,000 samples to screen for colonization by the following MDR organisms: carbapenem-resistant Enterobacteriaceae (CRE), Enterobacteriaceae resistant to third-generation cephalosporins (ESBL), and vancomycin-resistant enterococci (VRE). Over the 1-year follow-up period, 19% (P =.031) of patients had CRE colonization associated with subsequent infection, 41% (P = .003) had ESBL colonization, and 46% (P = .021) had VRE colonization, Dr. Uhlemann said at the annual meeting of the American Association for the Study of Liver Diseases. The researchers then selected 484 samples for sequencing of the 16S ribosomal RNA gene to determine the composition of gut microbiota.
The study used two indexes to determine the alpha diversity of microbiota: the Chao index to estimate richness and the Shannon diversity index to determine the abundance of species in different settings. “We observed dynamic temporal evolution of alpha diversity and taxa abundance over the 1-year follow-up period,” Dr. Uhlemann said. “The diagnosis, the Child-Pugh class, and changes in perioperative antibiotics were important predictors of posttransplant alpha diversity.”
The study also found that Enterobacteriaceae and enterococci increased post transplant in general and as MDR organisms, and that a patient’s MDR status was an important modulator of the posttransplant microbiome, as was the lack of protective operational taxonomic units (OTUs).
The researchers evaluated the relative abundance of taxa and beta diversity. For example, pretransplant patients with a Model for End-stage Liver Disease (MELD) score greater than 25 showed enrichment of Enterobacteriaceae as well as different taxa of the Bacteroidiaceae, while those with MELD scores below 25 showed enrichment of Veillonellaceae. “The significance of this is not clear yet,” Dr. Uhlemann said.
Liver disease severity can also influence gut microbes. Those with Child-Pugh class C disease have the highest numbers in terms of richness and lowest in terms of diversity, Dr. Uhlemann said. “However, at the moment when we are looking at the differential abundance of the taxa, we don’t see quite as clear a pattern, although we noticed in the high group a higher abundance of Bacteroidiaceae,” she said.
Hepatitis B and C patients also presented divergent microbiota profiles. Hepatitis B virus patients “in general are always relatively healthy, and we actually see that these indices are relatively preserved,” Dr. Uhlemann said. “When we look at hepatitis C, however, we see that these patients are starting off quite low and then have an increase in alpha-diversity measures at around month 6.” A subset of patients with alcoholic liver disease also didn’t reach higher Chao and Shannon levels until 6 months after transplant.
“We also find that adjustment of periodic antibiotics for allergy or history of prior infection is significantly associated with a decrease in alpha diversity several months into the posttransplant course,” said Dr. Uhlemann. This is driven by an increase in the abundance of Enterococcaceae and Enterobacteriaceae. “And when we look at MDR colonization as a predictor of alpha diversity, we see that those who have MDR colonization, irrespective of the species, also have the lower alpha diversity.”
The researchers also started to look at pretransplant alpha diversity as a predictor of transplant outcomes, and while the analysis is still in progress, the Shannon indices were significantly different between patients who died and those who survived a year. “There was a trend for significant differences for posttransplant infection and the length of the hospital stay,” Dr. Uhlemann said. “However, we did not see any association with posttransplant ICU readmission, rejection, or VRE complications.”
She added that future analyses are needed to further evaluate the interaction between the clinical comorbidities in the microbiome and vice versa.
Dr. Uhlemann disclosed links to Merck.
WASHINGTON – During and after liver transplant, the reaction of the intestinal microbiota may be a critical determinant of outcomes; preliminary data from a cohort study may provide some clarification of what modulates gut microbiota post transplantation and shed light on predictive factors.
Anna-Catrin Uhlemann, MD, PhD, of Columbia University Medical Center, New York, noted that several studies in recent years sought to clarify influences on gut microbiota in people receiving liver transplants, but “there are still a number of important gaps in knowledge, including what exactly is the longitudinal evolution of the host transplant microbiome and what is the predictive value of pre- and early posttransplant dysbiosis on outcomes and complications.”
The researchers collected more than 1,000 samples to screen for colonization by the following MDR organisms: carbapenem-resistant Enterobacteriaceae (CRE), Enterobacteriaceae resistant to third-generation cephalosporins (ESBL), and vancomycin-resistant enterococci (VRE). Over the 1-year follow-up period, 19% (P =.031) of patients had CRE colonization associated with subsequent infection, 41% (P = .003) had ESBL colonization, and 46% (P = .021) had VRE colonization, Dr. Uhlemann said at the annual meeting of the American Association for the Study of Liver Diseases. The researchers then selected 484 samples for sequencing of the 16S ribosomal RNA gene to determine the composition of gut microbiota.
The study used two indexes to determine the alpha diversity of microbiota: the Chao index to estimate richness and the Shannon diversity index to determine the abundance of species in different settings. “We observed dynamic temporal evolution of alpha diversity and taxa abundance over the 1-year follow-up period,” Dr. Uhlemann said. “The diagnosis, the Child-Pugh class, and changes in perioperative antibiotics were important predictors of posttransplant alpha diversity.”
The study also found that Enterobacteriaceae and enterococci increased post transplant in general and as MDR organisms, and that a patient’s MDR status was an important modulator of the posttransplant microbiome, as was the lack of protective operational taxonomic units (OTUs).
The researchers evaluated the relative abundance of taxa and beta diversity. For example, pretransplant patients with a Model for End-stage Liver Disease (MELD) score greater than 25 showed enrichment of Enterobacteriaceae as well as different taxa of the Bacteroidiaceae, while those with MELD scores below 25 showed enrichment of Veillonellaceae. “The significance of this is not clear yet,” Dr. Uhlemann said.
Liver disease severity can also influence gut microbes. Those with Child-Pugh class C disease have the highest numbers in terms of richness and lowest in terms of diversity, Dr. Uhlemann said. “However, at the moment when we are looking at the differential abundance of the taxa, we don’t see quite as clear a pattern, although we noticed in the high group a higher abundance of Bacteroidiaceae,” she said.
Hepatitis B and C patients also presented divergent microbiota profiles. Hepatitis B virus patients “in general are always relatively healthy, and we actually see that these indices are relatively preserved,” Dr. Uhlemann said. “When we look at hepatitis C, however, we see that these patients are starting off quite low and then have an increase in alpha-diversity measures at around month 6.” A subset of patients with alcoholic liver disease also didn’t reach higher Chao and Shannon levels until 6 months after transplant.
“We also find that adjustment of periodic antibiotics for allergy or history of prior infection is significantly associated with a decrease in alpha diversity several months into the posttransplant course,” said Dr. Uhlemann. This is driven by an increase in the abundance of Enterococcaceae and Enterobacteriaceae. “And when we look at MDR colonization as a predictor of alpha diversity, we see that those who have MDR colonization, irrespective of the species, also have the lower alpha diversity.”
The researchers also started to look at pretransplant alpha diversity as a predictor of transplant outcomes, and while the analysis is still in progress, the Shannon indices were significantly different between patients who died and those who survived a year. “There was a trend for significant differences for posttransplant infection and the length of the hospital stay,” Dr. Uhlemann said. “However, we did not see any association with posttransplant ICU readmission, rejection, or VRE complications.”
She added that future analyses are needed to further evaluate the interaction between the clinical comorbidities in the microbiome and vice versa.
Dr. Uhlemann disclosed links to Merck.
AT THE LIVER MEETING 2017
Key clinical point: The presence or lack of specific modulators of gut microbiota may influence outcomes of liver transplantation.
Major finding: Over a 1-year follow-up period, 19% of patients had colonization with carbapenem-resistant Enterobacteriaceae, 41% had Enterobacteriaceae resistant to third-generation cephalosporins, and 46% had vancomycin-resistant enterococci associated with subsequent infections.
Data source: A prospective longitudinal cohort study of 323 patients, 125 of whom completed 1 year of follow-up.
Disclosures: Dr. Uhlemann disclosed receiving research funding from Merck.
Nivolumab may extend survival in HCC patients
WASHINGTON – A multinational clinical trial has found that the metastatic cancer agent nivolumab can improve long-term survival and durable tumor responses in patients with advanced hepatocellular carcinoma (HCC) whether or not they’ve had previous treatment with a chemotherapy agent already approved for advanced primary liver cancer, a principal investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.
“Nivolumab has demonstrated clinically meaningful efficacy across etiologies in sorafenib-naive and -experienced patients with extended follow-up,” Bruno Sangro, MD, of the University of Navarra in Pamplona, Spain, said in reporting results of the CheckMate-040 trial. “The median overall survival is 15 and 15.6 months in patients who were sorafenib-experienced in both the dose-escalation and expansion cohorts.”
The dose-escalation cohort received 0.1 to 10 mg/kg of nivolumab (Opdivo) while the dose-expansion group received a steady dose of 3 mg/kg. In all, 262 patients participated in the trial, 80 of whom had never been on sorafenib (Nexavar) therapy. The survival outcome in these subgroups, Dr. Sangro said, “really speaks for the consistency and the robustness of the results.”
Trial participants had inoperable, usually metastatic HCC, with Child-Pugh scores up to and including 7 in the escalation group or up to and including 6 in the expansion group. Most of them were progressing to treatment with one or more prior systemic therapies, including sorafenib. Their aspartate aminotransferase and alanine aminotransferase scores were in the upper limits of normal, and bilirubin was less than or equal to 3 mg/dL. If they had hepatitis B (HBV), their viral load had to be less than 100 IU/mL and they had to be on effective antiviral therapy. Any history of hepatic encephalopathy or clinically significant ascites and an active HBV and hepatitis C (HCV) coinfection were grounds for exclusion.
“Most patients had to discontinue nivolumab because of disease progression,” Dr. Sangro noted, so that only 36 patients, or 14%, were continuing treatment at the time of this analysis. Thirteen patients in the total population that discontinued nivolumab did so because of toxicity, he said.
“Around 20% of patients achieved an objective remission that included complete responses in all subgroups of patients; 15% of progressors and 23% of sorafenib-intolerant patients had an objective response,” Dr. Sangro said. In terms of overall response, about half of all patients in the sorafenib-experienced subgroups had a complete or partial response or stable disease: 51% in the dose-escalation subgroup and 54% in the dose-expansion subgroup.
Although tumor responses were associated with declines in alpha-fetoprotein levels, “it’s unlikely that these biomarkers will be useful either for monitoring or selecting patients for treatment,” he added. “Indeed, baseline alpha-fetoprotein levels were comparable between responders and nonresponders to nivolumab” Dr. Sangro said.
“We also showed there was some impact on HCV viral kinetics in infected individuals,” Dr. Sangro noted. “The overall safety profile for the HCC population is consistent with other tumor types in which nivolumab is approved; these include patients who are infected with hepatitis B or C viruses.”
The study showed that 36% (19/53) of HCV infected patients had a greater than 1 log decrease in viral load. No signs of additional antiviral activity were detected among HBV-infected patients already on effective antiviral treatment: only 5% (3/59) posted a up to 1 log decrease in HB surface antigen levels, and 11% (7/64) of patients had increases in viral load. “These increases occurred in the setting of low-level viremia.” Dr. Sangro said. “They were asymptomatic and [nivolumab] did not result in changes in hepatic parameters or other serious adverse events.”
With regard to adverse events (AEs), 77% of all patients had some treatment-related AEs, ranging from fatigue to rash to dry mouth to increased lab levels, but only 20% were grade 3 or 4, and 88% of those resolved in an average of 8 weeks, Dr. Sangro said.
More research into nivolumab for HCC is needed, Dr. Sangro said. “Ongoing and future studies in patients with advanced tumors will evaluate nivolumab in the first-line setting or in combination with other agents,” he said.
Dr. Sangro disclosed relationships with Bayer Schering Pharma, Onxeo, Astra Zeneca, and Bristol-Myers Squibb. Bristol-Myers Squibb funded the trial, and Chrysalis Medical Communications assisted in reporting the study results.
WASHINGTON – A multinational clinical trial has found that the metastatic cancer agent nivolumab can improve long-term survival and durable tumor responses in patients with advanced hepatocellular carcinoma (HCC) whether or not they’ve had previous treatment with a chemotherapy agent already approved for advanced primary liver cancer, a principal investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.
“Nivolumab has demonstrated clinically meaningful efficacy across etiologies in sorafenib-naive and -experienced patients with extended follow-up,” Bruno Sangro, MD, of the University of Navarra in Pamplona, Spain, said in reporting results of the CheckMate-040 trial. “The median overall survival is 15 and 15.6 months in patients who were sorafenib-experienced in both the dose-escalation and expansion cohorts.”
The dose-escalation cohort received 0.1 to 10 mg/kg of nivolumab (Opdivo) while the dose-expansion group received a steady dose of 3 mg/kg. In all, 262 patients participated in the trial, 80 of whom had never been on sorafenib (Nexavar) therapy. The survival outcome in these subgroups, Dr. Sangro said, “really speaks for the consistency and the robustness of the results.”
Trial participants had inoperable, usually metastatic HCC, with Child-Pugh scores up to and including 7 in the escalation group or up to and including 6 in the expansion group. Most of them were progressing to treatment with one or more prior systemic therapies, including sorafenib. Their aspartate aminotransferase and alanine aminotransferase scores were in the upper limits of normal, and bilirubin was less than or equal to 3 mg/dL. If they had hepatitis B (HBV), their viral load had to be less than 100 IU/mL and they had to be on effective antiviral therapy. Any history of hepatic encephalopathy or clinically significant ascites and an active HBV and hepatitis C (HCV) coinfection were grounds for exclusion.
“Most patients had to discontinue nivolumab because of disease progression,” Dr. Sangro noted, so that only 36 patients, or 14%, were continuing treatment at the time of this analysis. Thirteen patients in the total population that discontinued nivolumab did so because of toxicity, he said.
“Around 20% of patients achieved an objective remission that included complete responses in all subgroups of patients; 15% of progressors and 23% of sorafenib-intolerant patients had an objective response,” Dr. Sangro said. In terms of overall response, about half of all patients in the sorafenib-experienced subgroups had a complete or partial response or stable disease: 51% in the dose-escalation subgroup and 54% in the dose-expansion subgroup.
Although tumor responses were associated with declines in alpha-fetoprotein levels, “it’s unlikely that these biomarkers will be useful either for monitoring or selecting patients for treatment,” he added. “Indeed, baseline alpha-fetoprotein levels were comparable between responders and nonresponders to nivolumab” Dr. Sangro said.
“We also showed there was some impact on HCV viral kinetics in infected individuals,” Dr. Sangro noted. “The overall safety profile for the HCC population is consistent with other tumor types in which nivolumab is approved; these include patients who are infected with hepatitis B or C viruses.”
The study showed that 36% (19/53) of HCV infected patients had a greater than 1 log decrease in viral load. No signs of additional antiviral activity were detected among HBV-infected patients already on effective antiviral treatment: only 5% (3/59) posted a up to 1 log decrease in HB surface antigen levels, and 11% (7/64) of patients had increases in viral load. “These increases occurred in the setting of low-level viremia.” Dr. Sangro said. “They were asymptomatic and [nivolumab] did not result in changes in hepatic parameters or other serious adverse events.”
With regard to adverse events (AEs), 77% of all patients had some treatment-related AEs, ranging from fatigue to rash to dry mouth to increased lab levels, but only 20% were grade 3 or 4, and 88% of those resolved in an average of 8 weeks, Dr. Sangro said.
More research into nivolumab for HCC is needed, Dr. Sangro said. “Ongoing and future studies in patients with advanced tumors will evaluate nivolumab in the first-line setting or in combination with other agents,” he said.
Dr. Sangro disclosed relationships with Bayer Schering Pharma, Onxeo, Astra Zeneca, and Bristol-Myers Squibb. Bristol-Myers Squibb funded the trial, and Chrysalis Medical Communications assisted in reporting the study results.
WASHINGTON – A multinational clinical trial has found that the metastatic cancer agent nivolumab can improve long-term survival and durable tumor responses in patients with advanced hepatocellular carcinoma (HCC) whether or not they’ve had previous treatment with a chemotherapy agent already approved for advanced primary liver cancer, a principal investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.
“Nivolumab has demonstrated clinically meaningful efficacy across etiologies in sorafenib-naive and -experienced patients with extended follow-up,” Bruno Sangro, MD, of the University of Navarra in Pamplona, Spain, said in reporting results of the CheckMate-040 trial. “The median overall survival is 15 and 15.6 months in patients who were sorafenib-experienced in both the dose-escalation and expansion cohorts.”
The dose-escalation cohort received 0.1 to 10 mg/kg of nivolumab (Opdivo) while the dose-expansion group received a steady dose of 3 mg/kg. In all, 262 patients participated in the trial, 80 of whom had never been on sorafenib (Nexavar) therapy. The survival outcome in these subgroups, Dr. Sangro said, “really speaks for the consistency and the robustness of the results.”
Trial participants had inoperable, usually metastatic HCC, with Child-Pugh scores up to and including 7 in the escalation group or up to and including 6 in the expansion group. Most of them were progressing to treatment with one or more prior systemic therapies, including sorafenib. Their aspartate aminotransferase and alanine aminotransferase scores were in the upper limits of normal, and bilirubin was less than or equal to 3 mg/dL. If they had hepatitis B (HBV), their viral load had to be less than 100 IU/mL and they had to be on effective antiviral therapy. Any history of hepatic encephalopathy or clinically significant ascites and an active HBV and hepatitis C (HCV) coinfection were grounds for exclusion.
“Most patients had to discontinue nivolumab because of disease progression,” Dr. Sangro noted, so that only 36 patients, or 14%, were continuing treatment at the time of this analysis. Thirteen patients in the total population that discontinued nivolumab did so because of toxicity, he said.
“Around 20% of patients achieved an objective remission that included complete responses in all subgroups of patients; 15% of progressors and 23% of sorafenib-intolerant patients had an objective response,” Dr. Sangro said. In terms of overall response, about half of all patients in the sorafenib-experienced subgroups had a complete or partial response or stable disease: 51% in the dose-escalation subgroup and 54% in the dose-expansion subgroup.
Although tumor responses were associated with declines in alpha-fetoprotein levels, “it’s unlikely that these biomarkers will be useful either for monitoring or selecting patients for treatment,” he added. “Indeed, baseline alpha-fetoprotein levels were comparable between responders and nonresponders to nivolumab” Dr. Sangro said.
“We also showed there was some impact on HCV viral kinetics in infected individuals,” Dr. Sangro noted. “The overall safety profile for the HCC population is consistent with other tumor types in which nivolumab is approved; these include patients who are infected with hepatitis B or C viruses.”
The study showed that 36% (19/53) of HCV infected patients had a greater than 1 log decrease in viral load. No signs of additional antiviral activity were detected among HBV-infected patients already on effective antiviral treatment: only 5% (3/59) posted a up to 1 log decrease in HB surface antigen levels, and 11% (7/64) of patients had increases in viral load. “These increases occurred in the setting of low-level viremia.” Dr. Sangro said. “They were asymptomatic and [nivolumab] did not result in changes in hepatic parameters or other serious adverse events.”
With regard to adverse events (AEs), 77% of all patients had some treatment-related AEs, ranging from fatigue to rash to dry mouth to increased lab levels, but only 20% were grade 3 or 4, and 88% of those resolved in an average of 8 weeks, Dr. Sangro said.
More research into nivolumab for HCC is needed, Dr. Sangro said. “Ongoing and future studies in patients with advanced tumors will evaluate nivolumab in the first-line setting or in combination with other agents,” he said.
Dr. Sangro disclosed relationships with Bayer Schering Pharma, Onxeo, Astra Zeneca, and Bristol-Myers Squibb. Bristol-Myers Squibb funded the trial, and Chrysalis Medical Communications assisted in reporting the study results.
AT THE LIVER MEETING 2017
Key clinical point: Nivolumab demonstrated long-term survival, durable tumor responses, and manageable overall and hepatic safety profiles, regardless of prior sorafenib treatment, in patients with advanced hepatocellular carcinoma.
Major finding: The 18-month overall survival rate was 57% in sorafenib-naive patients and 46% (dose-escalation) and 44% (dose-expansion) in sorafenib-experienced patients.
Data source: CheckMate-040 phase 1/2 dose-escalation and -expansion trial of 262 patients.
Disclosures: Dr. Sangro disclosed relationships with Bayer Schering Pharma, Onxeo, Astra Zeneca, and Bristol-Myers Squibb. Bristol-Myers Squibb funded the trial, and Chrysalis Medical Communications assisted in reporting the study results.